A Study of Switching to RPV Plus Other ARVs in HIV-1-infected Children (Aged 2 to <12 Years) Who Are Virologically Suppressed

• ClinicalTrials.gov Identifier: NCT04012931
• Recruitment Status: Completed
• First Posted: July 9, 2019
• Results First Posted: May 2, 2024
• Last Update Posted: May 2, 2024
• Sponsor: Janssen Research & Development, LLC
• Information provided by (Responsible Party): Janssen Research & Development, LLC

Study Description

Brief Summary:

The purpose of this study is to evaluate the steady state pharmacokinetics (PK) of rilpivirine (RPV) and determine the appropriate dose of RPV in combination with other antiretrovirals (ARVs) in participants aged greater than or equal to 2 to less than 12 years and to evaluate the safety and tolerability of RPV in combination with other ARVs in participants of same age group over a 48-week treatment period with primary endpoint at Week 24.

Condition or disease	Intervention/treatment	Phase
HIV	Drug: Rilpivirine; Drug: ARV Background Regimen	Phase 2

Detailed Description:

Participants infected with human immunodeficiency virus type 1 (HIV-1) are routinely treated with combinations of multiple drugs which reduces HIV-1 ribonucleic acid (RNA) to undetectable levels in a substantial proportion of participants and counteracts the risk of viral resistance development. RPV is a potent non-nucleoside reverse transcriptase inhibitor (NNRTI) with in vitro activity against wild type (WT) HIV-1 and against NNRTI-resistant HIV-1 mutants. A medical need still exists for the development of age/weight appropriate formulations in children less than (<) 12 years of age. In this study, participants will switch to RPV plus other ARVs. The primary analysis will be performed at Week 24. A participant will be considered to have completed the study if he or she has completed assessments at Week 48 of the study intervention phase. The total study duration for each participant, including screening and study intervention phases, will be approximately 54 weeks. Key efficacy assessments include determination of plasma HIV-1 RNA viral load and measurement of CD4+ cell count. Key safety assessments will include the monitoring of (serious) adverse events ([S]AEs) and HIV-related events, clinical laboratory tests, cardiovascular safety monitoring (vital signs and 12 lead electrocardiogram [ECGs]), and physical examination (including growth).

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 26 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2, Open-label, Single-arm, Multicenter Study to Evaluate the Pharmacokinetics, Safety, Tolerability, and Efficacy of Switching to RPV Plus Other ARVs in HIV-1-infected Children (Aged 2 to <12 Years) Who Are Virologically Suppressed
• Actual Study Start Date: July 18, 2019
• Actual Primary Completion Date: February 17, 2023
• Actual Study Completion Date: February 23, 2023

Arms and Interventions

Arm

Intervention/treatment

Experimental: Rilpivirine (RPV) (25 mg or adjusted weight-based dose); Participants will receive rilpivirine (RPV 25 milligram [mg], adjusted weight-based dose) orally once daily in combination with an investigator selected background regimen (that is investigator-selected antiretrovirals [ARVs] such as nucleoside/nucleotide reverse transcriptase inhibitor [N{t}RTIs] and integrase inhibitors) for 48 weeks.

Drug: Rilpivirine; Rilpivirine 25 mg tablets for the 25 mg daily dose, or tablets for or a weight-adjusted dose. Administered orally once daily.; Other Name: TMC278; Drug: ARV Background Regimen; The investigator-selected ARVs, including but not limited to N(t)RTIs (example, azidothymidine [AZT], abacavir [ABC], tenofovir alafenamide [TAF], or tenofovir disoproxil fumarate [TDF] in combination with emtricitabine [FTC] or lamivudine [3TC]), whichever are approved and marketed or considered local standard of care for children aged between 2 and < 12 years in a particular country are to be administered. Integrase inhibitors (for example, dolutegravir [DTG] or raltegravir) can also be administered in combination with RPV, as appropriate.

Outcome Measures

Primary Outcome Measures :

1. Area Under the Plasma Concentration-time Curve From Time of Administration up to 24 Hours Postdose (AUC[0-24h]) of Rilpivirine 12.5 mg (for <20 kg Group) [ Time Frame: Predose up to 24 hour post-dose at anytime during Day 28 to Day 32 (Week 4) ]
   AUC(0-24h) was defined the area under the plasma concentration-time curve from time of administration up to 24 hours postdose of rilpivirine. As planned, data was not summarized for arms where number of participants analyzed was less than 3. Only individual participant data was available and reported in this outcome measure. Out of the 2 participants weighing <20 kg who received rilpivirine 15 mg, 1 participant switched to rilpivirine 12.5 mg group after the first 4 weeks. This participant was counted in the <20 kg rilpivirine 12.5 mg group for the pharmacokinetic assessments, hence the number of participants analyzed for this outcome measure in this arm are exceeding the participants that started this arm. As per protocol, the intensive PK samples were collected at anytime during Day 28 to Day 32 after first dose at the specified dose regimen.
2. Area Under the Plasma Concentration-time Curve From Time of Administration up to 24 Hours Postdose (AUC[0-24h]) of Rilpivirine 15 mg (for <20 kg Group) [ Time Frame: Predose up to 24 hour post-dose at anytime during Day 28 to Day 32 (Week 4) ]
   AUC(0-24h) was defined the area under the plasma concentration-time curve from time of administration up to 24 hours postdose of rilpivirine. As per protocol, the intensive PK samples were collected at anytime during Day 28 to Day 32 after first dose at the specified dose regimen.
3. Area Under the Plasma Concentration-time Curve From Time of Administration up to 24 Hours Postdose (AUC[0-24h]) of Rilpivirine 15 mg (for 20 to <25 mg Group) [ Time Frame: Predose up to 24 hour post-dose at anytime during Day 28 to Day 32 (Week 4) ]
   AUC(0-24h) was defined the area under the plasma concentration-time curve from time of administration up to 24 hours postdose of rilpivirine. As per protocol, the intensive PK samples were collected at anytime during Day 28 to Day 32 after first dose at the specified dose regimen.
4. Area Under the Plasma Concentration-time Curve From Time of Administration up to 24 Hours Postdose (AUC[0-24h]) of Rilpivirine 25 mg (for >=25 kg Group) [ Time Frame: Predose up to 24 hour post-dose at anytime during Day 28 to Day 32 (Week 4) ]
   AUC(0-24h) was defined the area under the plasma concentration-time curve from time of administration up to 24 hours postdose of rilpivirine. As planned, data was not summarized for arms where number of participants analyzed was less than 3. Only individual participant data was available and reported in this outcome measure. As per protocol, the intensive PK samples were collected at anytime during Day 28 to Day 32 after first dose at the specified dose regimen.

Secondary Outcome Measures :

