| 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 | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10068341 |
| E.1.2 | Term | HIV-1 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 antiretroviral activity of doravirine/islatravir (DOR/ISL) compared to placebo, each given in combination with failing antiretroviral therapy (ART) as assessed by the percentage of participants achieving ≥0.5 log10 decrease in HIV-1 RNA from study baseline (Day 1) to Day 8 (Part 1)
2.To evaluate the safety and tolerability of DOR/ISL at Week 25 and Week 49 as assessed by review of the accumulated safety data through study duration.
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| E.2.2 | Secondary objectives of the trial |
1.To assess antiretroviral activity of DOR, ISL+failing antiretroviral therapy (ART) based on % of participants with ≥0.5 log10 decrease in HIV-1 RNA
2.To assess antiretroviral activity of DOR/ISL, DOR, or ISL+failing ART based on % of participants with ≥1.0 log10 decrease in HIV-1 RNA
3.To assess antiretroviral activity of DOR, ISL + failing ART based on % of participants with ≥0.5 log10 decrease in HIV-1 RNA; mean change in HIV-1 RNA; and % of participants with ≥1.0 log10 decrease in HIV-1 RNA
4.To assess antiretroviral activity of DOR, ISL, optimized background therapy (OBT) based on % of participants achieving ≥0.5 log10 and ≥1.0 log10 decrease in HIV-1 RNA; mean change in HIV-1 RNA; % of participants with HIV-1 RNA <50 and <200 copies/mL; and % of participants with HIV-1 RNA <40 copies/mL
5.To assess development of viral drug resistance to DOR, ISL, OBT
6.To assess the role of baseline antiviral resistance on virologic outcomes
7.To assess the change in CD4+ T-cell counts
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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 |
Merck will conduct Future Biomedical Research on DNA (Blood)
specimens collected during this clinical trial. Such research is for
biomarker testing to address emergent questions not described
elsewhere in the protocol (as part of the main trial) and will only be
conducted on specimens from appropriately consented subjects. The
objective of collecting specimens for Future Biomedical Research is to
explore and identify biomarkers that inform the scientific understanding diseases and/or their therapeutic treatments. The overarching goal is to use such information to develop safer, more effective drugs, and/or to ensure that subjects receive the correct dose of the correct drug at the correct time. |
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| E.3 | Principal inclusion criteria |
1. Is HIV-1 positive with plasma HIV-1 RNA ≥ 500 copies/mL at the Screening Visit and confirmed upon repeat testing (Visit 2 [or Visit 3 if required]) during the Run-in period.
In addition, the log change in HIV-1 RNA must meet 1 of the following criteria at a confirmation visit:
- < 0.5 log10 decline in HIV-1 RNA from the Screening Visit (Visit 1) to the Confirmation visit (Visit 2)
OR
- If ≥ 0.5 log10 decline in HIV-1 RNA at Visit 2, another confirmation test is required (Visit 3). In this case, there must be < 0.3 log10 decline in HIV-1 RNA from Visit 2
2. Has been receiving the same baseline ART for ≥3 months prior to signing the Informed Consent Form/Assent Form.
3. Has at least triple-class resistance (NRTI, NNRTI, and resistance to at least 1 other class [ie, resistance to at least 1 drug in each class]) based on resistance testing at the Screening Visit.
4. Has ≤1 fully active antiretroviral remaining that can be effectively combined to form a viable regimen based on resistance, tolerability, safety, drug access, or acceptability to participant.
5. Is male or female, from 12 years of age inclusive, and weighing ≥ 35 kg, at the time of signing the informed consent/assent (the Screening Visit).
6. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
- Is not a woman of childbearing potential (WOCBP)
OR
- Is a WOCBP and using an acceptable contraceptive method, or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis), during the intervention period and for at least 6 weeks, corresponding to the time needed to eliminate any study intervention(s) (eg, 5 terminal half-lives) after the last dose of study intervention. The investigator should evaluate the potential for contraceptive method failure (ie, noncompliance, recently initiated) in relationship to the first dose of study intervention.
- A WOCBP must have a negative highly sensitive pregnancy test ([urine or serum] as required by local regulations) within 24 hours before the first dose of study intervention.
- If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.
- The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.
7. The participant (or legally acceptable representative if applicable) provides written informed consent/assent for the study. The participant may also provide consent/assent for future biomedical research. However, the participant may participate in the main study without participating in future biomedical research. |
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| E.4 | Principal exclusion criteria |
1. Has HIV-2 infection.
2. Has hypersensitivity or other contraindication to any of the components of the study interventions as determined by the investigator.
3. Has HBV co-infection (defined as HBsAg-positive or HBV DNA positive) and is not currently being treated for HBV.
4. Has a history or current evidence of any condition, therapy (including active TB co-infection), laboratory abnormality or other circumstance (including drug or alcohol abuse or dependence) that might, in the opinion of the investigator, confound the results of the study or interfere with study participation for the full study duration.
5. Is taking or is anticipated to require any of the prohibited therapies from the Screening Visit and throughout the study treatment period.
6. Is taking DOR as part of his/her current failing antiretroviral regimen.
7. Is taking EFV, etravirine, or nevirapine.
8. Is currently participating in or has participated in an interventional clinical study with an investigational compound or device from the Screening Visit through the study treatment period.
9. Has exclusionary laboratory values (based on central laboratory results) at the Screening Visit
10. Is female and is expecting to conceive or donate eggs at any time during the study. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Percentage of participants receiving DOR/ISL with ≥0.5 log10 decrease from baseline in HIV-1 RNA compared to placebo treatment
2. Percentage of participants with ≥1 adverse events (AEs)
3. Percentage of participants withdrawing from study treatment due to AE(s)
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Day 1 (baseline) to Day 8
2. Up to 49 weeks
3. Up to 49 weeks
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| E.5.2 | Secondary end point(s) |
1. Percentage of participants receiving DOR or ISL (given with ART) with ≥0.5 log10 decrease in HIV-1 RNA compared to placebo treatment
2. Mean change from baseline in HIV-1 RNA following treatment with DOR/ISL (given with ART) , DOR, or ISL compared to placebo treatment
3. Percentage of participants receiving DOR/ISL (given with ART), DOR, or ISL with ≥1.0 log10 decrease from baseline in HIV-1 RNA compared to placebo treatment
4. Percentage of participants receiving DOR/ISL (given with ART) with ≥0.5 log10 decrease from baseline in HIV-1 RNA compared to DOR or ISL treatment
5. Mean change from baseline in HIV-1 RNA following treatment with DOR/ISL (given with ART) compared to DOR or ISL treatment
6. Percentage of participants receiving DOR/ISL (given with ART) with ≥1.0 log10 decrease from baseline in HIV-1 RNA compared to DOR or ISL treatment
7. Percentage of participants receiving DOR/ISL (given with ART) + OBT with ≥0.5 log10 decrease from baseline in HIV-1 RNA compared to DOR or ISL treatment
8. Percentage of participants receiving DOR/ISL (given with ART) + OBT with ≥0.5 log10 decrease from baseline in HIV-1 RNA compared to DOR or ISL treatment
9. Percentage of participants receiving DOR/ISL (given with ART) + OBT with ≥1.0 log10 decrease from baseline in HIV-1 RNA compared to DOR or ISL treatment
10. Percentage of participants receiving DOR/ISL (given with ART) + OBT with ≥1.0 log10 decrease from baseline in HIV-1 RNA compared to DOR or ISL treatment
11. Mean change from baseline in HIV-1 RNA following treatment with DOR/ISL (given with ART) + OBT
12. Mean change from baseline in HIV-1 RNA following treatment with DOR/ISL (given with ART) + OBT
13. Percentage of participants receiving DOR/ISL (given with ART) + OBT with HIV-1 RNA <200 copies mL
14. Percentage of participants receiving DOR/ISL (given with ART) + OBT with HIV-1 RNA <200 copies mL
15. Percentage of participants receiving DOR/ISL (given with ART) + OBT with HIV-1 RNA <50 copies mL
16. Percentage of participants receiving DOR/ISL (given with ART) + OBT with HIV-1 RNA <50 copies mL
17. Percentage of participants receiving DOR/ISL (given with ART) + OBT with HIV-1 RNA <40 copies mL
18. Percentage of participants receiving DOR/ISL (given with ART) + OBT with HIV-1 RNA <40 copies mL
19. Prevalence of viral drug resistance to DOR
20. Prevalence of viral drug resistance to DOR
21. Prevalence of viral drug resistance to ISL
22. Prevalence of viral drug resistance to ISL
23. Prevalence of viral drug resistance to OBT components
24. Prevalence of viral drug resistance to OBT components
25. Role of baseline antiviral resistance on viral resistance-associated substitutions (RAS)
26. Role of baseline antiviral resistance on viral RAS
27. Role of baseline antiviral resistance on HIV-1 RNA
28. Role of baseline antiviral resistance on HIV-1 RNA
29. Change from baseline in cluster of differentiation+ (CD4+) cell counts
30. Change from baseline in CD4+ cell counts
31. Change from baseline in CD4+ cell counts
32. Change from baseline in CD4+ cell counts
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1.to 6. Day 1 (baseline) to Day 8
7.Day 8 (baseline) to Week 25
8.Day 1 (baseline) to Week 49
9.Day 8 (baseline) to Week 25
10.Day 1 (baseline) to Week 49
11.Day 8 (baseline) to Week 25
12.Day 1 (baseline) to Week 49
13.Day 8 (baseline) to Week 25
14.Day 1 (baseline) to Week 49
15.Day 8 (baseline) to Week 25
16.Day 1 (baseline) to Week 49
17.Day 8 (baseline) to Week 25
18.Day 1 (baseline) to Week 49
19.Week 25
20.Week 49
21.Week 25
22.Week 49
23.Week 25
24.Week 49
25.Day 1 (baseline) to Week 25
26.Day 1 (baseline) to Week 49
27.Day 8 (baseline) to Week 25
28.Day 8 (baseline) to Week 49
29.Day 1 (baseline) to Week 25
30.Day 1 (baseline) to Week 49
31.Day 8 (baseline) to Week 25
32.Day 8 (baseline) to Week 49 |
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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 | 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 | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | Yes |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Open single group in Part 2 |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 5 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 11 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 43 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Chile |
| Colombia |
| Peru |
| Australia |
| Japan |
| Korea, Republic of |
| Mexico |
| Russian Federation |
| South Africa |
| United Kingdom |
| United States |
| France |
| Germany |
| Italy |
| Portugal |
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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.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| 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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