| 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.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Cohort 1:
1. To confirm the doses for oral CAB followed by injectable CAB LA in adolescents living with HIV who are virologically suppressed by evaluating:
- Safety and multiple dose PK of oral CAB through Week 4;
- Safety and multiple dose PK of CAB LA through Week 16
2. To confirm doses for injectable RPV LA in adolescents living with HIV who are virologically suppressed. by evaluating safety and multiple dose PK of RPV LA through Week 16.
Cohort 2:
1. To assess the safety of CAB + RPV in adolescents living with HIV who are virologically suppressed through:
- Week 24 (Cohort 2A: oral followed by injectable);
- Week 20 (Cohort 2B: injectable only). |
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| E.2.2 | Secondary objectives of the trial |
Cohort 1:
1. To monitor maintenance of viral suppression through Week 16 in adolescents living with HIV who are virologically suppressed
2. To evaluate the tolerability and acceptability of CAB LA through Week 16 in adolescents living with HIV who are virologically suppressed
3. To evaluate the tolerability and acceptability of RPV LA through Week 16 in adolescents living with HIV who are virologically suppressed
Cohort 2:
1. To assess safety of CAB LA + RPV LA in adolescents living with HIV who are virologically suppressed through the period mentioned in protocol.
2. To evaluate repeat-dose pharmacokinetics of CAB LA + RPV LA in adolescents living with HIV who are virologically suppressed through the period mentioned in protocol.
3. To assess antiviral activity of CAB LA + RPV LA in adolescents living with HIV who are virologically suppressed through the period mentioned in protocol. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Inclusion Criteria: Cohort 1 Step 1, Cohort 2A Step 3, and Cohort 2B Step 5
1. At enrollment, 12 to < 18 years of age
2. If not of legal age or otherwise not able to provide independent informed consent as determined by site SOPs and consistent with site institutional review board (IRB)/ ethics committee (EC) policies and procedures: Parent or legal guardian is willing and able to provide written informed consent for study participation and potential participant is willing and able to provide written assent for study participation
If of legal age or otherwise able to provide independent informed consent as determined by site SOPs and consistent with site IRB/EC policies and procedures: Willing and able to provide written informed consent for study participation
3. At enrollment, body weight ≥ 35 kg (77 lbs.)
4. For Cohort 1, at enrollment, body mass index (BMI) < 31.5 kg/m2
5. At enrollment, willing and able to comply with the study visit schedule and other study requirements, as determined by the site investigator or designee
6. Confirmed HIV-1 disease based on documented testing of two samples collected from two separate blood collection tubes per Sample #1 and Sample #2 requirements, at different time points. Test results may be obtained from medical records or from testing
performed during the study screening period as mentioned in protocol.
7. For at least 3 consecutive months (defined as 90 consecutive days) prior to screening, and prior to enrollment, has been on stable unchanged cART consisting of 2 or more drugs from 2 or more classes of antiretroviral drugs, ascertainment of this criterion may be based on parent or guardian report only, but available medical records should also be reviewed in relation to this criterion.
8. Has at least one documented plasma HIV-1 RNA result less than the lower limit of detection of the assay from a specimen collected in the 6 to 12 months (defined as 180 to 365 days) prior to entry OR
Has at least one documented plasma HIV-1 RNA result less than the lower limit of detection of the assay from a specimen less than 6 months (defined as within 179 days) prior to entry and at least one documented plasma HIV-1 RNA result less than the lower
limit of detection of the assay from a specimen collected in the 12-18 months (defined as 365 to 545 days) prior to entry. OR
For Cohort 1 participants enrolling to Cohort 2, has documented plasma HIV-1 RNA results less than the lower limit of detection of the assay from all indicated Cohort 1 study visits with their Cohort 1 Week 16 visit completed within 28 days prior to Cohort 2 entry
9. At screening, has Grade 2 or lower of all the laboratory test results as mentioned in protocol.
10. At screening, is on an atazanavir-containing (ATV) cART regimen and has total bilirubin ≤ 1.5 mg/dL or normal direct bilirubin
11. At screening, has documented plasma HIV-1 RNA < 50 copies/mL
12. At screening, mean value of QTc interval (automated machine readout or calculated using either Bazett or Fridericia) on ECG performed in triplicate, < 500 msec.
