| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Pediatric HIV-1 infection |
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| E.1.1.1 | Medical condition in easily understood language |
| Pediatric HIV-1 infection |
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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 | 20.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10020161 |
| E.1.2 | Term | HIV infection |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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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 |
1. To evaluate the pharmacokinetics (PK) of doravirine (DOR) at steady state when given with 2 nucleoside/nucleotide analog reverse transcriptase inhibitors (NRTIs).
2. To evaluate the safety and tolerability of DOR in combination with 2 NRTIs through Week 24.
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| E.2.2 | Secondary objectives of the trial |
1. To evaluate the PK of DOR in combination with 2 NRTIs as assessed by sparse PK sampling through Week 24.
2. To evaluate the safety and tolerability of DOR with 2 NRTIs through Weeks 48 and 96.
3. To evaluate the antiretroviral activity of DOR with 2 NRTIs separately in treatment-naïve (TN) and virologically-suppressed (VS) participants as assessed by % with HIV-1 RNA <50 copies/mL; HIV-1 RNA <200 copies/mL; HIV-1 RNA ≥50 copies/mL; d) Log10 drop from baseline (BL) in plasma HIV-1 RNA (TN only), at Weeks 24, 48, and 96.
4. To evaluate the immunologic effect of DOR with 2 NRTIs separately in TN and VS participants as measured by change from BL in CD4+ T-cell count at Weeks 24, 48, and 96.
5. To evaluate the emergence of genotypic or phenotypic resistance to DOR or other components of the regimen in the resistance analysis subset.
6. To evaluate adherence to DOR at Weeks 24, 48, and 96.
7. To evaluate the acceptability and palatability of oral pellets/granules of DOR.
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| Intensive PK sampling and analyses |
|
| E.3 | Principal inclusion criteria |
- Has HIV-1 infection confirmed at screening
- Has treatment history defined as either TN or with documented viral suppression (HIV-1 RNA <50 copies/mL)
- Body weight is >3 kg to <35 kg
- If female, is not pregnant or breastfeeding, and one of the following applies:
- is not a woman of childbearing potential (WOCBP)
- is a WOCBP using an acceptable form of contraception, or is abstinent
- if a WOCBP must have a negative pregnancy test (urine or serum) within 24 hours of the first dose of study intervention |
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| E.4 | Principal exclusion criteria |
- Has evidence of renal disease
- Demonstrates evidence of liver disease
- Has clinical or laboratory evidence of pancreatitis
- Has any history of malignancy
- Has presence of any active acquired immunodeficiency syndrome (AIDS)-defining Opportunistic Infection
- Has an active diagnosis of hepatitis, including hepatitis B co-infection
- Has current active tuberculosis and/or is being treated with a rifampicin-containing regimen
- Has a medical condition that precludes absorption or intake of oral pellets/granules
- Has a history or current evidence of any condition, therapy, laboratory abnormality, or other circumstance that might confound results of the study or interfere with participating for the entire duration of the study
- Is taking or is anticipated to require systemic immunosuppressive therapy, immune modulators, or other prohibited therapy
- Is currently participating in or has participated in an interventional clinical study with an investigational compound or device from 45 days prior to Day 1 through the treatment period
- Has a documented or known virologic resistance to DOR |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Area under the concentration-time curve from 0 to 24 hours postdose (AUC0-24hr) of DOR with 2 NRTIs in plasma at steady-state
2. Maximum concentration (Cmax) of DOR with 2 NRTIs in plasma at steady-state
3. Concentration at 24 hours (C24) of DOR with 2 NRTIs in plasma at steady-state
4. Time to maximum concentration (Tmax) of DOR with 2 NRTIs in plasma at steady-state
5. Percentage of participants with ≥1 adverse event (AE)
6. Percentage of participants with a Grade 3 or 4 AE
7. Overall mortality
8. Percentage of participants discontinuing from study treatment due to an AE
9. Percentage of participants discontinuing from study treatment due to a DOR-related AE
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Predose and 1, 2, 4, 12, and 24 hours postdose on Day 42
2. Predose and 1, 2, 4, 12, and 24 hours postdose on Day 42
3. 24 hours postdose on Day 42
4. Predose and 1, 2, 4, 12, and 24 hours postdose on Day 42
5. Up to 24 weeks
6. Up to 24 weeks
7. Up to 24 weeks
8. Up to 24 weeks
9. Up to 24 weeks
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| E.5.2 | Secondary end point(s) |
1. Plasma concentration of DOR with 2 NRTIs (sparse pharmacokinetics [PK])
2. Percentage of participants with ≥1 AE
3. Percentage of participants with Grade 3 or 4 AE
4. Overall mortality
5. Percentage of participants discontinuing from study treatment due to AE
6. Percentage of participants discontinuing from study treatment due to DOR-related AE
7. Percentage of participants with HIV-1 RNA <50 copies/mL
8. Percentage of participants with HIV-1 RNA <200 copies/mL
9. Percentage of VS participants with HIV-1 RNA ≥50 copies/mL
10. Percentage of TN participants with log10 change from BL in HIV-1 RNA
11. Percentage of TN participants with log10 change from BL in HIV-1 RNA
12. Percentage of TN participants with log10 change from BL in HIV-1 RNA
13. Change from baseline in CD4+ T-cell counts
14. Change from baseline in CD4+ T-cell counts
15. Change from baseline in CD4+ T-cell counts
16. Viral resistance-associated substitutions (RASs) to DOR or other treatment components
17. Adherence to DOR
18. Scores on a 5-point hedonic scale of oral pellets/granules of DOR
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Day 1 predose, Week 4 predose, Week 8 random, Week 12 random, and Week 24 predose and 0.5-2 hours postdose
2. Up to 48 and 96 weeks
3. Up to 48 and 96 weeks
4. Up to 48 and 96 weeks
5. Up to 48 and 96 weeks
6. Up to 48 and 96 weeks
7. Weeks 24, 48, and 96
8. Weeks 24, 48, and 96
9. Weeks 24, 48, and 96
10. Day 1 and Week 24
11. Day 1 and Week 48
12. Day 1 and Week 96
13. Day 1 and Week 24
14. Day 1 and Week 48
15. Day 1 and Week 96
16. Up to 96 weeks
17. Up to 96 weeks
18. Days 1 and 28
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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 | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| 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.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 |
| Mexico |
| Russian Federation |
| 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 | 7 |
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