Study to Evaluate Pharmacokinetics, Safety and Tolerability of Dolutegravir and Rilpivirine (JULUCA™) 50 Milligram (mg)/25 mg Tablets in Healthy Subjects of Japanese Descent

NCT03984838 | Completed Phase 1 Results FDA Drug

• 1 other identifier: 212312
• Study Type: interventional
• Target: 16
• Locations: 1 country
• Sites: 1

Brief Summary

Dolutegravir (DTG), a human immunodeficiency virus (HIV)-1 integrase inhibitor (INI), and Rilpivirine (RPV), a non-nucleoside HIV-1 reverse transcriptase inhibitor (NNRTI), are each approved in the United States (US), European Union, and other countries for the treatment of HIV-1 infection. JULUCA is a combination of Dolutegravir and Rilpivirine indicated for the treatment of HIV-1 infection in antiretroviral (ARV) experienced adult subjects who are switching from their current antiretroviral treatment to the 2-drug combination. Although, the pharmacokinetics (PK), safety and tolerability of DTG/RPV (50 milligram \[mg\]/25mg) fixed-dose combination (FDC) tablets have been extensively studied, these parameters have not been assessed exclusively in Japanese subjects. This study will evaluate the pharmacokinetics, safety and tolerability of a single dose DTG/RPV 50 mg/25 mg FDC in a healthy adult Japanese population to support a post-approval commitment for DTG/RPV 50 mg/25 mg FDC in Japan.

Conditions

HIV Infections

Keywords

Dolutegravir, Rilpivirine, HIV infection, Fixed-dose combination, Japanese, Pharmacokinetics

Outcome Measures

Primary Outcomes (30)

• Area Under the Concentration (AUC) Time Curve From Time Zero Extrapolated to Infinite Time (AUC [0-infinity]) of DTG

  Blood samples were collected at indicated time-points for analysis of AUC (0-infinity) of DTG. PK parameters were calculated by standard non-compartmental analysis.

  Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 12, 16, 24, 48, 72, and 120 hours post-dose

• AUC (0-infinity) of RPV

  Blood samples were collected at indicated time-points for analysis of AUC (0-infinity) of RPV. PK parameters were calculated by standard non-compartmental analysis.

  Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 12, 16, 24, 48, 72, 120, 168, 216, and 264 hours post-dose

• Area Under the Concentration Time Curve From Time Zero to Last Time of Quantifiable Concentration (AUC [0-t]) of DTG

  Blood samples were collected at indicated time-points for analysis of AUC (0-t) of DTG. PK parameters were calculated by standard non-compartmental analysis.

  Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 12, 16, 24, 48, 72, and 120 hours post-dose

• AUC (0-t) of RPV

  Blood samples were collected at indicated time-points for analysis of AUC (0-t) of RPV. PK parameters were calculated by standard non-compartmental analysis.

  Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 12, 16, 24, 48, 72, 120, 168, 216, and 264 hours post-dose

• Maximum Observed Plasma Concentration (Cmax) of DTG

  Blood samples were collected at indicated time-points for analysis of Cmax of DTG. PK parameters were calculated by standard non-compartmental analysis.

  Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 12, 16, 24, 48, 72, and 120 hours post-dose

• Cmax of RPV

  Blood samples were collected at indicated time-points for analysis of Cmax of RPV. PK parameters were calculated by standard non-compartmental analysis.

  Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 12, 16, 24, 48, 72, 120, 168, 216, and 264 hours post-dose

• Absorption Lag Time (Tlag) of DTG

  Blood samples were collected at indicated time-points for analysis of tlag of DTG. PK parameters were calculated by standard non-compartmental analysis.

  Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 12, 16, 24, 48, 72, and 120 hours post-dose

• Tlag of RPV

  Blood samples were collected at indicated time-points for analysis of tlag of RPV. PK parameters were calculated by standard non-compartmental analysis.

  Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 12, 16, 24, 48, 72, 120, 168, 216, and 264 hours post-dose

• Time to Reach Maximum Observed Concentration (Tmax) of DTG

  Blood samples were collected at indicated time-points for analysis of tmax of DTG. PK parameters were calculated by standard non-compartmental analysis.

  Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 12, 16, 24, 48, 72, and 120 hours post-dose

• Tmax of RPV

  Blood samples were collected at indicated time-points for analysis of tmax of RPV. PK parameters were calculated by standard non-compartmental analysis.

  Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 12, 16, 24, 48, 72, 120, 168, 216, and 264 hours post-dose

• Time of Last Quantifiable Concentration (Tlast) of DTG

  Blood samples were collected at indicated time-points for analysis of tlast of DTG. PK parameters were calculated by standard non-compartmental analysis.

  Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 12, 16, 24, 48, 72, and 120 hours post-dose

• Tlast of RPV

  Blood samples were collected at indicated time-points for analysis of tlast of RPV. PK parameters were calculated by standard non-compartmental analysis.

  Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 12, 16, 24, 48, 72, 120, 168, 216, and 264 hours post-dose

• Elimination Half-life (t1/2) of DTG

  Blood samples were collected at indicated time-points for analysis of t1/2 of DTG. PK parameters were calculated by standard non-compartmental analysis.

  Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 12, 16, 24, 48, 72, and 120 hours post-dose

• T1/2 of RPV

  Blood samples were collected at indicated time-points for analysis of t1/2 of RPV. PK parameters were calculated by standard non-compartmental analysis.

  Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 12, 16, 24, 48, 72, 120, 168, 216, and 264 hours post-dose

• Apparent Elimination Rate Constant (Lambda z) of DTG

  Blood samples were collected at indicated time-points for analysis of lambda z of DTG. PK parameters were calculated by standard non-compartmental analysis.

  Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 12, 16, 24, 48, 72, and 120 hours post-dose

• Lambda z of RPV

  Blood samples were collected at indicated time-points for analysis of lambda z of RPV. PK parameters were calculated by standard non-compartmental analysis.

  Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 12, 16, 24, 48, 72, 120, 168, 216, and 264 hours post-dose

• Percentage of AUC(0-infinity) That Was Extrapolated (%AUCex) of DTG

  Blood samples were collected at indicated time-points for analysis of percentage AUCex of DTG. PK parameters were calculated by standard non-compartmental analysis.

  Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 12, 16, 24, 48, 72, and 120 hours post-dose

• Percentage AUCex of RPV

  Blood samples were collected at indicated time-points for analysis of percentage AUCex of RPV. PK parameters were calculated by standard non-compartmental analysis.

  Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 12, 16, 24, 48, 72, 120, 168, 216, and 264 hours post-dose

• Area Under the Plasma Concentration Time Curve From Time Zero to 24 Hours (AUC[0-24]) of DTG

  Blood samples were collected at indicated time-points for analysis of AUC(0-24) of DTG. PK parameters were calculated by standard non-compartmental analysis.

  Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 12, 16, and 24 hours post-dose

• AUC (0-24) of RPV

  Blood samples were collected at indicated time-points for analysis of AUC (0-24) of RPV. PK parameters were calculated by standard non-compartmental analysis.

  Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 12, 16, and 24 hours post-dose

• Area Under the Plasma Concentration Time Curve From Time Zero to 72 Hours (AUC[0-72]) of DTG

  Blood samples were collected at indicated time-points for analysis of AUC(0-72) of DTG. PK parameters were calculated by standard non-compartmental analysis.

  Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 12, 16, 24, 48, and 72 hours post-dose

• AUC (0-72) of RPV

  Blood samples were collected at indicated time-points for analysis of AUC (0-72) of RPV. PK parameters were calculated by standard non-compartmental analysis.

  Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 12, 16, 24, 48 and 72 hours post-dose

• Apparent Oral Clearance (CL/F) of DTG

  Blood samples were collected at indicated time-points for analysis of CL/F of DTG. PK parameters were calculated by standard non-compartmental analysis.

  Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 12, 16, 24, 48, 72, and 120 hours post-dose

• CL/F of RPV

  Blood samples were collected at indicated time-points for analysis of CL/F of RPV. PK parameters were calculated by standard non-compartmental analysis.

  Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 12, 16, 24, 48, 72, 120, 168, 216, 264 hours post-dose

• Apparent Oral Volume of Distribution (Vz/F) of DTG

  Blood samples were collected at indicated time-points for analysis of Vz/F of DTG. PK parameters were calculated by standard non-compartmental analysis.

  Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 12, 16, 24, 48, 72, and 120 hours post-dose

• Vz/F of RPV

  Blood samples were collected at indicated time-points for analysis of Vz/F of RPV. PK parameters were calculated by standard non-compartmental analysis.

  Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 12, 16, 24, 48, 72, 120, 168, 216, and 264 hours post-dose

• Last Quantifiable Concentration (Ct) of DTG

  Blood samples were collected at indicated time-points for analysis of Ct of DTG. PK parameters were calculated by standard non-compartmental analysis.

  Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 12, 16, 24, 48, 72, and 120 hours post-dose

• Ct of RPV

  Blood samples were collected at indicated time-points for analysis of Ct of RPV. PK parameters were calculated by standard non-compartmental analysis.

  Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 12, 16, 24, 48, 72, 120, 168, 216, and 264 hours post-dose

• Concentration at 24-hour Post-dose (C24) of DTG

  Blood samples were collected at indicated time-points for analysis of C24 of DTG. PK parameters were calculated by standard non-compartmental analysis.

  At 24 hours post-dose

• C24 of RPV

  Blood samples were collected at indicated time-points for analysis of C24 of RPV. PK parameters were calculated by standard non-compartmental analysis.

