A Study to Evaluate the Pharmacokinetics, Safety, Tolerability, and Antiviral Activity of Rilpivirine (TMC278) in Human Immunodeficiency Virus Infected Adolescents and Children Aged Greater Than or Equal to 6 Years

A Phase II, Open Label, Single Arm Trial to Evaluate the Pharmacokinetics,Safety, Tolerability, and Antiviral Activity of Rilpivirine (TMC278) in Antiretroviral Naive HIV-1 Infected Adolescents and Children Aged >= 6 to <18 Years

The purpose of this study is to evaluate the pharmacokinetics, safety and antiviral activity of rilpivirine (TMC278) 25 milligram (mg) or adjusted dose once daily in combination with an investigator-selected background regimen containing 2 nucleoside/nucleotide reverse transcriptase inhibitors (N[t]RTIs) (zidovudine [AZT], abacavir [ABC], or tenofovir disoproxil fumarate [TDF] in combination with lamivudine [3TC] or emtricitabine [FTC] in antiretroviral (ARV) treatment-naïve adolescents and children aged greater than or equal to (>=) 6 to less than (<) 18 years.

Study Overview

• Status: Completed
• Conditions: HIV-1
• Intervention / Treatment: Drug: Rilpivirine; Drug: Zidovudine; Drug: Abacavir; Drug: Tenofovir disoproxil fumarate; Drug: Lamivudine; Drug: Emtricitabine

Detailed Description

This is a Phase II, open-label (all people involved know the identity of the assigned drug) and single arm study. The study will consist of a screening period of maximum 8 weeks, an initial treatment period of 48 weeks, a post week 48 treatment extension period of 4 years (Cohort 1 only), and a 4 week follow-up (cohort 2 only) period. Participants who withdraw from the trial on or before the Week 48 visit or subjects with ongoing (serious) adverse events ([S]AEs), laboratory abnormalities, or viral load increase at the last on-treatment visit in the extension, will be seen for a follow-up visit 4 weeks later. The initial 48-week treatment period will be structured into 2 age Cohorts; Cohort 1 (Aged greater than or equal to [>=] 12 to less than [<] 18 years) and Cohort 2 (Children Aged >= 6 to < 12 years). The trial is designed to evaluate the steady-state pharmacokinetic (PK) profile (based on intensive PK analysis) and the short-term safety and antiviral activity of rilpivirine (RPV). Participants will receive RPV 25 milligram (mg), or weight-adjusted dose orally once daily for 240 weeks when administered in combination with 2 nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs). The trial will also evaluate long-term (48 weeks and 240 weeks [Cohort 1]) safety, efficacy, and pharmacokinetics of rilpivirine in combination with the background regimen of 2 NRTIs. Patients safety will be monitored throughout the study and during the follow up visits.

• Study Type: Interventional
• Enrollment (Actual): 54
• Phase: Phase 2

Contacts and Locations

Study Locations

• India
  • Chennai, India
  • Mangalore, India
• Kenya
  • Nairobi, Kenya
• Romania
  • Bucuresti, Romania
• South Africa
  • Bloemfontein, South Africa
  • Dundee, South Africa
  • Middelburg, South Africa
  • Pretoria, South Africa
  • Thabazimbi, South Africa
  • Vosloorus, South Africa
• Thailand
  • Bangkok, Thailand
  • Nonthaburi, Thailand
• Uganda
  • Entebbe, Uganda
  • Kampala, Uganda
• Ukraine
  • Kiev, Ukraine
• United States
  • New York
    • Syracuse, New York, United States
  • Tennessee
    • Memphis, Tennessee, United States

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 years to 17 years (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Has documented human immuno deficiency virus (HIV-1) infection
• Patients who meet the following criteria; a) Cohort 1: Patients Aged greater than or equal to (>=) 12 to less than (<) 18 years, weight is >= 32 kilogram (kg), b) Cohort 2; Aged >= 6 to < 12 years, weight is >= 17 kg
• Must have HIV-1 plasma viral load at screening greater than equal to 500 HIV-1 ribonucleic acid (RNA) copies/mL
• Have not received treatment with a therapeutic HIV vaccine or an HIV drug with the exception of a single dose of nevirapine (NVP) (Cohort 1 and Cohort 2) or up to 6 weeks of zidovudine (AZT) use (Cohort 2 only) prior to screening to prevent mother-to-child transmission (MTCT)
• In the judgment of the investigator, it is appropriate to initiate antiretroviral therapy (ARV) therapy based on a patient's medical condition and taking into account guidelines for the treatment of HIV-1 infection in children of this age group

Exclusion Criteria:

• Any previous use of ARVs with the exception of single dose NVP (Cohort 1 and Cohort 2) or up to 6 weeks of AZT (Cohort 2 only) to prevent MTCT
• Plasma viral load at screening greater than 100,000 HIV-1 RNA copies/mL
• Documented genotypic evidence of non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance at screening or from historical data available in the source documents
• Use of disallowed concomitant therapy from 4 weeks prior to the baseline visit
• Patient has any currently active Acquired Immunodeficiency Syndrome (AIDS) defining illness
• Patient has active tuberculosis and/or is being treated for tuberculosis at screening
• Personal history of cardiac disease (including congenital heart disease), or symptomatic arrhythmias, with the exception of sinus arrhythmia; personal history of asymptomatic arrhythmias is excluded if the asymptomatic arrhythmia is clinically significant in the opinion of the investigator

