Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics Investigation of GSK3335065 Intravenous (IV) Infusion in Healthy Adults

NCT03245619 | Terminated Phase 1 Results

• 2 other identifiers: 2015702016-001303-22
• Study Type: interventional
• Target: 18
• Locations: 1 country
• Sites: 1

Brief Summary

GSK3335065 is being developed as a treatment for acute pancreatitis with the intent of reducing 3-hydroxykynurenine (3HK) levels to the normal range (or lower) and maintaining them at this level throughout the treatment period. This study will utilize an adaptive design and is divided into 3 parts. Part A will consist of 8 cohorts (1-8) and is Single Ascending Dose (SAD) of GSK3335065 by IV bolus in males. Part B will be initiated after completion of dosing in Part A. It will involve ascending IV bolus doses of GSK3335065 followed by IV constant infusion for 7 days in males and will consist of four cohorts (9-12). Part C consists of a single dose of GSK3335065 by IV bolus (cohort 13), and a single dose followed by continuous infusion over 7 days (cohort 14) in females of non-child bearing potential (WONCBP). Total 64 subjects will be evaluated in the study of which Part A will include 16 healthy male subjects, Part B will include 32 healthy male subjects and Part C will include 16 WONCBP. In Part A, cohorts 1 and 2 will last up to 19 weeks and cohorts 3 to 8 will last up to 7 weeks and Part B will last up to 13 weeks. In Part C cohort 7 will last up to 7 weeks and cohort 8 will last for 13 weeks.

Conditions

Pancreatitis, Acute Necrotizing

Keywords

3-hydroxykynurenine; Acute pancreatitis; Dose-escalation; Healthy subjects; GSK3335065

Outcome Measures

Primary Outcomes (18)

• Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)-Part A

  An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. An SAE is defined as any untoward medical occurrence that, at any dose: results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent disability/incapacity; is a congenital anomaly/birth defect; other important medical events that may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes listed before. All Subject Population comprised of all participants randomized to treatment who received at least one dose of study treatment. AEs and SAEs were collected from admission until follow-up. Placebo arms across similar dosing strategies were combined as pre-specified in reporting and analysis plan.

  Up to Day 22

• Number of Participants With AEs and SAEs-Part B

  An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. An SAE is defined as any untoward medical occurrence that, at any dose: results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent disability/incapacity; is a congenital anomaly/birth defect; other important medical events that may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes listed before. AEs and SAEs were planned to be collected from admission until follow-up.

  Up to Day 34

• Number of Participants With AEs and SAEs-Part C

  An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. An SAE is defined as any untoward medical occurrence that, at any dose: results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent disability/incapacity; is a congenital anomaly/birth defect; other important medical events that may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes listed before. AEs and SAEs were planned to be collected from admission until follow-up.

  Up to Day 34

• Number of Participants With Hematological Parameters of Potential Clinical Importance-Part A

  Blood samples were collected for the assessment of hematology parameters. The clinical concern range for the parameters were: hematocrit (high: \>0.54 proportion of red blood cells in blood); hemoglobin (high: \>180 grams per liter \[g/L\]), lymphocytes (low: \<0.8x10\^9 cells per liter \[cells/L\]); neutrophil count (low: \<1.5x10\^9 cells/L); platelet count (low: \<100x10\^9 cells/L and high: \>550x10\^9 cells/L); white blood cells count (low: \<3x10\^9 cells/L and high: \>20x10\^9 cells/L). Data for worst-case post-Baseline is presented. Baseline was defined as the latest pre-dose assessment. Placebo arms across similar dosing strategies were combined as pre-specified in reporting and analysis plan.

  Up to Day 22

• Number of Participants With Hematological Parameters of Potential Clinical Importance-Part B

  Blood samples were planned to be collected for the assessment of hematology parameters.

  Up to Day 34

• Number of Participants With Hematological Parameters of Potential Clinical Importance-Part C

  Blood samples were planned to be collected for the assessment of hematology parameters.

