Safety and Efficacy Study of GSK2838232 in Human Immunodeficiency Virus (HIV)-1 Infected Adults

NCT03045861 | Completed Phase 2 Results FDA Drug

• 1 other identifier: 200911
• Study Type: interventional
• Target: 33
• Locations: 2 countries
• Sites: 14

Brief Summary

GSK2838232 is a novel HIV-1 maturation inhibitor (MI) that is being developed for the treatment of HIV-1 infection in combination with other antiretroviral therapy (ART). This study will be a 10-day monotherapy, open-label, adaptive, dose ranging, repeat-dose study. This study will be conducted in two Parts (Part A and Part B) consisting single daily doses of GSK2838232 and Cobicistat from Day 1 to Day 10. This proof of concept open-label study will be aimed to characterize the acute antiviral activity, pharmacokinetics (PK), the relationship between PK and antiviral activity, and safety of GSK2838232/cobi administered across a range of doses over 10 days in HIV-1 infected patients. A cohort of 10 subjects will be studied in Part I followed by interim (go/no-go) analysis of Part A data. On completion of an interim analysis of part A data, further cohorts of 8 subjects will then be studied in Part B in a parallel design in two or more cohorts (depending upon the data obtained in Part A). Approximately 34 HIV-1 infected treatment-naive subjects will be enrolled during the study. Subjects in both parts will have a screening visit within 30 days prior to first dose and a follow-up visit 7-14 days after the last dose. Maximum duration of study participation will be approximately 6 Weeks.

Conditions

Infection, Human Immunodeficiency Virus; HIV Infections

Outcome Measures

Primary Outcomes (21)

• Maximum Decline From Baseline in Plasma HIV-1 Ribonucleic Acid (RNA)

  Plasma samples were collected for quantitative analysis of plasma HIV-1 RNA. An HIV-1 RNA polymerase chain reaction (PCR) assay with a lower limit of detection (LLOD) of 50 copies/milliliter (ultrasensitive assay) was used for post-baseline assessments. Baseline value was the value at latest pre-dose assessment. The maximum decline was determined using change from Baseline in plasma HIV-RNA values at each time point. The analysis was performed on Intent To Treat (ITT) Population which comprised of all participants who met study criteria and were enrolled into the study with documented evidence of having received at least 1 dose of treatment and at least one post-Baseline HIV-1 RNA measurement.

  Baseline (Day 1) to Day 21

• Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)

  An AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is defined as any untoward medical occurrence that, at any dose: results in death; is life threatening; requires hospitalization or prolongation of existing hospitalization; results in disability/incapacity; is a congenital anomaly/birth defect; other important medical events; is associated with liver injury and impaired liver function. Safety Population comprised of all participants who received at least one dose of study treatment.

  Up to Day 22

• Number of Participants With Clinical Chemistry Abnormalities of Potential Clinical Importance

  Blood samples were collected for the assessment of clinical chemistry parameters. The clinical concern range for the parameters were: carbon dioxide/bicarbonate (low: \<18 millimoles per liter \[mmol/L\] and high: \>32 mmol/L); urea (high: \>9 mmol/L); creatinine (high: change from Baseline \>44.2 micromoles per liter \[µmol/L\]), glucose (low: \<3 and high: \>9 mmol/L); potassium (low: \<3 and high: \>5.5 mmol/L); troponin I (high: \>=0.01 micrograms per liter \[µg/L\]) and sodium (low: \<130 mmol/L and high: \>150 mmol/L). Data for any visit post-Baseline is reported.

  Up to Day 22

• Number of Participants With Hematology Parameter Abnormalities of Potential Clinical Importance

  Blood samples were collected for the assessment of hematology parameters. The clinical concern range for the parameters were: hematocrit (high: \>0.54 proportion of red blood cells in blood); hemoglobin (high: \>180 grams per liter \[g/L\]), lymphocytes (low: \<0.8x10\^9 cells/L); neutrophil count (low: \<1.5x10\^9 cells/L); platelet count (low: \<100x10\^9 cells/L and high: \>550x10\^9 cells/L); white blood cells (low: \<3x10\^9 cells/L and high: \>20x10\^9cells/L). Data for any visit post-Baseline is reported.

  Up to Day 22

• Number of Participants With Liver Function Laboratory Abnormalities of Potential Clinical Importance

  Blood samples were collected for the assessment of liver function parameters. The clinical concern range for liver function parameters were: albumin (low: \<30 g/L), total protein (low: \<15 and high: \>15 g/L), alanine aminotransferase (high: \>=2 times upper limit of normal \[ULN\]); aspartate aminotransferase (high: \>=2 times ULN); alkaline phosphatase (high: \>=2 times ULN); total bilirubin (high: \>=1.5 times ULN); direct bilirubin (high: \>0.3 times ULN).