1. Percentage of Participants With HIV-1 Ribonucleic Acid (RNA) <50 and >=50 Copies/mL Through Weeks 24 and 48 [ Time Frame: From Day 1 up to Weeks 24 and 48 ]
   Percentage of participants with a HIV-1 RNA less than (<) 50 copies per mL and greater than or equal to (>=)50 copies/mL were assessed using Food and Drug Administration (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. HIV-1 RNA level <50 copies per mL, was considered as virologic success and >= 50 copies/mL was considered as virological failure as per the snapshot approach. The FDA snapshot analysis at Week 24 and Week 48 was based on the last observed plasma viral load data within the visit window (that is, Weeks 24 and 48).
2. Percentage of Participants With HIV-1 Ribonucleic Acid (RNA) <400 and >=400 Copies/mL Through Weeks 24 and 48 [ Time Frame: From Day 1 up to Weeks 24 and 48 ]
   Percentage of participants with viral load (plasma HIV-1 RNA levels) <400 copies/mL and >=400 copies/mL were assessed by the 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. HIV-1 RNA level <400 copies per mL, was considered as virologic success and >=400 copies/mL was considered as virological failure as per the snapshot approach. The FDA snapshot analysis at Week 24 and Week 48 was based on the last observed plasma viral load data within the visit window (that is, Weeks 24 and 48).
3. Change From Baseline in Cluster of Differentiation 4 (CD4+) Cell Count up to Week 24 and Week 48 [ Time Frame: From baseline (Day 1) up to Weeks 24 and 48 ]
   The immunologic change was determined by changes in CD4+ cell count using non-completer = failure imputation, that was, missing values after discontinuation were imputed with the baseline value, thus resulting in a 0 change. For intermittent missing data, last observation carried forward (LOCF) approach was applied.
4. Predose Plasma Concentration (C[0h]) of Rilpivirine 12.5 mg (for <20 kg Group) [ Time Frame: Predose at anytime during Day 28 to Day 32 (Week 4) ]
   C(0h) was defined as the predose plasma concentration of rilpivirine. As planned, data was not summarized for arms where number of participants analyzed was less than 3. Only individual participant data was available and reported in this outcome measure. Out of the 2 participants weighing <20 kg who received rilpivirine 15 mg, 1 participant switched to rilpivirine 12.5 mg group after the first 4 weeks. This participant was counted in the <20 kg rilpivirine 12.5 mg group for the pharmacokinetic assessments, hence the number of participants analyzed for this outcome measure in this arm are exceeding the participants that started this arm. As per protocol, the intensive PK samples were collected at anytime during Day 28 to Day 32 after first dose at the specified dose regimen.
5. Predose Plasma Concentration (C[0h]) of Rilpivirine 15 mg (for <20 kg Group) [ Time Frame: Predose at anytime during Day 28 to Day 32 (Week 4) ]
   C(0h) was defined as the predose plasma concentration of rilpivirine. As per protocol, the intensive PK samples were collected at anytime during Day 28 to Day 32 after first dose at the specified dose regimen.
6. Predose Plasma Concentration (C[0h]) of Rilpivirine 15 mg (for 20 to <25 kg Group) [ Time Frame: Predose at anytime during Day 28 to Day 32 (Week 4) ]
   C(0h) was defined as the predose plasma concentration of rilpivirine. As per protocol, the intensive PK samples were collected at anytime during Day 28 to Day 32 after first dose at the specified dose regimen.
7. Predose Plasma Concentration (C[0h]) of Rilpivirine 25 mg (for >=25 kg Group) [ Time Frame: Predose at anytime during Day 28 to Day 32 (Week 4) ]
   C(0h) was defined as the predose plasma concentration of rilpivirine. As planned, data was not summarized for arms where number of participants analyzed was less than 3. Only individual participant data was available and reported in this outcome measure. As per protocol, the intensive PK samples were collected at anytime during Day 28 to Day 32 after first dose at the specified dose regimen.
8. Maximum Observed Plasma Concentration (Cmax) of Rilpivirine 12.5 mg (for <20 kg Group) [ Time Frame: Predose up to 24 hour post-dose at anytime during Day 28 to Day 32 (Week 4) ]
   Cmax was defined as the maximum observed plasma concentration of rilpivirine. As planned, data was not summarized for arms where number of participants analyzed was less than 3. Only individual participant data was available and reported in this outcome measure. Out of the 2 participants weighing <20 kg who received rilpivirine 15 mg, 1 participant switched to rilpivirine 12.5 mg group after the first 4 weeks. This participant was counted in the <20 kg rilpivirine 12.5 mg group for the pharmacokinetic assessments, hence the number of participants analyzed for this outcome measure in this arm are exceeding the participants that started this arm. As per protocol, the intensive PK samples were collected at anytime during Day 28 to Day 32 after first dose at the specified dose regimen.
9. Maximum Observed Plasma Concentration (Cmax) of Rilpivirine 15 mg (for <20 kg Group) [ Time Frame: Predose up to 24 hour post-dose at anytime during Day 28 to Day 32 (Week 4) ]
   Cmax was defined as the maximum observed plasma concentration of rilpivirine. As per protocol, the intensive PK samples were collected at anytime during Day 28 to Day 32 after first dose at the specified dose regimen.
10. Maximum Observed Plasma Concentration (Cmax) of Rilpivirine 15 mg (for 20 to <25 mg Group) [ Time Frame: Predose up to 24 hour post-dose at anytime during Day 28 to Day 32 (Week 4) ]
    Cmax was defined as the maximum observed plasma concentration of rilpivirine. As per protocol, the intensive PK samples were collected at anytime during Day 28 to Day 32 after first dose at the specified dose regimen.
11. Maximum Observed Plasma Concentration (Cmax) of Rilpivirine 25 mg (for >=25 kg Group) [ Time Frame: Predose up to 24 hour post-dose at anytime during Day 28 to Day 32 (Week 4) ]
    Cmax was defined as the maximum observed plasma concentration of rilpivirine. As planned, data was not summarized for arms where number of participants analyzed was less than 3. Only individual participant data was available and reported in this outcome measure. As per protocol, the intensive PK samples were collected at anytime during Day 28 to Day 32 after first dose at the specified dose regimen.
12. Percentage of Participants With Viral Genotype at the Time of Virologic Failure at Weeks 24 and 48 [ Time Frame: Weeks 24 and 48 ]
    Percentage of participants with viral genotype at the time of virologic failure (that is, HIV 1 RNA >=50 copies/mL and >=400 copies/mL) per FDA snapshot approach were reported. Confirmed virologic failure was defined as 2 consecutive HIV-1 RNA plasma viral load measurements >=200 copies/mL and suspected virologic failure was defined as HIV-1 RNA >=200 copies/mL. No participant achieved virologic failure hence this outcome measure could not be evaluated.
13. Percentage of Participants With Treatment Adherence >95% Based on Tablet Count up to Weeks 24 and 48 [ Time Frame: From Day 1 up to Weeks 24 and 48 ]
    Percentage of participants with treatment adherence greater than (>) 95 percent (%) as assessed by tablet count (study intervention accountability) up to Weeks 24 and 48 of study treatment were reported. Treatment adherence was defined as having a treatment adherence of >95% by tablet count.
14. Change From Baseline in Percentage of Cluster of Differentiation 4 (CD4+) Cell Count up to Week 24 and Week 48 [ Time Frame: From baseline (Day 1) up to Weeks 24 and 48 ]
    The immunologic change was determined by changes in CD4+ cell count using non-completer = failure imputation, that was, missing values after discontinuation were imputed with the baseline value, thus resulting in a 0 change. For intermittent missing data, last observation carried forward (LOCF) approach was applied.