13. For females, has a negative (blood or urine) hCG laboratory test result at entry
14. For females of childbearing potential, at entry, currently using at least one allowable effective method of contraception, and agrees to use at least one allowable effective method of contraception throughout study participation, for at least 30 days after discontinuation of oral study product, and for at least 48 weeks after discontinuation of CAB LA and/or RPV LA, and intending to delay any planned pregnancies until 30 days after last oral study product use or until 48 weeks after last injectable study product use.
15. For Cohort 1 participants enrolling to Cohort 2, have completed all scheduled product injections and completed Week 16 visit in Cohort 1 Step 2
Inclusion Criteria, Step 2 (Cohort 1 Progression Criteria, Step 1 to Step 2):
1. Currently enrolled in Cohort 1, Step 1
2. At Cohort 1 Step 1 Week 4a study visit, or from confirmatory repeat testing of Cohort 1 Step 1 Week 4a study visit laboratory tests, has Grade 2 or lower of all the laboratory test results as mentioned in protocol
3. For females, at Cohort 1 Step 1 Week 4b study visit, has a negative hCG laboratory test result
For detailed list of criteria, please refer section 4.1, 4.3, 4.4, 4.5 of the protocol |
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| E.4 | Principal exclusion criteria |
Exclusion Criteria: Cohort 1 Step 1, Cohort 2A Step 3, and Cohort 2B Step 5
1. Within 6 months (defined as within 179 days) prior to entry, two consecutive documented HIV-1 RNA values greater than or equal to the lower limit of detection of the assay
2. For Cohort 1 participants enrolling to Cohort 2A Step 3 or to Cohort 2B Step 5, occurrence of any Grade 3 or higher adverse event assessed as related to study product or permanent discontinuation of study product due to an adverse event of any grade assessed as related to study product, during participation in Cohort 1 (including any long-term safety and washout PK follow-up visits).
3. For participants enrolling to Cohort 1 Step 1, based on available medical records, currently on either a cART regimen containing both a PI and an INSTI, or a cART regimen containing both an INSTI and a NNRTI.
4. As determined by the IoR or designee, and based on available medical records, known or suspected resistance to RPV
5. As determined by the IoR or designee based on available medical records, known or suspected resistance to INSTIs
6. History of congestive heart failure, symptomatic arrhythmia, or any clinically significant cardiac disease, as determined by the IoR or designee based on available medical records
7. At entry, known active tuberculosis infection, as determined by the Investigator of Record (IoR) or designee based on available medical records
8. Known hepatitis B or hepatitis C infection, as determined by the IoR or designee based on available medical records
9. Clinically significant hepatic disease, as determined by the IoR or designee based on available medical records
10. Current or anticipated need for chronic anti-coagulation, as determined by the IoR or designee, based on available medical records
11. History of sensitivity to heparin or heparin-induced thrombocytopenia, as determined by the IoR or designee, based on available medical records
12. History of known or suspected bleeding disorder including history of prolonged bleeding, as determined by the IoR or designee, based on available medical records
13. Known or suspected allergy to study product components
14. More than one seizure within one year (defined as within 365 days) prior to entry, or unstable or poorly controlled seizure disorder, as determined by the IoR or designee, based on available medical records.
15. At entry, participant is receiving (or has received in the last 7 days) any disallowed medication listed in Section 5.7.
16. Current inflammatory skin condition that compromises the safety of intramuscular
injections as determined by the IoR or designee.