  Up to Day 22

• Number of Participants With Abnormal Urine Parameters

  Urine samples were collected for the assessment of following urine parameters by dipstick method: pH, glucose, protein, blood and ketones. The number of participants with abnormal urine parameters is presented.

  Up to Day 22

• Number of Participants With Abnormal Electrocardiogram (ECG) Findings

  Triplicate 12-lead ECGs were obtained using an ECG machine that automatically calculated the heart rate and measured PR, QRS, QT, and corrected QT (QTc) intervals. Number of participants with abnormal ECG findings at worst-case post Baseline is presented.

  Up to Day 22

• Number of Participants With Vital Signs Data Outside Clinical Concern Range

  Vital signs were measured in a semi-supine position after 5 minutes rest and included temperature, systolic and diastolic blood pressure and pulse rate. The clinical concern range for vital signs were: systolic blood pressure (SBP) (low: \<85 and high: \>160 millimeters of mercury \[mmHg\]) and diastolic blood pressure (DBP) (low: \<45 and high: \>100 mmHg). Number of participants with vital signs data outside clinical concern range is presented.

  Day 1 (pre-dose)

• Number of Participants Who Were Administered Concomitant Medications

  Concomitant medications (prescription and non-prescription) were administered only as medically necessary during the study. Number of participants who received any concomitant medications is presented.

  Up to Day 22

• Area Under the Plasma Concentration Time Curve From Zero (Pre-dose) to 24 Hours (AUC[0 to 24]) for GSK2838232 on Day 1

  Serial plasma samples were collected at indicated time points for pharmacokinetic analysis of GSK2838232. The analysis was performed on Pharmacokinetic Population which comprised of participants who received GSK2838232 and underwent plasma pharmacokinetic sampling during the study.

  Pre dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose on Day 1

• Maximum Observed Concentration (Cmax) for GSK2838232 on Day 1

  Serial plasma samples were collected at indicated time points for pharmacokinetic analysis of GSK2838232.

  Pre dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose on Day 1

• Time to Maximum Observed Concentration (Tmax) for GSK2838232 on Day 1

  Serial plasma samples were collected at indicated time points for pharmacokinetic analysis of GSK2838232.

  Pre dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose on Day 1

• Absorption Lag Time (Tlag) for GSK2838232 on Day 1

  Serial plasma samples were collected at indicated time points for pharmacokinetic analysis of GSK2838232.

  Pre dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose on Day 1

• Concentration of GSK2838232 at 24 Hours Post-dose on Day 1

  Serial plasma samples were collected at indicated time points for pharmacokinetic analysis of GSK2838232.

  24 hours post-dose on Day 1

• Area Under the Concentration-time Curve Over the Dosing Interval (AUC [0 to Tau]) for GSK2838232 on Day 10

  Serial plasma samples were collected at indicated time points for pharmacokinetic analysis of GSK2838232.

  Pre dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose on Day 10

• Pre-dose Concentration (C0) of GSK2838232 on Day 10

  Serial plasma samples were collected at indicated time points for pharmacokinetic analysis of GSK2838232.

  Pre dose on Day 10

• Concentration at End of Dosing Interval (Ctau) for GSK2838232 on Day 10

  Serial plasma samples were collected at indicated time points for pharmacokinetic analysis of GSK2838232.

  24 hours post-dose on Day 10

• Cmax for GSK2838232 on Day 10

  Serial plasma samples were collected at indicated time points for pharmacokinetic analysis of GSK2838232.

  Pre dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose on Day 10

• Apparent Oral Clearance of GSK2838232 Following Administration on Day 10

  Serial plasma samples were collected at indicated time points for pharmacokinetic analysis of GSK2838232.

  Pre dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose on Day 10

• Terminal Elimination Half-life (T1/2) of GSK2838232 Following Administration on Day 10

  Serial plasma samples were collected at indicated time points for pharmacokinetic analysis of GSK2838232.

  Pre dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose on Day 10

• Tmax for GSK2838232 Following Administration on Day 10

  Serial plasma samples were collected at indicated time points for pharmacokinetic analysis of GSK2838232.

  Pre dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose on Day 10

Secondary Outcomes (12)

• Change From Baseline to Day 11 in log10 Plasma HIV-1 RNA Relative to Day 10 AUC (0 to Tau)

  Baseline (Day 1), Days 10 and 11

• Change From Baseline to Day 11 in log10 Plasma HIV-1 RNA Relative to Day 10 Cmax

  Baseline (Day 1), Days 10 and 11

• Change From Baseline to Day 11 in log10 Plasma HIV-1 RNA Relative to Day 10 Ctau

  Baseline (Day 1), Days 10 and 11

• Change From Baseline in Cluster of Differentiation 4+ (CD4+) Cell Count to Day 11

  Baseline (Day 1) and Day 11

• Change From Baseline to Day 11 in CD4+ Count Relative to Day 10 AUC (0 to Tau)

  Baseline (Day 1), Days 10 and 11

Study Arms (4)

Cohort 1-GSK2838232 100 mg + Cobicistat 150 mg in Part A

EXPERIMENTAL

During Part A (Cohort 1), subjects will receive a single dose of GSK2838232 100 mg and Cobicistat 150 mg once daily each morning with a light breakfast meal and 240 mL of water from Day 1 to Day 10. Subjects will be followed up to Day 22.

