GSK3739937 First-Time-In-Human (FTIH) Study in Healthy Volunteers

ViiV Healthcare

Status and phase: Completed; Phase 1

Conditions: HIV Infections

Treatments: Drug: GSK3739937 (PIB); Drug: Placebo; Drug: GSK3739937 (Tablet)

Study type: Interventional

Funder types: Industry

Identifiers

NCT04493684

212548

Details and patient eligibility

About

This study is a Phase 1, double-blind (sponsor-unblinded), randomized, placebo-controlled, single- and repeat-dose escalation study including a weekly oral dose (MAD) cohort and a relative bioavailability (RBA) and food effect (FE) cohort to investigate the safety, tolerability and PK of VH3739937 in healthy participants. This is a three part study. Part 1 and Part 2 is designed to gain information on the safety, tolerability, and pharmacokinetic (PK) properties of GSK3739937 when administered as powder-in-a-bottle (PiB). Part 3 will evaluate the RBA of the GSK3739937 PiB and GSK3739937 Tablet and the safety, tolerability and PK parameters of the tablet formulation when administered under fasting and fed conditions.

Enrollment: 91 patients

Sex: All

Ages: 18 to 55 years old

Volunteers: Accepts Healthy Volunteers

Inclusion criteria

• Participant must be 18 to 55 years of age inclusive, at the time of signing the informed consent.
• Participants who are overtly 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 (history and ECG).
• Participants who are negative on two consecutive tests for severe acute respiratory syndrome coronavirus-2 (SARs-CoV-2), performed at Screening and on admission and (re-)admission to the Phase I unit, using an approved molecular test polymerase chain reaction (PCR).
• Participants who are able to understand and comply with protocol requirements and timetables, instructions, and protocol-stated restrictions.
• Body weight >=50.0 kilograms (kg) (110 pound [lbs]) for men and >=45.0 kg (99 lbs) for women and body mass index within the range 18.5 to 32.0 kilogram per square meter (kg/m^2).
• Male participants are eligible to participate if they agree to use contraceptive methods
• A female participant is eligible to participate if she is not pregnant or breastfeeding, and is not a woman of childbearing potential (WOCBP). - Capable of giving signed informed consent

