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Phase 2 N=14 Randomized Double-blind Treatment

A Proof of Concept Study of GSK3640254 in Human Immunodeficiency Virus-1 (HIV-1) Infected Treatment-naive Adults

HIV Infections

Enrolled (actual)
14
Serious AEs
5.9%
Results posted
Feb 2021
Primary outcome: Primary: Part 1: Maximum Change From Baseline in Plasma Human Immunodeficiency Virus-1 (HIV-1) Ribonucleic Acid (RNA) at Day 11 — -8605.8; -100719.8; -3406.5 Copies per milliliter

Study Design & Population

Study type
Interventional
Phase
Phase 2
Interventions
GSK3640254 (Drug); Placebo matching GSK3640254 Mesylate salt (Drug)
Age
Adult, Older Adult · 18+ yrs
Sex
All
Sponsor
ViiV Healthcare
Primary completion
Feb 2020

Outcome Measures

OutcomeResultp-value
PRIMARY
Part 1: Maximum Change From Baseline in Plasma Human Immunodeficiency Virus-1 (HIV-1) Ribonucleic Acid (RNA) at Day 11
-8605.8; -100719.8; -3406.5
PRIMARY
Part 2: Maximum Change From Baseline in Plasma HIV-1 RNA at Day 8
-48655.0; -37904.3; -64904.2; -123478.5
SECONDARY
Part 1: Number of Participants With Non-Serious Adverse Events (Non-SAEs) and Serious Adverse Events (SAEs)
3; 5; 0; 1; 0; 0
SECONDARY
Part 2: Number of Participants With Non-SAEs and SAEs
5; 4; 4; 0; 0; 0
SECONDARY
Part 1: Change From Baseline in Hematology Parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Leukocytes, Platelet Count
0.005; -0.017; 0.015; -0.023; 0.058; -0.025
SECONDARY
Part 1: Change From Baseline in Hematology Parameter: Hemoglobin
-4.2; -1.8; -1.0
SECONDARY
Part 1: Change From Baseline in Hematology Parameter: Hematocrit
-0.0117; -0.0073; -0.0010
SECONDARY
Part 1: Change From Baseline in Hematology Parameter: Erythrocytes
-0.10; -0.07; 0.00
SECONDARY
Part 1: Change From Baseline in Hematology Parameter: Erythrocytes Mean Corpuscular Volume
0.0; -0.3; 0.0
SECONDARY
Part 1: Change From Baseline in Hematology Parameter: Erythrocytes Mean Corpuscular Hemoglobin
-0.08; 0.03; -0.15
SECONDARY
Part 1: Change From Baseline in Hematology Parameter: Reticulocytes/Erythrocyte
0.0042; 0.0012; 0.0020
SECONDARY
Part 2: Change From Baseline in Hematology Parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Leukocytes, Platelet Count
0.010; 0.020; 0.022; -0.005; -0.066; -0.047
SECONDARY
Part 2: Change From Baseline in Hematology Parameter: Hemoglobin
-8.0; -4.7; -1.7; -8.0
SECONDARY
Part 2: Change From Baseline in Hematology Parameter: Hematocrit
-0.0230; -0.0123; -0.0058; -0.0315
SECONDARY
Part 2: Change From Baseline in Hematology Parameter: Erythrocytes
-0.24; -0.17; -0.08; -0.30
SECONDARY
Part 2: Change From Baseline in Hematology Parameter: Erythrocytes Mean Corpuscular Volume
-0.2; 0.2; 0.2; -2.0
SECONDARY
Part 2: Change From Baseline in Hematology Parameter: Erythrocytes Mean Corpuscular Hemoglobin
-0.28; -0.05; -0.02; -0.05
SECONDARY
Part 2: Change From Baseline in Hematology Parameter: Reticulocytes/Erythro
0.0030; 0.0017; 0.0007; 0.0020
SECONDARY
Part 1: Change From Baseline in Chemistry Parameters: Glucose, Cholesterol, Triglycerides, Calcium, Chloride, Phosphate, Potassium, Magnesium, Sodium, Urea, High Density Lipoprotein (HDL) Cholesterol, Low Density Lipoprotein (LDL) Cholesterol
-0.20; 0.28; 0.00; -0.007; -0.027; 0.020
SECONDARY
Part 1: Change From Baseline in Chemistry Parameters: Alanine Aminotransferase (ALT), Alkaline Phosphatase (ALP), Aspartate Aminotransferase (AST)
2.7; -1.7; 9.5; 10.5; -3.5; -4.0
SECONDARY
Part 1: Change From Baseline in Chemistry Parameters: Creatinine, Bilirubin
1.77; -1.33; 0.00; -0.3; -2.0; 3.0
SECONDARY
Part 1: Change From Baseline in Chemistry Parameters: Protein
-1.3; -1.0; 1.0
SECONDARY
Part 1: Change From Baseline in Chemistry Parameters: Amylase, Lipase
0.0; -2.0
SECONDARY
Part 2: Change From Baseline in Chemistry Parameters: Glucose, Cholesterol, Triglycerides, Calcium, Chloride, Phosphate, Potassium, Magnesium, Sodium, Urea, HDL Cholesterol, LDL Cholesterol
-0.05; 0.18; -0.03; 0.50; -0.057; -0.027
SECONDARY
Part 2: Change From Baseline in Chemistry Parameters: ALT, ALP, AST
-3.8; -1.2; -6.2; -1.0; -3.2; -0.7
SECONDARY
Part 2: Change From Baseline in Chemistry Parameters: Creatinine, Bilirubin
1.35; -3.38; -0.17; -0.90; -0.3; 1.3
SECONDARY
Part 2: Change From Baseline in Chemistry Parameters: Protein
-2.2; -0.8; 1.5; -2.0
SECONDARY
Part 2: Change From Baseline in Chemistry Parameters: Amylase, Lipase
-2.3; 0.8; 6.7; -10.0; -1.0; -2.2
SECONDARY
Part 1: Change From Baseline in Urinalysis Parameter: Specific Gravity
0.0002; 0.0008; 0.0000
SECONDARY
Part 1: Change From Baseline in Urinalysis Parameter: Urobilinogen
4.50; 0.00; 0.00
SECONDARY
Part 1: Change From Baseline in Urinalysis Parameter: Potential of Hydrogen (pH)
0.17; -0.33; -0.50
SECONDARY
Part 2: Change From Baseline in Urinalysis Parameter: Specific Gravity
0.0010; -0.0022; 0.0018; -0.0110
SECONDARY
Part 2: Change From Baseline in Urinalysis Parameter: Urobilinogen
0.00; 4.50; 0.00; 0.00
SECONDARY
Part 2: Change From Baseline in Urinalysis Parameter: pH
0.17; -0.17; 0.08; 0.25
SECONDARY
Part 1: Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)
-2.5; 0.5; -1.5; -0.3; 0.8; 0.5
SECONDARY
Part 1: Change From Baseline in Respiratory Rate
-1.0; 0.2; -1.0
SECONDARY
Part 1: Change From Baseline in Pulse Rate
-5.2; 5.5; 6.0
SECONDARY
Part 2: Change From Baseline in SBP and DBP
1.0; -2.2; 7.3; 1.0; -1.8; -1.0
SECONDARY
Part 2: Change From Baseline in Respiratory Rate
-0.2; 0.2; -1.0; 0.5
SECONDARY
Part 2: Change From Baseline in Pulse Rate
4.2; 2.0; 2.8; 10.5
SECONDARY
Part 1: Change From Baseline in Electrocardiogram (ECG) Parameters: PR Interval, QRS Duration, QT Interval, Corrected QT Interval Using Bazett's Formula (QTcB), Corrected QT Interval Using Fridericia's Formula (QTcF)
-0.4; -7.6; -2.5; 1.4; -6.3; -11.5
SECONDARY
Part 2: Change From Baseline in ECG Parameters: PR Interval, QRS Duration, QT Interval, QTcB, QTcF
9.7; -1.1; -7.3; -7.3; 6.1; -2.4
SECONDARY
Part 1: Absolute Values for Hematology Parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Leukocytes, Platelet Count
0.052; 0.056; 0.030; 0.057; 0.037; 0.045
SECONDARY
Part 1: Absolute Values for Hematology Parameter: Hemoglobin
144.2; 135.4; 148.0; 140.0; 138.7; 147.0
SECONDARY
Part 1: Absolute Values for Hematology Parameter: Hematocrit
0.4338; 0.4112; 0.4395; 0.4222; 0.4158; 0.4385
SECONDARY
Part 1: Absolute Values for Hematology Parameter: Erythrocytes
4.90; 4.58; 4.90; 4.80; 4.63; 4.90
SECONDARY
Part 1: Absolute Values for Hematology Parameter: Erythrocytes Mean Corpuscular Volume
88.5; 90.2; 90.0; 88.5; 90.0; 90.0
SECONDARY
Part 1: Absolute Values for Hematology Parameter: Erythrocytes Mean Corpuscular Hemoglobin
29.38; 29.64; 30.25; 29.30; 29.97; 30.10
SECONDARY
Part 1: Absolute Values for Hematology Parameter: Reticulocytes/Erythro
0.0137; 0.0078; 0.0110; 0.0178; 0.0088; 0.0130
SECONDARY
Part 2: Absolute Values for Hematology Parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Leukocytes, Platelet Count
0.042; 0.042; 0.030; 0.040; 0.050; 0.062
SECONDARY
Part 2: Absolute Values for Hematology Parameter: Hemoglobin
136.3; 149.2; 141.2; 147.0; 129.4; 144.5
SECONDARY
Part 2: Absolute Values for Hematology Parameter: Hematocrit
0.4037; 0.4505; 0.4222; 0.4330; 0.3826; 0.4382
SECONDARY
Part 2: Absolute Values for Hematology Parameter: Erythrocytes
4.53; 5.17; 4.74; 4.80; 4.26; 5.00
SECONDARY
Part 2: Absolute Values for Hematology Parameter: Erythrocytes Mean Corpuscular Volume
88.8; 87.8; 89.2; 91.0; 89.6; 88.0
SECONDARY
Part 2: Absolute Values for Hematology Parameter: Erythrocytes Mean Corpuscular Hemoglobin
30.07; 29.15; 29.80; 30.95; 30.22; 29.10
SECONDARY
Part 2: Absolute Values for Hematology Parameter: Reticulocytes/Erythro
0.0102; 0.0082; 0.0108; 0.0070; 0.0124; 0.0098
SECONDARY
Part 1: Absolute Values for Chemistry Parameters: Glucose, Cholesterol, Triglycerides, Calcium, Chloride, Phosphate, Potassium, Magnesium, Sodium, Urea, HDL Cholesterol, LDL Cholesterol
5.28; 4.88; 5.40; 5.08; 5.17; 5.40
SECONDARY
Part 1: Absolute Values for Chemistry Parameters: ALT, ALP, AST
31.3; 19.7; 20.0; 34.0; 18.0; 29.5
SECONDARY
Part 1: Absolute Values for Chemistry Parameters: Creatinine, Bilirubin
82.05; 81.35; 88.40; 83.82; 80.02; 88.40
SECONDARY
Part 1: Absolute Values for Chemistry Parameters: Protein
72.2; 70.3; 69.0; 70.8; 69.3; 70.0
SECONDARY
Part 1: Absolute Values for Chemistry Parameters: Amylase, Lipase
57.0; 57.0; 28.5; 26.5
SECONDARY
Part 2: Absolute Values for Chemistry Parameters: Glucose, Cholesterol, Triglycerides, Calcium, Chloride, Phosphate, Potassium, Magnesium, Sodium, Urea, HDL Cholesterol, LDL Cholesterol
4.68; 4.72; 4.80; 4.90; 4.63; 4.90
SECONDARY
Part 2: Absolute Values for Chemistry Parameters: ALT, ALP, AST
18.3; 17.8; 33.2; 34.5; 14.5; 16.7
SECONDARY
Part 2: Absolute Values for Chemistry Parameters: Creatinine, Bilirubin
71.30; 73.67; 73.52; 86.65; 72.65; 70.28