  Up to Day 34

• Number of Participants With Clinical Chemistry Parameters of Potential Clinical Importance-Part A

  Blood samples were collected for the assessment of clinical chemistry parameters. The clinical concern range for the parameters were: albumin (low: \<30 millimoles per liter \[mmol/L\]); alanine aminotransferase (ALT) (high: \>=2xupper limit of normal \[ULN\]); aspartate aminotransferase (AST) (high: \>=2xULN); alkaline phosphatase (ALP) (high: \>=2xULN); total bilirubin (high: \>=1.5xULN); calcium (low: \<2 mmol/L and high: \>2.75 mmol/L); glucose (low: \<3 mmol/L and high: \>9 mmol/L); potassium (low: \<3 mmol/L and high: \>5.5 mmol/L) and sodium (low: \<130 mmol/L and high: \>150 mmol/L). Data for worst-case post-Baseline is presented. Baseline was defined as the latest pre-dose assessment. Placebo arms across similar dosing strategies were combined as pre-specified in reporting and analysis plan.

  Up to Day 22

• Number of Participants With Clinical Chemistry Parameters of Potential Clinical Importance-Part B

  Blood samples were planned to be collected for the assessment of clinical chemistry parameters.

  Up to Day 34

• Number of Participants With Clinical Chemistry Parameters of Potential Clinical Importance-Part C

  Blood samples were planned to be collected for the assessment of clinical chemistry parameters.

  Up to Day 34

• Number of Participants With Abnormal Urine Parameters-Part A

  Urine samples were taken for the assessment of following urine parameters: specific gravity, potential of hydrogen (pH), glucose, protein, blood and ketones by dipstick method. Microscopic examination was performed and collected for any abnormal dipstick results. Number of participants with abnormal urine parameters any time post-Baseline is presented. Baseline was defined as the latest pre-dose assessment. Placebo arms across similar dosing strategies were combined as pre-specified in reporting and analysis plan.

  Up to Day 22

• Number of Participants With Abnormal Urine Parameters-Part B

  Urine samples were planned to be collected for the assessment of urine parameters.

  Up to Day 34

• Number of Participants With Abnormal Urine Parameters-Part C

  Urine samples were planned to be collected for the assessment of urine parameters.

  Up to Day 34

• Number of Participants With Abnormal Electrocardiogram (ECG) Findings-Part A

  Triplicate 12-lead ECGs were obtained using an ECG machine that automatically calculated the heart rate and measured PR, QRS, QT, QT interval corrected using Fridericia's formula (QTcF) and Bazett's QT interval corrected for heart rate (QTcB). ECG measurements were preceded by at least 5 minutes rest for the participant in a semi-recumbent position. Number of participants with abnormal-clinically significant and abnormal-not clinically significant ECG findings at worst case post-Baseline is presented. Baseline was defined as the latest pre-dose assessment. Placebo arms across similar dosing strategies were combined as pre-specified in reporting and analysis plan.

  Up to Day 22

• Number of Participants With Abnormal ECG Findings-Part B

  Triplicate 12-lead ECGs were planned to be obtained using an ECG machine that automatically calculated the heart rate and measured PR, QRS, QT, QTcF and QTcB intervals.

  Up to Day 34

• Number of Participants With Abnormal ECG Findings-Part C

  Triplicate 12-lead ECGs were planned to be obtained using an ECG machine that automatically calculated the heart rate and measured PR, QRS, QT, QTcF and QTcB intervals.

  Up to Day 34

• Number of Participants With Abnormal Vital Signs-Part A

  Vital signs including systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate, respiration rate and temperature were measured in a semi-recumbent position with a completely automated device preceded by at least 5 minutes of rest for the participant in a quiet setting without distractions. Participants are counted in the worst case category that their value changes to (low, normal or high), unless there is no change in their category. Participants whose value category was unchanged (e.g., High to High), or whose value became normal, are recorded in the "To Normal or No Change" category. Data for worst case post-Baseline relative to Baseline is presented. Baseline was defined as the latest pre-dose assessment. Placebo arms across similar dosing strategies were combined as pre-specified in reporting and analysis plan.

  Up to Day 22

• Number of Participants With Abnormal Vital Signs-Part B

  Vital signs including SBP, DBP, heart rate, respiration rate and temperature were planned to be measured in a semi-recumbent position with a completely automated device preceded by at least 5 minutes of rest for the participant in a quiet setting without distractions.

  Up to Day 34

• Number of Participants With Abnormal Vital Signs-Part C

  Vital signs including SBP, DBP, heart rate, respiration rate and temperature were planned to be measured in a semi-recumbent position with a completely automated device preceded by at least 5 minutes of rest for the participant in a quiet setting without distractions.

  Up to Day 34

Secondary Outcomes (44)

• Area Under the Plasma Concentration-time Curve From Time 0 to Last Quantifiable Concentration (AUC[0-t]) for GSK3335065-Part A (Cohorts 1 and 2)

  1 hour pre-dose, 6, 12, 15, 20, and 30 minutes, 1, 2, 3, 6, 9, 12, 15, 18, 24, 30, 36, 42, 48, 60 and 72 hours post-dose

• AUC(0-t) for GSK3335065-Part A (Cohorts 3 to 8)

  1 hour pre-dose, 6, 12, 15, 20, and 30 minutes, 1, 2, 3, 6, 9, 12, 15, 18, 24, 30, 36, 42, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156 and 168 hours post-dose

• AUC(0-t) for GSK3335065-Part B

  Day1 (Pre-dose, 6, 15, 30 minutes, 1, 2, 3, 4.5, 6, 9, 12, 18hours post-infusion), Days2 to 7 (pre-dose), Day8 (end of infusion, 6 and 12 hours post-infusion), Day9 (18, 24, 36, 42, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156 and 168 hours post-infusion)

• AUC(0-t) for GSK3335065-Part C (Cohort 13)

  1 hour pre-dose, 6, 12, 15, 20, and 30 minutes, 1, 2, 3, 6, 9, 12, 15, 18, 24, 30, 36, 42, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156 and 168 hours post-dose

• AUC(0-t) for GSK3335065-Part C (Cohort 14)

  Day1 (Pre-dose, 6, 15, 30 minutes, 1, 2, 3, 4.5, 6, 9, 12, 18hours post-infusion), Days2 to 7 (pre-dose), Day8 (end of infusion, 6 and 12 hours post-infusion), Day9 (18, 24, 36, 42, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156 and 168 hours post-infusion)

Study Arms (8)

Subjects receiving GSK3335065 (Cohorts 1 to 8) in Part A

EXPERIMENTAL

Male subjects will be assigned to Cohorts 1 to 8. In each cohort, six subjects will be randomized to receive alternating and escalated doses of GSK3335065.

Drug: GSK3335065

Subjects receiving Placebo (Cohorts 1 to 8) in Part A

EXPERIMENTAL

Male subjects will be assigned to Cohort 1 and 2. In each cohort, two subjects will be randomized to receive placebo.

Drug: Placebo

Subjects receiving GSK3335065 (Cohort 9 to 12) in Part B

EXPERIMENTAL

Male subjects will be assigned to one of four cohorts (9, 10, 11 or 12). In each cohort, six subjects will be randomized to receive GSK3335065. In all cohorts each dose level will consist of an IV bolus on Day 1 subsequently followed by a continuous IV infusion for seven days.

Drug: GSK3335065

Subjects receiving Placebo (Cohort 9 to 12) in Part B

EXPERIMENTAL

Male subjects will be assigned to one of four cohorts (9, 10, 11 or 12). In each cohort, two subjects will be randomized to receive placebo.

Drug: Placebo

Subjects receiving GSK3335065 (Cohort 13) in Part C

EXPERIMENTAL

WONCBP will be assigned to cohort 13. Six subjects will be randomized to receive a single IV dose of GSK3335065.

Drug: GSK3335065

Subjects receiving Placebo (Cohort 13) in Part C

EXPERIMENTAL

WONCBP will be assigned to cohort 13. Two subjects will be randomized to receive placebo.

Drug: Placebo

Subjects receiving GSK3335065 (Cohort 14) in Part C

EXPERIMENTAL

WONCBP will be assigned to cohort 14. Six subjects will be randomized to receive a continuous IV infusion over 7 days of GSK3335065.

Drug: GSK3335065

Subjects receiving Placebo (Cohort 14) in Part C

EXPERIMENTAL

WONCBP will be assigned to cohort 14. Two subjects will be randomized to receive placebo.

Drug: Placebo

Interventions

GSK3335065 DRUG

GSK3335065 is being developed as a treatment for acute pancreatitis with the intent of reducing 3-hydroxykynurenine (3HK) levels to the normal range (or lower) and maintaining them at this level. GSK3335065 is a solution and will be administered as intravenous injection and infusion with dose strength of 5 milligram (mg)/mL that may be diluted in 0.9% weight by volume (w/v) sodium chloride.

Subjects receiving GSK3335065 (Cohort 13) in Part C; Subjects receiving GSK3335065 (Cohort 14) in Part C; Subjects receiving GSK3335065 (Cohort 9 to 12) in Part B; Subjects receiving GSK3335065 (Cohorts 1 to 8) in Part A

Placebo DRUG

Placebo solution to match GSK3335065 will be given as intravenous injection and infusion.

Subjects receiving Placebo (Cohort 13) in Part C; Subjects receiving Placebo (Cohort 14) in Part C; Subjects receiving Placebo (Cohort 9 to 12) in Part B; Subjects receiving Placebo (Cohorts 1 to 8) in Part A

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Subjects must be 18 to 50 years of age inclusive, at the time of signing the informed consent. In Part C (WONCBP) subjects must be between 18 and 60 years of age.
• Subjects who are overtly healthy as determined by medical evaluation including medical history, physical examination, laboratory tests, and cardiac monitoring.

You may not qualify if:

• Body weight greater than 50 kilogram (kg) and body mass index (BMI) within the range 18.5 - 32 kilogram per meter square (kg/m\^2).
• Length of time required for abstinence or use of contraceptives should take into account the reproductive toxicity profile including genotoxicity and teratogenicity, the size of the molecule, and the number of doses. Male subjects must agree to use contraception during the treatment period and for at least 2 days after the last dose of study treatment and refrain from donating sperm during this period. Only female subjects of WONCBP are eligible to participate.
• Capable of giving signed informed consent.
• ALT and bilirubin greater than 1.5 times upper limit of normal (ULN) (isolated bilirubin greater than 1.5 times ULN is acceptable if bilirubin is fractionated and direct bilirubin less than 35%).
• Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones)
• QTc corrected by Fridericia's formula(QTcF) greater than 450 millisecond (msec) from a mean of triplicate readings taken 5 mins apart
• Clinically significant abnormal echocardiogram
• The subject has a history or current evidence of depression, bipolar disorder, suicidal ideation and behavior, or a lifetime history of suicide attempt
• Cardiac troponin (cTn) or Brain natriuretic peptide (BNP) greater than ULN
• Use of prohibited medication
• The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).
• Exposure to more than four new chemical entities within 12 months prior to the first dosing day
• Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test result at screening or within 3 months prior to first dose of study treatment. For potent immunosuppressive agents, subjects with presence of hepatitis B core antibody (HBcAb) should also be excluded.
• A positive pre-study drug/alcohol screen
• A positive test for human immunodeficiency virus (HIV) antibody

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (1)

GSK Investigational Site

Cambridge, CB2 0GG, United Kingdom

Location

MeSH Terms

Conditions

Pancreatitis, Acute Necrotizing; Pancreatitis

Condition Hierarchy (Ancestors)

Pancreatic Diseases; Digestive System Diseases

Limitations and Caveats

Due to sample handling errors at clinical site, reported results (3HK/Kyn) in Cohort 3 are characterized by a consistent negative bias; therefore must not be compared with concentration data from Cohort 1 or 2.

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

GSKClinicalSupportHD@gsk.com

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 7, 2017
• First Posted: August 10, 2017
• Study Start: August 22, 2017
• Primary Completion: May 19, 2018
• Study Completion: May 19, 2018
• Last Updated: June 16, 2020
• Results First Posted: September 20, 2019

Record last verified: 2020-06

Locations

GB (1)