| 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 | 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 |
1) To evaluate the antiretroviral activity of different doses of MK-8591 administered with Doravirine (DOR) + Lamivudine (3TC) compared to MK-1439A, as assessed by the proportion of participants with HIV-1 RNA <50 copies/mL at Week 24 and at Week 48.
2) To evaluate the safety and tolerability of different doses of MK-8591 administered with DOR + 3TC compared to MK-1439A.
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| E.2.2 | Secondary objectives of the trial |
1) To evaluate the sustained antiretroviral suppression in participants on the selected dose of MK-8591 + DOR compared to MK-1439A as assessed by the proportion of participants with HIV-1 RNA <50 copies/mL 24 and 48 weeks after switching to Part 2
2) To evaluate the immunologic effect of different doses of MK-8591 administered with DOR + 3TC compared to MK-1439A at Week 24, Week 48, Week 96 and week 144
3) To evaluate the antiretroviral suppression and immunologic effect of MK-8591A administered during open-label dosing in Part 4 of the trial
4) To evaluate the safety and tolerability of different doses of MK-8591 administered with DOR compared to MK-1439A 24 weeks after switching to Part 2
5) To evaluate the safety and tolerability of the selected dose of MK-8591 administered with DOR compared to MK-1439A at Week 96 and through study duration.
6) To evaluate the safety and tolerability of MK-8591A during open label
dosing in Part 4 of the trial. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Has HIV-1 infection as determined by a positive enzyme-linked immunosorbent assay and a screening plasma HIV-1 RNA (completed by the central laboratory) ≥1,000 copies/mL within 60 days of the treatment phase of the study
2. Has a screening CD4+ T-cell count ≥200 cells/mm3 (completed by the central laboratory) within 60 days prior to the treatment phase of this study
3. Is naïve to ART
Note: Naïve is defined as having received no (0 days) ART therapy for the treatment of active HIV-1 infection including prevention of mother-to-child transmission
4. Has the following laboratory values (completed by the central laboratory) within 60 days prior to the treatment phase of this study:
a) International normalized ratio ≤1.2
b) Urine protein is within normal limits (no more than trace protein by urine dipstick)
c) Hemoglobin ≥9.0 g/dL if female or ≥10.0 g/dL if male
d) Absolute neutrophil count ≥1000/mm3
e) Platelet count ≥100,000/mm3
f) Total serum bilirubin ≤the upper limit of normal (ULN)
g) Alkaline phosphatase <1.5 × ULN
h) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <1.5 × ULN
5. Has a calculated creatinine clearance (Clcr) ≥50 mL/min within 60 days prior to the treatment phase of this study , based Cockcroft-Gault equations
6. In the opinion of the investigator, the participant should be considered clinically stable, with no signs or symptoms of acute infection, at the time of entry into the study (i.e., clinical status and all chronic medications should be unchanged for at least 2 weeks prior to the start of treatment in this study)
7. Is a male or female at least 18 years of age on the day informed consent is signed
8. A female participant is eligible to participate if she is not pregnant (see Appendix 5 of the protocol), not breastfeeding, and at least one of the following conditions applies:
a.) Not a woman of childbearing potential (WOCBP) as defined in Appendix 5
OR
b.) A WOCBP who agrees to follow the contraceptive guidance in Appendix 5 during the treatment period and for at least 6 weeks (corresponding to time needed to eliminate any study treatments (MK-8591, DOR, or 3TC) or MK-1439A after the last dose of study treatment
9. All participants, male and female, agree to use barrier methods of
contraception when engaged in any sexual activity during treatment and
for 6 weeks following treatment
10. The participant (or legally acceptable representative, if applicable) provides written informed consent for the trial. The participant (or legally acceptable representative, if applicable) may also provide consent for Future Biomedical Research. However, the participant may enroll in the main trial without consenting to Future Biomedical Research |
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| E.4 | Principal exclusion criteria |
1. Has a history or current evidence of any condition, therapy, laboratory abnormality or other circumstance that might, in the opinion of the investigator, confound the results of the study or interfere with the participant’s participation for the full duration of the study, such that it is not in the best interest of the participant to participate
2. Is, at the time of signing informed consent, a user of recreational or illicit drugs or has had a history of drug or alcohol abuse or dependence that may interfere with trial participation. The nature and potential clinical context of the participant's illicit drug use, in relation to their exclusion from this trial, will be at the discretion of the investigator
3. Has significant hypersensitivity or other contraindication to any of the components of the study drugs as determined by the investigator
4. Has a history of malignancy ≤5 years prior to signing informed consent except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer
5. Is female and is expecting to donate eggs at any time during the study (donation of sperm should follow local guidelines for HIV-positive individuals)
6. Is breastfeeding or expecting to conceive
7. A WOCBP who has a positive urine pregnancy test on Day 1 before the first dose of study treatment. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
8. Has been treated for a viral infection other than HIV-1, such as hepatitis B, with an agent that is active against HIV-1, including, but not limited to, the following: adefovir, TDF, TAF, entecavir, FTC, or 3TC
9. Has used systemic immunosuppressive therapy or immune modulators within 30 days prior to treatment in this study or is anticipated to need them during the course of the study
10. Requires or is anticipated to require any of the following prohibited medications: Carbamazepine, Phenobarbital, Phenytoin, Rifabutin, Rifampin, Herbal remedies, St. John’s Wort, Modafinil, Bosentan, Nafcillin, Pentostatin
11. Is currently participating in or has participated in an interventional clinical trial with an investigational compound or device within 30 days of signing informed consent to participate in this current trial
12. Has a documented or known virologic resistance to any approved HIV-1 reverse transcriptase inhibitor, protease inhibitor, integrase inhibitor, or any study drug, as demonstrated by any the following resistance substitutions (according to the 2017 IAS-USA drug resistance mutations list [Wensing, A. M., et al 2017]):
a) NRTI resistance substitutions: RT M41L, K65E/N/R, D67N, T69Insert, K70E/R, L74V, V75I, F77L, Y115F, F116Y, Q151M, M184I/V, L210W, T215F/Y, K219E/Q. This list includes all resistance substitutions that may also impact study drugs MK-8591, 3TC, or TDF
b) NNRTI resistance substitutions: RT L100I, K101E/P, K103N/S, V106A/I/M, V108I, E138A/G/K/Q/R, V179L, Y181C/I/V, Y188C/H/L, G190A/S, H221Y, P225H, F227C/L/V, M230I/L, L234I, P236L, or Y318F. This list includes all resistance substitutions that may also impact study drug DOR
c) Protease inhibitor resistance substitutions: Protease D30N, V32I, M46I/L, I47A/V, G48V, I50L/V, I54L/M, Q58E, T74P, L76V, V82A/F/L/S/T, N83D, I84V, N88S, orL90M
d) Integrase inhibitor resistance substitutions: Integrase T66I, E92Q, F121Y, 143C/H/R, S147G, Q148H/K/R, or N155H
13. Has active hepatitis C virus (HCV) coinfection (defined as detectable HCV RNA) or HBV co-infection (defined as hepatitis B surface antigen [HBsAg] positive) (completed by the central laboratory). Participants with prior/inactive HCV infection (defined as undetectable HCV RNA) or past HBV infection (defined as HBsAg-negative and positive for antibody against HBsAg) may be enrolled
14. Has a current (active) diagnosis of acute hepatitis due to any cause
15. Has previously been randomized in a study and received MK-8591, DOR, MK-1439A, or 3TC
16.Is or has an immediate family member (eg, spouse, parent/legal guardian, sibling or child) who is investigational site or sponsor staff directly involved with this trial |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Proportion of participants with HIV-1 RNA <50 copies/mL at Week 24 and at Week 48
2. Number of participants experiencing AEs, and discontinuing study drug due to AEs |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
1. Proportion of participants on the selected dose of MK-8591 with HIV-1 RNA <50 copies/mL 24 and 48 weeks after entering part 2
2. Change from baseline in CD4+ T-cell count at Week 24, Week 48, Week 96 and Week 144
3. Proportion of participants with HIV-1 RNA <50 copies/mL at Week 192 (48 weeks after entering Part 4)
4. Change from baseline in CD4+ T-cell count at Week 192
5. Number of participants experiencing AEs
6. Number of participants discontinuing study drug due to AEs |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Weeks 24, 48, 96, 144, 168 and 192 |
|
| 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 | Yes |
| E.6.10 | Pharmacogenetic | No |
| 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 | 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 label as of WK52 for arm 1-3 |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 13 |
| 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 |
| France |
| United Kingdom |
| 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.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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