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

Tracking Information

• First Submitted Date: July 8, 2019
• First Posted Date: July 9, 2019
• Results First Submitted Date: February 16, 2024
• Results First Posted Date: May 2, 2024
• Last Update Posted Date: May 2, 2024
• Actual Study Start Date: July 18, 2019
• Actual Primary Completion Date: February 17, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 5, 2024)

• 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.
• 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.
• 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.
• 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.

Original Primary Outcome Measures (submitted: July 8, 2019)

• Area Under the Plasma Concentration-time Curve from Time of Administration up to 24 Hours Postdose (AUC[24h]) of Rilpivirine (RPV) [ Time Frame: Up to 24 hours postdose ]
  AUC(24h) is area under the plasma concentration-time curve from time of administration to 24 hours postdose, calculated by linear-linear trapezoidal summation or population pharmacokinetic (PK) analysis.
• Percentage of Participants with Grade 3 and 4 Adverse Events (AEs) and Serious Adverse Events (SAEs) Through Week 24 [ Time Frame: Up to Week 24 ]
  Percentage of participants with Grade 3 and 4 AEs will be assessed on Division of Aids (DAIDS) grading table where Grade 3: Severe and Grade 4: Potentially Life-threatening. An AE is any untoward medical occurrence in a participant participating in a clinical study that does not necessarily have a causal relationship with the pharmaceutical/biological agent under study. An SAE is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly.
• Percentage of Participants with Human Immunodeficiency Virus (HIV)-Related Events [ Time Frame: Up to Week 24 ]
  Percentage of participants with HIV-related events through 24 weeks of study treatment will be reported.
• Percentage of Participants Experiencing Premature Discontinuation due to AEs Through Week 24 [ Time Frame: Up to Week 24 ]
  Percentage of participants who prematurely discontinued study due to AEs will be reported.

Current Secondary Outcome Measures (submitted: April 5, 2024)

• 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).
• 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).
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Original Secondary Outcome Measures (submitted: July 8, 2019)

• Percentage of Participants with AEs/Human Immunodeficiency Virus (HIV)-related Events Through 24 and 48 Weeks [ Time Frame: Up to 24 and 48 weeks ]
  Percentage of participants with AEs/HIV-related events through 24 and 48 weeks of study treatment will be reported.
• Severity of AEs/HIV-related Events Through 24 and 48 Weeks of Study Treatment [ Time Frame: Up to 24 and 48 weeks ]
  Severity of AEs/HIV-related events will be assessed based on DAIDS grading table where Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe; Grade 4: Potentially Life-threatening.
• Percentage of Participants with Abnormalities in Clinically Laboratory Parameters [ Time Frame: Up to 24 and 48 weeks ]
  Percentage of participants with abnormalities in Clinically Laboratory results will be reported.
• Percentage of Participants with Abnormalities in Electrocardiogram (ECG) [ Time Frame: Up to 24 and 48 weeks ]
  Percentage of participants with abnormalities in ECG will be reported.
• Percentage of Participants with Abnormalities in Vital Signs [ Time Frame: Up to 24 and 48 weeks ]
  Percentage of participants with abnormalities in vital signs will be reported.
• Percentage of Participants with Abnormalitie in Physical Examination [ Time Frame: Up to 24 and 48 weeks ]
  Percentage of participants with abnormalitie in physical examination will be reported.
• Percentage of Participants with HIV-1 Ribonucleic Acid (RNA) <50 and >=50 Copies/mL Through 24 and 48 Weeks [ Time Frame: Up to 24 and 48 weeks ]
  Percentage of participants having viral load (plasma HIV-1 RNA levels) less than (<) 50 copies/milliliter (mL) and >=50 copies/mL measured by the Food and Drug Administration (FDA) snapshot algorithm will be reported. The FDA snapshot analysis is based on the last observed plasma viral load data within the visit window (that is, Weeks 24 and 48).
• Cluster Differentiation 4 (CD4+) Cell Count Through 24 and 48 Weeks [ Time Frame: Up to 24 and 48 weeks ]
  CD4+ cell count for immunologic changes will be determined through Weeks 24 and 48.
• Predose Plasma Concentration (C0h) of RPV [ Time Frame: Predose ]
  C0h is defined as the predose plasma concentration or concentration just prior to study drug administration (observed and through population PK analysis).
• Maximum Observed Plasma Concentration (Cmax) of RPV [ Time Frame: Predose, 2, 4, 5, 6, 9, 12, 24 hours postdose ]
  Cmax is the maximum observed plasma concentration.
• Percentage of Participants with Virologic Failure [ Time Frame: Up to 24 and 48 weeks ]
  Percentage of participants with virologic failure (that is, HIV 1 RNA >=50 and >=400 copies/mL) per Snapshot approach will be reported.
• Percentage of Participants with Treatment Adherence Based on Tablet Count Through 24 and 48 Weeks [ Time Frame: Up to 24 and 48 weeks ]
  Percentage of participants with treatment adherence as assessed by tablet count (study intervention accountability) through 24 and 48 weeks of study treatment will be reported.
• Percentage of Participants with Treatment Adherence as Assessed by PENTA Adherence Questionnaire Through 24 and 48 Weeks [ Time Frame: Up to 24 and 48 weeks ]
  Percentage of participants with treatment adherence as assessed by Acquired Immune Deficiency Syndrome (AIDS) Pediatric European Network for the Treatment (PENTA) adherence questionnaire through 24 and 48 weeks of study treatment will be reported. The responses to the PENTA adherence questionnaire will be tabulated at each time point. Treatment adherence will be further summarized per time point based on a "worst case" combination of results for a number of sponsor-selected questions, categorizing participants into "treatment adherent" and "treatment non-adherent".

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study of Switching to RPV Plus Other ARVs in HIV-1-infected Children (Aged 2 to <12 Years) Who Are Virologically Suppressed
• 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
• 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.
• 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 Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: HIV

Intervention

• 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.

Study Arms

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.

Interventions:

• Drug: Rilpivirine
• Drug: ARV Background Regimen

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: October 25, 2022): 26
• Original Estimated Enrollment (submitted: July 8, 2019): 30
• Actual Study Completion Date: February 23, 2023
• Actual Primary Completion Date: February 17, 2023 (Final data collection date for primary outcome measure)

Eligibility 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 2 Years to 11 Years (Child)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Italy, Portugal, South Africa, Spain, Thailand, Uganda
• Removed Location Countries: Romania

Administrative Information

• NCT Number: NCT04012931
• Other Study ID Numbers: CR108606; 2018-004301-32 ( EudraCT Number ); TMC278HTX2002 ( Other Identifier: Janssen Research & Development, LLC )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• 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

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

• Current Responsible Party: Janssen Research & Development, LLC
• Original Responsible Party: Same as current
• Current Study Sponsor: Janssen Research & Development, LLC
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

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

• PRS Account: Janssen Research & Development, LLC
• Verification Date: April 2024