Clinical trial NCT03075410: First Time in Human (FTIH) Safety and Pharmacokinetics (PK) Study of GSK3036656 in Healthy Subjects
Official title: A Double Blind, Placebo-controlled First Time in Human Study to Evaluate the Safety, Tolerability and Pharmacokinetics of Single and Repeat Doses of GSK3036656 in Healthy Adult Volunteers
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Tuberculosis
Keywords: ascending dose
Pharmacokinetics
GSK3036656
FTIH
Safety
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2017-03-09
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: GSK3036656 is being developed by GSK for the treatment of tuberculosis (TB). This is the FTIH study for GSK3036656 to evaluate the safety, tolerability and PK of single ascending and repeat oral doses of GSK3036656 in healthy adult subjects. The results of this study are intended to be used to identify appropriate and well-tolerated doses of GSK3036656 to be used in further studies. A food effect assessment will also be undertaken to investigate the influence of food on the PK of GSK3036656. The study will be conducted in two parts: Part A (single dose) and Part B (repeat dose). Up to two cohorts will be included in Part A. 9 healthy adult subjects will be included in each cohort. Each cohort will participate in up to 4 treatment (dosing) periods including a food effect treatment period. During each treatment period, GSK3036656 will be administered to 6 subjects and placebo will be administered to 3 subjects. The starting dose in Part A will be 5 milligrams (mg), and the maximum dose will be 1500 mg. The two cohorts in Part A will be dosed sequentially (i.e., dosing in Cohort 2 starts after dosing in Cohort 1 is completed). Initially, there will be a 14 day wash out period for individual subjects between each dose level. Study progression to Part B from Part A will be based on an acceptable safety, tolerability and PK profile in Part A. Part B will comprise up to 4 cohorts (Cohorts 3, 4, 5, and 6) each containing 10 (8 active: 2 placebo) healthy adult subjects to examine the safety, tolerability and PK of a repeated daily dose of GSK3036656 over a period of up to 14 days. Appropriate doses and dose regimens for Part B will be selected based on available safety, tolerability and PK data from Part A and/or any preceding repeat dose cohorts from Part B. Dividing the total daily dose into 2 or 3 smaller doses may be done in both Part A and Part B. Up to 18 subjects will be enrolled into Part A and up to 40 subjects will be enrolled into Part B. The total duration of the study for each subject recruited into Part A and Part B will be approximately 12 weeks and 8 weeks, respectively.


Eligibility criteria: Inclusion Criteria:

* Between 18 and 55 years of age inclusive, at the time of signing the informed consent.
* Healthy as determined by the investigator or medically qualified designee based on a 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 \>=60 kilograms (kg) and body mass index (BMI) within the range 19 to 29.9 kg/meter\^2 inclusive.
* Male
* Female subjects of non-child bearing potential are eligible to participate. Non-child bearing potential is defined as:

  * Pre-menopausal females with one of the following: documented tubal ligation; documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion or documented bilateral salpingectomy; hysterectomy; documented bilateral oophorectomy.
  * Postmenopausal defined as 12 months of spontaneous amenorrhea. Post-menopausal status will be confirmed by a simultaneous follicle stimulating hormone (FSH) and estradiol levels test.
* Male subjects with female partners of child bearing potential must comply with the following contraception requirements from the time of first dose of study medication until 90 days after the last dose of study treatment (i.e. one sperm cycle).

  * Vasectomy with documentation of azoospermia.
  * Male condom plus partner use of one of the contraceptive options as follows: contraceptive subdermal implant; intrauterine device or intrauterine system; highly effective oral contraceptive, either combined or progestogen alone (provided it is associated with inhibition of ovulation); injectable progestogen; contraceptive vaginal ring; percutaneous contraceptive patches.
* These allowed methods of contraception are only effective when used consistently, correctly and in accordance with the product label. The investigator is responsible for ensuring that subjects understand how to properly use these methods of contraception.
* The subject is able to understand and comply with protocol requirements, instructions and protocol-stated restrictions.

