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

Study Overview
=================
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).

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

Conditions
-----------------
HIV

Intervention / Treatment
-----------------
* Drug: Rilpivirine
* Drug: ARV Background Regimen


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Weighing at least 11 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

Ages Eligible for Study
-----------------
Minimum Age: 2 Years
Maximum Age: 11 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rilpivirine (RPV) (25 mg or adjusted weight-based dose)<br>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<br>* Rilpivirine 25 mg tablets for the 25 mg daily dose, or tablets for or a weight-adjusted dose. Administered orally once daily.<br>* Other names: TMC278;Drug: ARV Background Regimen<br>* 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.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Plasma Concentration-time Curve from Time of Administration up to 24 Hours Postdose (AUC[24h]) of Rilpivirine (RPV) | 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. | Up to 24 hours postdose | 
| Percentage of Participants with Grade 3 and 4 Adverse Events (AEs) and Serious Adverse Events (SAEs) Through 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 deemed medically important, or is a suspected transmission of any infectious agent via a medicinal product, or is an AE resulting in any of the following outcomes: death, is life-threatening. | Up to Week 24 | 
| Percentage of Participants with Human Immunodeficiency Virus (HIV)-Related Events | Percentage of participants with HIV-related events HIV-related events (including acquired immune deficiency syndrome [AIDS]-defining illnesses and Stage-3-defining Opportunistic Illnesses in HIV Infection) through 24 weeks of study treatment will be reported. | Up to Week 24 | 
| Percentage of Participants Experiencing Premature Discontinuation due to AEs Through Week 24 | Percentage of participants who prematurely discontinued study due to AEs will be reported. | Up to Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants with AEs/Human Immunodeficiency Virus (HIV)-related Events Through 24 and 48 Weeks | Percentage of participants with AEs/HIV-related events through 24 and 48 weeks of study treatment will be reported. | Up to 24 and 48 weeks | 
| Severity of AEs/HIV-related Events Through 24 and 48 Weeks of Study Treatment | 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. | Up to 24 and 48 weeks | 
| Percentage of Participants with Abnormalities in Clinically Laboratory Parameters | Percentage of participants with abnormalities in Clinically Laboratory results will be reported. | Up to 24 and 48 weeks | 
| Percentage of Participants with Abnormalities in Electrocardiogram (ECG) | Percentage of participants with abnormalities in ECG will be reported. | Up to 24 and 48 weeks | 
| Percentage of Participants with Abnormalities in Vital Signs | Percentage of participants with abnormalities in vital signs will be reported. | Up to 24 and 48 weeks | 
| Percentage of Participants with Abnormalitie in Physical Examination | Percentage of participants with abnormalitie in physical examination will be reported. | Up to 24 and 48 weeks | 
| Percentage of Participants with HIV-1 Ribonucleic Acid (RNA) <50 and >=50 Copies/mL Through 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). | Up to 24 and 48 weeks | 
| Percentage of Participants with HIV-1 Ribonucleic Acid (RNA) <400 and >=400 Copies/mL Through 24 and 48 Weeks | Percentage of participants having viral load (plasma HIV-1 RNA levels) less than (<) 400 copies/milliliter (mL) and >=400 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). | Up to 24 and 48 weeks | 
| Cluster Differentiation 4 (CD4+) Cell Count Through 24 and 48 Weeks | CD4+ cell count for immunologic changes will be determined through Weeks 24 and 48. | Up to 24 and 48 weeks | 
| Predose Plasma Concentration (C0h) of RPV | C0h is defined as the predose plasma concentration or concentration just prior to study drug administration (observed and through population PK analysis). | Predose | 
| Maximum Observed Plasma Concentration (Cmax) of RPV | Cmax is the maximum observed plasma concentration. | Predose, 2, 4, 5, 6, 9, 12, 24 hours postdose | 
| Percentage of Participants with Virologic Failure | Percentage of participants with virologic failure (that is, HIV 1 RNA >=50 and >=400 copies/mL) per Snapshot approach will be reported. | Up to 24 and 48 weeks | 
| Percentage of Participants with Treatment Adherence Based on Tablet Count Through 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. | Up to 24 and 48 weeks | 
| Percentage of Participants with Treatment Adherence as Assessed by PENTA Adherence Questionnaire Through 24 and 48 Weeks | Percentage of participants with treatment adherence as assessed by the Pediatric European Network for the Treatment of AIDS (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. | Up to 24 and 48 weeks |