Pharmacokinetics, Safety, Tolerability of Dolutegravir/Rilpivirine in Pediatrics

Study Overview
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Brief Summary
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The purpose of this study is to provide data on the pharmacokinetic (PK), safety, tolerability, efficacy and acceptability of this fixed dose combination (FDC) single tablet 2-drug regimen for virologically suppressed (HIV-1 RNA [Ribonucleic Acid] < 50 [cells per milliliter] c/mL) children 6 to less than 12 years of age, weighing at least 25 kilogram (kg).

Official Title
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Phase 1/2 Study of Switching to Fixed Dose Combination Dolutegravir/Rilpivirine Among Virologically Suppressed Children, 6 to Less Than 12 Years of Age, Living With HIV-1

Conditions
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HIV Infections

Intervention / Treatment
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* Drug: Dolutegravir/Rilpivirine FDC


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Human immuno virus Type-1 (HIV-1) infected child 6 years to less than 12 years of age at the time of signing the informed consent form . Body weight greater than or equal to 25 kilogram (kg) at entry. Confirmed HIV-1-infection Participant has taken the same Antiretroviral therapy (ART) regimen in the 6 months (180 days) prior to Screening, as determined by the site investigator based on participant/parent/guardian report and available medical records. Has a plasma HIV-1 Ribonucleic Acid (RNA) result less than 50 copies/mL at Screening Has at least one documented plasma HIV-1 RNA result less than the lower limit of detection of the assay from a specimen collected in the 6-12 months (180-365 days) prior to Screening OR Has at least one documented plasma HIV-1 RNA result less than the lower limit of detection of the assay from a specimen collected less than 6 months (within 179 days) prior to entry and at least one documented plasma HIV-1 RNA result less than the lower limit of detection of the assay from a specimen collected in the 12-18 months (365-545 days) prior to Screening For participants of reproductive potential (defined as having reached menarche), not pregnant based on testing performed at Screening (i.e., from a specimen collected within 30 days prior to entry) and at Baseline/Day 1. For participants of reproductive potential who are engaging in sexual activity that could lead to pregnancy, willing to use two methods of contraception while receiving study drug and for approximately one month after permanently discontinuing study drug, based on participant/parent/guardian report at entry. For participants of reproductive potential, not breastfeeding based on participant/parent/ guardian report at Baseline/Day 1. Exclusion Criteria: Documented resistance (ever) to Non-nucleoside reverse transcriptase inhibitors (NNRTIs) or integrase inhibitors Documented HIV-1 RNA result greater than or equal to the lower limit of detection of the assay based on a specimen collected in the 12 months (365 days) prior to Screening Any change (ever) of any Antiretroviral (ARV) agent due to virologic failure, as determined by the site investigator based on participant/parent/guardian report and available medical records Has a history (ever) of allergy to DTG, RPV, or any other component of JULUCA as determined by the site investigator based on participant/parent/guardian report and available medical records. Has a history (ever) of congestive heart failure, symptomatic arrhythmia, or any clinically significant cardiac disease as determined by the site investigator based on participant/ parent/guardian report and available medical records Has a history (ever) of unstable liver disease (defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, or persistent jaundice), cirrhosis, or known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones) as determined by the site investigator based on participant/parent/guardian report and available medical records Has any of the following as determined by the site investigator based on participant/ parent/guardian report and available medical records: Current clinical evidence of pancreatitis; Currently active AIDS-defining (WHO Clinical Stage 4) opportunistic infection; Currently active TB and/or current rifamycin-containing TB treatment. Has an anticipated need for any HCV therapy during the first 24 weeks of study and for HCV therapy based on interferon or any drugs that have a potential for adverse drug: drug interactions with study treatment throughout the entire study period. Receipt of the following as determined by the site investigator based on participant/ parent/guardian report and available medical records: Any investigational agent within 90 days prior to entry; Any prohibited medication within 30 days prior to entry; Any medication with a known risk of Torsades de Pointes within seven days prior to entry Receipt (ever) of an ART regimen that included both DTG and RPV, as determined by the site investigator based on participant/parent/guardian report and available medical records Any ≥ grade 3 result for the following based on grading per the Division of Acquired Immunodeficiency Syndrome (AIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events: Haemoglobin (<8.5 gram per deciliter [g/dL] or <5.25 millimoles per liter [mmol/L]); Absolute neutrophil count (<600 cells/mm^3 or <0.600 x 109 cells/L); Platelet count (<50,000cells/mm^3 or <50.00 x 109 cells/L); Estimated glomerular filtration rate (eGFR: <60ml/min/1.73m^2); ALT (≥5.0 x Upper limit of Normal [ULN]); Aspartate Aminotransferase (AST) (≥5.0 x ULN) Has the following combination of laboratory test results at screening: Alanine transaminase [ALT] greater than or equal to 3 x ULN and total bilirubin greater than or equal to 1.5 x ULN and direct bilirubin greater than 35% of total bilirubin Evidence of Hepatitis B virus (HBV) infection based on the results of testing at Screening. QTc >450 milliseconds (msec) at Screening Severe acute malnutrition (Body Mass Index [BMI] for age <-3 or nutritional oedema) Has any documented or suspected clinically significant medical or psychiatric condition or any other condition that, in the opinion of the site investigator, would make participation in the study unsafe, complicate interpretation of study outcome data, or otherwise interfere with achieving study objectives. The child is a ward of State or government.

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dolutegravir(DTG)/Rilpivirine (RPV)<br> | Drug: Dolutegravir/Rilpivirine FDC<br>* Dolutegravir/Rilpivirine will be administered.<br>* Other names: JULUCA;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the curve (AUC0-24h) of DTG |  | Up to Week 24 | 
| Area under the curve (AUC0-24h) of RPV |  | Up to Week 24 | 
| Number of Participants with Adverse Events (AEs) at Week 24 |  | At Week 24 | 
| Number of Participants with Grade 3 or higher AEs at Week 24 |  | At Week 24 | 
| Number of Participants with Grade 3 or higher AEs assessed as related to study drug at Week 24 |  | At Week 24 | 
| Number of Participants with Fatal AEs assessed as related to study drug at Week 24 |  | At Week 24 | 
| Number of Participants with Serious Adverse Events (SAEs) assessed as related to study drug at Week 24 |  | At Week 24 | 
| Number of Participants with AEs assessed as related to study drug that led to permanent discontinuation of study drug at Week 24 |  | At Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Participants with HIV-1 RNA less than 50 copies per milliliter (c/mL) |  | At Week 24 and 48 | 
| Cluster of differentiation 4 (CD4+) Cell Count |  | At Week 24 and 48 | 
| Percentage of CD4+ Cell Count |  | At Week 24 and 48 | 
| Number of Participants with Adverse Events (AEs) at Week 48 |  | At Week 48 | 
| Number of Participants with Grade 3 or higher AEs at Week 48 |  | At Week 48 | 
| Number of Participants with Grade 3 or higher AEs assessed as related to study drug at Week 48 |  | At Week 48 | 
| Number of Participants with Fatal AEs assessed as related to study drug at Week 48 |  | At Week 48 | 
| Number of Participants with Serious Adverse Events (SAEs) assessed as related to study drug at Week 48 |  | At Week 48 | 
| Number of Participants with AEs assessed as related to study drug that led to permanent discontinuation of study drug at Week 48 |  | At Week 48 | 
| Minimum drug concentration (Cmin) of DTG |  | Up to Week 24 | 
| Cmin of RPV |  | Up to Week 24 | 
| Cmin of DTG at Week 4 Visit |  | Pre-dose, 1, 2, 4, 5, 6, 10 and 24 hours (h) post-dose at Week 4 | 
| Cmin of RPV at Week 4 Visit |  | Pre-dose, 1, 2, 4, 5, 6, 10 and 24 hours (h) post-dose at Week 4 | 
| Concentration of HIV-1 RNA |  | Baseline (Day 1), Week 4, 8, 12, 16, 20, 24, 36 and 48 | 
| Number of Participants with HIV-1 Genotype at the time of Virologic failure (HIV-1 RNA greater than or equal to 200 copies/mL) |  | Baseline (Day 1) and up to Week 48 | 
| Number of Participants with HIV-1 Phenotype at the time of Virologic failure (HIV-1 RNA greater than or equal to 200 copies/mL) |  | Up to Week 48 | 
| Number of Participants with HIV-1 genotypes at Baseline, Week 24 and 48 |  | Baseline (Day 1), Week 24 and 48 | 
| Number of Participants with Acceptability to JULUCA |  | At Week 4, 24 and 48 | 
| Number of Participants with Adherence to JULUCA |  | At Week 4, 24 and 48 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Dolutegravir, Rilpivirine, JULUCA