Clinical trial NCT03984838: Study to Evaluate Pharmacokinetics, Safety and Tolerability of Dolutegravir and Rilpivirine (JULUCA™) 50 Milligram (mg)/25 mg Tablets in Healthy Subjects of Japanese Descent
Official title: A Phase I, Open-label, Single-dose Study to Investigate the Pharmacokinetics, Safety and Tolerability of Dolutegravir + Rilpivirine (JULUCA™) 50 mg/25 mg Tablets in Healthy Participants of Japanese Descent
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: HIV Infections
Keywords: Dolutegravir, Rilpivirine, HIV infection, Fixed-dose combination, Japanese, Pharmacokinetics
Lead sponsor: ViiV Healthcare
Sponsor class: INDUSTRY
Collaborators: name: Janssen, LP
First posted: 2019-06-13
Enrollment: 16
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


Eligibility criteria: Inclusion Criteria:

* 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)
* The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy
* 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

Exclusion Criteria:

* 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
* Subjects with regular use of known drugs of abuse
* Subjects with creatinine clearance (CrCL) \<60 milliliter per minute
* Employment with Janssen, ViiV, GlaxoSmithKline(GSK), or with the Investigator or study site, with direct involvement in the proposed study or other studies under the direction of that Investigator or study site, as well as family members of the employees or the Investigator
* Subjects with urinary cotinine levels indicative of smoking or history or regular use of tobacco- or nicotine-containing products (e.g. nicotine patches or vaporizing devices) within 6 months prior to screening
* Subjects with regular alcohol consumption within 6 months prior to the study defined as: An average weekly intake of \>14 units for males or \>7 units for females. One unit is equivalent to 8 gram of alcohol: a half-pint (approximately 240mL) of beer, 1 glass (125mL) of wine or 1 (25mL) measure of spirits
* Subjects with sensitivity to heparin or heparin-induced thrombocytopenia
* Subjects with sensitivity to any of the study interventions, or components thereof, or drug or other allergy that, in the opinion of the investigator or medical monitor, contraindicates participation in the study

Primary outcomes:
measure: Area Under the Concentration (AUC) Time Curve From Time Zero Extrapolated to Infinite Time (AUC [0-infinity]) of DTG
timeFrame: 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
measure: AUC (0-infinity) of RPV
timeFrame: 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
measure: Area Under the Concentration Time Curve From Time Zero to Last Time of Quantifiable Concentration (AUC [0-t]) of DTG
timeFrame: 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
measure: AUC (0-t) of RPV
timeFrame: 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
measure: Maximum Observed Plasma Concentration (Cmax) of DTG
timeFrame: 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
measure: Cmax of RPV
timeFrame: 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
measure: Absorption Lag Time (Tlag) of DTG
timeFrame: 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
measure: Tlag of RPV
timeFrame: 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
measure: Time to Reach Maximum Observed Concentration (Tmax) of DTG
timeFrame: 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
measure: Tmax of RPV
timeFrame: 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
measure: Time of Last Quantifiable Concentration (Tlast) of DTG
timeFrame: 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
measure: Tlast of RPV
timeFrame: 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
measure: Elimination Half-life (t1/2) of DTG
timeFrame: 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
measure: T1/2 of RPV
timeFrame: 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
measure: Apparent Elimination Rate Constant (Lambda z) of DTG
timeFrame: 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
measure: Lambda z of RPV
timeFrame: 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
measure: Percentage of AUC(0-infinity) That Was Extrapolated (%AUCex) of DTG
timeFrame: 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
measure: Percentage AUCex of RPV
timeFrame: 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
measure: Area Under the Plasma Concentration Time Curve From Time Zero to 24 Hours (AUC[0-24]) of DTG
timeFrame: 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
measure: AUC (0-24) of RPV
timeFrame: 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
measure: Area Under the Plasma Concentration Time Curve From Time Zero to 72 Hours (AUC[0-72]) of DTG
timeFrame: 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
measure: AUC (0-72) of RPV
timeFrame: 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
measure: Apparent Oral Clearance (CL/F) of DTG
timeFrame: 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
measure: CL/F of RPV
timeFrame: 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
measure: Apparent Oral Volume of Distribution (Vz/F) of DTG
timeFrame: 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
measure: Vz/F of RPV
timeFrame: 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
measure: Last Quantifiable Concentration (Ct) of DTG
timeFrame: 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
measure: Ct of RPV
timeFrame: 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
measure: Concentration at 24-hour Post-dose (C24) of DTG
timeFrame: At 24 hours post-dose
measure: C24 of RPV
timeFrame: At 24 hours post-dose
Secondary outcomes:
measure: Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE)
timeFrame: Up to Day 18
measure: Change From Baseline in Neutrophil, Lymphocyte, Leukocyte, Monocyte, Eosinophil, Basophil and Platelet Count
timeFrame: Baseline (Day -1) and Day 3
measure: Absolute Values of Neutrophil, Lymphocyte, Leukocyte, Monocyte, Eosinophil, Basophil and Platelet Count
timeFrame: Baseline (Day -1) and Day 3
measure: Change From Baseline in Hemoglobin Level
timeFrame: Baseline (Day -1) and Day 3
measure: Absolute Values of Hemoglobin Level
timeFrame: Baseline (Day -1) and Day 3
measure: Change From Baseline in Hematocrit Level
timeFrame: Baseline (Day -1) and Day 3
measure: Absolute Values of Hematocrit Level
timeFrame: Baseline (Day -1) and Day 3
measure: Change From Baseline in Erythrocytes
timeFrame: Baseline (Day -1) and Day 3
measure: Absolute Values of Erythrocytes
timeFrame: Baseline (Day -1) and Day 3
measure: Change From Baseline in Mean Corpuscular Hemoglobin (MCH)
timeFrame: Baseline (Day -1) and Day 3
measure: Absolute Values of MCH
timeFrame: Baseline (Day -1) and Day 3
measure: Change From Baseline in Mean Corpuscular Volume (MCV)
timeFrame: Baseline (Day -1) and Day 3
measure: Absolute Values of MCV
timeFrame: Baseline (Day -1) and Day 3
measure: Change From Baseline in Reticulocytes
timeFrame: Baseline (Day -1) and Day 3
measure: Absolute Values of Reticulocytes
timeFrame: Baseline (Day -1) and Day 3
measure: Change From Baseline in Blood Urea Nitrogen (BUN), Glucose, Calcium, Sodium, and Potassium Levels
timeFrame: Baseline (Day -1) and Day 3
measure: Absolute Values of BUN, Glucose, Calcium, Sodium, and Potassium Levels
timeFrame: Baseline (Day -1) and Day 3
measure: Change From Baseline in Total and Direct Bilirubin, Creatinine and Protein Levels
timeFrame: Baseline (Day -1) and Day 3
measure: Absolute Values of Total and Direct Bilirubin, Creatinine and Protein Levels
timeFrame: Baseline (Day -1) and Day 3
measure: Change From Baseline in Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT) and Alkaline Phosphatase (ALP) Levels
timeFrame: Baseline (Day -1) and Day 3
measure: Absolute Values of AST, ALT and ALP Levels
timeFrame: Baseline (Day -1) and Day 3
measure: Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)
timeFrame: Baseline (Day 1, Pre-dose) and at Day 12
measure: Absolute Values of SBP and DBP
timeFrame: Baseline (Day 1, Pre-dose) and at Day 12
measure: Change From Baseline in Pulse Rate
timeFrame: Baseline (Day 1, Pre-dose) and at Day 12
measure: Absolute Values of Pulse Rate
timeFrame: Baseline (Day 1, Pre-dose) and at Day 12
measure: Change From Baseline in Body Temperature
timeFrame: Baseline (Day 1, Pre-dose) and at Day 12
measure: Absolute Values of Body Temperature
timeFrame: Baseline (Day 1, Pre-dose) and at Day 12
Other outcomes:
Locations:
city: Glendale
country: United States
facility: GSK Investigational Site
state: California
Study officials:
affiliation: ViiV Healthcare
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References: