Clinical trial NCT03984812: Evaluation of the Safety, Tolerability and Pharmacokinetics (PK) of GSK3732394 First-Time-in-Human (FTIH) Study
Official title: A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety, Tolerability and Pharmacokinetics of GSK3732394 in Healthy Participants
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: HIV Infections
Keywords: DAIDS, FTIH, HIV-1, MAD, SAD
Lead sponsor: ViiV Healthcare
Sponsor class: INDUSTRY
First posted: 2019-06-13
Enrollment: 24
Sex: ALL
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: In Part 1 of the study each of the subjects in the SAD cohorts (SAD Cohorts 1-5; SAD Cohort 6 is a possible expansion cohort that will be added as needed) will receive a single dose of blinded GSK3732394 or blinded PBO (GSK3732394: PBO = 6:2), per their randomization assignment. Part 2 will consist of up to three ascending repeat-dose cohorts (MAD Cohorts 1, 2, and 3), each with 8 subjects (blinded GSK3732394: blinded PBO = 6:2) will receive four weekly doses of GSK3732394 or PBO on Days 1, 8, 15, and 22.
Primary purpose: TREATMENT

Brief summary: This is a phase 1, 2-part, double-blind (sponsor-unblinded), randomized, placebo-controlled, FTIH study, that includes both single-ascending and multiple-ascending dose phase to assess the safety, tolerability, and pharmacokinetic (PK)/pharmacodynamic (PD) attributes of GSK3732394 in healthy subjects. The data gathered in this study will further enable clinical development of GSK3732394 in HIV-infected subjects. Approximately 72 healthy subjects will be randomized in the FTIH study. Part 1 will be the single ascending dose (SAD) phase and Part 2 will be the multiple ascending dose (MAD) phase. Each subject in the SAD cohort will receive a single dose of blinded GSK3732394 or blinded placebo (PBO) in 6:2 ratio. Part 1 will consist of five ascending single-dose cohorts with an additional expansion cohort included as needed. Part 2 will consist of up to three ascending repeat-dose cohorts (MAD Cohorts 1, 2, and 3), randomized to four weekly doses of blinded GSK3732394 or blinded PBO in 6:2 ratio to be administered on Days 1, 8, 15, and 22.


Eligibility criteria: Inclusion Criteria:

* Subjects must be 18 to 50 years of age inclusive, at the time of signing the informed consent.
* Subjects who are overtly healthy as determined by medical evaluation including medical history, physical examination, laboratory tests, and cardiac monitoring.
* Subjects who are able to understand and comply with protocol requirements and timetables, instructions, and protocol-stated restrictions
* Body mass index within the range 19 to 30 kilogram per meter square (kg/m2) inclusive, in addition to a weight range of 50kg to 100kg.
* Male and female healthy volunteers.
* All male subjects must agree to use contraception during the treatment period and for at least 100 days after the last dose of study treatment and refrain from donating sperm during this period.
* A female subject is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies; Not a woman of childbearing potential (WOCBP), A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 28 days prior to first dose, and 40 days after, the last dose of study treatment.
* Capable of giving signed informed consent.
* A signed and dated written informed consent must be completed prior to the subject's entry into the study.

Exclusion Criteria:

* Subject has a history or presence of cardiovascular, dermatological, respiratory, hepatic, renal, gastrointestinal, endocrine, hematological, or neurological disorders capable of significantly altering the absorption, metabolism, or elimination of drugs; constituting a risk when taking the study intervention; or interfering with the interpretation of data.
* Subject has abnormal blood pressure (as determined by the investigator).
* Subject had symptomatic herpes zoster within 3 months prior to screening.
* Evidence of active or latent tuberculosis (TB) as documented by medical history and examination, TB testing that includes a positive tuberculin skin test \[TST\]; defined as a skin induration greater than 5 millimeter \[mm\] at 48 to 72 hours,and regardless of Bacillus Calmette-Guerin \[BCG\] or other vaccination history) or a positive (not indeterminate) QuantiFERON-TB Gold test.
* Subjects with lymphoma, leukemia, or any malignancy within the past 5 years except for basal cell or squamous epithelial carcinomas of the skin that have been resected with no evidence of metastatic disease for 3 years.
* Subjects who had breast cancer within the past 10 years.
* Subjects who had history of severe injection site reaction (i.e., required emergency care or hospitalization) following any prior injection, including reaction to vaccines.
* Subjects with history of clinically significant allergy or prior hypersensitivity including those with a documented yeast allergy.
* Subjects with history of, or current concern for, a chronic immune deficiency disorder including, but not limited to: diabetes, sickle cell anemia, and malnutrition.
* Subjects having alanine transaminase (ALT) greater than 1.1 x upper limit of normal (ULN).