Eligibility Criteria

• Ages Eligible for Study: 2 Years to 11 Years (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Weighing at least 10 kilogram (kg) at screening
• Have documented chronic Human Immunodeficiency Virus (HIV-1) infection
• On a stable antiretroviral (ARV) regimen for at least 6 months prior to screening and virologically suppressed with documented evidence of at least 2 plasma viral loads less than (<) 50 HIV-1 ribonucleic acid (RNA) copies/milliliter (mL): one within 2-12 months prior to screening and one at screening
• Can switch from any ARV class
• Never been treated with a therapeutic HIV vaccine
• Historical HIV-1 genotyping result at screening for children aged >=2 to <6 years (and for children aged >=6 to <12 years if a historical HIV-1 genotyping result is available at screening) must demonstrate sensitivity to RPV and to the selected background ARVs

Exclusion Criteria:

• Have previously documented HIV-2 infection
• Have known or suspected acute (primary) HIV-1 infection
• Taken any disallowed concomitant therapies within 4 weeks before the planned first dose of study intervention
• Any current or history of adrenal disorder
• A history of virologic failure to ARVs with or without availability of an HIV-1 genotype result at the time of failure

Contacts and Locations

Locations

Italy

ASST Spedali Civili di Brescia

Brescia, Italy, 25123

Azienda Ospedaliera Universitaria Federico II

Napoli, Italy, 80131

IRCCS Ospedale Pediatrico Bambino Gesu

Roma, Italy, 00165

Portugal

Chln - Hosp. Santa Maria

Lisboa, Portugal, 1649-035

Chsj - Hosp. Sao Joao

Porto, Portugal, 4200 319

South Africa

Josha Research

Bloemfontein, South Africa, 9301

Family Clinical Research Unit FAM-CRU

Tygerberg, South Africa, 7505

Spain

Hosp. Sant Joan de Deu

Esplugues De Llobregat, Spain, 08950

Hosp. Univ. 12 de Octubre

Madrid, Spain, 28041

Hosp. Univ. La Paz

Madrid, Spain, 28046

Thailand

Siriraj Hospital Mahidol University

Bangkok, Thailand, 10700

Research Institute for Health Sciences

Chiang Mai, Thailand, 50200

Bamrasnaradura Infectious Disease Institute

Nonthaburi, Thailand, 11000

Uganda

Joint Clinical Research Centre

Kampala, Uganda, 10005

Sponsors and Collaborators

Janssen Research & Development, LLC

Investigators

• Study Director: Janssen Research & Development, LLC Clinical Trial; Janssen Research & Development, LLC

  Study Documents (Full-Text)

Documents provided by Janssen Research & Development, LLC:

Study Protocol  [PDF] February 22, 2021

Statistical Analysis Plan  [PDF] March 27, 2023

More Information

• Responsible Party: Janssen Research & Development, LLC
• ClinicalTrials.gov Identifier: NCT04012931
• Other Study ID Numbers: CR108606; 2018-004301-32 ( EudraCT Number ); TMC278HTX2002 ( Other Identifier: Janssen Research & Development, LLC )
• First Posted: July 9, 2019
• Results First Posted: May 2, 2024
• Last Update Posted: May 2, 2024
• Last Verified: April 2024

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: The data sharing policy of the Janssen Pharmaceutical Companies of Johnson & Johnson is available at www.janssen.com/clinical-trials/transparency. As noted on this site, requests for access to the study data can be submitted through Yale open Data Access (YODA) Project site at yoda.yale.edu
• URL: https://www.janssen.com/clinical-trials/transparency

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

Additional relevant MeSH terms:

Rilpivirine; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Antiviral Agents; Anti-Infective Agents; Anti-HIV Agents; Anti-Retroviral Agents