Trial of IW-1973, A Stimulator of Soluble Guanylate Cyclase (sGC) in Patients With Stable Type 2 Diabetes and Hypertension

NCT03091920 | Completed Phase 2 Results FDA Drug

• 1 other identifier: C1973-202
• Study Type: interventional
• Target: 26
• Locations: 1 country
• Sites: 1

Brief Summary

To compare the safety, tolerability, pharmacokinetic (PK) profile, and pharmacodynamic (PD) effects of 2 treatment regimens of IW-1973 tablet (40 mg per day) administered orally for 2 weeks to patients with stable type 2 diabetes mellitus and hypertension.

Conditions

Diabetes Mellitus, Type 2; Hypertension

Outcome Measures

Primary Outcomes (47)

• Change From Study Baseline Over Time in Supine Systolic Blood Pressure

  Study Baseline (Day 1 predose AM); Days 2-14: predose AM; Days 1, 2, 7, 8, 13: postdose AM 1 hour and 4 hour; Day 1: postdose AM 8 hour; Days 1, 2, 8, 13: predose PM; Days 1, 2: postdose PM 1 hour; Days 2, 3: postdose PM 4 hour; Days 15, 21, 42

• Change From Study Baseline Over Time in Supine Diastolic Blood Pressure

  Study Baseline (Day 1 predose AM); Days 2-14: predose AM; Days 1, 2, 7, 8, 13: postdose AM 1 hour and 4 hour; Day 1: postdose AM 8 hour; Days 1, 2, 8, 13: predose PM; Days 1, 2: postdose PM 1 hour; Days 2, 3: postdose PM 4 hour; Days 15, 21, 42

• Change From Study Baseline Over Time in Supine Pulse

  Study Baseline (Day 1 predose AM); Days 2-14: predose AM; Days 1, 2, 7, 8, 13: postdose AM 1 hour and 4 hour; Day 1: postdose AM 8 hour; Days 1, 2, 8, 13: predose PM; Days 1, 2: postdose PM 1 hour; Days 2, 3: postdose PM 4 hour; Days 15, 21, 42

• Percentage of Participants With Postdose Supine Blood Pressure Less Than 130/80 mmHg Over Time

  Baseline, Days 1-14, Day 15, 21, 42

• Orthostatic Systolic Blood Pressure Over Time

  An orthostatic measurement is obtained by subtracting the supine measurement from the standing measurement.

  Days -1, 1, 2, 7, 8, 13: 1 and 4 hour AM; Days -1, 1, 2, 8, 13: 0 hour PM; Days -1, 1, 2: 1 hour PM; Days 1, 2, 7, 8, 13: 0 hour AM; Day 1: 8 hour AM; Days 1, 2: 4 hour PM

• Orthostatic Diastolic Blood Pressure Over Time

  An orthostatic measurement is obtained by subtracting the supine measurement from the standing measurement.

  Days -1, 1, 2, 7, 8, 13: 1 and 4 hour AM; Days -1, 1, 2, 8, 13: 0 hour PM; Days -1, 1, 2: 1 hour PM; Days 1, 2, 7, 8, 13: 0 hour AM; Day 1: 8 hour AM; Days 1, 2: 4 hour PM

• Orthostatic Pulse Over Time

  An orthostatic measurement is obtained by subtracting the supine measurement from the standing measurement.

  Days -1, 1, 2, 7, 8, 13: 1 and 4 hour AM; Days -1, 1, 2, 8, 13: 0 hour PM; Days -1, 1, 2: 1 hour PM; Days 1, 2, 7, 8, 13: 0 hour AM; Day 1: 8 hour AM; Days 1, 2: 4 hour PM

• Change From Time-Matched Baseline Over Time in Ambulatory Blood Pressure Monitoring (ABPM) 24-hour Averages of Systolic Blood Pressure

  24-hour average is the average of ABPM assessments over 24 hour intervals from the time of dosing. Time-matched baseline is the 24 hours average during Day -1.

  Time Matched Baseline (Day -1), Days 1, 7, and 14

• Change From Time-Matched Baseline Over Time in ABPM Daytime (12-Hour) Averages of Systolic Blood Pressure

  Daytime 12-hour average is the average of ABPM assessments over daytime 12-hour intervals from the time of dosing. Time-matched baseline is the daytime 12 hours average during Day -1.

  Time Matched Baseline (Day -1), Days 1, 7, and 14

• Change From Time-Matched Baseline Over Time in ABPM Nighttime (12-Hour) Averages of Systolic Blood Pressure

  Nighttime 12-hour average is the average of ABPM assessments over nighttime 12-hour intervals from the time of dosing. Time-matched baseline is the nighttime 12 hours average during Day -1.

