Last updated: 08/30/2021 22:40:10

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics investigation of GSK3335065 Intravenous (IV) infusion in healthy adults

GSK study ID
201570
See study documents
Clinicaltrials.gov ID
NCT03245619
See results summary
EudraCT ID
2016-001303-22
EU CT Number
Not applicable
Trial status
Other
Other
Overview
Eligibility
Locations
Study documents
Results summary
Plain language summaries
Additional information

Trial overview

Official title: Randomized, Double-blind, Placebo Controlled Dose Escalation Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single Doses (Intravenous bolus) and constant intravenous infusion over 7 Days of GSK3335065 in Healthy Adult Subjects
Trial description: 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.
Primary purpose:
Treatment
Trial design:
Sequential Assignment
Masking:
Double (Participant, Investigator)
Allocation:
Randomized
Primary outcomes:

Number of subjects with adverse events (AEs) and serious AEs (SAEs): Cohort 1 and 2 (Part A)

Timeframe: Up to Day 77

Number of subjects with AEs and SAEs: Cohort 7 (Part C)

Timeframe: Up to Day 21

Number of subjects with AEs and SAEs: Cohorts 3-6 (Part B) and cohort 8 (Part C)

Timeframe: Up to Day 25

Number of subjects with abnormal hematology parameters: Cohort 1 and 2 (Part A)

Timeframe: Up to Day 77

Number of subjects with abnormal hematology parameters: Cohort 7 (Part C)

Timeframe: Up to Day 21

Number of subjects with abnormal hematology parameters: Cohorts 3-6 (Part B) and cohort 8 (Part C)

Timeframe: Up to Day 25

Number of subjects with abnormal clinical chemistry parameters: Cohort 1 and 2 (Part A)

Timeframe: Up to Day 77

Number of subjects with abnormal clinical chemistry parameters: Cohort 7 (Part C)

Timeframe: Up to Day 21

Number of subjects with abnormal clinical chemistry parameters: Cohorts 3-6 (Part B) and cohort 8 (Part C)

Timeframe: Up to Day 25

Number of subjects with abnormal urinalysis: Cohort 1 and 2 (Part A)

Timeframe: Up to Day 77

Number of subjects with abnormal urinalysis: Cohort 7 (Part C)

Timeframe: Up to Day 21

Number of subjects with abnormal urinalysis: Cohorts 3-6 (Part B) and cohort 8 (Part C)

Timeframe: Up to Day 25

Number of subjects with Electrocardiogram (ECG) findings: Cohort 1 and 2 (Part A)

Timeframe: Up to Day 77

Number of subjects with ECG findings: Cohort 7 (Part C)

Timeframe: Up to Day 21

Number of subjects with ECG findings: Cohorts 3-6 (Part B) and cohort 8 (Part C)

Timeframe: Up to Day 25

Number of subjects with abnormal systolic blood pressure (SBP) and diastolic blood pressure (DBP): Cohort 1 and 2 (Part A)

Timeframe: Up to Day 77

Number of subjects with abnormal SBP and DBP: Cohort 7 (Part C)

Timeframe: Up to Day 21

Number of subjects with abnormal SBP and DBP: Cohorts 3-6 (Part B) and cohort 8 (Part C)

Timeframe: Up to Day 25

Number of subjects with abnormal heart rate: Cohort 1 and 2 (Part A)

Timeframe: Up to Day 77

Number of subjects with abnormal heart rate: Cohort 7 (Part C)

Timeframe: Up to Day 21

Number of subjects with abnormal heart rate: Cohorts 3-6 (Part B) and cohort 8 (Part C)

Timeframe: Up to Day 25

Secondary outcomes:

Area under plasma concentration-time curve (AUC) from zero hours to last measurable concentration (AUC[0–t]) for GSK3335065: Cohort 1 and 2 (Part A)

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

AUC (0–t) for GSK3335065: Cohort 7 (Part C)

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

AUC (0–t) for GSK3335065: Cohorts 3-6 (Part B) and cohort 8 (Part C)

Timeframe: Day 1: 1 hour, 30 minutes pre-dose, 6, 15, 30 minutes and 1, 2, 3, 4.5, 6, 9, 12, 18 hours post-dose; Days 2, 3-7: before first meal of the day; Day 8 (infusion termination day): 6, 12, 18, 24, 36, 42, 48, 60, 72 hours of infusion termination.

AUC from zero hours extrapolated to infinity (AUC [0-inf]) for GSK3335065: : Cohort 1 and 2 (Part A)

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

AUC (0 – inf) for GSK3335065: Cohort 7 (Part C)

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

AUC (0-inf) for GSK3335065 : Cohorts 3-6 (Part B) and cohort 8 (Part C)

Timeframe: Day 1: 1 hour, 30 minutes pre-dose, 6, 15, 30 minutes and 1, 2, 3, 4.5, 6, 9, 12, 18 hours post-dose; Days 2, 3-7: before first meal of the day; Day 8 (infusion termination day): 6, 12, 18, 24, 36, 42, 48, 60, 72 hours of infusion termination.

Maximum plasma concentration (Cmax) for GSK3335065: Cohort 1 and 2 (Part A)

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

Cmax for GSK3335065: Cohort 7 (Part C)

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

Cmax for GSK3335065: Cohorts 3-6 (Part B) and cohort 8 (Part C)

Timeframe: Day 1: 1 hour, 30 minutes pre-dose, 6, 15, 30 minutes and 1, 2, 3, 4.5, 6, 9, 12, 18 hours post-dose; Days 2, 3-7: before first meal of the day; Day 8 (infusion termination day): 6, 12, 18, 24, 36, 42, 48, 60, 72 hours of infusion termination.

Average concentration (Cavg) for GSK3335065 for Part A (cohort 1 and 2) and Part C (cohort 7)

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

Cavg for GSK3335065 for Part B (cohort 3-6) and Part C (cohort 8)

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

Cavg for GSK3335065 for Part B (cohort 3-6) and Part C (cohort 8)

Timeframe: Day 1: 1 hour, 30 minutes pre-dose, 6, 15, 30 minutes and 1, 2, 3, 4.5, 6, 9, 12, 18 hours post-dose; Days 2, 3-7: before first meal of the day; Day 8 (infusion termination day): 6, 12, 18, 24, 36, 42, 48, 60, 72 hours of infusion termination.

Time to last observation (Tlast) for GSK3335065 for Part A (cohort 1 and 2) and Part C (cohort 7)

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

Tlast for GSK3335065 for Part B (cohort 3-6) and Part C (cohort 8)

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

Tlast for GSK3335065 for Part B (cohort 3-6) and Part C (cohort 8)

Timeframe: Day 1: 1 hour, 30 minutes pre-dose, 6, 15, 30 minutes and 1, 2, 3, 4.5, 6, 9, 12, 18 hours post-dose; Days 2, 3-7: before first meal of the day; Day 8 (infusion termination day): 6, 12, 18, 24, 36, 42, 48, 60, 72 hours of infusion termination.

Volume of distribution (V) for GSK3335065 in Part A (cohort 1 and 2) and Part C (cohort 7)

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

V for GSK3335065 in Part B (cohort 3-6) and Part C (cohort 8)

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

V for GSK3335065 in Part B (cohort 3-6) and Part C (cohort 8)

Timeframe: Day 1: 1 hour, 30 minutes pre-dose, 6, 15, 30 minutes and 1, 2, 3, 4.5, 6, 9, 12, 18 hours post-dose; Days 2, 3-7: before first meal of the day; Day 8 (infusion termination day): 6, 12, 18, 24, 36, 42, 48, 60, 72 hours of infusion termination.

Terminal elimination half life (T 1/2) for GSK3335065 in Part A (cohort 1 and 2) and Part C (cohort 7)

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

T 1/2 for GSK3335065 in Part B (cohort 3-6) and Part C (cohort 8)

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

T 1/2 for GSK3335065 in Part B (cohort 3-6) and Part C (cohort 8)

Timeframe: Day 1: 1 hour, 30 minutes pre-dose, 6, 15, 30 minutes and 1, 2, 3, 4.5, 6, 9, 12, 18 hours post-dose; Days 2, 3-7: before first meal of the day; Day 8 (infusion termination day): 6, 12, 18, 24, 36, 42, 48, 60, 72 hours of infusion termination.

Clearance (CL) for GSK3335065 in Part A (cohort 1 and 2) and Part C (cohort 7)

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

CL for GSK3335065 in Part B (cohort 3-6) and Part C (cohort 8)

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

CL for GSK3335065 in Part B (cohort 3-6) and Part C (cohort 8)

Timeframe: Day 1: 1 hour, 30 minutes pre-dose, 6, 15, 30 minutes and 1, 2, 3, 4.5, 6, 9, 12, 18 hours post-dose; Days 2, 3-7: before first meal of the day; Day 8 (infusion termination day): 6, 12, 18, 24, 36, 42, 48, 60, 72 hours of infusion termination.

Time to Cmax (Tmax) for GSK3335065 in Part A (cohort 1 and 2) and Part C (cohort 7)

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

Tmax for GSK3335065 in Part B (cohort 3-6) and Part C (cohort 8)

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

Tmax for GSK3335065 in Part B (cohort 3-6) and Part C (cohort 8)

Timeframe: Day 1: 1 hour, 30 minutes pre-dose, 6, 15, 30 minutes and 1, 2, 3, 4.5, 6, 9, 12, 18 hours post-dose; Days 2, 3-7: before first meal of the day; Day 8 (infusion termination day): 6, 12, 18, 24, 36, 42, 48, 60, 72 hours of infusion termination.

To assess change in the level of 3HK and kynurenine (KYN) : Cohort 1 and 2 (Part A)

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

To assess change in the level of 3HK and KYN: Cohort 7 (Part C)

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

To assess change in the level of 3HK and KYN: Cohorts 3-6 (Part B) and cohort 8 (Part C)

Timeframe: Day 1: 1 hour, 30 minutes pre-dose, 6, 15, 30 minutes and 1, 2, 3, 4.5, 6, 9, 12, 18 hours post-dose; Days 2, 3-7: before first meal of the day; Day 8 (infusion termination day): 6, 12, 18, 24, 36, 42, 48, 60, 72 hours of infusion termination.

Interventions:
  • Drug: GSK3335065
  • Drug: Placebo
    • Enrollment:
    18
    Primary completion date:
    2018-19-05
    Observational study model:
    Not applicable
    Time perspective:
    Not applicable
    Clinical publications:
    Disala Fernando, Richard Dimelow, Ciara Gorey, Xinyi Zhu, Catherine Muya, Connie Parker, Wayne Wright, Sara Soleman, Sarah Walsh, Madelein Crause, Georgios Vlasakakis, William Guiney, Nicola Robertson, Marylise Bergeal, Yi Cui, Alex Krug and Iain Uings. Assessment of the safety, pharmacokinetics and pharmacodynamics of GSK3335065, an inhibitor of kynurenine monooxygenase, in a randomised placebo controlled First Time in Human study in healthy volunteers. Br J Clin Pharmacol. 2021; DOI: 10.1111/bcp.15010 PMID: 34327739
    Medical condition
    Pancreatitis, Acute Necrotizing
    Product
    GSK3335065
    Collaborators
    Not applicable
    Study date(s)
    August 2017 to May 2018
    Type
    Interventional
    Phase
    1

    Participation criteria

    Sex
    Female & Male
    Age
    18 - 60 years
    Accepts healthy volunteers
    Yes
    • 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.
    Inclusion and exclusion criteria
    Inclusion 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.
    • A subject with a clinical abnormality or laboratory parameter(s) which is/are not specifically listed in the inclusion or exclusion criteria, outside the reference range for the population being studied may be included only if the investigator in consultation with the Medical Monitor if required agree and document that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures.
    • 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. Exclusion Criteria
    • 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.

    Trial location(s)

    Location
    Status
    Contact us
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    Location
    GSK Investigational Site
    Cambridge, United Kingdom, CB2 0GG
    Status
    Study Complete
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    Study documents

    Protocol
    Available language(s): English
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    Statistical analysis plan
    Available language(s): English
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    If you wish to request for full study report, please contact - [email protected]

    Results overview

    Results posted on ClinicalTrials.gov

    Recruitment status
    Other
    Actual primary completion date
    2018-19-05
    Actual study completion date
    2018-19-05

    Plain language summaries

    Plain language summaries of clinical trial results for Phase 2-4 clinical trials that were initiated on or after January 2022 will be posted by GSK within one year following study completion.

    Additional information about the trial

    Additional information
    Not applicable
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