  At 24 hours post-dose

Secondary Outcomes (27)

• Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE)

  Up to Day 18

• Change From Baseline in Neutrophil, Lymphocyte, Leukocyte, Monocyte, Eosinophil, Basophil and Platelet Count

  Baseline (Day -1) and Day 3

• Absolute Values of Neutrophil, Lymphocyte, Leukocyte, Monocyte, Eosinophil, Basophil and Platelet Count

  Baseline (Day -1) and Day 3

• Change From Baseline in Hemoglobin Level

  Baseline (Day -1) and Day 3

• Absolute Values of Hemoglobin Level

  Baseline (Day -1) and Day 3

Study Arms (1)

Subjects receiving Dolutegravir and Rilpivirine FDC

EXPERIMENTAL

Subjects will receive Dolutegravir/Rilpivirine 50mg/25mg fixed dose combination (FDC) tablet as a single oral dose in a fed state.

Drug: JULUCA (Dolutegravir and Rilpivirine) 50mg/25mg FDC tablet

Interventions

JULUCA (Dolutegravir and Rilpivirine) 50mg/25mg FDC tablet DRUG

JULUCA tablets will be administered orally once daily with a meal. It will be available as a fixed dose combination of Dolutegravir 50mg and Rilpivirine 25mg.

Subjects receiving Dolutegravir and Rilpivirine FDC

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Subject must be 18 to 55 years of age, at the time of signing the informed consent
• Subjects who were born in Japan with 4 ethnic Japanese grandparents. Subjects who have not lived outside Japan for more than 10 years and who are Japanese passport holders (current or expired)
• Subjects who are overtly healthy as determined by medical evaluation including medical history, physical examination, laboratory tests, and cardiac monitoring (history and electrocardiogram \[ECG\])
• Subjects with body weight \>=50 kilogram (kg) (110 pounds) for men and \>=45kg (99 pounds) for women and body mass index (BMI) within the range 18.5-31.0 kg per square meter (kg/m\^2)
• Male or female subjects; Male subjects with no specific restrictions
• A female subject is eligible to participate if she is not pregnant or breastfeeding, and not a woman of childbearing potential (WOCBP)
• Subjects capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol

You may not qualify if:

• Subjects with history of current cardiovascular, 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
• Subjects with abnormal blood pressure (as determined by the investigator)
• Subjects with alanine transaminase (ALT) \>1.5 times upper limit of normal (ULN)
• Subjects with bilirubin \>1.5 times ULN (isolated bilirubin \>1.5 times ULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%)
• Subjects with current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones)
• Subjects with QTcF \>460 millisecond (msec)(Based on the average of the 12-Lead-electrocardiogram (ECG) triplicate readings obtained at Screening) (Note: The QTc is the QT interval corrected for heart rate according to Fridericia's formula (QTcF), and/or another method, machine-read or manually over-read. The specific formula that will be used to determine eligibility and discontinuation for an individual subject should be determined prior to initiation of the study. In other words, several different formulae cannot be used to calculate the QTc for an individual subject and then the lowest QTc value used to include or discontinue the subject from the trial)
• Subjects with 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. Acetaminophen, at doses of \<=2 grams per day, is allowed for use any time during the study
• Participation in the study would result in loss of blood or blood products in excess of 500 milliliter (mL) within 56 days
• Exposure to more than 4 new chemical entities within 12 months prior to the first dosing day
• Current enrollment or past participation within the last 30 days before signing of consent in any other clinical study involving an investigational study intervention or any other type of medical research
• Subjects with presence of Hepatitis B surface antigen (HBsAg) at screening or within 3 months prior to first dose of study intervention
• Subjects with positive Hepatitis C antibody test result at screening or within 3 months prior to first dose of study intervention (Note: Subjects with positive Hepatitis C antibody due to prior resolved disease can be enrolled, only if a confirmatory negative Hepatitis C RNA test is obtained)
• Subjects with positive Hepatitis C RNA test result at screening or within 3 months prior to first dose of study intervention (Note: Test is optional and subjects with negative Hepatitis C antibody test are not required to also undergo Hepatitis C RNA testing)
• Subjects with positive pre-study drug or alcohol screen
• Subjects with positive human immunodeficiency virus (HIV) antibody test

Sponsors & Collaborators

• ViiV Healthcare: lead
• Janssen, LP: collaborator

Study Sites (1)

GSK Investigational Site

Glendale, California, 91206, United States

Location

MeSH Terms

Conditions

HIV Infections

Interventions

dolutegravir, rilpivirine drug combination; dolutegravir; Rilpivirine

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Nitriles; Organic Chemicals; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: GSK Response Center
• Organization: ViiV Healthcare

GSKClinicalSupportHD@gsk.com

8664357343

Study Officials

• GSK Clinical Trials

  ViiV Healthcare

  STUDY DIRECTOR

Publication Agreements

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

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 10, 2019
• First Posted: June 13, 2019
• Study Start: June 17, 2019
• Primary Completion: August 13, 2019
• Study Completion: August 13, 2019
• Last Updated: July 14, 2020
• Results First Posted: July 14, 2020

Record last verified: 2020-06

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: IPD will be made available within 6 months of publishing the results of the primary endpoints of the study.
• 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 (1)