  Time Matched Baseline (Day -1), Days 1, 7, and 14

• Change From Time-Matched Baseline Over Time in ABPM 4-hour Averages of Systolic Blood Pressure

  Postdose is the average of assessments over 4-hour intervals from the time of dosing that day. Time-matched baseline is the corresponding 4-hour average on Day -1.

  Time-matched baseline (Day -1), Days 1, 7, 14: 0-4, 4-8, 8-12, 12-16, 16-20, 20-24 hours postdose

• Change From Time-Matched Baseline Over Time in ABPM 24-hour Averages of Mean Arterial Pressure

  24-hour average is the average of ABPM assessments over 24 hour intervals from the time of dosing. Time-matched baseline is the 24 hours average during Day -1.

  Time Matched Baseline (Day -1), Days 1, 7, and 14

• Change From Time-Matched Baseline Over Time in ABPM Daytime (12-hour) Averages of Mean Arterial Pressure

  Daytime 12-hour average is the average of ABPM assessments over daytime 12-hour intervals from the time of dosing. Time-matched baseline is the daytime 12 hours average during Day -1.

  Time Matched Baseline (Day -1), Days 1, 7, and 14

• Change From Time-Matched Baseline Over Time in ABPM Nighttime (12-Hour) Averages of Mean Arterial Pressure

  Nighttime 12-hour average is the average of ABPM assessments over nighttime 12-hour intervals from the time of dosing. Time-matched baseline is the nighttime 12 hours average during Day -1.

  Time Matched Baseline (Day -1), Days 1, 7, and 14

• Change From Time-Matched Baseline Over Time in ABPM 4-hour Averages of Mean Arterial Pressure

  Postdose is the average of assessments over 4-hour intervals from the time of dosing that day. Time-matched baseline is the corresponding 4-hour average on Day -1.

  Time-matched baseline (Day -1), Days 1, 7, 14: 0-4, 4-8, 8-12, 12-16, 16-20, 20-24 hours postdose

• Change From Time-Matched Baseline Over Time in ABPM 24-hour Averages of Diastolic Blood Pressure

  24-hour average is the average of ABPM assessments over 24 hour intervals from the time of dosing. Time-matched baseline is the 24 hours average during Day -1.

  Time Matched Baseline (Day -1), Days 1, 7, and 14

• Change From Time-Matched Baseline Over Time in ABPM Daytime (12-hour) Averages of Diastolic Blood Pressure

  Daytime 12-hour average is the average of ABPM assessments over daytime 12-hour intervals from the time of dosing. Time-matched baseline is the daytime 12 hours average during Day -1.

  Time Matched Baseline (Day -1), Days 1, 7, and 14

• Change From Time-Matched Baseline Over Time in ABPM Nighttime (12-Hour) Averages of Diastolic Blood Pressure

  Nighttime 12-hour average is the average of ABPM assessments over nighttime 12-hour intervals from the time of dosing. Time-matched baseline is the nighttime 12 hours average during Day -1.

  Time Matched Baseline (Day -1), Days 1, 7, and 14

• Change From Time-Matched Baseline Over Time in ABPM 4-hour Averages of Diastolic Blood Pressure

  Postdose is the average of assessments over 4-hour intervals from the time of dosing that day. Time-matched baseline is the corresponding 4-hour average on Day -1.

  Time-matched baseline (Day -1), Days 1, 7, 14: 0-4, 4-8, 8-12, 12-16, 16-20, 20-24 hours postdose

• Change From Time-Matched Baseline Over Time in ABPM 24-hour Averages of Pulse

  24-hour average is the average of ABPM assessments over 24 hour intervals from the time of dosing. Time-matched baseline is the 24 hours average during Day -1.

  Time Matched Baseline (Day -1), Days 1, 7, and 14

• Change From Time-Matched Baseline Over Time in ABPM Daytime (12-hour) Averages of Pulse

  Daytime 12-hour average is the average of ABPM assessments over daytime 12-hour intervals from the time of dosing. Time-matched baseline is the daytime 12 hours average during Day -1.

  Time Matched Baseline (Day -1), Days 1, 7, and 14

• Change From Time-Matched Baseline Over Time in ABPM Nighttime (12-Hour) Averages of Pulse

  Nighttime 12-hour average is the average of ABPM assessments over nighttime 12-hour intervals from the time of dosing. Time-matched baseline is the nighttime 12 hours average during Day -1.