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Rilpivirine (TMC278); The patients received rilpivirine with 2 nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) as a background regimen in cohort 1 [aged greater than or equal to (> =) 12 to less than (<) 18 years] for up to 240 weeks which is already completed and recruitment closed and will receive this treatment in cohort 2 (children aged > = 6 to < 12 years) for up to 48 weeks. The NRTIs include zidovudine, abacavir, or tenofovir disoproxil fumarate in combination with lamivudine or emtricitabine.

Drug: Rilpivirine; Patients will receive rilpivirine (RPV) tablet 25 milligram dose or an adjusted dose orally once daily in Cohort 1 (adolescents aged >=12 to <18 years) up to 240 weeks. Patients will receive RPV weight-adjusted dose orally once daily in Cohort 2 (children aged >=6 to <12 years) or 25 mg once daily for up to 48 weeks.; Drug: Zidovudine; Type=exact, form= appropriate pediatric formulation, unit=mg, route=oral. The patients may receive this selected NRTI together with another NRTI once daily for up to 48 weeks (Cohort 2) and 240 weeks (Cohort 1).; Drug: Abacavir; Type=exact, form=appropriate pediatric formulation, unit=mg, route=oral. The patients may receive this selected NRTI together with another NRTI once daily for up to 48 weeks (Cohort 2) and 240 weeks (Cohort 1).; Drug: Tenofovir disoproxil fumarate; Type=exact, form=appropriate pediatric formulation, unit=mg, route=oral. The patients may receive this selected NRTI together with another NRTI once daily for 240 weeks (Cohort 1).; Drug: Lamivudine; Type=exact, form=appropriate pediatric formulation, unit=mg, route=oral. The patients may receive this selected NRTI together with another NRTI once daily for up to 48 weeks (Cohort 2) and 240 weeks (Cohort 1).; Drug: Emtricitabine; Type=exact, form=appropriate pediatric formulation, unit=mg, route=oral. The patients may receive this selected NRTI together with another NRTI once daily for up to 48 weeks (Cohort 2) and 240 weeks (Cohort 1).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cohorts 1 and 2: Pharmacokinetics (PK) of Rilpivirine (TMC278) as Measured by Maximum Observed Plasma Concentration at Steady State (Cmax,ss)	Cmax,ss was the maximum observed plasma concentration of rilpivirine at steady state (steady state starting from Day 14).	Pre-dose, 0, 2, 4, 5, 6, 9, 12 and 24 hours post dose at steady-state (any time during Day 14 to Day 18)
Cohort 2: Pharmacokinetics (PK) of Rilpivirine (TMC278) as Measured by Maximum Plasma Concentration at Steady State (Cmax,ss)	Cmax,ss was the maximum plasma concentration of rilpivirine at steady state (steady state starting from Day 14). In the below data table, the measure type "Number" corresponds to Cmax,ss concentration.	Pre-dose, 0, 2, 4, 5, 6, 9, 12 and 24 hours post dose at steady-state (any time during Day 14 to Day 18)
Cohorts 1 and 2: Pharmacokinetics of Rilpivirine as Measured by Area Under the Plasma Concentration Curve at Steady State (AUC24, ss)	AUC24,ss was defined as the area under the plasma concentration versus time curve from time 0 to 24 hours post dosing of rilpivirine at steady state (steady state starting from Day 14).	Pre-dose, 0, 2, 4, 5, 6, 9, 12 and 24 hours post dose at steady-state (any time during Day 14 to Day 18)
Cohort 2: Pharmacokinetics of Rilpivirine as Measured by Area Under the Plasma Concentration Curve at Steady State (AUC24, ss)	AUC24,ss was defined as the area under the plasma concentration versus time curve from time 0 to 24 hours post dosing of rilpivirine at steady state (steady state starting from Day 14). In the below data table, the measure type "Number" corresponds to AUC24, ss concentration.	Pre-dose, 0, 2, 4, 5, 6, 9, 12 and 24 hours post dose at steady-state (any time during Day 14 to Day 18)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cohorts 1 and 2: Number of Participants With Adverse Events (AEs)	An AE is any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non-investigational) product and did not necessarily have a causal relationship with the treatment.	Cohort 1: From baseline (Day 1) up to Week 240; Cohort 2: From Baseline (Day 1) up to 240 weeks (for participants recruited up to protocol amendment 9); up to 48 weeks (for participants recruited after implementation of protocol amendment 10)
Cohorts 1 and 2: Percentage of Participants With Plasma Human Immunodeficiency Virus -1 (HIV-1) Ribonucleic Acid (RNA) Level Less Than (<) 50 Copies/mL by Time to Loss of Virologic Response (TLOVR) Method	Percentage of participants with plasma HIV-1 RNA <50 copies per milliliter (Copies/mL) assessed by TLOVR method was reported. TLOVR requires sustained HIV-1 RNA < 50 copies/mL; confirmed HIV-1 RNA more than or equal to (>=) 50 copies/mL is considered as non-response (rebound); participant was considered non-responder after permanent discontinuation. Responder is defined as the participant with confirmed plasma viral load <50 copies/mL. As planned, combined data for cohort 2 was collected, analyzed and reported for this outcome measure.	At Week 48 (for Cohorts 1 and 2) and at Week 240 (for Cohort 1 only)
Cohorts 1 and 2: Percentage of Participants With Plasma HIV-1 RNA <50 Copies/mL by Food and Drug Administration (FDA) Snapshot Approach	Percentage of participants with a HIV-1 RNA <50 copies per mL were assessed using FDA snapshot approach which defines a participant's virologic response status using only the viral load at the predefined time point within a window of time, along with study drug discontinuation status. If HIV-1 RNA level is < 50 copies per mL, it is considered as virologic success as per the snapshot approach. As planned, combined data for cohort 2 was collected, analyzed and reported for this outcome measure.	At Week 48 (for Cohorts 1 and 2) and at Week 240 (for Cohort 1 only)
Cohorts 1 and 2: Number of Participants With Post Baseline Genotype Data	Number of participants with post baseline genotype (nucleoside analogue reverse transcriptase inhibitors [NRTI] and non-nucleoside reverse transcriptase inhibitors [NNRTI] resistance) data were reported. As planned, combined data for cohort 2 was collected, analyzed and reported for this outcome measure.	Cohort 1: From baseline (Day 1) up to Week 240; Cohort 2: From baseline (Day 1) up to 240 weeks (for participants recruited up to protocol amendment 9); up to 48 weeks (for participants recruited after implementation of protocol amendment 10)
Cohorts 1 and 2: Percentage of Participants With Treatment Adherence >95% Based on Drug Accountability	Percentage of participants with treatment adherence >95% based on drug accountability from baseline up to Week 240 for Cohort 1 and from baseline up to 240 weeks (for participants recruited up to protocol amendment 9); up to 48 weeks (for participants recruited after implementation of protocol amendment 10) for cohort 2 were reported. Treatment adherence was defined as having a treatment adherence of greater than (>) 95 percent (%) by pill count. Drug accountability included dispensation, receipt, and return, or if applicable, destruction of RPV documented by using the appropriate forms. As planned, combined data for cohort 2 was collected, analyzed and reported for this outcome measure.	Cohort 1: From baseline (Day 1) up to Week 240; Cohort 2: From baseline (Day 1) up to 240 weeks (for participants recruited up to protocol amendment 9); up to 48 weeks (for participants recruited after implementation of protocol amendment 10)
Cohorts 1 and 2: Change From Baseline in Cluster of Differentiation (CD4+) Cells	The immunologic change was determined by changes in Cluster of CD4+ cell count using non-completer =failure imputation, that is discontinuation was imputed with baseline value resulting in change=0, other missing data using last observation carried forward (LOCF). Change from baseline in CD4+ cell count at Week 48 for Cohort 1 and 2; and at Week 240 for Cohort 1 only were assessed. As planned, combined data for cohort 2 was collected, analyzed and reported for this outcome measure.	Baseline (Day 1) and Week 48 for Cohorts 1 and 2; Week 240 for Cohort 1 alone