* Subjects with Hemoglobin levels below the normal range.
* Subjects with Platelet count \<130,000 per cubic millimeters.
* Subjects with Creatinine clearance (CrCL) \<90 milliliters per minute.
* Subjects with bilirubin greater than 1.1xULN (isolated bilirubin greater than 1.1xULN is acceptable if bilirubin is fractionated and direct bilirubin greater than 35%).
* Subjects who has current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
* Subjects having Fridericia QT correction formula (QTcF) greater than 450 milliseconds (msec).
* Subjects who had intended use of over-the-counter or prescription medication within 7 days prior to dosing.
* Subjects who had live vaccine(s) within 1 month prior to screening, or plans to receive such vaccines during the study.
* Subjects who had treatment with biologic agents (such as monoclonal antibodies including marketed drugs) within 3 months or 5 half-lives (whichever is longer) prior to dosing.
* Subjects who had exposure to immune-modulating medications (including corticosteroids) within 30-days of Screening.
* Subjects whose participation in the study would result in loss of blood or blood products in excess of 500 (milliliter) mL within 56 days.
* Subjects who had Exposure to more than four new chemical entities within 12 months prior to the first dosing day.
* Subjects with current enrollment or past participation within the last 30 days before signing of consent in this or any other clinical study involving an investigational study intervention or any other type of medical research.
* Absolute CD4+ T-cell count and CD4 percent (CD4%) outside of the normal range for the reference laboratory (to be confirmed at baseline, e.g., Day -1).
* Subjects who had presence of Hepatitis B surface antigen (HBsAg) at screening.
* Subjects with positive Hepatitis C antibody test result at screening.
* Subjects with positive Hepatitis C RNA test result at screening or within 3 months prior to first dose of study intervention.
* Subjects with positive pre-study drug/alcohol screen.
* Subjects with positive human immunodeficiency virus (HIV) antibody test.
* Subjects with history of regular alcohol consumption within 6 months of the study defined as: an average weekly intake of greater than 14 units. One unit is equivalent to 8 grams (g) of alcohol: a half pint (\~240 mL) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits.
* Subjects with 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.
* Subjects who has 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.

Primary outcomes:
measure: Part 1: Number of Participants With Non-serious Adverse Event (SAEs) and SAEs
timeFrame: Up to Day 28
measure: Part 2: Number of Participants With Non-SAEs and SAEs
timeFrame: Up to Day 49
measure: Part 1: Number of Participants With Clinical Chemistry Parameters by Maximum Grade Increase Post-Baseline
timeFrame: Up to Day 28
measure: Part 2: Number of Participants With Clinical Chemistry Parameters by Maximum Grade Increase Post-Baseline
timeFrame: Up to Day 49
measure: Part 1: Number of Participants With Hematology Parameters by Maximum Grade Increase Post-Baseline
timeFrame: Up to Day 28
measure: Part 2: Number of Participants With Hematology Parameters by Maximum Grade Increase Post-Baseline
timeFrame: Up to Day 49
measure: Part 1: Number of Participants With Urinalysis Parameters by Any Increase in Discrete or Character Values Post Baseline
timeFrame: Up to Day 28
measure: Part 2: Number of Participants With Urinalysis Parameters by Any Increase in Discrete or Character Values Post Baseline
timeFrame: Up to Day 49
measure: Part 1: Number of Participants With Worst Case Pulse Rate Post Baseline
timeFrame: Up to Day 28
measure: Part 2: Number of Participants With Worst Case Pulse Rate Post Baseline
timeFrame: Up to Day 49
measure: Part 1: Change From Baseline in Body Temperature
timeFrame: Baseline and at Day 1 (1, 2, 4, 8, 12 hours), Days 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 17, 21, 24 and 28
measure: Part 2: Change From Baseline in Body Temperature
timeFrame: Baseline and Up to Day 49