  Time Matched Baseline (Day -1), Days 1, 7, and 14

• Change From Time-Matched Baseline Over Time in ABPM 4-hour Averages of Pulse

  Postdose is the average of assessments over 4-hour intervals from the time of dosing that day. Time-matched baseline is the corresponding 4-hour average on Day -1.

  Time-matched baseline (Day -1), Days 1, 7, 14: 0-4, 4-8, 8-12, 12-16, 16-20, 20-24 hours postdose

• Change From Baseline in Reactive Hyperemia Index (RHI) on Day 13

  RHI is a measure of the extent of vessel dilatation and augmentation in vascular blood flow after a prespecified period of flow interruption. RHI is determined as the ratio of the post-to-pre- occlusion peripheral arterial tonometry amplitude of the tested (occluded) arm, divided by the post to-pre-occlusion ratio of the control arm. RHI values \>1.67 indicate normal endothelial function, while values ≤1.67 indicate endothelial dysfunction.

  Baseline, Day 13 predose AM

• Post-Baseline Platelet Reactivity on Days 8 and 14: P2Y12 Reaction Units (PRU) Assay

  Platelet reactivity, as measured by VerifyNow PRU assay, and presented as number of participants with \< 180 PRU or ≥ 180 PRU post-baseline (Days 8 and 14), by baseline category. The VerifyNow PRU assay measures effects on platelet activation caused by inhibition of the platelet receptor, P2Y12. This receptor is activated by adenosine 5'-diphosphate (ADP) in the cascade leading to platelet aggregation but can be blocked by P2Y12 inhibitor drugs, such as clopidogrel. Blockage of this receptor diminishes platelet activation and the ability of platelets to bind to fibrinogen. VerifyNow PRU assay values \< 180 units indicate impairment of platelet aggregation.

  Baseline, Day 8, Day 14

• Post-Baseline Platelet Reactivity on Days 8 and 14: Aspirin Reaction Units (ARU) Assay

  Platelet reactivity, as measured by VerifyNow ARU assay, and presented as number of participants with ≤ 549 ARU or \> 549 ARU post-baseline (Days 8 and 14), by baseline category. Aspirin irreversibly inhibits cyclooxygenase 1, which converts arachidonic acid to thromboxane A2, which in turn is involved in the activation of the glycoprotein (GP)IIb/IIIa receptor necessary to initiate platelet aggregation. Impairment of platelet aggregation of the aspirin type is defined for the VerifyNow aspirin assay as values ≤ 549 ARU.

  Baseline, Day 8, Day 14

• Change From Study Baseline Over Time in Platelet Function Assessments: PRU Assay

  The VerifyNow PRU assay measures effects on platelet activation caused by inhibition of the platelet receptor, P2Y12. This receptor is activated by adenosine 5'-diphosphate (ADP) in the cascade leading to platelet aggregation but can be blocked by P2Y12 inhibitor drugs, such as clopidogrel. Blockage of this receptor diminishes platelet activation and the ability of platelets to bind to fibrinogen. VerifyNow PRU assay values \<180 PRU indicate impairment of platelet aggregation.

  Study Baseline (Day 1 predose), Day 8 (predose AM), Day 14 (predose AM)

• Change From Study Baseline Over Time in Platelet Function Assessments: ARU Assay

  Aspirin irreversibly inhibits cyclooxygenase 1, which converts arachidonic acid to thromboxane A2, which in turn is involved in the activation of the GPIIb IIIa receptor necessary to initiate platelet aggregation. Impairment of platelet aggregation of the aspirin type is defined for the VerifyNow aspirin assay as values ≤ 549 ARU.

  Study Baseline (Day 1 predose), Day 8 (pre AM dose), Day 14 (pre AM dose)

• Percent Change From Study Baseline Over Time in HOMA-IR in Participants Without Concomitant Use of Insulin

  Blood samples were taken for fasting glucose and insulin levels. From these results, insulin resistance was then estimated using the updated homeostasis model assessment method for insulin resistance (HOMA-IR) computer algorithm. A higher HOMA-IR indicates a higher degree of insulin resistance. Typically a cutoff of HOMA-IR for identifying those with insulin resistance is 2.5.

  Study baseline (defined as the last non-missing assessment before the first administration of study drug), Day 8, pre-AM dose, Day 15

• IW-1973 Pharmacokinetics: Area Under the Plasma Concentration Time Curve During a Dosing Interval (AUCtau) on Days 1 and 7

  Equivalent to AUC from time 0 to the last measurable concentration (AUClast), with time of last measurable concentration (Tlast)=12 hours for BID dosing and Tlast=24 hours for QD dosing.

  Days 1 and 7 (AM): 1, 3, and 6 hours postdose

• IW-1973 Pharmacokinetics: Maximum Observed Plasma Concentration (Cmax) on Days 1 and 7

  Days 1 and 7 (AM): 1, 3, and 6 hours postdose

• IW-1973 Pharmacokinetics: Time to Cmax on Days 1 and 7

  Days 1 and 7 (AM): 1, 3, and 6 hours postdose

• IW-1973 Pharmacokinetics: Trough Plasma Concentrations at the End of the Dosing Interval (Ctrough) on Days 1, 2, 6, 7

  Days 1 and 7: predose; Day 2 (BID AM): predose; Day 6 (BID PM/QD): predose

• IW-1973 Pharmacokinetics: Area Under the Plasma Concentration Time Curve From Time Zero to the Last Measurable Plasma Concentration (AUClast) on Days 8 and 14

  Day 8 and 14: 1, 3, 6h (± 5 min) postdose

• IW-1973 Pharmacokinetics: AUCtau on Day 14

  Day 14: 1, 3, 6h (± 5 min) postdose

• IW-1973 Pharmacokinetics: Tmax on Days 8 and 14

  Day 8 and 14: 1, 3, 6h (± 5 min) postdose

• IW-1973 Pharmacokinetics: Cmax on Days 8 and 14

  Day 8 and 14: 1, 3, 6h (± 5 min) postdose

• IW-1973 Pharmacokinetics: Ctrough on Days 13 and 14

  Days 13 and 14: predose

• IW-1973 Pharmacokinetics: Apparent Total Body Clearance (CL/F) on Day 14

  Day 14: 1, 3, 6h (± 5 min) postdose

• IW-1973 Pharmacokinetics: Apparent Volume of Distribution During the Terminal Phase (Vz/F) on Day 14

  Day 14: 1, 3, 6h (± 5 min) postdose

• IW-1973 Pharmacokinetics: Apparent Terminal Elimination Phase Half-Life (t1/2)

  Day 14 (final dose) time points 12 hours, 24 hours, 7 days after final dose (Day 21), and 28 days after final dose(Day 42)

• Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to TEAEs

  An adverse event (AE) is any untoward medical occurrence, which does not necessarily have to have a causal relationship with study treatment. An SAE is defined as any AE occurring at any dose that results in any of the following outcomes: death; life-threatening; hospitalization or prolongation of existing hospitalization; persistent or significant disability/incapacity; congenital anomaly/birth defect; important medical events. TEAEs are defined as those AEs that started or worsened in severity after the initiation of study drug administration. AEs of clinical interest (AECI) included those related to bleeding and to hypotension. Study drug causality as assessed by the Investigator who was blinded to study drug assignment.

  From first dose of study drug to End of Trial Visit (42 [± 3] days)

• Number of Participants With Clinically Meaningful Postbaseline Laboratory Test Results

  From first dose of study drug to End of Trial Visit (42 [± 3] days)

• Number of Participants With Notable Changes in Postbaseline Blood Pressure and Heart Rate Values

  Supine systolic blood pressure (SSBP): ≥ 180 mmHg and increase (↑) from baseline (BL) ≥ 30 mmHg; ≤ 90 mmHg and decrease (↓) from BL ≥ 30 mmHg. Supine diastolic blood pressure (SDBP): ≥ 105 mmHg and ↑ from BL ≥ 20 mmHg; ≤ 50 mmHg and ↓ from BL ≥ 20 mmHg. Supine heart rate (SHR): ≥ 110 bpm and ↑ from BL ≥ 20 bpm; ≤ 50 bpm and ↓ from BL ≥ 20 bpm. Standing systolic blood pressure (StSBP): ≥ 180 mmHg and increase (↑) from baseline (BL) ≥ 30 mmHg; ≤ 90 mmHg and decrease (↓) from BL ≥ 30 mmHg. Standing Diastolic Blood Pressure (StDBP): ≥ 105 mmHg and ↑ from BL ≥ 20 mmHg; ≤ 50 mmHg and ↓ from BL ≥ 20 mmHg. Standing heart rate (StHR): ≥ 110 bpm and ↑ from BL ≥ 20 bpm; ≤ 50 bpm and ↓ from BL ≥ 20 bpm. Orthostatic systolic blood pressure (SBP): ↓ \> 20 mmHg from supine to standing. Orthostatic diastolic blood pressure (DBP): ↓ \> 15 mmHg from supine to standing. Orthostatic HR: ↓ \> 30 bpm from supine to standing.

  From first dose of study drug to End of Trial Visit (42 [± 3] days)

• Number of Participants With Clinically Significant Post-Randomization Physical Examination Findings

  Physical examinations included examination and assessment of the following: general appearance, lymph nodes, skin, cardiovascular system, head, eyes, ears, nose, and throat, central nervous system, respiratory system, neck, peripheral nervous system, abdomen/liver/spleen, musculoskeletal system.

  Post-randomization to End of Trial Visit (42 [± 3] days)

• Number of Participants With Clinically Significant Postbaseline 12-Lead Electrocardiogram (ECG) Results

  From first dose of study drug to End of Trial Visit (42 [± 3] days)

• Change From Study Baseline Over Time in Estimated Glomerular Filtration Rate (eGFR)

  Study Baseline, Day 15/Discharge, Day 42/End of Trial

Study Arms (3)

IW-1973 QD/QD

EXPERIMENTAL

On Days 1-14: IW-1973 40 mg taken once daily (QD) in morning (AM) and placebo taken QD at night (PM).

Drug: IW-1973; Drug: Placebo

IW-1973 BID (Twice Daily)/QD

EXPERIMENTAL

On Days 1-7: IW-1973 20 mg taken in AM and IW-1973 20 mg taken in PM. On Days 8-14: IW-1973 40 mg taken QD in AM and placebo taken QD in PM.

Drug: IW-1973; Drug: Placebo

Placebo

PLACEBO COMPARATOR

On Days 1-14: Placebo taken in AM and in PM.

Drug: Placebo

Interventions

IW-1973 DRUG

Oral Tablet

IW-1973 BID (Twice Daily)/QD; IW-1973 QD/QD

Placebo DRUG

Oral Tablet

IW-1973 BID (Twice Daily)/QD; IW-1973 QD/QD; Placebo

Eligibility Criteria

• Age: 30 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patient is ambulatory male or female
• Patient's body mass index score is \> 20 and \< 40 kg/m\^2 at the Screening Visit
• Women of childbearing potential must have a negative pregnancy test at the time of screening and check-in and must agree to use protocol-specified contraception throughout the duration of the study
• Patient's health is stable with no clinically significant findings on physical examination
• Patient has type 2 (ie, adult onset) diabetes mellitus diagnosed by a physician or nurse practitioner \> 6 months before the Screening Visit, is on a stable glycemic control medication, and protocol specified hemoglobin (Hb)A1c values at the Screening Visit
• Patient has hypertension diagnosed by a physician or nurse practitioner \> 6 months before the Screening Visit, and blood pressure (BP) within the protocol's acceptable range
• Patients must be on a stable regimen for hypertension control that includes an angiotensin converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB), stable for 28 days

You may not qualify if:

• Patient has a clinically significant active or unstable medical condition that, in the opinion of the Investigator, would preclude trial participation
• Patient is on medication(s) that, when co-administered with a sGC stimulator, could increase the risk of hypotension
• Patient has evidence of severe or active end-organ damage
• Patient is an active smoker or has used any nicotine-containing products (cigarettes, e-cigarettes, vape pens, cigars, chewing tobacco, gum, patches) during the 6 months before Check-in. Use of nicotine is excluded during the study until after the End of Trial Visit.

Sponsors & Collaborators

• Cyclerion Therapeutics: lead

Study Sites (1)

ProSciento, Inc.

Chula Vista, California, 91911, United States

Location

Related Publications (1)

• Hanrahan JP, Seferovic JP, Wakefield JD, Wilson PJ, Chickering JG, Jung J, Carlson KE, Zimmer DP, Frelinger AL 3rd, Michelson AD, Morrow L, Hall M, Currie MG, Milne GT, Profy AT. An exploratory, randomised, placebo-controlled, 14 day trial of the soluble guanylate cyclase stimulator praliciguat in participants with type 2 diabetes and hypertension. Diabetologia. 2020 Apr;63(4):733-743. doi: 10.1007/s00125-019-05062-x. Epub 2019 Dec 19.

  PMID: 31858186 DERIVED

MeSH Terms

Conditions

Diabetes Mellitus, Type 2; Hypertension

Interventions

praliciguat

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Vascular Diseases; Cardiovascular Diseases

Results Point of Contact

• Title: Senior Medical Director
• Organization: Cyclerion Therapeutics, Inc.

info@cyclerion.com

1-857-327-8778

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Masking Details: Double-Blind
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 8, 2017
• First Posted: March 27, 2017
• Study Start: February 28, 2017
• Primary Completion: August 3, 2017
• Study Completion: August 3, 2017
• Last Updated: August 31, 2020
• Results First Posted: August 31, 2020

Record last verified: 2020-08

Locations

US (1)