Clinical trial NCT03575962: A Study to Compare the Relative Bioavailability of Two Different Formulations of GSK3640254
Official title: A Single Centre, 2-period, Randomized, Open-label Phase 1 Study to Assess the Relative Bioavailability of a Mesylate Salt Capsule of GSK3640254 Compared to a Hydrochloride Salt Capsule in Healthy Participants
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: HIV Infections
Keywords: 2-period
Pharmacokinetics
FTIH
GSK3640254
healthy subject
bioavailability
Lead sponsor: ViiV Healthcare
Sponsor class: INDUSTRY
First posted: 2018-07-03
Enrollment: 14
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: Subjects will receive GSK3640254 bis-hydrochloride salt capsule followed by mesylate salt capsule or vice versa in two treatment periods.
Primary purpose: TREATMENT

Brief summary: This is a first time in human (FTIH), 2-period study, to assess the relative bioavailability of a mesylate salt capsule of GSK3640254, compared to a bis- hydrochloride salt capsule of GSK3640254, in healthy subjects, administered following a moderate calorie and fat meal. The subjects will be randomized to 2 sequences, Regimen AB or Regimen BA. For Regimen AB: The Regimen A, which will include oral administration of GSK3640254 bis-hydrochloride Capsule 200 milligram (mg) (reference), which will be administered, in Period 1 and Regimen B will include GSK3640254 Mesylate salt capsule (test), 200 mg, which will be administered in Period 2. For the regimen BA, the regimen B, will be administered, in Period 1 and regimen A, in Period 2. Each of the regimens will be given orally as 2 capsules in the morning, as per randomization sequence. There will be a minimum washout of 7 days between each dose of study treatment. A total, of 14 subjects, are planned to be enrolled in the study. The maximum duration of the study from screening to follow-up is approximately 7 weeks.


Eligibility criteria: Inclusion Criteria:

* Subject must be 18 to 55 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.
* Body weight \>= 50 kilogram (kg) for men and \>= 45 kg for women, and body mass index (BMI) within the range 19.0 to 32.0 kg per meter square (kg/m\^2) (inclusive).
* Male or female subjects, where a male subject must agree to use contraception, during the treatment period and for at least 14-weeks following the last dose, corresponding to the time needed to eliminate study treatment for potential genotoxic and teratogenic study treatments plus an additional 90 days (spermatogenesis cycle). In addition, male subjects must refrain from donating sperm during this period and the female subjects who is eligible to participate if she is not a woman of childbearing potential (WOCBP).
* Capable of giving signed informed consent

Exclusion Criteria:

* History of or current cardiovascular, respiratory, hepatic, renal, gastrointestinal (GI), endocrine, hematological, or neurological disorders capable of significantly altering the absorption, metabolism, or elimination of drugs; constituting a risk when taking the study treatment; or interfering with the interpretation of data.
* History of clinically significant psychiatric disorders as judged by the investigator. Psychiatric disorder requiring pharmacologic treatment in the last 5 years.
* Any positive (abnormal) response confirmed by the investigator on a screening clinician (or qualified designee) administered Columbia Suicide Severity Rating Scale (CSSRS).
* History or current evidence of febrile seizures, epilepsy, convulsions, significant head injury, or other significant neurologic conditions.
* History of GI surgery (with exception of appendectomy).
* History of Cholecystectomy
* Any history of GI ulceration (esophageal, stomach, duodenal).
* Any history of GI symptoms requiring treatment in the last 3 months
* History of unexplained vaginal bleeding, endometrial hyperplasia with atypia or endometrial carcinoma
* Presence or history of clinically significant allergy requiring treatment, as judged by the investigator. Hayfever, is allowed unless it is active.
* ALT \>1.5x upper limit of normal (ULN).
* Bilirubin \>1.5xULN (isolated bilirubin \>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin \<35% of total).
* Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome).
* Medical history of cardiac arrhythmias or cardiac disease or a family or personal history of long QT syndrome.
* ECG, screening details where heart rate (\<40 or \>100 beats per minute \[bpm\]), PR interval (\<120 or \>220 millisecond \[msec\]), QRS duration (\<70 or \>120 msec), QT interval by Fridericia's correction formula (QTcF) interval (\>450 msec) for male subjects and heart rate of \<50 or \>100 bpm for female subjects.
* Evidence of previous myocardial infarction (does not include ST segment changes associated with re-polarization).
* Any conduction abnormality (including but not specific to left or right complete bundle branch block, atrioventricular (AV) block \[2nd degree or higher\], Wolf Parkinson- White \[WPW\] syndrome).
* Sinus Pauses \>3 seconds
* Any significant arrhythmia which, in the opinion of the Investigator OR GlaxoSmithKline (GSK)/ViiV Medical monitor, will interfere with the safety for the individual subject.
* Non-sustained or sustained ventricular tachycardia (with consecutive ventricular ectopic beats).
* Prior or concomitant therapy, where past or intended use of over-the-counter or prescription medication, including herbal medications within 7 days (or 14 days if the drug is a potential enzyme inducer), or 5 half-lives (whichever is longer) prior to dosing (paracetamol/acetaminophen \[up to 2 grams per day\], and 2.5%, hydrocortisone \[for ECG lead contact dermatitis\] is permitted any time during the study).
* Prior or concurrent clinical study experience where, participation in the study would result in loss of blood or blood products in excess of 500 mL within a 56 day period; therefore donation or loss of greater than 400 mL of blood within the previous 3 months.
* Current enrollment or past participation within the last 3 months before signing of consent in this or any other clinical study involving an investigational study treatment or any other type of medical research.
* Subjects, who have previously been enrolled in this study.
* Presence of Hepatitis B surface antigen (HBsAg) at screening or positive Hepatitis C antibody test result at screening or within 3 months prior to first dose.
* Confirmed positive pre-study drug/alcohol screen.
* Positive human immunodeficiency virus (HIV) antibody test.
* Regular use of known drugs of abuse, or history of drug or alcohol abuse in the past 5 years.
* Regular alcohol consumption within 6 months prior to the study defined as an average weekly intake of \>21 units for males or \>14 units for females. One unit is equivalent to 8 gram of alcohol: a half-pint (approximately 240 mL) of beer or 1 (25 mL) measure of spirits. One glass (125 mL) of wine is equivalent to 1.5 to 2 units, depending on type)
* Current use or history of regular use of tobacco- or nicotine-containing products within 6 months prior to screening. A confirmed carbon monoxide breath test reading of greater than 10 parts per million.
* Sensitivity to any of the study treatments, or components thereof, or drug or other allergy that, in the opinion of the investigator or medical monitor, contraindicates participation in the study.
* Subjects who do not have suitable veins for multiple venepunctures/cannulation as assessed by the investigator at screening.
* Subjects who do not have the ability to swallow size 00 capsules.
* Subjects who are study site employees, or immediate family members of a study site or sponsor employee.

