| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Virus Diseases [C02] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 16.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10020192 |
| E.1.2 | Term | HIV-1 |
| E.1.2 | System Organ Class | 100000004862 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
- To determine the appropriate dose of RPV in combination with two NRTIs for antiretroviral naïve HIV-1 infected children < 12 years of age.
- To evaluate the steady-state pharmacokinetics of RPV in combination with two NRTIs in antiretroviral naïve HIV-1 infected children < 12 years of age.
- To assess the safety and tolerability of RPV in combination with two NRTIs through 24 weeks of therapy in antiretroviral naïve HIV-1 infected children < 12 years of age.
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| E.2.2 | Secondary objectives of the trial |
- To examine steady-state RPV pharmacokinetic parameters after intense PK sampling and evaluate the short term tolerability, safety, and antiviral activity of RPV in approximately 10 to 12 subjects allowing the selection of a dose for further study in Stage 2 (Stage 1 only).
-To assess the antiretroviral activity of RPV in combination with two NRTIs through 24 and 48 weeks of therapy
-To determine the immunological changes through 24 and 48 weeks of RPV therapy in combination with two NRTIs
-To determine the safety and tolerability of RPV in combination with two NRTIs through 48 weeks of therapy
-To assess the evolution of viral resistance of RPV in combination with 2 NRTIs through 48 weeks of therapy
-To explore the PK-PD relationship between RPV exposure and the efficacy and safety/tolerability of RPV
-To examine the association of CYP3A4 genetic variants with RPV pharmacokinetics
-To evaluate the long-term safety and efficacy of RPV up to 240 weeks of treatment
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Inclusion Criteria - Stage 1, Step 1 and Stage 2:
- A confirmed HIV-1 infection. More information on this criterion can be found in the protocol.
- Participant has never been treated with an HIV vaccine
- No evidence of prior ARV drug use with the exception of prior use of zidovudine (AZT) for up to 6 weeks to prevent mother-to-child transmission
- HIV-1 plasma viral load (VL) at screening greater than 500 HIV-1 RNA copies/mL but less than or equal to 100,000 HIV-1 RNA copies/mL (assayed by RNA polymerase chain reaction [PCR] standard specimen procedure) Note: Participants may be re-screened once only, if their baseline VL does not meet the entry criteria.
- In the judgment of the investigator, it is appropriate to initiate ARV therapy based on the participant's medical condition and taking into account guidelines for the treatment of HIV-1 infection in children
- Results from the genotypic resistance testing at screening demonstrate sensitivity to the selected NRTIs for the chosen background regimen
- Able to swallow whole tablets (Cohort 1 initial dose only)
- Female participants who are of child bearing potential and who are engaging in sexual activity that could lead to pregnancy, must use two adequate birth control methods while on study and for 4 weeks after stopping study drug. More information on this criterion can be found in the protocol.
- Children ages ≥ 2 years to < 12 years
Inclusion Criteria - Stage 1, Step 2:
- Participants belonging to a cohort that failed Stage 1 Step 1 initial dose that meet the following criteria (as determined by the study team): Are able to have an adjustment in study drug dose (and the new dose would not exceed 25 mg) and appear to have room to stay within therapeutic range on the new dose
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| E.4 | Principal exclusion criteria |
Exclusion Criteria - Stage 1, Step 1 and Stage 2:
- Having documented genotypic evidence of RPV resistance. More information on this criterion can be found in the protocol.
- Documented evidence of infection during breastfeeding by a mother taking NNRTI-based ART. If there are no data or no history available then the participant would be eligible as long as all other inclusion and exclusion criteria are fulfilled.
- Documented evidence of maternal NNRTI use during pregnancy. If there are no data or no history available then the participant would be eligible as long as all other inclusion and exclusion criteria are fulfilled.
- Previously documented HIV-2 infection in participant or participant's mother. If there are no data or no history available then the participant would be eligible as long as all other inclusion and exclusion criteria are fulfilled.
- Use of disallowed medication from 4 weeks prior to the entry visit or anticipated use of any disallowed medications
- Participant has used chronic systemic immunosuppressive agents within 30 days prior to entry or is anticipated to need chronic systemic immunosuppressive agents during the study. Short courses of systemic corticosteroids (e.g., prednisone or equivalent up to 2 mg/kg/day for 7 days) are permitted. Inhaled and intranasal steroids are permitted.
- Participant has any active AIDS-defining illness (Category C conditions according to the Centers for Disease Control and Prevention [CDC] revised Classification System for HIV Infection 1994), within 30 days prior to screening. Stable not currently active conditions that are not likely to interfere with safety assessments may be allowed with permission from the protocol team.
- Any active clinically significant disease or findings (other than HIV infection) during screening or medical history or physical examination that in the investigator's opinion, would compromise the outcome of the study
- Any confirmed Grade 3 or 4 laboratory toxicity according to the Division of AIDS (DAIDS) grading table at screening, except for: asymptomatic Grade 3 absolute neutrophil count decrease; asymptomatic Grade 3 platelet count decrease; asymptomatic Grade 3 total amylase, triglyceride, cholesterol elevation
- Participant has active tuberculosis and/or is being treated for tuberculosis at screening
- Participant has one or more of the following risk factors for ECG QTc prolongation:
◦A confirmed prolongation of QT/QTc interval, (e.g., repeated demonstration of QTcF [Fridericia correction] interval greater than 450 ms in the screening ECG (i.e., retesting to reassess eligibility will be allowed once using an unscheduled visit during the screening period)
◦Pathological Q-waves (defined as Q-wave greater than 40 ms or depth greater than 0.4-0.5 mV)
◦Evidence of ventricular pre-excitation
◦Electrocardiographic evidence of complete right or complete or incomplete left bundle branch block
◦Evidence of second or third degree heart block
◦Intraventricular conduction delay with QRS duration greater than 120 ms
◦Bradycardia as defined by sinus rate less than 50 bpm
◦Personal or family history of long QT syndrome
◦Personal history of cardiac disease, symptomatic or asymptomatic arrhythmias, with the exception of sinus arrhythmia
◦Syncopal episodes
◦Risk factors for Torsade de Pointes (e.g., heart failure, hypokalemia)
- Participant's family is unlikely to adhere to the study procedures, keep appointments, or is planning to relocate to a non-IMPAACT study site during the study.
- Hepatitis B virus surface antigen (HBsAg) positive or hepatitis C virus (HCV) antibody positive
- Any history of malignancy
- Participant enrolled in another clinical trial of an investigational agent or experimental vaccine or a compound or device which is not commercially available
- Any history of adrenal insufficiency
- Pregnancy or breastfeeding if of childbearing potential |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
1 - Failure to meet PK guidelines
2 - Toxicity endpoint: termination from treatment due to a suspected adverse drug reaction (SADR)
3 - Toxicity endpoint: adverse events (AEs) or laboratory toxicities of Grade 3 or higher severity judged to be at least possibly attributable to the study medication
4 - Toxicity endpoint: death |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1 - Measured through week 48
2 - Measured through week 24
3 - Measured through week 24
4 - Measured through week 24 |
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| E.5.2 | Secondary end point(s) |
1 - Adverse events or laboratory toxicities of Grade 3 or higher severity judged to be at least possibly attributable to the study medications
2 - Adverse events meeting the International Conference on Harmonisation (ICH) seriousness criteria
3 - Treatment discontinued due to toxicity or virologic failure
4 - Failure to suppress plasma HIV RNA to less than 400 copies/mL
5 - Failure to achieve undetectable plasma HIV RNA (less than 40 copies/mL on Abbott RealTime HIV-1 assay, confirmed within 2 to 4 weeks)
6 - Virologic outcome as per Snapshot and time to loss of virologic response
7 - Sustained decline in absolute CD4 percent of greater than 5% any time after 12 weeks of therapy
8 - Long-term safety (AEs, toxicities of Grade 3 or higher severity, or deaths at least possibly related to treatment) after 48 weeks |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1 - Measured through Week 48
2 - Measured through participant's last study visit (through Week 48 or, for participants in long-term safety follow-up, through Week 240)
3 - Measured through participant's last study visit (through Week 48 or, for participants in long-term safety follow-up, through Week 240)
4 - Measured at Week 24 and Week 48
5 - Measured at Week 24 and Week 48
6 - Measured at Week 24 and Week 48
7 - Measured through Week 48
8 - Measured through Week 48 |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
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| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
Will this trial be conducted at a single site globally?
| No |
| E.8.4 | Will this trial be conducted at multiple sites globally? | Yes |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Yes |
| E.8.6.3 | Specify the countries outside of the EEA in which trial sites are planned |
| Botswana |
| Brazil |
| Malawi |
| South Africa |
| Tanzania, United Republic of |
| Uganda |
| United States |
| Zambia |
| Zimbabwe |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
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