Exclusion criteria

• Signs and symptoms which in the opinion of the investigator are suggestive of coronavirus disease 2019 (COVID-19) (i.e. fever, cough etc) within 14 days of inpatient admission.
• Contact with known COVID-19 positive persons in the 14 days prior to inpatient admission.
• History or presence of cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, hematological, or neurological disorders capable of significantly altering the absorption, distribution, metabolism, or elimination of drugs; constituting a risk when taking the study intervention or interfering with the interpretation of data.
• Pre-existing clinically relevant, in the opinion of the principal investigator (PI), gastro-intestinal pathology or diagnosis - e.g. irritable bowel syndrome, inflammatory bowel disease, and/or significant baseline signs and symptoms.
• Medical history of cardiac arrhythmias or cardiac disease or a family and personal history of long QT syndrome.
• Any known or suspected pre-existing psychiatric condition
• Any positive (abnormal) response confirmed by the investigator or clinician (or qualified designee) administered Columbia Suicide Severity Rating Scale (CSSRS) at screening .
• Any other clinical condition (including but not limited to active substance use) or prior therapy that, in the opinion of the Investigator, would make the participant unsuitable for the study; unable to comply with dosing requirements; or unable to comply with study visits; or a condition that could affect the absorption, distribution, metabolism or excretion of the drug.
• Estimated glomerular filtration rate (eGFR) <90 milliliters/minute (mL/min) or serum creatinine >1.1 x upper limit of normal (ULN).
• Hemoglobin <12.5 grams/deciliter (g/dL) for men and <11 g/dL for women.
• ALT or AST >1.1x ULN.
• Bilirubin >1.1 x ULN (isolated bilirubin >1.1 x ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
• Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones)
• Any significant arrhythmia or ECG finding (e.g., prior myocardial infarction in the past 3 months (does not include ST segment changes associated with repolarization), symptomatic bradycardia, non-sustained or sustained atrial arrhythmias, non-sustained or sustained ventricular tachycardia (>=3 consecutive ventricular ectopic beats), second-degree atrioventricular (AV) block Mobitz Type II, third-degree atrioventricular block, complete heart block, or conduction abnormality (including but not specific to left or right complete bundle branch; AV block [2nd degree or higher]; Wolff-Parkinson-White [WPW] syndrome), Sinus Pauses > 3 seconds, which, in the opinion of the investigator or ViiV Healthcare (VH)/ GlaxoSmithKline (GSK) Medical Monitor, will interfere with the safety for the individual participant.
• Exclusion criteria for Screening ECG. Heart rate <45 or >100 beats per minute (bpm) for males and <50 or >100 bpm for females; PR interval <120 or >220 millisecond (msec); QRS duration <70 or >120 msec; the Fridericia's QT correction formula (QTcF) interval >450 msec.
• Past or intended use of over-the-counter or prescription medication [including cytochrome p450 enzyme inducers or inhibitors, vitamins, herbal and dietary supplements ] within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to dosing and for the duration of the study, unless in the opinion of the Investigator and Sponsor, the medication will not interfere with the study medications, procedures, or compromise participant safety.
• Unwillingness to abstain from ingestion of any food or drink containing grapefruit and grapefruit juice, Seville oranges, blood oranges, or pomelos within 7 days prior to the first dose of study treatments or until the end of the study.
• Participation in the study would result in loss of blood or blood products in excess of 500 mL within 56 days
• Exposure to more than 4 new chemical entities within 12 months prior to the first dosing day
• Current enrolment or past participation within the last 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer) before signing of consent in this or any other clinical study involving an investigational study intervention or any other type of medical research
• Presence of Hepatitis B surface antigen (HBsAg) at screening or within 3 months prior to first dose of study intervention
• Positive Hepatitis C antibody test result at screening or within 3 months prior to first dose of study intervention.
• Positive Hepatitis C ribonucleic acid (RNA) test result at screening or within 3 months prior to first dose of study intervention
• Positive pre-study drug/alcohol screen
• Positive HIV antibody/antigen test
• Regular use of known drugs of abuse
• Regular alcohol consumption within 6 months prior to the study defined as: An average weekly intake of >14 units for males or >7 units for females.
• Urinary cotinine levels indicative of smoking or history or regular use of tobacco- or nicotine-containing products (e.g. nicotine patches or vaporizing devices) within 6 months prior to screening and at admission.
• Sensitivity to any of the study interventions, or components thereof, or drug or other allergy that, in the opinion of the investigator or medical monitor, contraindicates participation in the study.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Sequential Assignment

Masking: Double Blind

---

91 participants in 15 patient groups, including a placebo group

Part 1: Cohort 1: Participants receiving GSK3739937

Experimental group

Description:

Part 1 cohort 1 may contain up to 4 escalating doses (Period 1- 10 milligram \[mg\], Period 2- 80 mg, and Period 3- 320 mg, Period 4- 800 mg) of GSK3739937.

Treatment:

Drug: GSK3739937 (PIB)

Part 1: Cohort 1: Participants receiving Placebo

Placebo Comparator group

Description:

In this cohort, participants will be randomized to receive placebo.

Treatment:

Drug: Placebo

Part 1: Cohort 2: Participants receiving GSK3739937

Experimental group

Description:

Part 1 cohort 2 may contain up to 3 escalating doses ( Period 1- 30 mg, Period 2- 160 mg, and Period 3- 640 mg) of GSK3739937.

Treatment:

Drug: GSK3739937 (PIB)

Part 1: Cohort 2: Participants receiving Placebo

Placebo Comparator group

Description:

In this cohort, participants will be randomized to receive placebo.

Treatment:

Drug: Placebo

Part 2: Cohort 3: Participants receiving GSK3739937

Experimental group

Description:

Eligible participants in part 2 cohort 3, will consist of approximately 10 participants out of 7 participants will be randomized to receive a once-daily dose of 25 mg GSK3739937 for 14 days.

Treatment:

Drug: GSK3739937 (PIB)

Part 2: Cohort 3: Participants receiving Placebo

Placebo Comparator group

Description:

Eligible participants in part 2 cohort 3, will consist of approximately 10 participants out of 3 participants will be randomized to receive a once-daily dose of placebo for 14 days.

Treatment:

Drug: Placebo

Part 2: Cohort 4: Participants receiving GSK3739937

Experimental group

Description:

Eligible participants in part 2 cohort 4, will consist of approximately 10 participants out of 7 participants will be randomized to receive a once-daily dose of 50 mg GSK3739937 for 14 days.

Treatment:

Drug: GSK3739937 (PIB)

Part 2: Cohort 4: Participants receiving Placebo

Placebo Comparator group

Description:

Eligible participants in part 2 cohort 4, will consist of approximately 10 participants out of 3 participants will be randomized to receive a once-daily dose of placebo for 14 days.

Treatment:

Drug: Placebo

Part 2: Cohort 5: Participants receiving GSK3739937

Experimental group

Description:

Eligible participants in part 2 cohort 5, will consist of approximately 10 participants out of 7 participants will be randomized to receive a once-daily dose of 100 mg GSK3739937 for 18 days.

Treatment:

Drug: GSK3739937 (PIB)

Part 2: Cohort 5: Participants receiving placebo

Placebo Comparator group

Description:

Eligible participants in part 2 cohort 5, will consist of approximately 10 participants out of 3 participants will be randomized to receive a once-daily dose of placebo for 18 days.

Treatment:

Drug: Placebo

Part 2: Cohort 6: Participants receiving GSK3739937

Experimental group

Description:

Eligible participants in part 2 cohort 6, will consist of approximately 10 participants out of 7 participants will be randomized to receive three 500 mg doses of GSK3739937 administered at once weekly intervals over two weeks.

Treatment:

Drug: GSK3739937 (PIB)

Part 2: Cohort 6: Participants receiving placebo

Placebo Comparator group

Description:

Eligible participants in part 2 cohort 6, will consist of approximately 10 participants out of 3 participants will be randomized to receive three doses of placebo administered at once weekly intervals over two weeks.

Treatment:

Drug: Placebo

Part 3: Cohort 7: Participants receiving treatment sequence ABC

Experimental group

Description:

Participants will receive Treatment A: GSK3739937 PiB, 100 mg administered under moderate fat conditions in Period 1; Treatment B: GSK3739937 Tablet, 100 mg administered under moderate fat conditions in Period 2; and Treatment C: GSK3739937 Tablet, 100 mg administered under fasted conditions in Period 3.

Treatment:

Drug: GSK3739937 (Tablet)

Drug: GSK3739937 (PIB)

Part 3: Cohort 7: Participants receiving treatment sequence BCA

Experimental group

Description:

Participants will receive Treatment B: GSK3739937 Tablet, 100 mg administered under moderate fat conditions in Period 1; Treatment C: GSK3739937 Tablet, 100 mg administered under fasted conditions in Period 2; and Treatment A: GSK3739937 PiB, 100 mg administered under moderate fat conditions in Period 3.

Treatment:

Drug: GSK3739937 (Tablet)

Drug: GSK3739937 (PIB)

Part 3: Cohort 7: Participants receiving treatment sequence CAB

Experimental group

Description:

Participants will receive Treatment C: GSK3739937 Tablet, 100 mg administered under fasted conditions in Period 1; Treatment A: GSK3739937 PiB, 100 mg administered under moderate fat conditions in Period 2; and Treatment B: GSK3739937 Tablet, 100 mg administered under moderate fat conditions in Period 3.

Treatment:

Drug: GSK3739937 (Tablet)

Drug: GSK3739937 (PIB)