| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| HIV-1 infection and naïve to antiretroviral therapy |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 |
|
| 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 bictegravir/emtricitabine/tenofovir alafenamide
(BIC/FTC/TAF) as assessed by the percentage of participants with
human immunodeficiency virus 1 (HIV-1) ribonucleic acid (RNA) <50
copies/mL at Week 48
2. To evaluate the safety and tolerability of DOR/ISL compared to
BIC/FTC/TAF as assessed by review of the accumulated safety data
through Week 48
|
|
| E.2.2 | Secondary objectives of the trial |
1. To evaluate the antiretroviral activity of DOR/ISL compared to
BIC/FTC/TAF based on the percentage of participants with HIV-1 RNA
<50 copies/mL at Week 96 and week 144
2. To evaluate the antiretroviral activity of DOR/ISL compared to
BIC/FTC/TAF based on the percentage of participants with HIV-1 RNA
<40 and <200 copies/mL at Week 48, Week 96, and Week 144
3. To evaluate the immunologic effect of DOR/ISL as measured by the
change from baseline in cluster of differentiation 4+ (CD4+) T-cell count
at Week 48, Week 96 and Week 144.
4. To evaluate the development of viral drug resistance in participants
who receive DOR/ISL and in those who receive BIC/FTC/TAF
5. To evaluate the effect of DOR/ISL compared to BIC/FTC/TAF on
weight, as measured by the mean change from baseline to Week 48,
Week 96 and Week 144
6. To evaluate the safety and tolerability of DOR/ISL compared to
BIC/FTC/TAF through the duration of the study |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Is HIV-1 positive with plasma HIV-1 RNA ≥500 copies/mL at screening.
2. Is naïve to ART defined as having received ≤10 days of prior therapy with any antiretroviral agent following a diagnosis of HIV-1 infection including prevention of mother-to-child transmission up to 1 month prior to screening.
3. Is male or female ≥18 years of age inclusive at the time of signing informed consent.
4. 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), as described in Appendix 5 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.
Additional requirements for pregnancy testing during and after study intervention are located in the protocol.
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.
5. The participant (or legally acceptable representative) has provided
documented i informed consent for the study. The participant may also
provide consent for future biomedical research. However, the participant
may participate in the main study without participating in future
biomedical research. |
|
| 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 an active diagnosis of hepatitis due to any cause, including active HBV infection (defined as HBsAg-positive or HBV DNA positive).
4. Has a history of malignancy ≤5 years prior to signing informed consent except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or cutaneous Kaposi’s sarcoma.
5. Has a history or current evidence of any condition (including active tuberculosis infection), therapy, laboratory abnormality or other circumstance (including drug or alcohol use or dependence) 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.
6. 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, FTC, or 3TC.
7. Is taking or is anticipated to require systemic immunosuppressive therapy, immune modulators, or any of the prohibited therapies outlined in Section 6.5 from 45 days prior to Day 1 through the study intervention period.
8. Is currently participating in or has participated in a clinical study with an investigational compound or device from 45 days prior to Day 1 through the study intervention period.
9. Has a documented or known virologic resistance to any approved HIV-1 reverse transcriptase inhibitor, or any study intervention, as demonstrated by any of the following resistance substitutions (according to the 2017 IAS-USA drug resistance mutations list)
[Wensing, A. M., et al 2017]:
a. FTC: K65R/E/N or M184I/V
b. TAF: K65R/E/N or K70E
c. Multi-NRTI resistance substitutions: T69insert, Q151M, or 3 or more of thymidine analogue-associated mutations (M41L, D67N, K70R, L210W, T215F/Y, K219E/Q).
d. DOR resistance substitutions: V106A/M, V108I, Y188L, H221Y, P225H, F227C/L, M230I/L, L234I, P236L, or Y318F.
10. Has exclusionary laboratory values within 45 days prior to Day 1
11. Is female and is expecting to conceive or donate eggs at any time
during the study |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Percentage of participants with HIV-1 RNA <50 copies/mL
2. Percentage of participants experiencing ≥1 adverse events (AEs)
3. Percentage of participants discontinuing from study treatment due to AE(s)
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Week 48
2. Up to 48 weeks
3. Up to 46 weeks
|
|
| E.5.2 | Secondary end point(s) |
1. Percentage of participants with HIV-1 RNA <50 copies/mL
2. Percentage of participants with HIV-1 RNA <50 copies/mL
3. Percentage of participants with HIV-1 RNA <40 copies/mL
4. Percentage of participants with HIV-1 RNA <200 copies/mL
5. Percentage of participants with HIV-1 RNA <40 copies/mL
6. Percentage of participants with HIV-1 RNA <200 copies/mL
7. Percentage of participants with HIV-1 RNA <40 copies/mL
8. Percentage of participants with HIV-1 RNA <200 copies/mL
9. Change from baseline in CD4+ T-cell counts
10. Change from baseline in CD4+ T-cell counts
11. Change from baseline in CD4+ T-cell counts
12. Incidence of viral resistance-associated substitutions (RASs)
13. Incidence of viral resistance-associated substitutions (RASs).
14. Incidence of viral resistance-associated substitutions (RASs)
15. Change from baseline in body weight
16. Change from baseline in body weight
17. Percentage of participants experiencing ≥1 adverse events (AEs)
18. Percentage of participants discontinuing from study treatment due to
AE(s) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Week 96
2. Week 144
3. Week 48
4. Week 48
5. Week 96
6. Week 96
7. Week 144
8. Week 144
9. Day 1 (baseline) and Week 48
10. Day 1 (baseline) and Week 96
11. Day 1 (baseline) and Week 144
12. Up to 48 weeks
13. Up to 96 weeks
14. Up to 144 weeks
15. Day 1 (baseline) and Week 96
16. Day 1 (baseline) and Week 144
17. Up to 156 weeks
18. Up to 144 weeks |
|
| 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 | 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 | No |
| 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 | 2 |
| 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 39 |
| 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 |
| Argentina |
| Chile |
| Colombia |
| Taiwan |
| Canada |
| Israel |
| Japan |
| South Africa |
| United States |
| France |
| Germany |
| Italy |
| Spain |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| 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 | 5 |
| 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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