Pilot Study of Loop Diuretics Among Individuals Receiving Hemodialysis

NCT04622709 | Completed Phase 2 Results DMC FDA Drug

• 2 other identifiers: 19-35501R03DK124651-01
• Study Type: interventional
• Target: 39
• Locations: 1 country
• Sites: 5

Brief Summary

Individuals with kidney failure receiving maintenance hemodialysis (HD) have high mortality rates, driven largely by cardiovascular causes. Volume-related factors are critical, modifiable contributors to cardiovascular complications. Reversing volume overload has been shown to improve blood pressure and cardiac remodeling. Use of loop diuretics may represent a pragmatic, low-cost, and low-burden strategy to improve outcomes in people receiving HD. Lack of data on optimal furosemide dosing, safety, and acceptability are barriers to expanded use. This study investigates whether oral furosemide is safe and effective at increasing urine volume in HD patients.

Conditions

Chronic Kidney Disease Requiring Chronic Dialysis

Keywords

Hemodialysis; Dialysis; End Stage Renal Disease; Patient-reported Outcomes; Symptoms; Diuretic; Furosemide; Lasix

Outcome Measures

Primary Outcomes (214)

• Percentage of Participants Who Have a Defined Increase in 24-hour Urine Volume From Baseline to Week 5

  Participants will follow standard dialysis clinic protocols for 24-urine volume collection. Classifying participants as has having an increase in 24-hour urine volume will be contingent on the amount of urine the participant makes at baseline. * Among participants with baseline 24-hour urine volume ≥200 mL: ≥25% increase in urine volume is considered an increase. * Among participants with baseline 24-hour urine volume \<200 mL: ≥50 mL increase in urine volume to a urine volume of at least 100 mL/24-hours is considered an increase. The percentage of participants who have a defined increase in 24-urine volume from baseline to week 5 will be determined.

  Baseline and study week 5 (5 weeks after study medication start

• Percentage of Participants Who Have a Defined Increase in 24-hour Urine Volume From Baseline to Week 12

  Participants will follow standard dialysis clinic protocols for 24-urine volume collection. Classifying participants as has having an increase in 24-hour urine volume will be contingent on the amount of urine the participant makes at baseline. * Among participants with baseline 24-hour urine volume ≥200 mL: ≥25% increase in urine volume is considered an increase. * Among participants with baseline 24-hour urine volume \<200 mL: ≥50 mL increase in urine volume to a urine volume of at least 100 mL/24-hours is considered an increase. The percentage of participants who have a defined increase in 24-urine volume from baseline to week 12 will be determined.

  Baseline and study week 12 (12 weeks after study medication start)

• Percentage of Participants Who Have a Defined Increase in 24-hour Urine Volume From Baseline to Week 18

  Participants will follow standard dialysis clinic protocols for 24-urine volume collection. Classifying participants as has having an increase in 24-hour urine volume will be contingent on the amount of urine the participant makes at baseline. * Among participants with baseline 24-hour urine volume ≥200 mL: ≥25% increase in urine volume is considered an increase. * Among participants with baseline 24-hour urine volume \<200 mL: ≥50 mL increase in urine volume to a urine volume of at least 100 mL/24-hours is considered an increase. The percentage of participants who have a defined increase in 24-urine volume from baseline to week 18 will be determined.

  Baseline and study week 18 (18 weeks after study medication start)

• Percentage of Participants With A Serum Potassium <3.2 mEq/L at Week 1

  Blood samples will be collected from participants prior to their dialysis treatments at the week 1 study visit. The percentage of participants who have a serum potassium \<3.2 mEq/L will be determined.

  Study week 1 (1 week after study medication start)

• Percentage of Participants With a Serum Potassium <3.2 mEq/L at Week 2

  Blood samples will be collected from participants prior to their dialysis treatments at the week 2 study visit. The percentage of participants who have a serum potassium \<3.2 mEq/L will be determined.

  Study week 2 (2 weeks after study medication start)

• Percentage of Participants With a Serum Potassium <3.2 mEq/L at Week 3

  Blood samples will be collected from participants prior to their dialysis treatments at the week 3 study visit. The percentage of participants who have a serum potassium \<3.2 mEq/L will be determined.

  Study week 3 (3 weeks after study medication start)

• Percentage of Participants With a Serum Potassium <3.2 mEq/L at Week 4

  Blood samples will be collected from participants prior to their dialysis treatments at the week 4 study visit. The percentage of participants who have a serum potassium \<3.2 mEq/L will be determined.

  Study week 4 (4 weeks after study medication start)

• Percentage of Participants With a Serum Potassium <3.2 mEq/L at Week 5

  Blood samples will be collected from participants prior to their dialysis treatments at the week 5 study visit. The percentage of participants who have a serum potassium \<3.2 mEq/L will be determined.

  Study week 5 (5 weeks after study medication start)

• Percentage of Participants With a Serum Potassium <3.2 mEq/L at Week 6

  Blood samples will be collected from participants prior to their dialysis treatments at the week 6 study visit. The percentage of participants who have a serum potassium \<3.2 mEq/L will be determined.

  Study week 6 (6 weeks after study medication start)

• Percentage of Participants With a Serum Potassium <3.2 mEq/L at Week 9

  Blood samples will be collected from participants prior to their dialysis treatments at the week 9 study visit. The percentage of participants who have a serum potassium \<3.2 mEq/L will be determined.

  Study week 9 (9 weeks after study medication start)

• Percentage of Participants With a Serum Potassium <3.2 mEq/L at Week 13

  Blood samples will be collected from participants prior to their dialysis treatments at the week 13 study visit. The percentage of participants who have a serum potassium \<3.2 mEq/L will be determined.

  Study week 13 (13 weeks after study medication start)

• Percentage of Participants With a Serum Potassium <3.2 mEq/L at Week 17

  Blood samples will be collected from participants prior to their dialysis treatments at the week 17 study visit. The percentage of participants who have a serum potassium \<3.2 mEq/L will be determined.

  Study week 17 (17 weeks after study medication start)

• Percentage of Participants With a Serum Magnesium <0.8 mEq/L at Week 1

  Blood samples will be collected from participants prior to their dialysis treatments at the week 1 study visit. The percentage of participants who have a serum magnesium \<0.8 mEq/L will be determined.

  Study week 1 (1 week after study medication start)

• Percentage of Participants With a Serum Magnesium <0.8 mEq/L at Week 2

  Blood samples will be collected from participants prior to their dialysis treatments at the week 2 study visit. The percentage of participants who have a serum magnesium \<0.8 mEq/L will be determined.

  Study week 2 (2 weeks after study medication start)

• Percentage of Participants With a Serum Magnesium <0.8 mEq/L at Week 3

  Blood samples will be collected from participants prior to their dialysis treatments at the week 3 study visit. The percentage of participants who have a serum magnesium \<0.8 mEq/L will be determined.

  Study week 3 (3 weeks after study medication start)

• Percentage of Participants With a Serum Magnesium <0.8 mEq/L at Week 4

  Blood samples will be collected from participants prior to their dialysis treatments at the week 4 study visit. The percentage of participants who have a serum magnesium \<0.8 mEq/L will be determined.

  Study week 4 (4 weeks after study medication start)

• Percentage of Participants With a Serum Magnesium <0.8 mEq/L at Week 5

  Blood samples will be collected from participants prior to their dialysis treatments at the week 5 study visit. The percentage of participants who have a serum magnesium \<0.8 mEq/L will be determined.

  Study week 5 (5 weeks after study medication start)

• Percentage of Participants With a Serum Magnesium <0.8 mEq/L at Week 6

  Blood samples will be collected from participants prior to their dialysis treatments at the week 6 study visit. The percentage of participants who have a serum magnesium \<0.8 mEq/L will be determined.

  Study week 6 (6 weeks after study medication start)

• Percentage of Participants With a Serum Magnesium <0.8 mEq/L at Week 9

  Blood samples will be collected from participants prior to their dialysis treatments at the week 9 study visit. The percentage of participants who have a serum magnesium \<0.8 mEq/L will be determined.

  Study week 9 (9 weeks after study medication start)

• Percentage of Participants With a Serum Magnesium <0.8 mEq/L at Week 13

  Blood samples will be collected from participants prior to their dialysis treatments at the week 13 study visit. The percentage of participants who have a serum magnesium \<0.8 mEq/L will be determined.

  Study week 13 (13 weeks after study medication start)

• Percentage of Participants With a Serum Magnesium <0.8 mEq/L at Week 17

  Blood samples will be collected from participants prior to their dialysis treatments at the week 17 study visit. The percentage of participants who have a serum magnesium \<0.8 mEq/L will be determined.

  Study week 17 (17 weeks after study medication start)

• Percentage of Participants With a Serum Corrected Calcium <7.0 mg/dL at Week 1

  Blood samples will be collected from participants prior to their dialysis treatments at the week 1 study visit. The percentage of participants who have a serum corrected calcium \<7.0 mg/dL will be determined.

  Study week 1 (1 week after study medication start)

• Percentage of Participants With a Serum Corrected Calcium <7.0 mg/dL at Week 2

  Blood samples will be collected from participants prior to their dialysis treatments at the week 2 study visit. The percentage of participants who have a serum corrected calcium \<7.0 mg/dL will be determined.

  Study week 2 (2 weeks after study medication start)

• Percentage of Participants With a Serum Corrected Calcium <7.0 mg/dL at Week 3

  Blood samples will be collected from participants prior to their dialysis treatments at the week 3 study visit. The percentage of participants who have a serum corrected calcium \<7.0 mg/dL will be determined.

  Study week 3 (3 weeks after study medication start)

• Percentage of Participants With a Serum Corrected Calcium <7.0 mg/dL at Week 4

  Blood samples will be collected from participants prior to their dialysis treatments at the week 4 study visit. The percentage of participants who have a serum corrected calcium \<7.0 mg/dL will be determined.

  Study week 4 (4 weeks after study medication start)

• Percentage of Participants With a Serum Corrected Calcium <7.0 mg/dL at Week 5

  Blood samples will be collected from participants prior to their dialysis treatments at the week 5 study visit. The percentage of participants who have a serum corrected calcium \<7.0 mg/dL will be determined.

  Study week 5 (5 weeks after study medication start)

• Percentage of Participants With a Serum Corrected Calcium <7.0 mg/dL at Week 6

  Blood samples will be collected from participants prior to their dialysis treatments at the week 6 study visit. The percentage of participants who have a serum corrected calcium \<7.0 mg/dL will be determined.

  Study week 6 (6 weeks after study medication start)

• Percentage of Participants With a Serum Corrected Calcium <7.0 mg/dL at Week 9

  Blood samples will be collected from participants prior to their dialysis treatments at the week 9 study visit. The percentage of participants who have a serum corrected calcium \<7.0 mg/dL will be determined.

  Study week 9 (9 weeks after study medication start)

• Percentage of Participants With a Serum Corrected Calcium <7.0 mg/dL at Week 13

  Blood samples will be collected from participants prior to their dialysis treatments at the week 13 study visit. The percentage of participants who have a serum corrected calcium \<7.0 mg/dL will be determined.

  Study week 13 (13 weeks after study medication start)

• Percentage of Participants With a Serum Corrected Calcium <7.0 mg/dL at Week 17

  Blood samples will be collected from participants prior to their dialysis treatments at the week 17 study visit. The percentage of participants who have a serum corrected calcium \<7.0 mg/dL will be determined.

  Study week 17 (17 weeks after study medication start)

• Percentage of Participants With a Serum Furosemide Level >12 Micrograms/L at Week 1.

  Blood samples will be collected from participants prior to their dialysis treatments at the week 1 study visit. The percentage of participants who have a serum furosemide level \>12 micrograms/L will be determined.

  Study week 1 (1 week after study medication start)

• Percentage of Participants With a Serum Furosemide Level >12 Micrograms/L at Week 2.

  Blood samples will be collected from participants prior to their dialysis treatments at the week 2 study visit. The percentage of participants who have a serum furosemide level \>12 micrograms/L will be determined.

  Study week 2 (2 weeks after study medication start)

• Percentage of Participants With a Serum Furosemide Level >12 Micrograms/L at Week 3.

  Blood samples will be collected from participants prior to their dialysis treatments at the week 3 study visit. The percentage of participants who have a serum furosemide level \>12 micrograms/L will be determined.

  Study week 3 (3 weeks after study medication start)

• Percentage of Participants With a Serum Furosemide Level >12 Micrograms/L at Week 4.

  Blood samples will be collected from participants prior to their dialysis treatments at the week 4 study visit. The percentage of participants who have a serum furosemide level \>12 micrograms/L will be determined.

  Study week 4 (4 weeks after study medication start)

• Percentage of Participants With a Serum Furosemide Level >12 Micrograms/L at Week 5.

  Blood samples will be collected from participants prior to their dialysis treatments at the week 5 study visit. The percentage of participants who have a serum furosemide level \>12 micrograms/L will be determined.

  Study week 5 (5 weeks after study medication start)

• Percentage of Participants With a Serum Furosemide Level >12 Micrograms/L at Week 6.

  Blood samples will be collected from participants prior to their dialysis treatments at the week 6 study visit. The percentage of participants who have a serum furosemide level \>12 micrograms/L will be determined.

  Study week 6 (6 weeks after study medication start)

• Percentage of Participants With a Serum Furosemide Level >12 Micrograms/L at Week 9.

  Blood samples will be collected from participants prior to their dialysis treatments at the week 9 study visit. The percentage of participants who have a serum furosemide level \>12 micrograms/L will be determined.

  Study week 9 (9 weeks after study medication start)

• Percentage of Participants With a Serum Furosemide Level >12 Micrograms/L at Week 13.

  Blood samples will be collected from participants prior to their dialysis treatments at the week 13 study visit. The percentage of participants who have a serum furosemide level \>12 micrograms/L will be determined.

  Study week 13 (13 weeks after study medication start)

• Percentage of Participants With a Serum Furosemide Level >12 Micrograms/L at Week 17.

  Blood samples will be collected from participants prior to their dialysis treatments at the week 17 study visit. The percentage of participants who have a serum furosemide level \>12 micrograms/L will be determined.

  Study week 17 (17 weeks after study medication start)

• Percentage of Participants That Experience Dialysis-associated Hypotension up to Week 1

  Participants' blood pressure will be measured with an upper extremity cuff in a seated position at 15-minute intervals during each hemodialysis treatment per standard dialysis clinic protocols. Dialysis-associated hypotension will be defined as hypotension during dialysis requiring hospitalization or treatment in an emergency room and not attributable to overt sepsis, acute myocardial infarction, or other cardiovascular event (e.g. aortic dissection). The percentage of participants who have dialysis-associated hypotension up to week 1 will be determined.

  Up to study week 1 (1 week after study medication start)

• Percentage of Participants That Experience Dialysis-associated Hypotension up to Week 2

  Participants' blood pressure will be measured with an upper extremity cuff in a seated position at 15-minute intervals during each hemodialysis treatment per standard dialysis clinic protocols. Dialysis-associated hypotension will be defined as hypotension during dialysis requiring hospitalization or treatment in an emergency room and not attributable to overt sepsis, acute myocardial infarction, or other cardiovascular event (e.g. aortic dissection). The percentage of participants who have dialysis-associated hypotension up to week 2 will be determined.

  Up to study week 2 (2 weeks after study medication start)

• Percentage of Participants That Experience Dialysis-associated Hypotension up to Week 3

  Participants' blood pressure will be measured with an upper extremity cuff in a seated position at 15-minute intervals during each hemodialysis treatment per standard dialysis clinic protocols. Dialysis-associated hypotension will be defined as hypotension during dialysis requiring hospitalization or treatment in an emergency room and not attributable to overt sepsis, acute myocardial infarction, or other cardiovascular event (e.g. aortic dissection). The percentage of participants who have dialysis-associated hypotension up to week 3 will be determined.

  Up to study week 3 (3 weeks after study medication start)

• Percentage of Participants That Experience Dialysis-associated Hypotension up to Week 4

  Participants' blood pressure will be measured with an upper extremity cuff in a seated position at 15-minute intervals during each hemodialysis treatment per standard dialysis clinic protocols. Dialysis-associated hypotension will be defined as hypotension during dialysis requiring hospitalization or treatment in an emergency room and not attributable to overt sepsis, acute myocardial infarction, or other cardiovascular event (e.g. aortic dissection). The percentage of participants who have dialysis-associated hypotension up to week 4 will be determined.

  Up to study week 4 (4 weeks after study medication start)

• Percentage of Participants That Experience Dialysis-associated Hypotension up to Week 5

  Participants' blood pressure will be measured with an upper extremity cuff in a seated position at 15-minute intervals during each hemodialysis treatment per standard dialysis clinic protocols. Dialysis-associated hypotension will be defined as hypotension during dialysis requiring hospitalization or treatment in an emergency room and not attributable to overt sepsis, acute myocardial infarction, or other cardiovascular event (e.g. aortic dissection). The percentage of participants who have dialysis-associated hypotension up to week 5 will be determined.

  Up to study week 5 (5 weeks after study medication start)

• Percentage of Participants That Experience Dialysis-associated Hypotension up to Week 6

  Participants' blood pressure will be measured with an upper extremity cuff in a seated position at 15-minute intervals during each hemodialysis treatment per standard dialysis clinic protocols. Dialysis-associated hypotension will be defined as hypotension during dialysis requiring hospitalization or treatment in an emergency room and not attributable to overt sepsis, acute myocardial infarction, or other cardiovascular event (e.g. aortic dissection). The percentage of participants who have dialysis-associated hypotension up to week 6 will be determined.

  Up to study week 6 (6 weeks after study medication start)

• Percentage of Participants That Experience Dialysis-associated Hypotension up to Week 7

  Participants' blood pressure will be measured with an upper extremity cuff in a seated position at 15-minute intervals during each hemodialysis treatment per standard dialysis clinic protocols. Dialysis-associated hypotension will be defined as hypotension during dialysis requiring hospitalization or treatment in an emergency room and not attributable to overt sepsis, acute myocardial infarction, or other cardiovascular event (e.g. aortic dissection). The percentage of participants who have dialysis-associated hypotension up to week 7 will be determined.

  Up to study week 7 (7 weeks after study medication start)

• Percentage of Participants That Experience Dialysis-associated Hypotension up to Week 8

  Participants' blood pressure will be measured with an upper extremity cuff in a seated position at 15-minute intervals during each hemodialysis treatment per standard dialysis clinic protocols. Dialysis-associated hypotension will be defined as hypotension during dialysis requiring hospitalization or treatment in an emergency room and not attributable to overt sepsis, acute myocardial infarction, or other cardiovascular event (e.g. aortic dissection). The percentage of participants who have dialysis-associated hypotension up to week 8 will be determined.

  Up to study week 8 (8 weeks after study medication start)

• Percentage of Participants That Experience Dialysis-associated Hypotension up to Week 9

  Participants' blood pressure will be measured with an upper extremity cuff in a seated position at 15-minute intervals during each hemodialysis treatment per standard dialysis clinic protocols. Dialysis-associated hypotension will be defined as hypotension during dialysis requiring hospitalization or treatment in an emergency room and not attributable to overt sepsis, acute myocardial infarction, or other cardiovascular event (e.g. aortic dissection). The percentage of participants who have dialysis-associated hypotension up to week 9 will be determined.

  Up to study week 9 (9 weeks after study medication start)

• Percentage of Participants That Experience Dialysis-associated Hypotension up to Week 10

  Participants' blood pressure will be measured with an upper extremity cuff in a seated position at 15-minute intervals during each hemodialysis treatment per standard dialysis clinic protocols. Dialysis-associated hypotension will be defined as hypotension during dialysis requiring hospitalization or treatment in an emergency room and not attributable to overt sepsis, acute myocardial infarction, or other cardiovascular event (e.g. aortic dissection). The percentage of participants who have dialysis-associated hypotension up to week 10 will be determined.

  Up to study week 10 (10 weeks after study medication start)

• Percentage of Participants That Experience Dialysis-associated Hypotension up to Week 11

  Participants' blood pressure will be measured with an upper extremity cuff in a seated position at 15-minute intervals during each hemodialysis treatment per standard dialysis clinic protocols. Dialysis-associated hypotension will be defined as hypotension during dialysis requiring hospitalization or treatment in an emergency room and not attributable to overt sepsis, acute myocardial infarction, or other cardiovascular event (e.g. aortic dissection). The percentage of participants who have dialysis-associated hypotension up to week 11 will be determined.

  Up to study week 11 (11 weeks after study medication start)

• Percentage of Participants That Experience Dialysis-associated Hypotension up to Week 12

  Participants' blood pressure will be measured with an upper extremity cuff in a seated position at 15-minute intervals during each hemodialysis treatment per standard dialysis clinic protocols. Dialysis-associated hypotension will be defined as hypotension during dialysis requiring hospitalization or treatment in an emergency room and not attributable to overt sepsis, acute myocardial infarction, or other cardiovascular event (e.g. aortic dissection). The percentage of participants who have dialysis-associated hypotension up to week 12 will be determined.

  Up to study week 12 (12 weeks after study medication start)

• Percentage of Participants That Experience Dialysis-associated Hypotension up to Week 13

  Participants' blood pressure will be measured with an upper extremity cuff in a seated position at 15-minute intervals during each hemodialysis treatment per standard dialysis clinic protocols. Dialysis-associated hypotension will be defined as hypotension during dialysis requiring hospitalization or treatment in an emergency room and not attributable to overt sepsis, acute myocardial infarction, or other cardiovascular event (e.g. aortic dissection). The percentage of participants who have dialysis-associated hypotension up to week 13 will be determined.

  Up to study week 13 (13 weeks after study medication start)

• Percentage of Participants That Experience Dialysis-associated Hypotension up to Week 14

  Participants' blood pressure will be measured with an upper extremity cuff in a seated position at 15-minute intervals during each hemodialysis treatment per standard dialysis clinic protocols. Dialysis-associated hypotension will be defined as hypotension during dialysis requiring hospitalization or treatment in an emergency room and not attributable to overt sepsis, acute myocardial infarction, or other cardiovascular event (e.g. aortic dissection). The percentage of participants who have dialysis-associated hypotension up to week 14 will be determined.

  Up to study week 14 (14 weeks after study medication start)

• Percentage of Participants That Experience Dialysis-associated Hypotension up to Week 15

  Participants' blood pressure will be measured with an upper extremity cuff in a seated position at 15-minute intervals during each hemodialysis treatment per standard dialysis clinic protocols. Dialysis-associated hypotension will be defined as hypotension during dialysis requiring hospitalization or treatment in an emergency room and not attributable to overt sepsis, acute myocardial infarction, or other cardiovascular event (e.g. aortic dissection). The percentage of participants who have dialysis-associated hypotension up to week 15 will be determined.

  Up to study week 15 (15 weeks after study medication start)

• Percentage of Participants That Experience Dialysis-associated Hypotension up to Week 16

  Participants' blood pressure will be measured with an upper extremity cuff in a seated position at 15-minute intervals during each hemodialysis treatment per standard dialysis clinic protocols. Dialysis-associated hypotension will be defined as hypotension during dialysis requiring hospitalization or treatment in an emergency room and not attributable to overt sepsis, acute myocardial infarction, or other cardiovascular event (e.g. aortic dissection). The percentage of participants who have dialysis-associated hypotension up to week 16 will be determined.

  Up to study week 16 (16 weeks after study medication start)

• Percentage of Participants That Experience Dialysis-associated Hypotension up to Week 17

  Participants' blood pressure will be measured with an upper extremity cuff in a seated position at 15-minute intervals during each hemodialysis treatment per standard dialysis clinic protocols. Dialysis-associated hypotension will be defined as hypotension during dialysis requiring hospitalization or treatment in an emergency room and not attributable to overt sepsis, acute myocardial infarction, or other cardiovascular event (e.g. aortic dissection). The percentage of participants who have dialysis-associated hypotension up to week 17 will be determined.

  Up to study week 17 (17 weeks after study medication start)

• Percentage of Participants That Experience Dialysis-associated Hypotension up to Week 18

  Participants' blood pressure will be measured with an upper extremity cuff in a seated position at 15-minute intervals during each hemodialysis treatment per standard dialysis clinic protocols. Dialysis-associated hypotension will be defined as hypotension during dialysis requiring hospitalization or treatment in an emergency room and not attributable to overt sepsis, acute myocardial infarction, or other cardiovascular event (e.g. aortic dissection). The percentage of participants who have dialysis-associated hypotension up to week 18 will be determined.

  Up to study week 18 (18 weeks after study medication start)

• Percentage of Participants Reporting a Severe or Very Severe Rash Attributable to Furosemide at Week 1

  Participants' dialysis-related symptoms during the prior week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 1. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious rash will be defined as rash ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting a severe or very severe rash attributable to furosemide will be determined.

  Study week 1 (1 week after study medication start)

• Percentage of Participants Reporting a Severe or Very Severe Rash Attributable to Furosemide at Week 2

  Participants' dialysis-related symptoms during the prior week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 2. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious rash will be defined as rash ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting a severe or very severe rash attributable to furosemide will be determined.

  Study week 2 (2 weeks after study medication start)

• Percentage of Participants Reporting a Severe or Very Severe Rash Attributable to Furosemide at Week 3

  Participants' dialysis-related symptoms during the prior week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 3. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious rash will be defined as rash ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting a severe or very severe rash attributable to furosemide will be determined.

  Study week 3 (3 weeks after study medication start)

• Percentage of Participants Reporting a Severe or Very Severe Rash Attributable to Furosemide at Week 4

  Participants' dialysis-related symptoms during the prior week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 4. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious rash will be defined as rash ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting a severe or very severe rash attributable to furosemide will be determined.

  Study week 4 (4 weeks after study medication start)

• Percentage of Participants Reporting a Severe or Very Severe Rash Attributable to Furosemide at Week 5

  Participants' dialysis-related symptoms during the prior week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 5. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious rash will be defined as rash ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting a severe or very severe rash attributable to furosemide will be determined.

  Study week 5 (5 weeks after study medication start)

• Percentage of Participants Reporting a Severe or Very Severe Rash Attributable to Furosemide at Week 6

  Participants' dialysis-related symptoms during the prior week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 6. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious rash will be defined as rash ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting a severe or very severe rash attributable to furosemide will be determined.

  Study week 6 (6 weeks after study medication start)

• Percentage of Participants Reporting a Severe or Very Severe Rash Attributable to Furosemide at Week 8

  Participants' dialysis-related symptoms during the prior week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 8. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious rash will be defined as rash ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting a severe or very severe rash attributable to furosemide will be determined.

  Study week 8 (8 weeks after study medication start)

• Percentage of Participants Reporting a Severe or Very Severe Rash Attributable to Furosemide at Week 10

  Participants' dialysis-related symptoms during the prior week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 10. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious rash will be defined as rash ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting a severe or very severe rash attributable to furosemide will be determined.

  Study week 10 (10 weeks after study medication start)

• Percentage of Participants Reporting a Severe or Very Severe Rash Attributable to Furosemide at Week 12

  Participants' dialysis-related symptoms during the prior week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 12. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious rash will be defined as rash ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting a severe or very severe rash attributable to furosemide will be determined.

  Study week 12 (12 weeks after study medication start)

• Percentage of Participants Reporting a Severe or Very Severe Rash Attributable to Furosemide at Week 14

  Participants' dialysis-related symptoms during the prior week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 14. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious rash will be defined as rash ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting a severe or very severe rash attributable to furosemide will be determined.

  Study week 14 (14 weeks after study medication start)

• Percentage of Participants Reporting a Severe or Very Severe Rash Attributable to Furosemide at Week 16

  Participants' dialysis-related symptoms during the prior week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 16. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious rash will be defined as rash ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting a severe or very severe rash attributable to furosemide will be determined.

  Study week 16 (16 weeks after study medication start)

• Percentage of Participants Reporting a Severe or Very Severe Rash Attributable to Furosemide at Week 18

  Participants' dialysis-related symptoms during the prior week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 18. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious rash will be defined as rash ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting a severe or very severe rash attributable to furosemide will be determined.

  Study week 18 (18 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Tinnitus Attributable to Furosemide at Week 1

  Participants' dialysis-related symptoms during the prior week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 1. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious tinnitus will be defined as tinnitus ranked as severe or very severe and attributable to furosemide. Incidence will be defined as percentage of participants who have serious tinnitus. The percentage of participants reporting severe or very severe tinnitus attributable to furosemide will be determined.

  Study week 1 (1 week after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Tinnitus Attributable to Furosemide at Week 2

  Participants' dialysis-related symptoms during the prior week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 2. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious tinnitus will be defined as tinnitus ranked as severe or very severe and attributable to furosemide. Incidence will be defined as percentage of participants who have serious tinnitus. The percentage of participants reporting severe or very severe tinnitus attributable to furosemide will be determined.

  Study week 2 (2 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Tinnitus Attributable to Furosemide at Week 3

  Participants' dialysis-related symptoms during the prior week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 3. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious tinnitus will be defined as tinnitus ranked as severe or very severe and attributable to furosemide. Incidence will be defined as percentage of participants who have serious tinnitus. The percentage of participants reporting severe or very severe tinnitus attributable to furosemide will be determined.

  Study week 3 (3 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Tinnitus Attributable to Furosemide at Week 4

  Participants' dialysis-related symptoms during the prior week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 4. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious tinnitus will be defined as tinnitus ranked as severe or very severe and attributable to furosemide. Incidence will be defined as percentage of participants who have serious tinnitus. The percentage of participants reporting severe or very severe tinnitus attributable to furosemide will be determined.

  Study week 4 (4 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Tinnitus Attributable to Furosemide at Week 5

  Participants' dialysis-related symptoms during the prior week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 5. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious tinnitus will be defined as tinnitus ranked as severe or very severe and attributable to furosemide. Incidence will be defined as percentage of participants who have serious tinnitus. The percentage of participants reporting severe or very severe tinnitus attributable to furosemide will be determined.

  Study week 5 (5 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Tinnitus Attributable to Furosemide at Week 6

  Participants' dialysis-related symptoms during the prior week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 6. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious tinnitus will be defined as tinnitus ranked as severe or very severe and attributable to furosemide. Incidence will be defined as percentage of participants who have serious tinnitus. The percentage of participants reporting severe or very severe tinnitus attributable to furosemide will be determined.

  Study week 6 (6 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Tinnitus Attributable to Furosemide at Week 8

  Participants' dialysis-related symptoms during the prior week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 8. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious tinnitus will be defined as tinnitus ranked as severe or very severe and attributable to furosemide. Incidence will be defined as percentage of participants who have serious tinnitus. The percentage of participants reporting severe or very severe tinnitus attributable to furosemide will be determined.

  Study week 8 (8 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Tinnitus Attributable to Furosemide at Week 10

  Participants' dialysis-related symptoms during the prior week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 10. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious tinnitus will be defined as tinnitus ranked as severe or very severe and attributable to furosemide. Incidence will be defined as percentage of participants who have serious tinnitus. The percentage of participants reporting severe or very severe tinnitus attributable to furosemide will be determined.

  Study week 10 (10 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Tinnitus Attributable to Furosemide at Week 12

  Participants' dialysis-related symptoms during the prior week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 12. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious tinnitus will be defined as tinnitus ranked as severe or very severe and attributable to furosemide. Incidence will be defined as percentage of participants who have serious tinnitus. The percentage of participants reporting severe or very severe tinnitus attributable to furosemide will be determined.

  Study week 12 (12 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Tinnitus Attributable to Furosemide at Week 14

  Participants' dialysis-related symptoms during the prior week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 14. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious tinnitus will be defined as tinnitus ranked as severe or very severe and attributable to furosemide. Incidence will be defined as percentage of participants who have serious tinnitus. The percentage of participants reporting severe or very severe tinnitus attributable to furosemide will be determined.

  Study week 14 (14 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Tinnitus Attributable to Furosemide at Week 16

  Participants' dialysis-related symptoms during the prior week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 16. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious tinnitus will be defined as tinnitus ranked as severe or very severe and attributable to furosemide. Incidence will be defined as percentage of participants who have serious tinnitus. The percentage of participants reporting severe or very severe tinnitus attributable to furosemide will be determined.

  Study week 16 (16 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Tinnitus Attributable to Furosemide at Week 18

  Participants' dialysis-related symptoms during the prior week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 18. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious tinnitus will be defined as tinnitus ranked as severe or very severe and attributable to furosemide. Incidence will be defined as percentage of participants who have serious tinnitus. The percentage of participants reporting severe or very severe tinnitus attributable to furosemide will be determined.

  Study week 18 (18 weeks after study medication start)

• Percentage of Participants Reporting a Severe or Very Severe Hearing Change Attributable to Furosemide at Week 1

  Participants' dialysis-related symptoms during the prior week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 1. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious hearing change will be defined as hearing change ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting a severe or very severe hearing change attributable to furosemide will be determined.

  Study week 1 (1 week after study medication start)

• Percentage of Participants Reporting a Severe or Very Severe Hearing Change Attributable to Furosemide at Week 2

  Participants' dialysis-related symptoms during the prior week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 2. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious hearing change will be defined as hearing change ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting a severe or very severe hearing change attributable to furosemide will be determined.

  Study week 2 (2 weeks after study medication start)

• Percentage of Participants Reporting a Severe or Very Severe Hearing Change Attributable to Furosemide at Week 3

  Participants' dialysis-related symptoms during the prior week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 3. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious hearing change will be defined as hearing change ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting a severe or very severe hearing change attributable to furosemide will be determined.

  Study week 3 (3 weeks after study medication start)

• Percentage of Participants Reporting a Severe or Very Severe Hearing Change Attributable to Furosemide at Week 4

  Participants' dialysis-related symptoms during the prior week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 4. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious hearing change will be defined as hearing change ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting a severe or very severe hearing change attributable to furosemide will be determined.

  Study week 4 (4 weeks after study medication start)

• Percentage of Participants Reporting a Severe or Very Severe Hearing Change Attributable to Furosemide at Week 5

  Participants' dialysis-related symptoms during the prior week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 5. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious hearing change will be defined as hearing change ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting a severe or very severe hearing change attributable to furosemide will be determined.

  Study week 5 (5 weeks after study medication start)

• Percentage of Participants Reporting a Severe or Very Severe Hearing Change Attributable to Furosemide at Week 6

  Participants' dialysis-related symptoms during the prior week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 6. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious hearing change will be defined as hearing change ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting a severe or very severe hearing change attributable to furosemide will be determined.

  Study week 6 (6 weeks after study medication start)

• Percentage of Participants Reporting a Severe or Very Severe Hearing Change Attributable to Furosemide at Week 8

  Participants' dialysis-related symptoms during the prior week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 8. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious hearing change will be defined as hearing change ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting a severe or very severe hearing change attributable to furosemide will be determined.

  Study week 8 (8 weeks after study medication start)

• Percentage of Participants Reporting a Severe or Very Severe Hearing Change Attributable to Furosemide at Week 10

  Participants' dialysis-related symptoms during the prior week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 10. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious hearing change will be defined as hearing change ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting a severe or very severe hearing change attributable to furosemide will be determined.

  Study week 10 (10 weeks after study medication start)

• Percentage of Participants Reporting a Severe or Very Severe Hearing Change Attributable to Furosemide at Week 12

  Participants' dialysis-related symptoms during the prior week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 12. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious hearing change will be defined as hearing change ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting a severe or very severe hearing change attributable to furosemide will be determined.

  Study week 12 (12 weeks after study medication start)

• Percentage of Participants Reporting a Severe or Very Severe Hearing Change Attributable to Furosemide at Week 14

  Participants' dialysis-related symptoms during the prior week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 14. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious hearing change will be defined as hearing change ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting a severe or very severe hearing change attributable to furosemide will be determined.

  Study week 14 (14 weeks after study medication start)

• Percentage of Participants Reporting a Severe or Very Severe Hearing Change Attributable to Furosemide at Week 16

  Participants' dialysis-related symptoms during the prior week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 16. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious hearing change will be defined as hearing change ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting a severe or very severe hearing change attributable to furosemide will be determined.

  Study week 16 (16 weeks after study medication start)

• Percentage of Participants Reporting a Severe or Very Severe Hearing Change Attributable to Furosemide at Week 18

  Participants' dialysis-related symptoms during the prior week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 18. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious hearing change will be defined as hearing change ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting a severe or very severe hearing change attributable to furosemide will be determined.

  Study week 18 (18 weeks after study medication start)

• Change in the Inner EAR Instrument Score From Baseline to Week 1

  Participants' hearing ability during the last week will be assessed using the Inner Effectiveness of Auditory Rehabilitation (Inner EAR) 11-question validated questionnaire administered during study week 1. The total instrument score will be tallied at each administration \[range: 10 (low hearing ability) - 59 (high hearing ability)\]. Serious hearing change will be defined as a ≥10-point decrease in the Inner EAR instrument score from baseline score.

  Baseline and study week 1 (1 week after study medication start)

• Percentage of Participants With a Defined Decrease in the Inner EAR Instrument Score From Baseline to Week 2

  Participants' hearing ability during the last week will be assessed using the Inner Effectiveness of Auditory Rehabilitation (Inner EAR) 11-question validated questionnaire administered during study week 2. The total instrument score will be tallied at each administration \[range: 10 (low hearing ability) - 59 (high hearing ability)\]. Serious hearing change will be defined as a ≥10-point decrease in the Inner EAR instrument score from baseline score. The percentage of participants with a defined decrease in the Inner EAR instrument score will be determined.

  Baseline and study week 2 (2 weeks after study medication start)

• Change in the Inner EAR Instrument Score From Baseline to Week 3

  Participants' hearing ability during the last week will be assessed using the Inner Effectiveness of Auditory Rehabilitation (Inner EAR) 11-question validated questionnaire administered during study week 3. The total instrument score will be tallied at each administration \[range: 10 (low hearing ability) - 59 (high hearing ability)\]. Serious hearing change will be defined as a ≥10-point decrease in the Inner EAR instrument score from baseline score.

  Baseline and study week 3 (3 weeks after study medication start)

• Percentage of Participants With a Defined Decrease in the Inner EAR Instrument Score From Baseline to Week 4

  Participants' hearing ability during the last week will be assessed using the Inner Effectiveness of Auditory Rehabilitation (Inner EAR) 11-question validated questionnaire administered during study week 4. The total instrument score will be tallied at each administration \[range: 10 (low hearing ability) - 59 (high hearing ability)\]. Serious hearing change will be defined as a ≥10-point decrease in the Inner EAR instrument score from baseline score. The percentage of participants with a defined decrease in the Inner EAR instrument score will be determined.

  Baseline and study week 4 (4 weeks after study medication start)

• Change in the Inner EAR Instrument Score From Baseline to Week 5

  Participants' hearing ability during the last week will be assessed using the Inner Effectiveness of Auditory Rehabilitation (Inner EAR) 11-question validated questionnaire administered during study week 5. The total instrument score will be tallied at each administration \[range: 10 (low hearing ability) - 59 (high hearing ability)\]. Serious hearing change will be defined as a ≥10-point decrease in the Inner EAR instrument score from baseline score.

  Baseline and study week 5 (5 weeks after study medication start)

• Percentage of Participants With a Defined Decrease in the Inner EAR Instrument Score From Baseline to Week 6

  Participants' hearing ability during the last week will be assessed using the Inner Effectiveness of Auditory Rehabilitation (Inner EAR) 11-question validated questionnaire administered during study week 6. The total instrument score will be tallied at each administration \[range: 10 (low hearing ability) - 59 (high hearing ability)\]. Serious hearing change will be defined as a ≥10-point decrease in the Inner EAR instrument score from baseline score. The percentage of participants with a defined decrease in the Inner EAR instrument score will be determined.

  Baseline and study week 6 (6 weeks after study medication start)

• Change in the Inner EAR Instrument Score From Baseline to Week 8

  Participants' hearing ability during the last week will be assessed using the Inner Effectiveness of Auditory Rehabilitation (Inner EAR) 11-question validated questionnaire administered during study week 8. The total instrument score will be tallied at each administration \[range: 10 (low hearing ability) - 59 (high hearing ability)\]. Serious hearing change will be defined as a ≥10-point decrease in the Inner EAR instrument score from baseline score.

  Baseline and study week 8 (8 weeks after study medication start)

• Percentage of Participants With a Defined Decrease in the Inner EAR Instrument Score From Baseline to Week 10

  Participants' hearing ability during the last week will be assessed using the Inner Effectiveness of Auditory Rehabilitation (Inner EAR) 11-question validated questionnaire administered during study week 10. The total instrument score will be tallied at each administration \[range: 10 (low hearing ability) - 59 (high hearing ability)\]. Serious hearing change will be defined as a ≥10-point decrease in the Inner EAR instrument score from baseline score. The percentage of participants with a defined decrease in the Inner EAR instrument score will be determined.

  Baseline and study week 10 (10 weeks after study medication start)

• Change in the Inner EAR Instrument Score From Baseline to Week 12

  Participants' hearing ability during the last week will be assessed using the Inner Effectiveness of Auditory Rehabilitation (Inner EAR) 11-question validated questionnaire administered during study week 12. The total instrument score will be tallied at each administration \[range: 10 (low hearing ability) - 59 (high hearing ability)\]. Serious hearing change will be defined as a ≥10-point decrease in the Inner EAR instrument score from baseline score.

  Baseline and study week 12 (12 weeks after study medication start)

• Percentage of Participants With a Defined Decrease in the Inner EAR Instrument Score From Baseline to Week 14

  Participants' hearing ability during the last week will be assessed using the Inner Effectiveness of Auditory Rehabilitation (Inner EAR) 11-question validated questionnaire administered during study week 14. The total instrument score will be tallied at each administration \[range: 10 (low hearing ability) - 59 (high hearing ability)\]. Serious hearing change will be defined as a ≥10-point decrease in the Inner EAR instrument score from baseline score. The percentage of participants with a defined decrease in the Inner EAR instrument score will be determined.

  Baseline and study week 14 (14 weeks after study medication start)

• Change in the Inner EAR Instrument Score From Baseline to Week 16

  Participants' hearing ability during the last week will be assessed using the Inner Effectiveness of Auditory Rehabilitation (Inner EAR) 11-question validated questionnaire administered during study week 16. The total instrument score will be tallied at each administration \[range: 10 (low hearing ability) - 59 (high hearing ability)\]. Serious hearing change will be defined as a ≥10-point decrease in the Inner EAR instrument score from baseline score.

  Baseline and study week 16 (16 weeks after study medication start)

• Percentage of Participants With a Defined Decrease in the Inner EAR Instrument Score From Baseline to Week 18

  Participants' hearing ability during the last week will be assessed using the Inner Effectiveness of Auditory Rehabilitation (Inner EAR) 11-question validated questionnaire administered during study week 18. The total instrument score will be tallied at each administration \[range: 10 (low hearing ability) - 59 (high hearing ability)\]. Serious hearing change will be defined as a ≥10-point decrease in the Inner EAR instrument score from baseline score. The percentage of participants with a defined decrease in the Inner EAR instrument score will be determined.

  Baseline and study week 18 (18 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Cramping Attributable to Furosemide at Week 1

  Participants' dialysis-related symptoms during the prior week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 1. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious cramping will be defined as cramping ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting severe or very severe cramping attributable to furosemide will be determined.

  Study week 1 (1 week after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Cramping Attributable to Furosemide at Week 2

  Participants' dialysis-related symptoms during the prior week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 2. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious cramping will be defined as cramping ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting severe or very severe cramping attributable to furosemide will be determined.

  Study week 2 (2 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Cramping Attributable to Furosemide at Week 3

  Participants' dialysis-related symptoms during the prior week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 3. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious cramping will be defined as cramping ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting severe or very severe cramping attributable to furosemide will be determined.

  Study week 3 (3 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Cramping Attributable to Furosemide at Week 4

  Participants' dialysis-related symptoms during the prior week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 4. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious cramping will be defined as cramping ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting severe or very severe cramping attributable to furosemide will be determined.

  Study week 4 (4 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Cramping Attributable to Furosemide at Week 5

  Participants' dialysis-related symptoms during the prior week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 5. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious cramping will be defined as cramping ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting severe or very severe cramping attributable to furosemide will be determined.

  Study week 5 (5 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Cramping Attributable to Furosemide at Week 6

  Participants' dialysis-related symptoms during the prior week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 6. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious cramping will be defined as cramping ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting severe or very severe cramping attributable to furosemide will be determined.

  Study week 6 (6 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Cramping Attributable to Furosemide at Week 8

  Participants' dialysis-related symptoms during the prior week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 8. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious cramping will be defined as cramping ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting severe or very severe cramping attributable to furosemide will be determined.

  Study week 8 (8 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Cramping Attributable to Furosemide at Week 10

  Participants' dialysis-related symptoms during the prior week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 10. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious cramping will be defined as cramping ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting severe or very severe cramping attributable to furosemide will be determined.

  Study week 10 (10 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Cramping Attributable to Furosemide at Week 12

  Participants' dialysis-related symptoms during the prior week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 12. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious cramping will be defined as cramping ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting severe or very severe cramping attributable to furosemide will be determined.

  Study week 12 (12 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Cramping Attributable to Furosemide at Week 14

  Participants' dialysis-related symptoms during the prior week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 14. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious cramping will be defined as cramping ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting severe or very severe cramping attributable to furosemide will be determined.

  Study week 14 (14 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Cramping Attributable to Furosemide at Week 16

  Participants' dialysis-related symptoms during the prior week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 16. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious cramping will be defined as cramping ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting severe or very severe cramping attributable to furosemide will be determined.

  Study week 16 (16 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Cramping Attributable to Furosemide at Week 18

  Participants' dialysis-related symptoms during the prior week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 18. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious cramping will be defined as cramping ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting severe or very severe cramping attributable to furosemide will be determined.

  Study week 18 (18 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Dizziness/Pre-syncope Attributable to Furosemide at Week 1

  Participants' dialysis-related symptoms during the prior week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 1. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious dizziness/pre-syncope will be defined as dizziness/pre-syncope ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting severe or very severe dizziness/pre-syncope attributable to furosemide will be determined.

  Study week 1 (1 week after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Dizziness/Pre-syncope Attributable to Furosemide at Week 2

  Participants' dialysis-related symptoms during the prior week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 2. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious dizziness/pre-syncope will be defined as dizziness/pre-syncope ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting severe or very severe dizziness/pre-syncope attributable to furosemide will be determined.

  Study week 2 (2 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Dizziness/Pre-syncope Attributable to Furosemide at Week 3

  Participants' dialysis-related symptoms during the prior week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 3. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious dizziness/pre-syncope will be defined as dizziness/pre-syncope ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting severe or very severe dizziness/pre-syncope attributable to furosemide will be determined.

  Study week 3 (3 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Dizziness/Pre-syncope Attributable to Furosemide at Week 4

  Participants' dialysis-related symptoms during the prior week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 4. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious dizziness/pre-syncope will be defined as dizziness/pre-syncope ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting severe or very severe dizziness/pre-syncope attributable to furosemide will be determined.

  Study week 4 (4 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Dizziness/Pre-syncope Attributable to Furosemide at Week 5

  Participants' dialysis-related symptoms during the prior week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 5. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious dizziness/pre-syncope will be defined as dizziness/pre-syncope ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting severe or very severe dizziness/pre-syncope attributable to furosemide will be determined.

  Study week 5 (5 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Dizziness/Pre-syncope Attributable to Furosemide at Week 6

  Participants' dialysis-related symptoms during the prior week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 6. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious dizziness/pre-syncope will be defined as dizziness/pre-syncope ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting severe or very severe dizziness/pre-syncope attributable to furosemide will be determined.

  Study week 6 (6 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Dizziness/Pre-syncope Attributable to Furosemide at Week 8

  Participants' dialysis-related symptoms during the prior week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 8. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious dizziness/pre-syncope will be defined as dizziness/pre-syncope ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting severe or very severe dizziness/pre-syncope attributable to furosemide will be determined.

  Study week 8 (8 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Dizziness/Pre-syncope Attributable to Furosemide at Week 10

  Participants' dialysis-related symptoms during the prior week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 10. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious dizziness/pre-syncope will be defined as dizziness/pre-syncope ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting severe or very severe dizziness/pre-syncope attributable to furosemide will be determined.

  Study week 10 (10 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Dizziness/Pre-syncope Attributable to Furosemide at Week 12

  Participants' dialysis-related symptoms during the prior week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 12. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious dizziness/pre-syncope will be defined as dizziness/pre-syncope ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting severe or very severe dizziness/pre-syncope attributable to furosemide will be determined.

  Study week 12 (12 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Dizziness/Pre-syncope Attributable to Furosemide at Week 14

  Participants' dialysis-related symptoms during the prior week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 14. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious dizziness/pre-syncope will be defined as dizziness/pre-syncope ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting severe or very severe dizziness/pre-syncope attributable to furosemide will be determined.

  Study week 14 (14 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Dizziness/Pre-syncope Attributable to Furosemide at Week 16

  Participants' dialysis-related symptoms during the prior week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 16. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious dizziness/pre-syncope will be defined as dizziness/pre-syncope ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting severe or very severe dizziness/pre-syncope attributable to furosemide will be determined.

  Study week 16 (16 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Dizziness/Pre-syncope Attributable to Furosemide at Week 18

  Participants' dialysis-related symptoms during the prior week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 18. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious dizziness/pre-syncope will be defined as dizziness/pre-syncope ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting severe or very severe dizziness/pre-syncope attributable to furosemide will be determined.

  Study week 18 (18 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Unusual Tiredness/Weakness Attributable to Furosemide at Week 1

  Participants' dialysis-related symptoms during the prior week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 1. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious unusual tiredness/weakness will be defined as unusual tiredness/weakness ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting severe or very severe unusual tiredness/weakness will be determined.

  Study week 1 (1 week after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Unusual Tiredness/Weakness Attributable to Furosemide at Week 2

  Participants' dialysis-related symptoms during the prior week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 2. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious unusual tiredness/weakness will be defined as unusual tiredness/weakness ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting severe or very severe unusual tiredness/weakness will be determined.

  Study week 2 (2 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Unusual Tiredness/Weakness Attributable to Furosemide at Week 3

  Participants' dialysis-related symptoms during the prior week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 3. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious unusual tiredness/weakness will be defined as unusual tiredness/weakness ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting severe or very severe unusual tiredness/weakness will be determined.

  Study week 3 (3 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Unusual Tiredness/Weakness Attributable to Furosemide at Week 4

  Participants' dialysis-related symptoms during the prior week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 4. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious unusual tiredness/weakness will be defined as unusual tiredness/weakness ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting severe or very severe unusual tiredness/weakness will be determined.

  Study week 4 (4 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Unusual Tiredness/Weakness Attributable to Furosemide at Week 5

  Participants' dialysis-related symptoms during the prior week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 5. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious unusual tiredness/weakness will be defined as unusual tiredness/weakness ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting severe or very severe unusual tiredness/weakness will be determined.

  Study week 5 (5 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Unusual Tiredness/Weakness Attributable to Furosemide at Week 6

  Participants' dialysis-related symptoms during the prior week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 6. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious unusual tiredness/weakness will be defined as unusual tiredness/weakness ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting severe or very severe unusual tiredness/weakness will be determined.

  Study week 6 (6 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Unusual Tiredness/Weakness Attributable to Furosemide at Week 8

  Participants' dialysis-related symptoms during the prior week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 8. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious unusual tiredness/weakness will be defined as unusual tiredness/weakness ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting severe or very severe unusual tiredness/weakness will be determined.

  Study week 8 (8 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Unusual Tiredness/Weakness Attributable to Furosemide at Week 10

  Participants' dialysis-related symptoms during the prior week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 10. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious unusual tiredness/weakness will be defined as unusual tiredness/weakness ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting severe or very severe unusual tiredness/weakness will be determined.

  Study week 10 (10 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Unusual Tiredness/Weakness Attributable to Furosemide at Week 12

  Participants' dialysis-related symptoms during the prior week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 12. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious unusual tiredness/weakness will be defined as unusual tiredness/weakness ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting severe or very severe unusual tiredness/weakness will be determined.

  Study week 12 (12 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Unusual Tiredness/Weakness Attributable to Furosemide at Week 14

  Participants' dialysis-related symptoms during the prior week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 14. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious unusual tiredness/weakness will be defined as unusual tiredness/weakness ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting severe or very severe unusual tiredness/weakness will be determined.

  Study week 14 (14 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Unusual Tiredness/Weakness Attributable to Furosemide at Week 16

  Participants' dialysis-related symptoms during the prior week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 16. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious unusual tiredness/weakness will be defined as unusual tiredness/weakness ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting severe or very severe unusual tiredness/weakness will be determined.

  Study week 16 (16 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Unusual Tiredness/Weakness Attributable to Furosemide at Week 18

  Participants' dialysis-related symptoms during the prior week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 18. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious unusual tiredness/weakness will be defined as unusual tiredness/weakness ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting severe or very severe unusual tiredness/weakness will be determined.

  Study week 18 (18 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Chest Pain Attributable to Furosemide at Week 1

  Participants' dialysis-related symptoms during the last week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 1. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious chest pain will be defined as chest pain ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting severe or very severe chest pain will be determined.

  Study week 1 (1 week after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Chest Pain Attributable to Furosemide at Week 2

  Participants' dialysis-related symptoms during the last week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 2. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious chest pain will be defined as chest pain ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting severe or very severe chest pain will be determined.

  Study week 2 (2 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Chest Pain Attributable to Furosemide at Week 3

  Participants' dialysis-related symptoms during the last week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 3. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious chest pain will be defined as chest pain ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting severe or very severe chest pain will be determined.

  Study week 3 (3 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Chest Pain Attributable to Furosemide at Week 4

  Participants' dialysis-related symptoms during the last week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 4. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious chest pain will be defined as chest pain ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting severe or very severe chest pain will be determined.

  Study week 4 (4 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Chest Pain Attributable to Furosemide at Week 5

  Participants' dialysis-related symptoms during the last week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 5. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious chest pain will be defined as chest pain ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting severe or very severe chest pain will be determined.

  Study week 5 (5 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Chest Pain Attributable to Furosemide at Week 6

  Participants' dialysis-related symptoms during the last week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 6. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious chest pain will be defined as chest pain ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting severe or very severe chest pain will be determined.

  Study week 6 (6 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Chest Pain Attributable to Furosemide at Week 8

  Participants' dialysis-related symptoms during the last week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 8. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious chest pain will be defined as chest pain ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting severe or very severe chest pain will be determined.

  Study week 8 (8 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Chest Pain Attributable to Furosemide at Week 10

  Participants' dialysis-related symptoms during the last week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 10. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious chest pain will be defined as chest pain ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting severe or very severe chest pain will be determined.

  Study week 10 (10 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Chest Pain Attributable to Furosemide at Week 12

  Participants' dialysis-related symptoms during the last week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 12. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious chest pain will be defined as chest pain ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting severe or very severe chest pain will be determined.

  Study week 12 (12 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Chest Pain Attributable to Furosemide at Week 14

  Participants' dialysis-related symptoms during the last week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 14. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious chest pain will be defined as chest pain ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting severe or very severe chest pain will be determined.

  Study week 14 (14 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Chest Pain Attributable to Furosemide at Week 16

  Participants' dialysis-related symptoms during the last week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 16. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious chest pain will be defined as chest pain ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting severe or very severe chest pain will be determined.

  Study week 16 (16 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Chest Pain Attributable to Furosemide at Week 18

  Participants' dialysis-related symptoms during the last week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 18. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious chest pain will be defined as chest pain ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting severe or very severe chest pain will be determined.

  Study week 18 (18 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Nausea Attributable to Furosemide at Week 1

  Participants' dialysis-related symptoms during the last week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 1. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious nausea will be defined as nausea ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting severe or very severe nausea will be determined.

  Study week 1 (1 week after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Nausea Attributable to Furosemide at Week 2

  Participants' dialysis-related symptoms during the last week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 2. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious nausea will be defined as nausea ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting severe or very severe nausea will be determined.

  Study week 2 (2 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Nausea Attributable to Furosemide at Week 3

  Participants' dialysis-related symptoms during the last week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 3. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious nausea will be defined as nausea ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting severe or very severe nausea will be determined.

  Study week 3 (3 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Nausea Attributable to Furosemide at Week 4

  Participants' dialysis-related symptoms during the last week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 4. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious nausea will be defined as nausea ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting severe or very severe nausea will be determined.

  Study week 4 (4 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Nausea Attributable to Furosemide at Week 5

  Participants' dialysis-related symptoms during the last week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 5. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious nausea will be defined as nausea ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting severe or very severe nausea will be determined.

  Study week 5 (5 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Nausea Attributable to Furosemide at Week 6

  Participants' dialysis-related symptoms during the last week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 6. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious nausea will be defined as nausea ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting severe or very severe nausea will be determined.

  Study week 6 (6 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Nausea Attributable to Furosemide at Week 8

  Participants' dialysis-related symptoms during the last week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 8. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious nausea will be defined as nausea ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting severe or very severe nausea will be determined.

  Study week 8 (8 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Nausea Attributable to Furosemide at Week 10

  Participants' dialysis-related symptoms during the last week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 10. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious nausea will be defined as nausea ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting severe or very severe nausea will be determined.

  Study week 10 (10 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Nausea Attributable to Furosemide at Week 12

  Participants' dialysis-related symptoms during the last week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 12. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious nausea will be defined as nausea ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting severe or very severe nausea will be determined.

  Study week 12 (12 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Nausea Attributable to Furosemide at Week 14

  Participants' dialysis-related symptoms during the last week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 14. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious nausea will be defined as nausea ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting severe or very severe nausea will be determined.

  Study week 14 (14 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Nausea Attributable to Furosemide at Week 16

  Participants' dialysis-related symptoms during the last week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 16. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious nausea will be defined as nausea ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting severe or very severe nausea will be determined.

  Study week 16 (16 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Nausea Attributable to Furosemide at Week 18

  Participants' dialysis-related symptoms during the last week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 18. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious nausea will be defined as nausea ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting severe or very severe nausea will be determined.

  Study week 18 (18 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Vomiting Attributable to Furosemide at Week 1

  Participants' dialysis-related symptoms during the last week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 1. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious vomiting will be defined as vomiting ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting severe or very severe vomiting will be determined.

  Study week 1 (1 week after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Vomiting Attributable to Furosemide at Week 2

  Participants' dialysis-related symptoms during the last week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 2. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious vomiting will be defined as vomiting ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting severe or very severe vomiting will be determined.

  Study week 2 (2 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Vomiting Attributable to Furosemide at Week 3

  Participants' dialysis-related symptoms during the last week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 3. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious vomiting will be defined as vomiting ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting severe or very severe vomiting will be determined.

  Study week 3 (3 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Vomiting Attributable to Furosemide at Week 4

  Participants' dialysis-related symptoms during the last week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 4. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious vomiting will be defined as vomiting ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting severe or very severe vomiting will be determined.

  Study week 4 (4 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Vomiting Attributable to Furosemide at Week 5

  Participants' dialysis-related symptoms during the last week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 5. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious vomiting will be defined as vomiting ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting severe or very severe vomiting will be determined.

  Study week 5 (5 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Vomiting Attributable to Furosemide at Week 6

  Participants' dialysis-related symptoms during the last week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 6. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious vomiting will be defined as vomiting ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting severe or very severe vomiting will be determined.

  Study week 6 (6 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Vomiting Attributable to Furosemide at Week 8

  Participants' dialysis-related symptoms during the last week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 8. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious vomiting will be defined as vomiting ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting severe or very severe vomiting will be determined.

  Study week 8 (8 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Vomiting Attributable to Furosemide at Week 10

  Participants' dialysis-related symptoms during the last week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 10. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious vomiting will be defined as vomiting ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting severe or very severe vomiting will be determined.

  Study week 10 (10 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Vomiting Attributable to Furosemide at Week 12

  Participants' dialysis-related symptoms during the last week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 12. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious vomiting will be defined as vomiting ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting severe or very severe vomiting will be determined.

  Study week 12 (12 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Vomiting Attributable to Furosemide at Week 14

  Participants' dialysis-related symptoms during the last week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 14. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious vomiting will be defined as vomiting ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting severe or very severe vomiting will be determined.

  Study week 14 (14 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Vomiting Attributable to Furosemide at Week 16

  Participants' dialysis-related symptoms during the last week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 16. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious vomiting will be defined as vomiting ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting severe or very severe vomiting will be determined.

  Study week 16 (16 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Vomiting Attributable to Furosemide at Week 18

  Participants' dialysis-related symptoms during the last week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 18. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious vomiting will be defined as vomiting ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting severe or very severe vomiting will be determined.

  Study week 18 (18 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Diarrhea Attributable to Furosemide at Week 1

  Participants' dialysis-related symptoms during the last week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 1. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious diarrhea will be defined as diarrhea ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting severe or very severe diarrhea will be determined.

  Study week 1 (1 week after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Diarrhea Attributable to Furosemide at Week 2

  Participants' dialysis-related symptoms during the last week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 2. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious diarrhea will be defined as diarrhea ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting severe or very severe diarrhea will be determined.

  Study week 2 (2 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Diarrhea Attributable to Furosemide at Week 3

  Participants' dialysis-related symptoms during the last week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 3. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious diarrhea will be defined as diarrhea ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting severe or very severe diarrhea will be determined.

  Study week 3 (3 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Diarrhea Attributable to Furosemide at Week 4

  Participants' dialysis-related symptoms during the last week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 4. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious diarrhea will be defined as diarrhea ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting severe or very severe diarrhea will be determined.

  Study week 4 (4 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Diarrhea Attributable to Furosemide at Week 5

  Participants' dialysis-related symptoms during the last week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 5. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious diarrhea will be defined as diarrhea ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting severe or very severe diarrhea will be determined.

  Study week 5 (5 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Diarrhea Attributable to Furosemide at Week 6

  Participants' dialysis-related symptoms during the last week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 6. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious diarrhea will be defined as diarrhea ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting severe or very severe diarrhea will be determined.

  Study week 6 (6 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Diarrhea Attributable to Furosemide at Week 8

  Participants' dialysis-related symptoms during the last week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 8. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious diarrhea will be defined as diarrhea ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting severe or very severe diarrhea will be determined.

  Study week 8 (8 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Diarrhea Attributable to Furosemide at Week 10

  Participants' dialysis-related symptoms during the last week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 10. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious diarrhea will be defined as diarrhea ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting severe or very severe diarrhea will be determined.

  Study week 10 (10 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Diarrhea Attributable to Furosemide at Week 12

  Participants' dialysis-related symptoms during the last week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 12. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious diarrhea will be defined as diarrhea ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting severe or very severe diarrhea will be determined.

  Study week 12 (12 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Diarrhea Attributable to Furosemide at Week 14

  Participants' dialysis-related symptoms during the last week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 14. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious diarrhea will be defined as diarrhea ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting severe or very severe diarrhea will be determined.

  Study week 14 (14 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Diarrhea Attributable to Furosemide at Week 16

  Participants' dialysis-related symptoms during the last week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 16. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious diarrhea will be defined as diarrhea ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting severe or very severe diarrhea will be determined.

  Study week 16 (16 weeks after study medication start)

• Percentage of Participants Reporting Severe or Very Severe Diarrhea Attributable to Furosemide at Week 18

  Participants' dialysis-related symptoms during the last week will be assessed using an investigator-developed 13-question symptom questionnaire administered at study week 18. Each symptom will be graded using a 5-point symptom severity Likert scale (response options: none, mild, moderate, severe, very severe). Serious diarrhea will be defined as diarrhea ranked as severe or very severe and attributable to furosemide. The percentage of participants reporting severe or very severe diarrhea will be determined.

  Study week 18 (18 weeks after study medication start)

• Percentage of Participants Reporting Acceptance of Furosemide at Week 1

  Participants' acceptance of furosemide will be assessed using an investigator-developed 1-question questionnaire administered at study week 1. Patient-reported acceptance of furosemide at the dose during which the questionnaire is administered will be defined as an affirmative response ("yes") to the question "If recommended, would you be willing to stay on the dose of furosemide you have received during the last week?". The percentage of participants reporting acceptance of furosemide will be determined.

  Study week 1 (1 week after study medication start)

• Percentage of Participants Reporting Acceptance of Furosemide at Week 2

  Participants' acceptance of furosemide will be assessed using an investigator-developed 1-question questionnaire administered at study week 2. Patient-reported acceptance of furosemide at the dose during which the questionnaire is administered will be defined as an affirmative response ("yes") to the question "If recommended, would you be willing to stay on the dose of furosemide you have received during the last week?". The percentage of participants reporting acceptance of furosemide will be determined.

  Study week 2 (2 weeks after study medication start)

• Percentage of Participants Reporting Acceptance of Furosemide at Week 3

  Participants' acceptance of furosemide will be assessed using an investigator-developed 1-question questionnaire administered at study week 3. Patient-reported acceptance of furosemide at the dose during which the questionnaire is administered will be defined as an affirmative response ("yes") to the question "If recommended, would you be willing to stay on the dose of furosemide you have received during the last week?". The percentage of participants reporting acceptance of furosemide will be determined.

  Study week 3 (3 weeks after study medication start)

• Percentage of Participants Reporting Acceptance of Furosemide at Week 4

  Participants' acceptance of furosemide will be assessed using an investigator-developed 1-question questionnaire administered at study week 4. Patient-reported acceptance of furosemide at the dose during which the questionnaire is administered will be defined as an affirmative response ("yes") to the question "If recommended, would you be willing to stay on the dose of furosemide you have received during the last week?". The percentage of participants reporting acceptance of furosemide will be determined.

  Study week 4 (4 weeks after study medication start)

• Percentage of Participants Reporting Acceptance of Furosemide at Week 5

  Participants' acceptance of furosemide will be assessed using an investigator-developed 1-question questionnaire administered at study week 5. Patient-reported acceptance of furosemide at the dose during which the questionnaire is administered will be defined as an affirmative response ("yes") to the question "If recommended, would you be willing to stay on the dose of furosemide you have received during the last week?". The percentage of participants reporting acceptance of furosemide will be determined.

  Study week 5 (5 weeks after study medication start)

• Percentage of Participants Reporting Acceptance of Furosemide at Week 6

  Participants' acceptance of furosemide will be assessed using an investigator-developed 1-question questionnaire administered at study week 6. Patient-reported acceptance of furosemide at the dose during which the questionnaire is administered will be defined as an affirmative response ("yes") to the question "If recommended, would you be willing to stay on the dose of furosemide you have received during the last week?". The percentage of participants reporting acceptance of furosemide will be determined.

  Study week 6 (6 weeks after study medication start)

• Percentage of Participants Reporting Acceptance of Furosemide at Week 8

  Participants' acceptance of furosemide will be assessed using an investigator-developed 1-question questionnaire administered at study week 8. Patient-reported acceptance of furosemide at the dose during which the questionnaire is administered will be defined as an affirmative response ("yes") to the question "If recommended, would you be willing to stay on the dose of furosemide you have received during the last week?". The percentage of participants reporting acceptance of furosemide will be determined.

  Study week 8 (8 weeks after study medication start)

• Percentage of Participants Reporting Acceptance of Furosemide at Week 10

  Participants' acceptance of furosemide will be assessed using an investigator-developed 1-question questionnaire administered at study week 10. Patient-reported acceptance of furosemide at the dose during which the questionnaire is administered will be defined as an affirmative response ("yes") to the question "If recommended, would you be willing to stay on the dose of furosemide you have received during the last week?". The percentage of participants reporting acceptance of furosemide will be determined.

  Study week 10 (10 weeks after study medication start)

• Percentage of Participants Reporting Acceptance of Furosemide at Week 12

  Participants' acceptance of furosemide will be assessed using an investigator-developed 1-question questionnaire administered at study week 12. Patient-reported acceptance of furosemide at the dose during which the questionnaire is administered will be defined as an affirmative response ("yes") to the question "If recommended, would you be willing to stay on the dose of furosemide you have received during the last week?". The percentage of participants reporting acceptance of furosemide will be determined.

  Study week 12 (12 weeks after study medication start)

• Percentage of Participants Reporting Acceptance of Furosemide at Week 14

  Participants' acceptance of furosemide will be assessed using an investigator-developed 1-question questionnaire administered at study week 14. Patient-reported acceptance of furosemide at the dose during which the questionnaire is administered will be defined as an affirmative response ("yes") to the question "If recommended, would you be willing to stay on the dose of furosemide you have received during the last week?". The percentage of participants reporting acceptance of furosemide will be determined.

  Study week 14 (14 weeks after study medication start)

• Percentage of Participants Reporting Acceptance of Furosemide at Week 16

  Participants' acceptance of furosemide will be assessed using an investigator-developed 1-question questionnaire administered at study week 16. Patient-reported acceptance of furosemide at the dose during which the questionnaire is administered will be defined as an affirmative response ("yes") to the question "If recommended, would you be willing to stay on the dose of furosemide you have received during the last week?". The percentage of participants reporting acceptance of furosemide will be determined.

  Study week 16 (16 weeks after study medication start)

• Percentage of Participants Reporting Acceptance of Furosemide at Week 18

  Participants' acceptance of furosemide will be assessed using an investigator-developed 1-question questionnaire administered at study week 18. Patient-reported acceptance of furosemide at the dose during which the questionnaire is administered will be defined as an affirmative response ("yes") to the question "If recommended, would you be willing to stay on the dose of furosemide you have received during the last week?". The percentage of participants reporting acceptance of furosemide will be determined.

  Study week 18 (18 weeks after study medication start)

• Percentage of Participants Who Are Adherent to Furosemide (<20% Pills Remaining at Scheduled Pill Counts) at Week 1

  Participants' adherence to furosemide will be assessed at scheduled pill counts conducted by the study team at study week 1. Participants' adherence to furosemide will be defined \<20% pills remaining at the scheduled pill counts. The percentage of participants who are adherent to furosemide will be determined.