Drug: GSK2838232; Drug: Cobicistat

Cohort 2-GSK2838232 200 mg + Cobicistat 150 mg in Part B

EXPERIMENTAL

During Part B (Cohort 2), subjects will receive a single dose of GSK2838232 200 mg and Cobicistat 150 mg once daily each morning with a light breakfast meal and 240 mL of water from Day 1 to Day 10. Subjects will be followed up to Day 22.

Drug: GSK2838232; Drug: Cobicistat

Cohort 3-GSK2838232 50 mg + Cobicistat 150 mg in Part B

EXPERIMENTAL

During Part B (Cohort 3), subjects will receive a single dose of GSK2838232 50 mg and Cobicistat 150 mg once daily each morning with a light breakfast meal and 240 mL of water from Day 1 to Day 10. Subjects will be followed up to Day 22.

Drug: GSK2838232; Drug: Cobicistat

Cohort 4-GSK2838232 20 mg + Cobicistat 150 mg in Part B

EXPERIMENTAL

During Part B (Cohort 4), subjects will receive a single dose of GSK2838232 20 mg and Cobicistat 150 mg once daily each morning with a light breakfast meal and 240 mL of water from Day 1 to Day 10. Subjects will be followed up to Day 22.

Drug: GSK2838232; Drug: Cobicistat

Interventions

GSK2838232 DRUG

GSK2838232 capsules will be supplied as swedish orange, unmarked capsule (50 mg), and white, unmarked capsules (10 mg) in high-density polyethylene bottles.

Cohort 1-GSK2838232 100 mg + Cobicistat 150 mg in Part A; Cohort 2-GSK2838232 200 mg + Cobicistat 150 mg in Part B; Cohort 3-GSK2838232 50 mg + Cobicistat 150 mg in Part B; Cohort 4-GSK2838232 20 mg + Cobicistat 150 mg in Part B

Cobicistat DRUG

Cobicistat tablets 150 mg will be supplied as an orange, round, biconvex, film-coated tablet in bulk containers for individualized dosing.

Cohort 1-GSK2838232 100 mg + Cobicistat 150 mg in Part A; Cohort 2-GSK2838232 200 mg + Cobicistat 150 mg in Part B; Cohort 3-GSK2838232 50 mg + Cobicistat 150 mg in Part B; Cohort 4-GSK2838232 20 mg + Cobicistat 150 mg in Part B

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Between 18 and 55 years of age inclusive, at the time of signing the informed consent.
• Healthy (other than HIV infection) male or female as determined by the investigator or medically qualified designee based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring, defined as no other chronic medical conditions and taking no chronic medications.

You may not qualify if:

• A creatinine clearance \>80 mL/minute as determined by Cockcroft-Gault equation creatinine clearance CLcr (mL/minute) = (140 - age) x weight (Wt) divided by (72 x serum creatinine \[Scr\]) (times 0.85 if female) where age is in years, Wt is in kilogram (kg), and Scr is in units of mg/decilitre (dL).
• Confirmed HIV positive; CD4+ cell count \>=350 cells/millimetre (mm)\^3 and plasma HIV-1 RNA \>=5000 copies/mL at screening.
• No current and no prior ART.
• Body weight \>=50 kg (110 pound \[lbs.\]) for men and \>=45 kg (99 lbs) for women and body mass index (BMI) within the range 18.5-31.0 kg/meter\^2 (inclusive)
• A female subject of reproductive or non-reproductive potential is eligible to participate if she is not pregnant (as confirmed by a negative serum or urine human chorionic gonadotrophin (hCG) test at screening and prior to first dose), not lactating, and at least one of the following conditions applies: females of reproductive potential may only be enrolled if they are using two forms of complementary contraception, which must include one barrier method. They will be counselled on safer sex practices; there is no definitive drug-drug interaction (DDI) information with GSK2838232 and an interaction with oral contraceptives is possible, so other (barrier, inter-uterine device etc.) methods of contraception will be required; fertile females, who have an established, long-term lifestyle of sexual abstinence, or only same sex partners, require no other means of birth control. Pre-menopausal females with one of the following: documented tubal ligation; documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion; hysterectomy; documented bilateral oophorectomy; postmenopausal defined as 12 months of spontaneous amenorrhea in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) and estradiol levels consistent with menopause. Females on hormone replacement therapy (HRT) must discontinue HRT to allow confirmation of post-menopausal status prior to study enrolment.
• Male subjects with female partners of child bearing potential must comply with the following contraception requirements from the time of first dose of study medication until one week after the last dose of study medication; vasectomy with documentation of azoospermia; male condom plus partner use of one of the contraceptive options as: Contraceptive sub dermal implant including a \<1 percent rate of failure per year; intrauterine device or intrauterine system including a \<1 percent rate of failure per year; oral contraceptive, either combined or progestogen alone or injectable progestogen; contraceptive vaginal ring; percutaneous contraceptive patches. These allowed methods of contraception are only effective when used consistently, correctly and in accordance with the product label. The investigator is responsible for ensuring that subjects understand how to properly use these methods of contraception.
• Capable of giving signed informed consent.
• Alanine aminotransferase (ALT) and bilirubin (BIL) \>1.5 x upper limit of normal (ULN), isolated BIL \>1.5xULN is acceptable if BIL is fractionated and direct BIL \<35 percent.
• Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones); hepatitis B virus (HBV) and/or hepatitis C virus (HCV) positive.
• Subjects who have any other chronic medical condition, including cardiovascular (CV), respiratory, neurologic, psychiatric, renal, gastrointestinal (GI), oncologic, rheumatologic, or dermatologic.
• Medical history of cardiac arrhythmias or cardiac disease or a family or personal history of long QT syndrome.
• Unable to refrain from the use of prescription or non-prescription drugs, including vitamins, herbal and dietary supplements (including St John's Wort) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study medication, unless in the opinion of the Investigator and GSK medical monitor the medication will not interfere with the study procedures or compromise subject safety.
• History of regular alcohol consumption within 6 months of the study defined as: an average weekly intake of \>14 drinks for males or \>7 drinks for females. One drink is equivalent to 12 grams (g) of alcohol: 12 ounces (360 mL) of beer, 5 ounces (150 mL) of wine or 1.5 ounces (45 mL) of 80 proof distilled spirits.
• History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or medical monitor, contraindicates their participation.
• Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test result at screening or within 3 months prior to first dose of study treatment.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (14)

GSK Investigational Site

Birmingham, Alabama, 35226, United States

Location

GSK Investigational Site

Bakersfield, California, 93301, United States

Location

GSK Investigational Site

Los Angeles, California, 90027, United States

Location

GSK Investigational Site

Los Angeles, California, 90069, United States

Location

GSK Investigational Site

Ft. Pierce, Florida, 34982, United States

Location

GSK Investigational Site

Miami, Florida, 33133, United States

Location

GSK Investigational Site

Orlando, Florida, 32803, United States

Location

GSK Investigational Site

Springfield, Massachusetts, 01107, United States

Location

GSK Investigational Site

Berkley, Michigan, 48072, United States

Location

GSK Investigational Site

Newark, New Jersey, 07102, United States

Location

GSK Investigational Site

Dallas, Texas, 75246, United States

Location

GSK Investigational Site

Longview, Texas, 75602, United States

Location

GSK Investigational Site

Toronto, Ontario, M5G 2C4, Canada

Location

GSK Investigational Site

Montreal, Quebec, H2L 4P9, Canada

Location

Related Publications (1)

• DeJesus E, Harward S, Jewell RC, Johnson M, Dumont E, Wilches V, Halliday F, Talarico CL, Jeffrey J, Gan J, Xu J, Felizarta F, Scribner A, Ramgopal M, Benson P, Johns BA. A Phase IIa Study Evaluating Safety, Pharmacokinetics, and Antiviral Activity of GSK2838232, a Novel, Second-generation Maturation Inhibitor, in Participants With Human Immunodeficiency Virus Type 1 Infection. Clin Infect Dis. 2020 Aug 22;71(5):1255-1262. doi: 10.1093/cid/ciz938.

  PMID: 31769793 BACKGROUND

MeSH Terms

Conditions

Infections; Acquired Immunodeficiency Syndrome; HIV Infections

Interventions

GSK-2838232; Cobicistat

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Slow Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Intervention Hierarchy (Ancestors)

Carbamates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Thiazoles; Sulfur Compounds; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

GSKClinicalSupportHD@gsk.com

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 12, 2017
• First Posted: February 8, 2017
• Study Start: March 17, 2017
• Primary Completion: April 23, 2018
• Study Completion: April 23, 2018
• Last Updated: March 11, 2020
• Results First Posted: May 29, 2019

Record last verified: 2020-03

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: IPD is available via the Clinical Study Data Request site (click on the link provided below)
• Access Criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.

Locations

US (12); CA (2)