17. Has a tattoo or other dermatological condition overlying the buttock region which, in the opinion of the IoR or designee, may interfere with interpretation of injection site reactions
18. Surgically‐placed, or planned, buttock implants, per self‐report
19. For females, lactating (per self-report and/or parent/guardian report) at entry
20. Enrolled in another clinical trial of an investigational agent, device, or vaccine
21. Any other condition or social circumstance situation that, in the opinion of the IoR or designee, would make study participation unsafe, complicate interpretation of study outcome data, or otherwise interfere with achieving the study objectives
Exclusion Criteria, Step 2 (Cohort 1 Progression Criteria, Step 1 to Step 2):
1. Has permanently discontinued oral study product
2. Occurrence of any grade 3 or higher adverse event assessed as related to study product during participation in Step 1
3. Any other condition or social circumstance that, in the opinion of the IoR or designee, would make study participation unsafe, complicate interpretation of study outcome data, or otherwise interfere with achieving the study objectives.
For detailed list of criteria, please refer section 4.2, 4.3, 4.4, 4.5 of the protocol |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Pharmacokinetic output measures as data permit:
• Cohort 1C – Step 1 PO dosing: Wk. 2 AUC, CL/F, Cmax, Tmax, and pre-dose concentrations (C0).
• Cohort 1C – Step 2 LA dosing: Wk. 16 concentrations (C16WK), Cmax, Tmax (Dose 1) and C0 prior to IM doses.
• Cohort 1R – Step 2 LA dosing: Wk. 16 concentrations (C16WK), Cmax, Tmax (Dose 1) and C0 prior to IM doses. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Cohort 1: Week 4 through Week 16
Cohort 2A: Through Week 24
Cohort 2B: Through Week 20 |
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| E.5.2 | Secondary end point(s) |
Pharmacokinetic outcome measures as data permit
• Cohort 2A (oral followed by injectable): CAB and RPV pre-dose concentrations following PO administration at Step 3 Wk. 2.
• Cohort 2A (oral followed by injectable): CAB and RPV concentrations following IM administration at Step 4 from Wk. 8 (after the first LA injections) to Wk. 24 and accumulation ratio (Wk. 24 Pre-dose Conc: Wk. 8 Pre-dose concentration).
• Cohort 2B (injectable only): CAB and RPV concentrations following IM administration at Step 5 from Wk. 4 (after the first LA injections) to Wk. 20 and accumulation ratio (Wk. 20 Pre-dose Conc: Wk. 4 Pre-dose
concentration).
• Cohort 2A (oral followed by injectable): CAB and RPV concentrations following IM administration at Step 4 from Wk. 8 (after the first LA injections) to Wk. 48 and accumulation ratio (Wk. 48 Pre-dose Conc: Wk. 8 Pre-dose concentration).
• Cohort 2B (injectable only): CAB and RPV concentrations following IM administration at Step 5 from Wk. 4 (after the first LA injections) to Wk. 44 and accumulation ratio (Wk. 44 Pre-dose Conc: Wk. 4 Pre-dose concentration)
• Cohort 2A (oral followed by injectable): CAB and RPV concentrations following IM administration at Step 4 from Wk. 16 (after the first LA injections) to Wk. 24 and accumulation ratio (Wk. 24 Pre-dose Conc: Wk. 16 Pre-dose concentration).
• Cohort 2B (injectable only): CAB and RPV concentrations following IM administration at Step 5 from Wk. 12 (after the first LA injections) to Wk. 20 and accumulation ratio (Wk. 20 Pre-dose Conc: Wk. 12 Pre-dose concentration).
• Cohort 2A (oral followed by injectable): CAB and RPV concentrations following IM administration at Step 4 from Wk. 16 (after the first LA injections) to Wk. 48 and accumulation ratio (Wk. 48 Pre-dose Conc: Wk. 16 Pre-dose concentration).
• Cohort 2B (injectable only): CAB and RPV concentrations following IM administration at Step 5 Wk. 12 (after the first LA injections) to Wk. 44 and accumulation ratio (Wk. 44 Pre-dose Conc: Wk. 12 Pre-dose concentration). |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Cohort 1: Through Week 16
Cohort 2A: Through Week 24 and Week 48
Cohort 2B: Through Week 20 and Week 44 |
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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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| 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 |
| Uganda |
| South Africa |
| Thailand |
| United States |
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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 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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