  Study week 1 (1 week after study medication start)

• Percentage of Participants Who Are Adherent to Furosemide (<20% Pills Remaining at Scheduled Pill Counts) at Week 2

  Participants' adherence to furosemide will be assessed at scheduled pill counts conducted by the study team at study week 2. Participants' adherence to furosemide will be defined \<20% pills remaining at the scheduled pill counts. The percentage of participants who are adherent to furosemide will be determined.

  Study week 2 (2 weeks after study medication start)

• Percentage of Participants Who Are Adherent to Furosemide (<20% Pills Remaining at Scheduled Pill Counts) at Week 3

  Participants' adherence to furosemide will be assessed at scheduled pill counts conducted by the study team at study week 3. Participants' adherence to furosemide will be defined \<20% pills remaining at the scheduled pill counts. The percentage of participants who are adherent to furosemide will be determined.

  Study week 3 (3 weeks after study medication start)

• Percentage of Participants Who Are Adherent to Furosemide (<20% Pills Remaining at Scheduled Pill Counts) at Week 4

  Participants' adherence to furosemide will be assessed at scheduled pill counts conducted by the study team at study week 4. Participants' adherence to furosemide will be defined \<20% pills remaining at the scheduled pill counts. The percentage of participants who are adherent to furosemide will be determined.

  Study week 4 (4 weeks after study medication start)

• Percentage of Participants Who Are Adherent to Furosemide (<20% Pills Remaining at Scheduled Pill Counts) at Week 5

  Participants' adherence to furosemide will be assessed at scheduled pill counts conducted by the study team at study week 5. Participants' adherence to furosemide will be defined \<20% pills remaining at the scheduled pill counts. The percentage of participants who are adherent to furosemide will be determined.

  Study week 5 (5 weeks after study medication start)

• Percentage of Participants Who Are Adherent to Furosemide (<20% Pills Remaining at Scheduled Pill Counts) at Week 6

  Participants' adherence to furosemide will be assessed at scheduled pill counts conducted by the study team at study week 6. Participants' adherence to furosemide will be defined \<20% pills remaining at the scheduled pill counts. The percentage of participants who are adherent to furosemide will be determined.

  Study week 6 (6 weeks after study medication start)

• Percentage of Participants Who Are Adherent to Furosemide (<20% Pills Remaining at Scheduled Pill Counts) at Week 8

  Participants' adherence to furosemide will be assessed at scheduled pill counts conducted by the study team at study week 8. Participants' adherence to furosemide will be defined \<20% pills remaining at the scheduled pill counts. The percentage of participants who are adherent to furosemide will be determined.

  Study week 8 (8 weeks after study medication start)

• Percentage of Participants Who Are Adherent to Furosemide (<20% Pills Remaining at Scheduled Pill Counts) at Week 10

  Participants' adherence to furosemide will be assessed at scheduled pill counts conducted by the study team at study week 10. Participants' adherence to furosemide will be defined \<20% pills remaining at the scheduled pill counts. The percentage of participants who are adherent to furosemide will be determined.

  Study week 10 (10 weeks after study medication start)

• Percentage of Participants Who Are Adherent to Furosemide (<20% Pills Remaining at Scheduled Pill Counts) at Week 12

  Participants' adherence to furosemide will be assessed at scheduled pill counts conducted by the study team at study week 12. Participants' adherence to furosemide will be defined \<20% pills remaining at the scheduled pill counts. The percentage of participants who are adherent to furosemide will be determined.

  Study week 12 (12 weeks after study medication start)

• Percentage of Participants Who Are Adherent to Furosemide (<20% Pills Remaining at Scheduled Pill Counts) at Week 14

  Participants' adherence to furosemide will be assessed at scheduled pill counts conducted by the study team at study week 14. Participants' adherence to furosemide will be defined \<20% pills remaining at the scheduled pill counts. The percentage of participants who are adherent to furosemide will be determined.

  Study week 14 (14 weeks after study medication start)

• Percentage of Participants Who Are Adherent to Furosemide (<20% Pills Remaining at Scheduled Pill Counts) at Week 16

  Participants' adherence to furosemide will be assessed at scheduled pill counts conducted by the study team at study week 16. Participants' adherence to furosemide will be defined \<20% pills remaining at the scheduled pill counts. The percentage of participants who are adherent to furosemide will be determined.

  Study week 16 (16 weeks after study medication start)

• Percentage of Participants Who Are Adherent to Furosemide (<20% Pills Remaining at Scheduled Pill Counts) at Week 18

  Participants' adherence to furosemide will be assessed at scheduled pill counts conducted by the study team at study week 18. Participants' adherence to furosemide will be defined \<20% pills remaining at the scheduled pill counts. The percentage of participants who are adherent to furosemide will be determined.

  Study week 18 (18 weeks after study medication start)

• Percentage of Participants Who Are Adherent to Furosemide (<20% Pills Remaining at Scheduled Pill Counts) at Week 19

  Participants' adherence to furosemide will be assessed at scheduled pill counts conducted by the study team at study week 19. Participants' adherence to furosemide will be defined \<20% pills remaining at the scheduled pill counts. The percentage of participants who are adherent to furosemide will be determined.

  Study week 19 (19 weeks after study medication start)

Study Arms (1)

Study drug administration: furosemide

EXPERIMENTAL

Study participants will receive furosemide oral tablets to be taken twice daily. During study period 1 (first 6 weeks), the drug dose will be escalated every 2 weeks if safe, tolerated, and acceptable to the participant. During study period 2 (subsequent 12 weeks), participants will take the maximum tolerated dose from study period 1, received every 4 weeks if safe, tolerated, and acceptable to the participant.

Drug: Furosemide (loop diuretic) Tablets

Interventions

Furosemide (loop diuretic) Tablets DRUG

Open label dose escalation study of furosemide in people receiving maintenance hemodialysis. Participants will take furosemide oral tablets twice daily for 18 weeks. Doses will be titrated every 2 weeks for 6 weeks if safe, effective, tolerated, and accepted by the participant. First 2 weeks of the study: participants not taking oral furosemide at enrollment will take 80mg furosemide twice daily, those taking oral furosemide at enrollment will stay on their prescribed dose, and those taking another loop diuretic at enrollment will discontinue their prescription and take an equivalent oral furosemide dose. At week 4: dose escalation if tolerated (from 80mg to 120mg twice daily for the 1st group, and a 50% increased dose not \>320mg/day for the 2nd \& 3rd groups). At week 6: dose escalation if tolerated (from 120mg to 160mg twice daily for the 1st group, and a 50% increased dose not \>320mg/day for the 2nd \& 3rd groups). Final 12 weeks: all participants will take the maximum tolerated dose.

Study drug administration: furosemide

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patient self-report of at least 1 cup urine/24-hours
• Age ≥18 years
• Receipt of thrice weekly in-center HD at a participating clinic (UNC-associated Carolina Dialysis- Carrboro, Siler City, Pittsboro, Sanford, and Lee County)
• ≥60 days receiving in-center HD
• Willingness to take study medication and undergo study testing
• Ability to provide informed consent

You may not qualify if:

• Known allergy to loop diuretic
• History of poor adherence to HD or medical regimen per nephrologist
• \>1 hospitalization in prior 30-days
• Frequent hypotension (systolic BP \<80 mmHg at \>30% of HD treatments in prior 30-days)
• Cirrhosis per nephrologist
• Hearing disorder per nephrologist
• Serum potassium \<3.5 mEq/L, magnesium \<1 mg/dL, or corrected calcium \<8 mg/dL in prior 30-days
• Taking a non-loop diuretic (e.g. spironolactone, eplerenone, ethacrynic acid, thiazides)
• Taking an aminoglycoside, cisplatin, methotrexate, cyclosporine, adrenocorticotropic hormone (ACTH), lithium, phenytoin, or oral/intravenous steroid
• Natural licorice consumption
• Prisoners, patients with significant mental illness
• Pregnant patients and nursing mothers

Sponsors & Collaborators

• University of North Carolina, Chapel Hill: lead
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): collaborator

Study Sites (5)

Carolina Dialysis - Carrboro

Carrboro, North Carolina, 27510, United States

Location

Carolina Dialysis - Pittsboro

Pittsboro, North Carolina, 27312, United States

Location

Carolina Dialysis - Sanford

Sanford, North Carolina, 27330, United States

Location

Carolina Dialysis - Lee County

Sanford, North Carolina, 27332, United States

Location

Carolina Dialysis - Siler City

Siler City, North Carolina, 27344, United States

Location

MeSH Terms

Conditions

Kidney Failure, Chronic

Interventions

Furosemide; Sodium Potassium Chloride Symporter Inhibitors; Tablets

Condition Hierarchy (Ancestors)

Renal Insufficiency, Chronic; Renal Insufficiency; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Sulfanilamides; Sulfonamides; Amides; Organic Chemicals; Aniline Compounds; Amines; Sulfones; Sulfur Compounds; Membrane Transport Modulators; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Diuretics; Natriuretic Agents; Physiological Effects of Drugs; Dosage Forms; Pharmaceutical Preparations

Results Point of Contact

• Title: Jennifer E. Flythe, MD, MPH
• Organization: University of North Carolina, Chapel Hill

jflythe@med.unc.edu

(919) 445-2656

Study Officials

• Jennifer Flythe, MD, MPH

  University of North Carolina, Chapel Hill

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: This is a single-center (multi-clinic), open-label, non-randomized pilot study to test whether oral furosemide is safe and effective at increasing urine volume in HD patients. The study will consist of 2 periods: a 6-week dose escalation period (period 1) and a subsequent 12-week follow-up period (period 2). During period 1, all participants will receive escalating doses of furosemide as tolerated, and the short-term safety, tolerability, and efficacy of furosemide will be examined. During period 2, all participants will continue the maximally tolerated period 1 furosemide dose, and the acceptability of and adherence to furosemide and the longer-term safety and efficacy of furosemide will be examined.

Study Record Dates

• First Submitted: October 2, 2020
• First Posted: November 10, 2020
• Study Start: October 7, 2020
• Primary Completion: June 8, 2021
• Study Completion: June 22, 2021
• Last Updated: June 13, 2022
• Results First Posted: June 13, 2022

Record last verified: 2022-03

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: From 9 months through 36 months after publication
• Access Criteria: The investigator who proposes to use the data has approval from an IRB, IEC, or REB, as applicable, and an executed data use/sharing agreement with UNC.

Locations

US (5)