Exclusion criteria:

* Alanine aminotransferase (ALT) and bilirubin \>1.5 times of upper limit of normal (ULN) (isolated bilirubin \>1.5 times of ULN may be acceptable, after consultation with the GlaxoSmithKline (GSK) medical monitor, if bilirubin is fractionated and direct bilirubin \<35 percent)
* Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
* QTcF \>450 milliseconds.
* Presence of moderate or severe valve disorder or any other clinically significant abnormality.
* Subjects with a history of photosensitivity.
* Females of non-childbearing potential who are susceptible to heavy periods or vaginal bleeding or spotting.
* Pregnant females. A human chorionic gonadotrophin (hCG) test will be performed on Day -1 of each treatment (dosing) period in Part A and Part B for women for whom post-menopausal status has not been confirmed by FSH/estradiol testing. No pregnancy tests will be required for female subjects confirmed as post-menopausal by FSH/estradiol testing.
* Lactating females.
* Use of prescription or non-prescription drugs, including high-dose vitamins, herbal and dietary supplements (including Saint John's Wort) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study medication, unless in the opinion of the investigator and sponsor, the medication will not interfere with the study procedures or compromise subject safety. Paracetamol for mild analgesia will be permitted.
* Breath carbon monoxide test indicative of smoking or history of current use of tobacco- or nicotine-containing products.
* Current regular alcohol consumption defined as an average weekly intake of \>21 units for males or \>14 units for females. One unit is equivalent to 8 grams (g) of alcohol: a half-pint (approximately 240 milliliter \[mL\]) of beer, 1 glass (125 ml) of wine or 1 (25 ml) measure of spirits.
* Subjects must not sunbathe or use a tanning device whilst taking the study medication and until at least 2 weeks after their last dose. Subjects are to be advised that they should wear protective clothing (e.g. sun hat, long sleeves) and use a broad spectrum ultraviolet A/ ultraviolet B sunscreen (sun protection factor \>=30) when outdoors.
* History of sensitivity to heparin or heparin-induced thrombocytopenia.
* 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.
* 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.
* A positive test for human immunodeficiency virus (HIV) antibody.
* A positive pre-study drug/alcohol screen.
* 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: 3 months, 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.