SECONDARY
Part 2: Absolute Values for Chemistry Parameters: Protein
78.8; 73.3; 76.7; 73.5; 76.7; 72.5
SECONDARY
Part 2: Absolute Values for Chemistry Parameters: Amylase, Lipase
47.2; 51.0; 55.2; 56.0; 44.8; 51.8
SECONDARY
Part 1: Absolute Values for Urinalysis Parameter: Specific Gravity
1.0238; 1.0233; 1.0240; 1.0240; 1.0242; 1.0240
SECONDARY
Part 1: Absolute Values for Urinalysis Parameter: Urobilinogen
3.40; 3.40; 3.40; 7.90; 3.40; 3.40
SECONDARY
Part 1: Absolute Values for Urinalysis Parameter: pH
5.67; 5.75; 5.75; 5.83; 5.42; 5.25
SECONDARY
Part 2: Absolute Values for Urinalysis Parameter: Specific Gravity
1.0223; 1.0272; 1.0255; 1.0375; 1.0233; 1.0250
SECONDARY
Part 2: Absolute Values for Urinalysis Parameter: Urobilinogen
3.40; 3.40; 3.40; 3.40; 3.40; 7.90
SECONDARY
Part 2: Absolute Values for Urinalysis Parameter: pH
5.33; 5.83; 5.25; 5.50; 5.50; 5.67
SECONDARY
Part 1: Absolute Values for SBP and DBP
120.2; 121.8; 106.0; 117.7; 122.3; 104.5
SECONDARY
Part 1: Absolute Values for Respiratory Rate
16.0; 16.2; 15.0; 15.0; 16.3; 14.0
SECONDARY
Part 1: Absolute Values for Pulse Rate
81.8; 65.8; 60.0; 76.7; 71.3; 66.0
SECONDARY
Part 2: Absolute Values for SBP and DBP
117.0; 116.5; 112.2; 105.5; 118.0; 114.3
SECONDARY
Part 2: Absolute Values for Respiratory Rate
17.3; 17.2; 17.2; 16.0; 17.2; 17.3
SECONDARY
Part 2: Absolute Values for Pulse Rate
68.3; 74.5; 77.0; 64.5; 72.5; 76.5
SECONDARY
Part 1: Absolute Values for ECG Parameters: PR, QRS, QT, QTcB and QTcF Intervals
136.6; 168.4; 176.5; 136.2; 160.8; 174.0
SECONDARY
Part 2: Absolute Values for ECG Parameters: PR, QRS, QT, QTcB and QTcF Intervals
156.8; 162.9; 162.8; 144.3; 166.5; 161.8
SECONDARY
Part 1: Area Under the Plasma Concentration Time Curve From Zero to 24 (AUC[0-24]) Following Administration of GSK3640254 on Day 1
0.6946; 12.3929
SECONDARY
Part 1: Maximum Observed Concentration (Cmax) Following Administration of GSK3640254 on Day 1
0.0591; 0.9381
SECONDARY
Part 1: Time to Maximum Observed Concentration (Tmax) Following Administration of GSK3640254 on Day 1
2.9250; 5.5250
SECONDARY
Part 1: Concentration at 24 Hours Post-dose (C24) Following Administration of GSK3640254 on Day 1
0.0180; 0.3553
SECONDARY
Part 1: Absorption Lag Time (Tlag) Following Administration of GSK3640254 on Day 1
0.500; 0.000
SECONDARY
Part 2: AUC(0-24) Following Administration of GSK3640254 on Day 1
3.2527; 6.1228; 14.0335
SECONDARY
Part 2: Cmax Following Administration of GSK3640254 on Day 1
0.2316; 0.4329; 0.9178
SECONDARY
Part 2: Tmax Following Administration of GSK3640254 on Day 1
4.4167; 4.0750; 5.5083
SECONDARY
Part 2: C24 Following Administration of GSK3640254 on Day 1
0.0951; 0.1856; 0.4207
SECONDARY
Part 2: Tlag Following Administration of GSK3640254 on Day 1
0.483; 0.000; 0.000
SECONDARY
Part 1: Area Under the Plasma Drug Concentration-time Curve From Pre-dose to the End of the Dosing Interval at Steady State (AUC[0-tau]) Following Repeat Dose Administration of GSK3640254 on Days 8 to 10
0.9082; 27.9363
SECONDARY
Part 1: Cmax Following Repeat Dose Administration of GSK3640254 on Days 8 to 10
0.0549; 1.8559
SECONDARY
Part 1: Tmax Following Repeat Dose Administration of GSK3640254 on Days 8 to 10
4.0167; 5.4833
SECONDARY
Part 1: Pre-dose Concentration (C0) Following Repeat Dose Administration of GSK3640254 on Days 8 to 10
0.0268; 0.6928
SECONDARY
Part 1: Concentration at End of Dosing Interval (Ctau) Following Repeat Dose Administration of GSK3640254 on Days 8 to 10
0.0267; 0.7033
SECONDARY
Part 1: Apparent Terminal Phase Half-life (t1/2) Following Repeat Dose Administration of GSK3640254 on Days 8 to 10
NA; NA
SECONDARY
Part 1: Apparent Oral Clearance (CL/F) Following Repeat Dose Administration of GSK3640254 on Days 8 to 10
11010.5393; 7159.1443
SECONDARY
Part 2: AUC(0-tau) Following Repeat Dose Administration of GSK3640254 on Day 7
7.4626; 11.8256; 29.2952
SECONDARY
Part 2: Cmax Following Repeat Dose Administration of GSK3640254 on Day 7
0.4692; 0.7470; 1.8574
SECONDARY
Part 2: Tmax Following Repeat Dose Administration of GSK3640254 on Day 7
4.0583; 4.5750; 4.0750
SECONDARY
Part 2: C0 Following Repeat Dose Administration of GSK3640254 on Day 7
0.2155; 0.3575; 0.7520
SECONDARY
Part 2: Ctau Following Repeat Dose Administration of GSK3640254 on Day 7
0.2187; 0.3599; 0.7979
SECONDARY
Part 2: t1/2 Following Repeat Dose Administration of GSK3640254 on Day 7
NA; NA; NA
SECONDARY
Part 2: CL/F Following Repeat Dose Administration of GSK3640254 on Day 7
5360.0526; 6764.9862; 4778.9430
SECONDARY
Part 1 and Part 2: Change From Baseline in Plasma HIV-1 RNA Relative to Day 8 AUC(0-tau)
12071.4; -113331.4; -48655.0; -37904.3; -64861.5
SECONDARY
Part 1 and Part 2: Change From Baseline in Plasma HIV-1 RNA Relative to Day 8 Cmax
12071.4; -113331.4; -48655.0; -37904.3; -64861.5
SECONDARY
Part 1 and Part 2: Change From Baseline in Plasma HIV-1 RNA Relative to Day 8 Ctau
12071.4; -113331.4; -48655.0; -37904.3; -64861.5
SECONDARY
Part 1: Accumulation Ratio Following Repeat Dose Administration of GSK3640254
1.5352; 2.2542; 0.9287; 1.9785; 1.4790; 1.9796
SECONDARY
Part 2: Accumulation Ratio Following Repeat Dose Administration of GSK3640254
2.2943; 1.9314; 2.0875; 2.0258; 1.7258; 2.0236
SECONDARY
Part 1 and Part 2: Dose Proportionality of GSK3640254 Administered on Day 1 Based on AUC(0-24)
1.018
SECONDARY
Part 1 and Part 2: Dose Proportionality of GSK3640254 Administered on Day 1 Based on Cmax
0.964
SECONDARY
Part 1 and Part 2: Dose Proportionality of GSK3640254 Administered on Day 1 Based on C24
1.061
SECONDARY
Part 1 and Part 2: Dose Proportionality of GSK3640254 Following Repeat Dose Administration Based on AUC(0-tau)
1.179
SECONDARY
Part 1 and Part 2: Dose Proportionality of GSK3640254 Following Repeat Dose Administration Based on Cmax
1.204
SECONDARY
Part 1 and Part 2: Dose Proportionality of GSK3640254 Following Repeat Dose Administration Based on Ctau
1.137

