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

NCT ID: NCT03245619

Last Updated: 2020-06-16

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE1
• Total Enrollment: 18 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-08-22
• Study Completion Date: 2018-05-19

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

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

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.

Group Type: EXPERIMENTAL

GSK3335065

Intervention Type: 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 Placebo (Cohorts 1 to 8) in Part A

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

Group Type: EXPERIMENTAL

Placebo

Intervention Type: DRUG

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

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

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.

Group Type: EXPERIMENTAL

GSK3335065

Intervention Type: 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 Placebo (Cohort 9 to 12) in Part B

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.

Group Type: EXPERIMENTAL

Placebo

Intervention Type: DRUG

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

Subjects receiving GSK3335065 (Cohort 13) in Part C

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

Group Type: EXPERIMENTAL

GSK3335065

Intervention Type: 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 Placebo (Cohort 13) in Part C

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

Group Type: EXPERIMENTAL

Placebo

Intervention Type: DRUG

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

Subjects receiving GSK3335065 (Cohort 14) in Part C

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

Group Type: EXPERIMENTAL

GSK3335065

Intervention Type: 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 Placebo (Cohort 14) in Part C

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

Group Type: EXPERIMENTAL

Placebo

Intervention Type: DRUG

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

Interventions

GSK3335065

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.

Intervention Type: DRUG

Placebo

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

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• 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.

Exclusion Criteria

• 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
• Where participation in the study would result in donation of blood or blood products in excess of 500 milliliter (mL) within 84 days.
• Poor or unsuitable venous access
• History of regular alcohol consumption within 6 months of the study defined as: an average weekly intake of >14 units. One unit is equivalent to 8 gram of alcohol: a half-pint (~240 mL) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits.
• History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or Medical Monitor, contraindicates their participation.
• History of smoking within 6 months of the study.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 60 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

GlaxoSmithKline

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

GSK Clinical Trials

Role: STUDY_DIRECTOR

GlaxoSmithKline

Locations

GSK Investigational Site

Cambridge, , United Kingdom

Countries

United Kingdom

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

2016-001303-22

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

201570

Identifier Type: -

Identifier Source: org_study_id