Primary outcomes:
measure: Area Under the Concentration-time Curve From Time Zero (Pre-dose) Extrapolated to Infinite Time (AUC[0-infinity]) of GSK3640254 Following Single Oral Dose in Healthy Participants
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48 and 72 hours post-dose in each treatment period
measure: Area Under the Concentration-time Curve From Zero to Time of Last Sample Taken (AUC[0-t]) of GSK3640254 Following Single Oral Dose in Healthy Participants
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, and 72 hours post-dose in each treatment period
measure: Maximum Observed Concentration (Cmax) of GSK3640254 Following Single Oral Dose in Healthy Participants
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, and 72 hours post-dose in each treatment period
measure: Time to Reach Maximum Observed Concentration (Tmax) of GSK3640254 Following Single Oral Dose in Healthy Participants
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, and 72 hours post-dose in each treatment period
measure: Concentration at 24 Hours Post-dose (C24h) of GSK3640254 Following Single Oral Dose in Healthy Participants
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12 and 24 hours post-dose in each treatment period
Secondary outcomes:
measure: Number of Participants With Non-serious Adverse Events (Non-SAEs) and Serious Adverse Events (SAEs)
timeFrame: Up to 25 days
measure: Change From Baseline in Clinical Chemistry Parameters; Alanine Aminotransferase (ALT), Alkaline Phosphatase (ALP) and Aspartate Aminotransferase (AST)
timeFrame: Baseline (Day -1) and Day 3
measure: Change From Baseline in Clinical Chemistry Parameters; Bicarbonate, Calcium, Chloride, Glucose (Fasting), Potassium, Sodium and Urea
timeFrame: Baseline (Day -1) and Day 3
measure: Change From Baseline in Clinical Chemistry Parameters; Bilirubin, Creatinine and Direct Bilirubin
timeFrame: Baseline (Day -1) and Day 3
measure: Change From Baseline in Clinical Chemistry Parameter; Protein
timeFrame: Baseline (Day -1) and Day 3
measure: Number of Participants With Worst Case Hematology Results by Potential Clinical Importance (PCI) Criteria
timeFrame: Up to 22 days
measure: Number of Participants With Urinalysis Results by Dipstick Method by Visit
timeFrame: Day -1 and Day 3
measure: Number of Participants With Clinically Significant Abnormal Findings for Electrocardiogram (ECG) Parameters
timeFrame: Day -1, pre-dose, 2, 4, 6, 24 and 72 hours post-dose in each treatment period
measure: Diastolic Blood Pressure (DBP) and Systolic Blood Pressure (SBP) at Indicated Time-points
timeFrame: Day -1, pre-dose, 2, 4, 6, 24 and 72 hours post-dose in each treatment period
measure: Pulse Rate (PR) at Indicated Time-points
timeFrame: Day -1, pre-dose, 2, 4, 6, 24 and 72 hours post-dose in each treatment period
measure: Respiratory Rate (RR) at Indicated Time-points
timeFrame: Day -1, pre-dose, 2, 4, 6, 24 and 72 hours post-dose in each treatment period
measure: Temperature at Indicated Time-points
timeFrame: Day -1, pre-dose, 2, 4, 6, 24 and 72 hours post-dose in each treatment period
measure: Number of Participants With the Indicated Assessment Events of Suicidal Behavior (SB) and Suicidal Ideation (SI) Via the Columbia Suicide Severity Rating Scale (C-SSRS)
timeFrame: Day 3 in each treatment period
Other outcomes:
Locations:
city: Nottingham
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: ViiV Healthcare
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Joshi SR, Fernando D, Igwe S, McKenzie L, Krishnatry AS, Halliday F, Zhan J, Greene TJ, Xu J, Ferron-Brady G, Lataillade M, Min S. Phase I evaluation of the safety, tolerability, and pharmacokinetics of GSK3640254, a next-generation HIV-1 maturation inhibitor. Pharmacol Res Perspect. 2020 Dec;8(6):e00671. doi: 10.1002/prp2.671.