Summary

Infection with HIV-1 continues to be a serious health threat throughout the world. Chronic exposure to combination anti-retroviral therapy identified anti-retroviral associated long-term toxicities. Hence, there is a need to prevent these co-morbidities. GSK3640254 is a next-generation HIV-1 Maturation Inhibitor (MI) which may be effective for HIV-1 infection. This study will evaluate the antiviral effect, safety, tolerability and pharmacokinetics/ pharmacodynamics of GSK3640254 in HIV-1 infected treatment-naive adults. This study will consists of two parts; Part 1 and Part 2. Part 1 will evaluate two active doses of GSK3640254, 200 milligrams (mg) (Cohort 1) and 10 mg (Cohort 2) along with placebo to match GSK3640254 Mesylate salt. Part 2 will evaluate three active doses of GSK3640254. Dose level 1 of GSK3640254 that can provide at least 30 percent of the maximum effect (Cohort 1), dose level 2 of GSK3640254 that can provide at least 75 percent of the maximum effect (Cohort 2) and dose level 3 of GSK3640254 that can provide at least 90 percent of the maximum effect (Cohort 3). These doses are anticipated to be 5 mg, 40 mg and 100 mg respectively, but could be modified based on data obtained in Part 1. Subjects will also receive placebo to match GSK3640254 Mesylate salt in Part 2 of the study. All doses will be administered after a moderate fat meal. This study will consist of Screening period (up to 14 days), Treatment period (Day 1- Day 10), post-dose Follow-up (Day 11- Day 17) and final Follow-up (Day 18-24). A total of approximately 34 subjects will be enrolled, of which, 14 subjects will be randomized in Part 1 and 20 in Part 2 of the study. Six subjects will be enrolled in each of the active dose cohorts and 2 subjects will be enrolled in each of the placebo cohorts.

Eligibility Criteria

Inclusion Criteria

  • Subject must be 18 to 65 years of age inclusive, at the time of signing the informed consent.
  • Subjects who are healthy (other than HIV infection) as determined by the Investigator or medically qualified designee based on a medical evaluation including medical history, laboratory tests, and cardiac monitoring.
  • Screening Cluster of designation 4 positive (CD4+) T-cell count >=350 cells per millimeter cube (cells/mm^3).
  • Documented HIV infection and Screening plasma HIV-1 RNA >=5000 copies/milliliter (mL). A single repeat of this test is allowed within a single Screening period to determine eligibility.
  • Treatment-naive: No anti-retrovirals (in combination or monotherapy) received after the diagnosis of HIV-1 infection.
  • Body weight >=50.0 kilograms (kg) (110 Pounds) for men and >=45.0 kg (99 pounds) for women and body mass index (BMI) within the range 18.5-31.0 kg/meter square (kg/m^2) (inclusive).
  • A female subject is eligible to participate if she is not pregnant, not breastfeeding, and not a woman of childbearing potential (WOCBP).
  • Capable of giving signed informed consent.
  • For subjects enrolled in France: a subject will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category.

Exclusion Criteria

  • Presence of Hepatitis B surface antigen (HBsAg) at screening or within 3 months prior to starting study treatment.
  • Positive Hepatitis C antibody test result at screening or within 3 months prior to starting study treatment and positive on reflex to Hepatitis C RNA.
  • ALT >2 times upper limit of normal (ULN). A single repeat of ALT is allowed within a single Screening period to determine eligibility.
  • Bilirubin >1.5 times ULN (isolated bilirubin >1.5 times ULN is acceptable if bilirubin is fractionated and direct bilirubin 6 months) outpatient treatment. Subjects with other conditions such as adjustment disorder or dysthymia that have required shorter term medical therapy ( 100 beats per minute (bpm) for males and 100 bpm for females; PR Interval of 200 milliseconds (msec) for both males and females; QRS duration of 110 msec for both males and females; QT interval corrected (QTc) for heart rate according to Fridericia's formula (QTcF) of >450 msec for males and >470 msec for females. A heart rate from 100 to 110 bpm can be rechecked by electrocardiogram or vitals within 30 minutes to verify eligibility. QTcF is either machine read or manually over-read.
  • Any significant arrhythmia or electrocardiogram finding (e.g., prior myocardial infarction, sinoatrial pauses, bundle branch block, or conduction abnormality) which, in the opinion of the Investigator OR ViiV Medical Monitor, will interfere with the safety for the individual subject.
View full record on ClinicalTrials.gov →

Data sourced from ClinicalTrials.gov (NCT03784079). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication.

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