measure: Part 1: Change From Baseline in Respiratory Rate
timeFrame: Baseline and at Day 1 (1, 2, 4, 8, 12 hours), Days 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 17, 21, 24 and 28
measure: Part 2: Change From Baseline in Respiratory Rate
timeFrame: Baseline and Up to Day 49
measure: Part 1: Number of Participants With Worst Case Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Post Baseline
timeFrame: Up to Day 28
measure: Part 2: Number of Participants With Worst Case SBP and DBP Post Baseline
timeFrame: Up to Day 49
measure: Part 1: Number of Participants With Clinical Significant Abnormal Electrocardiogram (ECG) Findings
timeFrame: Pre-dose, 4, 12 hours on Day 1, 24 hours on Day 2, Days 8, 14, 17 and 28
measure: Part 2: Number of Participants With Clinical Significant Abnormal ECG Findings
timeFrame: Up to Day 49
Secondary outcomes:
measure: Part 1: Area Under the Plasma Concentration Time Curve From Zero to t (AUC[0-t]) Following Single Dose Administration of GSK3732394
timeFrame: Day 1 (Pre-dose, 0.5, 1, 2, 4, 8, 12 hours), Day 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 17, 21, 24 and 28
measure: Part 2: AUC(0-t) After Repeat Dosing of GSK3732394 in First Week
timeFrame: Day 1 (pre-dose, 0.5, 1, 2, 4, 8 and 12 hours), Days 2, 3, 4, 5, 6 and 7
measure: Part 1: Area Under the Concentration-time Curve From Time Zero (Pre-dose) Extrapolated to Infinite Time (AUC[0-infinity]) Following Single Dose Administration of GSK3732394
timeFrame: Day 1 (Pre-dose, 0.5, 1, 2, 4, 8, 12 hours), Day 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 17, 21, 24 and 28
measure: Part 2: AUC(0-infinity) After Repeat Dosing of GSK3732394 in First Week
timeFrame: Day 1 (pre-dose, 0.5, 1, 2, 4, 8 and 12 hours), Days 2, 3, 4, 5, 6 and 7
measure: Part 1: Maximum Observed Concentration (Cmax) Following Single Dose Administration of GSK3732394
timeFrame: Day 1 (Pre-dose, 0.5, 1, 2, 4, 8, 12 hours), Day 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 17, 21, 24 and 28
measure: Part 2: Cmax After Repeat Dosing of GSK3732394 in First Week
timeFrame: Day 1 (pre-dose, 0.5, 1, 2, 4, 8 and 12 hours), Days 2, 3, 4, 5, 6 and 7
measure: Part 2: Cmax After Repeat Dosing of GSK3732394 in Last Week
timeFrame: Day 22 (pre-dose, 0.5, 1, 2, 4, 8 and 12 hours), Days 23, 24, 25, 26, 27 and 28
measure: Part 1: Time of Occurrence of Cmax (Tmax) After Single Dose Administration of GSK3732394
timeFrame: Day 1 (Pre-dose, 0.5, 1, 2, 4, 8, 12 hours), Day 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 17, 21, 24 and 28
measure: Part 2: Tmax After Repeat Dosing of GSK3732394 in First Week
timeFrame: Day 1 (pre-dose, 0.5, 1, 2, 4, 8 and 12 hours), Days 2, 3, 4, 5, 6 and 7
measure: Part 2: Tmax After Repeat Dosing of GSK3732394 in Last Week
timeFrame: Day 22 (pre-dose, 0.5, 1, 2, 4, 8 and 12 hours), Days 23, 24, 25, 26, 27 and 28
measure: Part 1: Lag Time Before Observation of Drug Concentrations (Tlag) After Single Dose Administration of GSK3732394
timeFrame: Day 1 (Pre-dose, 0.5, 1, 2, 4, 8, 12 hours), Day 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 17, 21, 24 and 28
measure: Part 2: Tlag After Repeat Dosing of GSK3732394 in First Week
timeFrame: Day 1 (pre-dose, 0.5, 1, 2, 4, 8 and 12 hours), Days 2, 3, 4, 5, 6 and 7
measure: Part 1: Last Observable Concentration (Clast) After Single Dose Administration of GSK3732394
timeFrame: Day 1 (Pre-dose, 0.5, 1, 2, 4, 8, 12 hours), Day 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 17, 21, 24 and 28
measure: Part 1: Time of Last Observable Concentration (Tlast) After Single Dose Administration of GSK3732394
timeFrame: Day 1 (Pre-dose, 0.5, 1, 2, 4, 8, 12 hours), Day 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 17, 21, 24 and 28
measure: Part 1: Apparent Terminal Phase Half-life (t1/2) After Single Dose Administration of GSK3732394
timeFrame: Day 1 (Pre-dose, 0.5, 1, 2, 4, 8, 12 hours), Day 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 17, 21, 24 and 28
measure: Part 2: T1/2 After Repeat Dosing of GSK3732394 in Last Week
timeFrame: Day 22 (pre-dose, 0.5, 1, 2, 4, 8 and 12 hours), Days 23, 24, 25, 26, 27 and 28
measure: Part 1: Apparent Clearance (CL/F) After Single Dose Administration of GSK3732394
timeFrame: Day 1 (Pre-dose, 0.5, 1, 2, 4, 8, 12 hours), Day 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 17, 21, 24 and 28
measure: Part 2: CL/F After Repeat Dosing of GSK3732394 in Last Week
timeFrame: Day 22 (pre-dose, 0.5, 1, 2, 4, 8 and 12 hours), Days 23, 24, 25, 26, 27 and 28
measure: Part 2: Area Under the Concentration Time Curve at Steady State Within the Dosing Interval (AUC[0-tau]) After Repeat Dosing of GSK3732394 in Last Week
timeFrame: Day 22 (pre-dose, 0.5, 1, 2, 4, 8 and 12 hours), Days 23, 24, 25, 26, 27 and 28
measure: Part 2: Trough Concentration (Ctrough) After Repeat Dosing of GSK3732394 in Last Week
timeFrame: Day 22 (pre-dose, 0.5, 1, 2, 4, 8 and 12 hours), Days 23, 24, 25, 26, 27 and 28
measure: Part 2: Accumulation Ratio Using AUC(0-tau) (RAUC[0-tau]) After Repeat Dosing of GSK3732394
timeFrame: Days 1 and 22 (pre-dose, 0.5, 1, 2, 4, 8 and 12 hours), Days 2, 3, 4, 5, 6, 7, 23, 24, 25, 26, 27 and 28
measure: Part 2: Accumulation Ratio Using Cmax (RCmax) After Repeat Dosing of GSK3732394
timeFrame: Days 1 and 22 (pre-dose, 0.5, 1, 2, 4, 8 and 12 hours), Days 2, 3, 4, 5, 6, 7, 23, 24, 25, 26, 27 and 28
measure: Part 2: Accumulation Ratio Using Ctrough (RCtrough) After Repeat Dosing of GSK3732394
timeFrame: Days 1 and 22 (pre-dose, 0.5, 1, 2, 4, 8 and 12 hours), Days 2, 3, 4, 5, 6, 7, 23, 24, 25, 26, 27 and 28
measure: Part 1: Change From Baseline in Percent of CD4 Receptor Occupancy (RO) After Single Dose Administration of GSK3732394
timeFrame: Baseline, Day 1 (0.5, 1, 2, 4, 8, 12 hours), Day 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 17, 21, 24 and 28
measure: Part 2: Change From Baseline in Percent of CD4 RO After Multiple Dose Administration of GSK3732394
timeFrame: Baseline and up to Day 49
measure: Part 1: Change From Baseline in CD3+ Cells Following Single Dose Administration of GSK3732394
timeFrame: Baseline, Days 2, 3, 5, 8, 11, 14, 17, 21, 24 and 28
measure: Part 2: Change From Baseline in CD3+ Cells Following Multiple Dose Administration of GSK3732394
timeFrame: Baseline and up to Day 49
measure: Part 1: Change From Baseline in CD4+ Cells Following Single Dose Administration of GSK3732394
timeFrame: Baseline, Days 2, 3, 5, 8, 11, 14, 17, 21, 24 and 28
measure: Part 2: Change From Baseline in CD4+ Cells Following Multiple Dose Administration of GSK3732394
timeFrame: Baseline and up to Day 49
measure: Part 1: Change From Baseline in CD8+ Cells Following Single Dose Administration of GSK3732394
timeFrame: Baseline, Days 2, 3, 5, 8, 11, 14, 17, 21, 24 and 28
measure: Part 2: Change From Baseline in CD8+ Cells Following Multiple Dose Administration of GSK3732394
timeFrame: Baseline and up to Day 49
measure: Part 1: Change From Baseline in CD4+ Cell Median Fluorescence Intensity (MFI) Following Single Dose Administration of GSK3732394
timeFrame: Baseline, Day 1 (0.5, 1, 2, 4, 8, 12 hours), Day 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 17, 21, 24 and 28
measure: Part 2: Change From Baseline in CD4+ Cell MFI Following Multiple Dose Administration of GSK3732394
timeFrame: Baseline and up to Day 49
measure: Part 1: Number of Participants With Anti-GSK3732394 Antibodies on Day 28
timeFrame: Day 28
measure: Part 2: Number of Participants With Anti-GSK3732394 Antibodies
timeFrame: Up to Day 49
measure: Part 1: Titer of Anti-drug Antibodies (ADAs) Against GSK3732394 on Day 28
timeFrame: Day 28
measure: Part 2: Titer of ADAs Against GSK3732394
timeFrame: Up to Day 49
Other outcomes:
Locations:
city: Baltimore
country: United States
facility: GSK Investigational Site
state: Maryland
Study officials:
affiliation: ViiV Healthcare
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Krystal M, Chabria S, Austin D, Wolstenholme A, Wensel D, Lataillade M, Abberbock J, Baker M, Ackerman P. A Phase 1 randomized study of GSK3732394, an investigational long-acting biologic treatment regimen for HIV-1 infection. Antivir Ther. 2022 Oct;27(5):13596535221131164. doi: 10.1177/13596535221131164.