Collaborators and Investigators

• Sponsor: Janssen Sciences Ireland UC
• Investigators: Study Director: Janssen Sciences Ireland UC Clinical Trial, Janssen Sciences Ireland UC

Publications and helpful links

General Publications

• Lombaard J, Ssali F, Thanyawee P, Fourie J, Vanveggel S, Linthicum C, Van Eygen V, Van Solingen-Ristea R. Phase 2 Open-Label Study of Long-Term Safety, Tolerability, and Antiviral Activity of Rilpivirine in Antiretroviral-Naive Adolescents Living with HIV-1. Antimicrob Agents Chemother. 2022 Feb 15;66(2):e0091621. doi: 10.1128/AAC.00916-21. Epub 2021 Dec 6.

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2011
• Primary Completion (Actual): August 1, 2022
• Study Completion (Actual): August 1, 2022

Study Registration Dates

• First Submitted: November 26, 2008
• First Submitted That Met QC Criteria: November 28, 2008
• First Posted (Estimated): December 1, 2008

Study Record Updates

• Last Update Posted (Actual): June 25, 2024
• Last Update Submitted That Met QC Criteria: May 30, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Keywords: HIV-1; Children; Pediatric; HIV Infection; AIDS; Antiretroviral; Rilpivirine (TMC278)
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Antimetabolites; Tenofovir; Emtricitabine; Lamivudine; Zidovudine; Rilpivirine; Abacavir
• Other Study ID Numbers: CR002677; TMC278-TiDP38-C213 (Other Identifier: Janssen Sciences Ireland UC); 2008-001696-30 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated device product: No