Primary outcomes:
measure: Number of Participants With Non-serious Adverse Events (nSAE) and Serious Adverse Events (SAEs) for Part A
timeFrame: Up to 12 weeks
measure: Number of Participants With nSAE and SAEs for Part B
timeFrame: Up to 8 weeks
measure: Number of Participants With Abnormal Electrocardiogram (ECG) Findings for Part A
timeFrame: Up to 6 weeks
measure: Number of Subjects With Clinically Relevant Changes in ECG in Part B
timeFrame: Up to 8 weeks
measure: Number of Participants With Abnormal Cardiac Telemetry Findings for Part A
timeFrame: 25 hours for each period
measure: Number of Participants With Abnormal Cardiac Telemetry Findings for Part B
timeFrame: 25 hours for each period
measure: Number of Participants With Vital Sign Parameters Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) of Potential Clinical Importance (PCI) for Part A
timeFrame: Up to 6 weeks
measure: Number of Participants With Vital Sign Parameters SBP and DBP of PCI for Part B
timeFrame: Up to 8 weeks
measure: Number of Participants With Vital Sign Parameter Heart Rate of PCI for Part A
timeFrame: Up to 6 weeks
measure: Number of Participants With Vital Sign Parameter Heart Rate of PCI for Part B
timeFrame: Up to 8 weeks
measure: Number of Participants With Vital Sign Parameter Temperature of PCI for Part A
timeFrame: Up to 6 weeks
measure: Number of Participants With Vital Sign Parameter Temperature of PCI for Part B
timeFrame: Up to 8 weeks
measure: Number of Participants With Clinical Chemistry Parameters of PCI for Part A
timeFrame: Up to 12 weeks
measure: Number of Participants With Clinical Chemistry Parameters of PCI for Part B
timeFrame: Up to 8 weeks
measure: Number of Participants With Hematology Parameters of PCI for Part A
timeFrame: Up to 12 weeks
measure: Number of Participants With Hematology Parameters of PCI for Part B
timeFrame: Up to 8 weeks
measure: Number of Participants With Abnormal Urinalysis Parameters for Part A
timeFrame: Up to 72 hours post-dose
measure: Urine Potential of Hydrogen (pH) Analysis by Dipstick Method for Part A
timeFrame: Up to 72 hours post-dose
measure: Number of Participants With Abnormal Urinalysis Parameters for Part B
timeFrame: Up to 8 weeks
measure: Urine pH Analysis by Dipstick Method for Part B
timeFrame: Up to 8 weeks
measure: Area Under the Plasma Concentration-time Curve (AUC) From Time Zero to the Time of Last Quantifiable Concentration (AUC[0-t]) Following Single Dose Administration of GSK3036656 for Part A
timeFrame: Pre-dose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 15, 24, 36, 48 and 72 hour post-dose on Day 1 in each period
measure: AUC From Time Zero Extrapolated to Infinite Time (AUC[0-infinity]) of GSK3036656 Following Single Dose Administration for Part A
timeFrame: Pre-dose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 15, 24, 36, 48 and 72 hour post-dose on Day 1 in each period
measure: Maximum Observed Plasma Drug Concentration (Cmax) of GSK3036656 Following Single Dose Administration for Part A
timeFrame: Pre-dose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 15, 24, 36, 48 and 72 hour post-dose on Day 1 in each period
measure: Time to Maximum Observed Plasma Drug Concentration (Tmax) of GSK3036656 Following Single Dose Administration for Part A
timeFrame: Pre-dose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 15, 24, 36, 48 and 72 hour post-dose on Day 1 in each period
measure: Apparent Terminal Half-life (t1/2) of GSK3036656 Following Single Dose Administration for Part A
timeFrame: Pre-dose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 15, 24, 36, 48 and 72 hour post-dose on Day 1 in each period
measure: AUC[0-t] Following Repeated Dose Administration of GSK3036656 for Part B
timeFrame: Pre-dose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 15, 24, 36, 48 and 72 hour post-dose on Day 1
measure: AUC From Time Zero During a Dosing Interval of Duration Tau (AUC[0-tau]) of GSK3036656 Following Repeated Dose Administration for Part B
timeFrame: Pre-dose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 15, 24, 36, 48 and 72 hour post-dose on Day 14
measure: Cmax of GSK3036656 Following Repeated Dose Administration for Part B
timeFrame: Pre-dose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 15, 24, 36, 48 and 72 hour post-dose on Day 1; at pre-dose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 15, 24, 36, 48 and 72 hour post-dose on Day 14; and at pre-dose on Days 12 and 13
measure: Tmax of GSK3036656 Following Repeat Dose Administration for Part B
timeFrame: Pre-dose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 15, 24, 36, 48 and 72 hour post-dose on Day 1; at pre-dose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 15, 24, 36, 48 and 72 hour post-dose on Day 14; and at pre-dose on Days 12 and 13
measure: t1/2 of GSK3036656 Following Repeated Dose Administration for Part B
timeFrame: Pre-dose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 15, 24, 36, 48 and 72 hour post-dose on Day 14.
Secondary outcomes:
measure: AUC (0-t) of GSK3036656 Following Single Dose Administration in Fed Condition in Part A
timeFrame: Pre-dose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 15, 24, 36, 48 and 72 hour post-dose on Day 1 in each period
measure: AUC (0-infinity) of GSK3036656 Following Single Dose Administration in Fed Condition in Part A
timeFrame: Pre-dose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 15, 24, 36, 48 and 72 hour post-dose on Day 1 in each period
measure: Cmax of GSK3036656 Following Single Dose Administration in Fed Condition in Part A
timeFrame: Pre-dose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 15, 24, 36, 48 and 72 hour post-dose on Day 1 in each period
measure: t1/2 of GSK3036656 Following Single Dose Administration in Fed Condition in Part A
timeFrame: Pre-dose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 15, 24, 36, 48 and 72 hour post-dose on Day 1 in each period
measure: Tmax of GSK3036656 Following Single Dose Administration in Fed Condition in Part A
timeFrame: Pre-dose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 15, 24, 36, 48 and 72 hour post-dose on Day 1 in each period
measure: Observed Accumulation Ratio Based on AUC (AUC [Ro]) of GSK3036656 in Part B
timeFrame: Pre-dose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 15, 24, 36, 48 and 72 hour post-dose on Day 1; at pre-dose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 15, 24, 36, 48 and 72 hour post-dose on Day 14
measure: Observed Accumulation Ratio Based on Cmax (RCmax) of GSK3036656 in Part B
timeFrame: Pre-dose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 15, 24, 36, 48 and 72 hour post-dose on Day 1; at pre-dose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 15, 24, 36, 48 and 72 hour post-dose on Day 14
measure: Steady State Ratio (Rss) of GSK3036656 in Part B
timeFrame: Pre-dose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 15, 24, 36, 48 and 72 hour post-dose on Day 1; at pre-dose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 15, 24, 36, 48 and 72 hour post-dose on Day 14
measure: Trough Plasma Concentrations at the End of the Dosing Interval (Ctau) of GSK3036656 Following Repeat Dose Administrations in Part B
timeFrame: Day 1 (24 hours), Day 12 (Pre-dose ), Day 13 (Pre-dose ), Day 14 (Pre-dose), Day 14 (24 hours)
measure: AUC (0-infinity) as a Measure of Dose Proportionality of GSK3036656 Following Single Dose Administrations for Part A
timeFrame: Pre-dose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 15, 24, 36, 48 and 72 hour post-dose on Day 1 in each period
measure: AUC (0-t) as a Measure of Dose Proportionality of GSK3036656 Following Single Dose Administrations for Part A
timeFrame: Pre-dose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 15, 24, 36, 48 and 72 hour post-dose on Day 1 in each period
measure: Cmax as a Measure of Dose Proportionality of GSK3036656 Following Single Dose Administrations for Part A
timeFrame: Pre-dose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 15, 24, 36, 48 and 72 hour post-dose on Day 1 in each period
measure: AUC (0-tau) as a Measure of Dose Proportionality of GSK3036656 Following Repeat Dose Administrations for Part B
timeFrame: Pre-dose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 15, 24, 36, 48 and 72 hour post-dose on Day 1; at pre-dose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 15, 24, 36, 48 and 72 hour post-dose on Day 14; and at pre-dose on Days 12 and 13
measure: Cmax as a Measure of Dose Proportionality of GSK3036656 Following Repeat Dose Administrations for Part B
timeFrame: Pre-dose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 15, 24, 36, 48 and 72 hour post-dose on Day 1; at pre-dose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 15, 24, 36, 48 and 72 hour post-dose on Day 14; and at pre-dose on Days 12 and 13
Other outcomes:
Locations:
city: London
country: United Kingdom
facility: GSK Investigational Site
city: London
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
affiliation: GlaxoSmithKline (for GlaxoSmithKline; Human Genome Sciences Inc., a GSK Company; Sirtris, a GSK Company; Stiefel, a GSK Company; ViiV Healthcare)
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Tenero D, Derimanov G, Carlton A, Tonkyn J, Davies M, Cozens S, Gresham S, Gaudion A, Puri A, Muliaditan M, Rullas-Trincado J, Mendoza-Losana A, Skingsley A, Barros-Aguirre D. First-Time-in-Human Study and Prediction of Early Bactericidal Activity for GSK3036656, a Potent Leucyl-tRNA Synthetase Inhibitor for Tuberculosis Treatment. Antimicrob Agents Chemother. 2019 Jul 25;63(8):e00240-19. doi: 10.1128/AAC.00240-19. Print 2019 Aug.