Clinical trial NCT05631704: A Study to Investigate Safety, Tolerability, and Pharmacokinetics (PK) of VH4524184 and the Potential for Changes in Cytochrome P450 3A (CYP3A) Activity
Official title: A Phase 1 Double-Blind (Sponsor-unblinded), Placebo-Controlled Randomized, Single and Multiple Ascending Dose First-Time-in-Human Study to Investigate the Safety, Tolerability, and Pharmacokinetics of VH4524184 and the Potential for Changes in Cytochrome P450 3A (CYP3A) Activity
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE1
Conditions: HIV Infections
Keywords: First-time-in-human
GSK4524184
Healthy volunteers
Multiple Ascending Dose
Single Ascending Dose
VH4524184
Lead sponsor: ViiV Healthcare
Sponsor class: INDUSTRY
First posted: 2022-11-30
Enrollment: 105
Sex: ALL
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: Participants will receive escalating doses of VH4524184 or placebo in Part 1 and Part 2 of the study. In Part 3, participants will receive VH4524184 under fasted and fed conditions.
Primary purpose: TREATMENT

Brief summary: This study is designed to investigate the safety, tolerability and PK of VH4524184 (GSK4524184) and the potential of VH4524184 to inhibit or induce CYP3A activity in healthy participants.


Eligibility criteria: Inclusion Criteria:

* Participant must be 18 to 50 years of age.
* Participants who are overtly healthy.
* Body weight \>=50.0 kilograms (kg) (110 pounds \[lbs\]) for men and \>=45.0 kg (99 lbs) for women and body mass index within the range 18.5 to 32.0 kilograms per meter square (kg/m\^2) (inclusive).
* Male or female. Male Participants: No contraceptive restrictions for male participants. Female Participants: A female participant (female sex assigned at birth) is eligible to participate if she is not pregnant, or breastfeeding and is not physically able to have a baby.

Exclusion Criteria:

* History or presence of clinical condition that could significantly alter how medicines are absorbed, broken down or eliminated from the body; be risky to the participant, or make it difficult to interpret the data from the study.
* Pre-existing clinically relevant gastro-intestinal disorders.
* Abnormal blood pressure.
* Certain blood or other cancers within the past 5 years.
* Breast cancer within the past 10 years
* Current or chronic history of liver disease or liver or bile tract abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
* QT interval corrected for heart rate according to Fridericia's formula (QTcF) \>450 milliseconds (msec).
* Medical history of cardiac arrhythmias or cardiac disease or a family and personal history of long QT syndrome.
* History of seizure
* Any known or suspected pre-existing psychiatric condition, including depression, anxiety and insomnia/sleep disturbances.
* Any positive (abnormal) response to the Columbia Suicide Severity Rating Scale (CSSRS).
* Past or intended use of over-the-counter or prescription medication 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.
* Receipt of any live vaccine(s) or vaccines against Coronavirus disease 2019 (Covid-19) within 28 days prior to screening or plans to receive such vaccines during the study.
* Exposure to more than 4 new investigational products (including long-acting investigational products) within 12 months prior to the first dosing day.
* Current enrollment or past participation in another investigational study in which an investigational intervention (e.g., drug, human blood product, monoclonal antibody, vaccine, invasive device) was administered 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 (OR screening) any other clinical study.
* Participation in the study would result in loss of blood or blood products in excess of 500 milliliters (mL) over a 56-day period.
* Current enrollment or past participation in this clinical study.
* Estimated Glomerular Filtration Rate (eGFR) \<90 milliliters per minute (mL/min) (calculated using Chronic Kidney Disease Epidemiology Collaboration equation) or serum creatinine \>1.1 times Upper limit of normal (ULN).
* Hemoglobin \<12.5 grams per deciliter (g/dL) for men and \<11 g/dL for women
* ALT or AST \>1.5 times ULN
* Total bilirubin \>1.5 times ULN (isolated bilirubin \>1.5 times ULN is acceptable if bilirubin is fractionated and direct bilirubin \<35 percent \[%\]).
* Any significant arrhythmia or Electrocardiogram (ECG) finding
* Exclusion criteria for Screening ECG (a single repeat is allowed for eligibility determination): Heart rate:\<45 or \>100 beats per minute (bpm) (Males), \<50 or \>100 bpm (Females); PR interval: \<120 or \>220 msec; QRS duration: \<70 or \>120 msec and QTcF interval: \>450 msec.
* Presence of hepatitis B surface antigen (HBsAg) at screening.
* Positive Hepatitis C antibody test result at screening
* Positive pre-study drug/alcohol screen.
* Positive human immunodeficiency virus (HIV) antibody test.
* Regular alcohol consumption within 6 months prior to the study
* Regular use of known drugs of abuse
* Urinary cotinine levels indicative of smoking or history or regular use of tobacco- or nicotine-containing products within 6 months prior to screening and at admission.
* Sensitivity to the study drug, or components thereof, midazolam (For Part 2, midazolam probe cohort), excipients contained therein, benzodiazepines, or other drug or other allergy that, in the opinion of the investigator or Sponsor Medical Monitor, contraindicates participation in the study.

Primary outcomes:
measure: Part 1: Number of participants with serious adverse events (SAE) and non-serious adverse events (non-SAE)
timeFrame: Up to 4 weeks
measure: Part 2: Number of participants with SAE and non-SAE
timeFrame: Up to 6.5 weeks
measure: Part 3: Number of participants with SAE and non-SAE
timeFrame: Up to 6.5 weeks
measure: Part 1: Number of participants with adverse events based on severity
timeFrame: Up to 4 weeks
measure: Part 2: Number of participants with adverse events by severity
timeFrame: Up to 6.5 weeks
measure: Part 3: Number of participants with adverse events based on severity
timeFrame: Up to 6.5 weeks
measure: Part 1: Percentage of participants who discontinue treatment due to adverse events (AE)
timeFrame: Up to 4 weeks
measure: Part 2: Percentage of participants who discontinue treatment due to AE
timeFrame: Up to 6.5 weeks
measure: Part 3: Percentage of participants who discontinue treatment due to AE
timeFrame: Up to 6.5 weeks
measure: Part 1: Change from Baseline in Aspartate aminotransferase (AST), Alanine aminotransferase (ALT) and Alkaline phosphatase (ALP) (International units per liter)
timeFrame: Baseline (Day 1) and up to 4 weeks
measure: Part 2: Change from Baseline in AST, ALT and ALP (International units per liter)
timeFrame: Baseline (Day 1) and up to 6.5 weeks
measure: Part 3: Change from Baseline in AST, ALT and ALP (International units per liter)
timeFrame: Baseline (Day 1) and up to 6.5 weeks
measure: Part 1: Change from Baseline in Total bilirubin and Direct bilirubin (Micromoles per liter)
timeFrame: Baseline (Day 1) and up to 4 weeks
measure: Part 2: Change from Baseline in Total bilirubin and Direct bilirubin (Micromoles per liter)
timeFrame: Baseline (Day 1) and up to 6.5 weeks
measure: Part 3: Change from Baseline in Total bilirubin and Direct bilirubin (Micromoles per liter)
timeFrame: Baseline (Day 1) and up to 6.5 weeks
measure: Part 1: Change from Baseline in Prothrombin time and Partial Thromboplastin Time (Seconds)
timeFrame: Baseline (Day 1) and up to 4 weeks
measure: Part 2: Change from Baseline in Prothrombin time and Partial Thromboplastin Time (Seconds)
timeFrame: Baseline (Day 1) and up to 6.5 weeks
measure: Part 3: Change from Baseline in Prothrombin time and Partial Thromboplastin Time (Seconds)
timeFrame: Baseline (Day 1) and up to 6.5 weeks
measure: Part 1: Change from Baseline in International normalized ratio (INR) (Ratio)
timeFrame: Baseline (Day 1) and up to 4 weeks
measure: Part 2: Change from Baseline in INR (Ratio)
timeFrame: Baseline (Day 1) and up to 6.5 weeks
measure: Part 3: Change from Baseline in INR (Ratio)
timeFrame: Baseline (Day 1) and up to 6.5 weeks
measure: Part 1: Number of participants with maximum toxicity grade increase from Baseline in liver panel laboratory parameters; AST, ALT, ALP, Total bilirubin, Direct bilirubin, Prothrombin time, Partial Thromboplastin Time and INR
timeFrame: Baseline (Day 1) and up to 4 weeks
measure: Part 2: Number of participants with maximum toxicity grade increase from Baseline in liver panel laboratory parameters; AST, ALT, ALP, Total bilirubin, Direct bilirubin, Prothrombin time, Partial Thromboplastin Time and INR
timeFrame: Baseline (Day 1) and up to 6.5 weeks
measure: Part 3: Number of participant with maximum toxicity grade increase from Baseline in liver panel laboratory parameters; AST, ALT, ALP, Total bilirubin, Direct bilirubin, Prothrombin time, Partial Thromboplastin Time and INR
timeFrame: Baseline (Day 1) and up to 6.5 weeks
measure: Part 1: Area under the plasma-concentration time curve from zero (pre-dose) extrapolated to infinite time (AUC[0-infinity]) following dosing of VH4524184
timeFrame: Up to 4 weeks
measure: Part 2: Area under the plasma concentration-time curve from zero (pre-dose) to the end of the dosing interval at steady state (AUC[0-tau]) following dosing of VH4524184
timeFrame: Up to 6.5 weeks
measure: Part 1: Maximum observed plasma drug concentration (Cmax) following dosing of VH4524184
timeFrame: Up to 4 weeks
measure: Part 2: Cmax following dosing of VH4524184
timeFrame: Up to 6.5 weeks
measure: Part 1: Time to maximum observed plasma drug concentration (tmax) following dosing of VH4524184
timeFrame: Up to 4 weeks
measure: Part 2: Tmax following dosing of VH4524184
timeFrame: Up to 6.5 weeks
measure: Part 1: Apparent terminal half-life (t1/2) following dosing of VH4524184
timeFrame: Up to 4 weeks
measure: Part 2: T1/2 following dosing of VH4524184
timeFrame: Up to 6.5 weeks
Secondary outcomes:
measure: Part 1: Number of participants with treatment emergent Grade 3 or Grade 4 laboratory abnormalities
timeFrame: Up to 4 weeks
measure: Part 2: Number of participants with treatment emergent Grade 3 or Grade 4 laboratory abnormalities
timeFrame: Up to 6.5 weeks
measure: Part 3: Number of participants with treatment emergent Grade 3 or Grade 4 laboratory abnormalities
timeFrame: Up to 6.5 weeks
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: