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Doravirine/Islatravir (DOR/ISL) in Heavily Treatment-Experienced (HTE) Participants for Human Immunodeficiency Virus Type 1 (HIV-1) Infection (MK-8591A-019)

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ClinicalTrials.gov Identifier: NCT04233216
Recruitment Status : Recruiting
First Posted : January 18, 2020
Last Update Posted : January 19, 2021
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.

Brief Summary:
This is a 2-part, phase 3 clinical study evaluating the antiretroviral activity and safety/tolerability of islatravir (ISL), doravirine (DOR), and a fixed dose combination (FDC) of DOR/ISL (also known as MK-8591A) in heavily treatment-experienced (HTE) participants with human immunodeficiency virus type 1 (HIV-1) infection. It is hypothesized that the percentage of participants receiving DOR/ISL to achieve ≥0.5 log10 decrease in HIV-1 ribonucleic acid (RNA) from study baseline (Day 1) to Day 8 is superior to placebo, each given in combination with failing antiretroviral therapy (ART).

Condition or disease Intervention/treatment Phase
HIV-1 Infection Drug: ISL Drug: DOR Drug: DOR/ISL Drug: Placebo to ISL Drug: Placebo to DOR Phase 3

Detailed Description:
Part 1 of this study (Day 1 to Day 7) is the double-blind period in which participants receive either ISL, DOR, DOR/ISL, or placebo. Part 2 of this study (Day 8 to Week 97) is the open-label period in which all participants receive DOR/ISL + optimized background therapy (OBT).

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 100 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: A Phase 3, Randomized, Clinical Study in HIV-1-Infected Heavily Treatment-Experienced Participants Evaluating the Antiretroviral Activity of Blinded Islatravir (ISL), Doravirine (DOR), and Doravirine/Islatravir (DOR/ISL), Each Compared to Placebo, and the Antiretroviral Activity, Safety, and Tolerability of Open-Label DOR/ISL
Actual Study Start Date : March 18, 2020
Estimated Primary Completion Date : August 1, 2025
Estimated Study Completion Date : August 1, 2025

Resource links provided by the National Library of Medicine

MedlinePlus related topics: HIV/AIDS

Arm Intervention/treatment
Experimental: Part 1, Group 1: ISL + ART
HTE participants with HIV-1 infection take ISL 0.75 mg once daily (QD) in combination with failing ART from Day 1 to Day 7 in Part 1.
Drug: ISL
ISL 0.75 mg capsule taken by mouth.
Other Names:
  • Islatravir
  • MK-8591

Experimental: Part 1, Group 2: DOR + ART
HTE participants with HIV-1 infection take DOR 100 mg QD in combination with failing ART from Day 1 to Day 7 in Part 1.
Drug: DOR
DOR 100 mg tablet taken by mouth.
Other Names:
  • Doravirine
  • MK-1439

Experimental: Part 1, Group 3: DOR/ISL + ART
HTE participants with HIV-1 infection take 100 mg DOR/0.75 mg ISL FDC QD in combination with failing ART from Day 1 to Day 7 in Part 1.
Drug: DOR/ISL
100 mg DOR/0.75 mg ISL FDC taken by mouth.
Other Names:
  • Doravirine/Islatravir
  • MK-8591A

Placebo Comparator: Part 1, Group 4: Placebo + ART
HTE participants with HIV-1 infection take placebo QD in combination with failing ART from Day 1 to Day 7 in Part 1.
Drug: Placebo to ISL
Placebo capsule matched to ISL taken by mouth.

Drug: Placebo to DOR
Placebo tablet matched to DOR taken by mouth.

Experimental: Part 2, Group 5: Open-Label DOR/ISL + OBT
HTE participants from Groups 1 to 4 with HIV-1 infection take open-label 100 mg DOR/0.75 mg ISL + OBT in Part 2 (Day 8 to Week 97).
Drug: DOR/ISL
100 mg DOR/0.75 mg ISL FDC taken by mouth.
Other Names:
  • Doravirine/Islatravir
  • MK-8591A




Primary Outcome Measures :
  1. Percentage of participants receiving doravirine/islatravir (DOR/ISL) with ≥0.5 log10 decrease from baseline in human immunodificiency virus type 1 (HIV-1) ribonucleic acid (RNA) compared to placebo treatment [ Time Frame: Day 1 (baseline) and Day 8 ]
    The change from baseline in HIV-1 RNA will be determined at the central laboratory with an Abbott Real Time Polymerase Chain Reaction (PCR) assay with a lower limit of detection (LLOD) of 40 copies/mL.

  2. Percentage of participants with ≥1 adverse events (AEs) [ Time Frame: Up to 49 weeks ]
    An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment.

  3. Percentage of participants withdrawing from study treatment due to AE(s) [ Time Frame: Up to 49 weeks ]
    An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment.


Secondary Outcome Measures :
  1. Percentage of participants with ≥1 adverse events (AEs) [ Time Frame: Up to 97 weeks ]
    An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention.

  2. Percentage of participants discontinuing from study therapy due to AE(s) [ Time Frame: Up to 97 weeks ]
    An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention.

  3. Percentage of participants receiving DOR or ISL (given with antiretoviral therapy [ART]) with ≥0.5 log10 decrease in HIV-1 RNA compared to placebo treatment [ Time Frame: Day 1 (baseline) and Day 8 ]
    The percentage of participants with ≥0.5 log10 change from baseline in HIV-1 RNA will be determined. The central laboratory will measure plasma HIV-1 RNA using an Abbott Real Time PCR assay with a LLOD of 40 copies/mL.

  4. Mean change from baseline in HIV-1 RNA following treatment with DOR/ISL (given with ART), DOR, or ISL compared to placebo treatment [ Time Frame: Day 1 (baseline) and Day 8 ]
    The mean change from baseline in HIV-1 RNA will be determined. The central laboratory will measure plasma HIV-1 RNA using an Abbott Real Time PCR assay with a LLOD of 40 copies/mL.

  5. 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 [ Time Frame: Day 1 (baseline) and Day 8 ]
    The percentage of participants with ≥1.0 log10 change from baseline in HIV-1 RNA will be determined. The central laboratory will measure plasma HIV-1 RNA using an Abbott Real Time PCR assay with a LLOD of 40 copies/mL.

  6. 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 [ Time Frame: Day 1 (baseline) and Day 8 ]
    The percentage of participants with ≥0.5 log10 change from baseline in HIV-1 RNA will be determined. The central laboratory will measure plasma HIV-1 RNA using an Abbott Real Time PCR assay with a LLOD of 40 copies/mL.

  7. Mean change from baseline in HIV-1 RNA following treatment with DOR/ISL (given with ART) compared to DOR or ISL treatment [ Time Frame: Day 1 (baseline) and Day 8 ]
    The mean change from baseline in HIV-1 RNA will be determined. The central laboratory will measure plasma HIV-1 RNA using an Abbott Real Time PCR assay with a LLOD of 40 copies/mL.

  8. 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 [ Time Frame: Day 1 (baseline) and Day 8 ]
    The percentage of participants with ≥1.0 log10 change from baseline in HIV-1 RNA will be determined. The central laboratory will measure plasma HIV-1 RNA using an Abbott Real Time PCR assay with a LLOD of 40 copies/mL.

  9. 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 [ Time Frame: Day 8 (baseline) and Week 25 ]
    The percentage of participants with ≥0.5 log10 change from baseline in HIV-1 RNA will be determined. The central laboratory will measure plasma HIV-1 RNA using an Abbott Real Time PCR assay with a LLOD of 40 copies/mL.

  10. 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 [ Time Frame: Day 1 (baseline) and Week 49 ]
    The percentage of participants with ≥0.5 log10 change from baseline in HIV-1 RNA will be determined. The central laboratory will measure plasma HIV-1 RNA using an Abbott Real Time PCR assay with a LLOD of 40 copies/mL.

  11. 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 [ Time Frame: Day 1 (baseline) and Week 97 ]
    The percentage of participants with ≥0.5 log10 change from baseline in HIV-1 RNA will be determined. The central laboratory will measure plasma HIV-1 RNA using an Abbott Real Time PCR assay with a LLOD of 40 copies/mL.

  12. 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 [ Time Frame: Day 8 (baseline) and Week 25 ]
    The percentage of participants with ≥1.0 log10 change from baseline in HIV-1 RNA will be determined. The central laboratory will measure plasma HIV-1 RNA using an Abbott Real Time PCR assay with a LLOD of 40 copies/mL.

  13. 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 [ Time Frame: Day 1 (baseline) and Week 49 ]
    The percentage of participants with ≥1.0 log10 change from baseline in HIV-1 RNA will be determined. The central laboratory will measure plasma HIV-1 RNA using an Abbott Real Time PCR assay with a LLOD of 40 copies/mL.

  14. 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 [ Time Frame: Day 1 (baseline) and Week 97 ]
    The percentage of participants with ≥1.0 log10 change from baseline in HIV-1 RNA will be determined. The central laboratory will measure plasma HIV-1 RNA using an Abbott Real Time PCR assay with a LLOD of 40 copies/mL.

  15. Mean change from baseline in HIV-1 RNA following treatment with DOR/ISL (given with ART) + OBT [ Time Frame: Day 8 (baseline) and Week 25 ]
    The mean change from baseline in HIV-1 RNA will be determined. The central laboratory will measure plasma HIV-1 RNA using an Abbott Real Time PCR assay with a LLOD of 40 copies/mL.

  16. Mean change from baseline in HIV-1 RNA following treatment with DOR/ISL (given with ART) + OBT [ Time Frame: Day 1 (baseline) and Week 49 ]
    The mean change from baseline in HIV-1 RNA will be determined. The central laboratory will measure plasma HIV-1 RNA using an Abbott Real Time PCR assay with a LLOD of 40 copies/mL.

  17. Mean change from baseline in HIV-1 RNA following treatment with DOR/ISL (given with ART) + OBT [ Time Frame: Day 8 (baseline) and Week 97 ]
    The mean change from baseline in HIV-1 RNA will be determined. The central laboratory will measure plasma HIV-1 RNA using an Abbott Real Time PCR assay with a LLOD of 40 copies/mL.

  18. Percentage of participants receiving DOR/ISL (given with ART) + OBT with HIV-1 RNA <200 copies mL [ Time Frame: Day 8 (baseline) and Week 25 ]
    The percentage of participants with HIV-1 RNA <200 copies mL will be determined. The central laboratory will measure plasma HIV-1 RNA using an Abbott Real Time PCR assay with a LLOD of 40 copies/mL.

  19. Percentage of participants receiving DOR/ISL (given with ART) + OBT with HIV-1 RNA <200 copies mL [ Time Frame: Day 1 (baseline) and Week 49 ]
    The percentage of participants with HIV-1 RNA <200 copies mL will be determined. The central laboratory will measure plasma HIV-1 RNA using an Abbott Real Time PCR assay with a LLOD of 40 copies/mL.

  20. Percentage of participants receiving DOR/ISL (given with ART) + OBT with HIV-1 RNA <200 copies mL [ Time Frame: Day 1 (baseline) and Week 97 ]
    The percentage of participants with HIV-1 RNA <200 copies mL will be determined. The central laboratory will measure plasma HIV-1 RNA using an Abbott Real Time PCR assay with a LLOD of 40 copies/mL.

  21. Percentage of participants receiving DOR/ISL (given with ART) + OBT with HIV-1 RNA <50 copies mL [ Time Frame: Day 8 (baseline) and Week 25 ]
    The percentage of participants with HIV-1 RNA <50 copies mL will be determined. The central laboratory will measure plasma HIV-1 RNA using an Abbott Real Time PCR assay with a LLOD of 40 copies/mL.

  22. Percentage of participants receiving DOR/ISL (given with ART) + OBT with HIV-1 RNA <50 copies mL [ Time Frame: Day 1 (baseline) and Week 49 ]
    The percentage of participants with HIV-1 RNA <50 copies mL will be determined. The central laboratory will measure plasma HIV-1 RNA using an Abbott Real Time PCR assay with a LLOD of 40 copies/mL.

  23. Percentage of participants receiving DOR/ISL (given with ART) + OBT with HIV-1 RNA <50 copies mL [ Time Frame: Day 1 (baseline) and Week 97 ]
    The percentage of participants with HIV-1 RNA <50 copies mL will be determined. The central laboratory will measure plasma HIV-1 RNA using an Abbott Real Time PCR assay with a LLOD of 40 copies/mL.

  24. Percentage of participants receiving DOR/ISL (given with ART) + OBT with HIV-1 RNA <40 copies mL [ Time Frame: Day 8 (baseline) and Week 25 ]
    The percentage of participants with HIV-1 RNA <40 copies mL will be determined. The central laboratory will measure plasma HIV-1 RNA using an Abbott Real Time PCR assay with a LLOD of 40 copies/mL.

  25. Percentage of participants receiving DOR/ISL (given with ART) + OBT with HIV-1 RNA <40 copies mL [ Time Frame: Day 1 (baseline) and Week 49 ]
    The percentage of participants with HIV-1 RNA <40 copies mL will be determined. The central laboratory will measure plasma HIV-1 RNA using an Abbott Real Time PCR assay with a LLOD of 40 copies/mL.

  26. Percentage of participants receiving DOR/ISL (given with ART) + OBT with HIV-1 RNA <40 copies mL [ Time Frame: Day 1 (baseline) and Week 97 ]
    The percentage of participants with HIV-1 RNA <40 copies mL will be determined. The central laboratory will measure plasma HIV-1 RNA using an Abbott Real Time PCR assay with a LLOD of 40 copies/mL.

  27. Prevalence of viral drug resistance to DOR [ Time Frame: Week 25 ]
    The prevalence of viral drug resistance to DOR will be determined. Viral resistance testing will be performed by the central laboratory.

  28. Prevalence of viral drug resistance to DOR [ Time Frame: Week 49 ]
    The prevalence of viral drug resistance to DOR will be determined. Viral resistance testing will be performed by the central laboratory.

  29. Prevalence of viral drug resistance to ISL [ Time Frame: Week 25 ]
    The prevalence of viral drug resistance to ISL will be determined. Viral resistance testing will be performed by the central laboratory.

  30. Prevalence of viral drug resistance to ISL [ Time Frame: Week 49 ]
    The prevalence of viral drug resistance to ISL will be determined. Viral resistance testing will be performed by the central laboratory.

  31. Prevalence of viral drug resistance to optimized background therapy (OBT) components [ Time Frame: Week 25 ]
    The prevalence of viral drug resistance to OBT components will be determined. Viral resistance testing will be performed by the central laboratory.

  32. Prevalence of viral drug resistance to OBT components [ Time Frame: Week 49 ]
    The prevalence of viral drug resistance to OBT components will be determined. Viral resistance testing will be performed by the central laboratory.

  33. Role of baseline antiviral resistance on viral resistance-associated substitutions (RASs) [ Time Frame: Day 1 (baseline) and Week 25 ]
    The role of baseline antiviral resistance on viral RAS will be determined.

  34. Role of baseline antiviral resistance on viral RASs [ Time Frame: Day 1 (baseline) and Week 49 ]
    The role of baseline antiviral resistance on viral RAS will be determined.

  35. Role of baseline antiviral resistance on viral RASs [ Time Frame: Day 1 (baseline) and Week 97 ]
    The role of baseline antiviral resistance on viral RAS will be determined.

  36. Role of baseline antiviral resistance on HIV-1 RNA [ Time Frame: Day 8 (baseline) and Week 25 ]
    The role of baseline antiviral resistance on HIV-1 RNA will be determined.

  37. Role of baseline antiviral resistance on HIV-1 RNA [ Time Frame: Day 8 (baseline) and Week 49 ]
    The role of baseline antiviral resistance on HIV-1 RNA will be determined.

  38. Role of baseline antiviral resistance on HIV-1 RNA [ Time Frame: Day 8 (baseline) and Week 97 ]
    The role of baseline antiviral resistance on HIV-1 RNA will be determined.

  39. Change from baseline in cluster of differentiation 4+ (CD4+) T-cell counts [ Time Frame: Day 1 (baseline) and Week 25 ]
    The change from baseline in CD4+ T-cell counts will be determined. CD4+ T-cell counts will be determined by the central laboratory.

  40. Change from baseline in CD4+ T-cell counts [ Time Frame: Day 1 (baseline) and Week 49 ]
    The change from baseline in CD4+ T-cell counts will be determined. CD4+ T-cell counts will be determined by the central laboratory.

  41. Change from baseline in CD4+ T-cell counts [ Time Frame: Day 1 (baseline) and Week 97 ]
    The change from baseline in CD4+ T-cell counts will be determined. CD4+ T-cell counts will be determined by the central laboratory.

  42. Change from baseline in CD4+ T-cell counts [ Time Frame: Day 8 (baseline) and Week 25 ]
    The change from baseline in CD4+ T-cell counts will be determined. CD4+ T-cell counts will be determined by the central laboratory.

  43. Change from baseline in CD4+ T-cell counts [ Time Frame: Day 8 (baseline) and Week 49 ]
    The change from baseline in CD4+ T-cell counts will be determined. CD4+ T-cell counts will be determined by the central laboratory.

  44. Change from baseline in CD4+ T-cell counts [ Time Frame: Day 8 (baseline) and Week 97 ]
    The change from baseline in CD4+ T-cell counts will be determined. CD4+ T-cell counts will be determined by the central laboratory.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Is HIV-1 positive.
  • Has been receiving the same baseline ART for ≥3 months prior to signing the Informed Consent Form/Assent Form.
  • Weighs ≥35 kg.
  • Has at least triple-class resistance (nucleoside reverse transcriptase inhibitor [NRTI], non-nucleoside reverse transcriptase inhibitor [NNRTI], and resistance to at least 1 other class [i.e., resistance to at least 1 drug in each class]) based on resistance testing at the Screening Visit.
  • 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.
  • If female, is not pregnant or breastfeeding, and is: 1) not a woman of childbearing potential (WOCBP); 2) a WOCBP and uses an acceptable method of contraception/is abstinent; or 3) a WOCBP and has a negative pregnancy test within 24 hours of the first dose of study medication.

Exclusion Criteria:

  • Has HIV type 2 (HIV-2) infection.
  • Has hypersensitivity or other contraindication to any of the components of the study interventions as determined by the investigator.
  • Has hepatitis B virus (HBV) co-infection (defined as hepatitis B surface antigen [HBsAg]-positive or HBV deoxyribonucleic acid [DNA] positive) and is not currently being treated for HBV.
  • 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.
  • Is taking or is anticipated to require any of the prohibited therapies from the Screening Visit and throughout the study treatment period.
  • Is taking DOR as part of his/her current failing antiretroviral regimen.
  • Is taking efavirenz (EFV), etravirine, or nevirapine.
  • 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.
  • Is female and is expecting to conceive or donate eggs at any time during the study.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04233216


Contacts
Layout table for location contacts
Contact: Toll Free Number 1-888-577-8839 Trialsites@merck.com

Locations
Show Show 88 study locations
Sponsors and Collaborators
Merck Sharp & Dohme Corp.
Investigators
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Study Director: Medical Director Merck Sharp & Dohme Corp.
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Responsible Party: Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier: NCT04233216    
Other Study ID Numbers: 8591A-019
MK-8591A-019 ( Other Identifier: Merck Protocol Number )
2019-000588-26 ( EudraCT Number )
205243 ( Registry Identifier: JAPIC-CTI )
First Posted: January 18, 2020    Key Record Dates
Last Update Posted: January 19, 2021
Last Verified: January 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
URL: http://engagezone.msd.com/ds_documentation.php

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Infection
4'-ethynyl-2-fluoro-2'-deoxyadenosine
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents