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
Overview
- Phase
- Phase 3
- Intervention
- ISL
- Conditions
- HIV-1 Infection
- Sponsor
- Merck Sharp & Dohme LLC
- Enrollment
- 35
- Locations
- 98
- Primary Endpoint
- Percentage of Participants Receiving Doravirine/Islatravir (DOR/ISL) With ≥0.5 log10 Change From Day 1 Baseline to Day 8 in Human Immunodeficiency Virus Type 1 (HIV-1) Ribonucleic Acid (RNA) Compared to Placebo Treatment
- Status
- Completed
- Last Updated
- last year
Overview
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).
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).
Investigators
Eligibility 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 (must include nucleoside reverse transcriptase inhibitor \[NRTI\], non-nucleoside reverse transcriptase inhibitor \[NNRTI\], and resistance to either protease inhibitor (PI) or integrase strand transfer inhibitor (InSTI), based on central laboratory-based resistance or proviral DNA resistance testing at the Screening Visit, or historical resistance testing within 12 months of screening.
- •Has ≤2 fully active antiretroviral drugs remaining among all antiretroviral classes 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.
Arms & Interventions
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; followed by open-label 100 mg DOR/0.75 mg ISL fixed dose combination (FDC) QD + OBT from Day 8 to Week 97.
Intervention: ISL
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; followed by open-label 100 mg DOR/0.75 mg ISL fixed dose combination (FDC) QD + OBT from Day 8 to Week 97.
Intervention: DOR/ISL
DOR + ART
HTE participants with HIV-1 infection take DOR 100 mg QD in combination with failing ART from Day 1 to Day 7; followed by open-label 100 mg DOR/0.75 mg ISL FDC QD + OBT from Day 8 to Week 97.
Intervention: DOR
DOR + ART
HTE participants with HIV-1 infection take DOR 100 mg QD in combination with failing ART from Day 1 to Day 7; followed by open-label 100 mg DOR/0.75 mg ISL FDC QD + OBT from Day 8 to Week 97.
Intervention: DOR/ISL
Placebo + ART
HTE participants with HIV-1 infection take placebo QD in combination with failing ART from Day 1 to Day 7; followed by open-label 100 mg DOR/0.75 mg ISL FDC QD + OBT from Day 8 to Week 97.
Intervention: Placebo to DOR
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; followed by open-label 100 mg DOR/0.75 mg ISL FDC QD + OBT from Day 8 to Week 97.
Intervention: DOR/ISL
Placebo + ART
HTE participants with HIV-1 infection take placebo QD in combination with failing ART from Day 1 to Day 7; followed by open-label 100 mg DOR/0.75 mg ISL FDC QD + OBT from Day 8 to Week 97.
Intervention: DOR/ISL
Placebo + ART
HTE participants with HIV-1 infection take placebo QD in combination with failing ART from Day 1 to Day 7; followed by open-label 100 mg DOR/0.75 mg ISL FDC QD + OBT from Day 8 to Week 97.
Intervention: Placebo to ISL
Outcomes
Primary Outcomes
Percentage of Participants Receiving Doravirine/Islatravir (DOR/ISL) With ≥0.5 log10 Change From Day 1 Baseline to Day 8 in Human Immunodeficiency Virus Type 1 (HIV-1) Ribonucleic Acid (RNA) Compared to Placebo Treatment
Time Frame: Day 1 (baseline) and Day 8
Participants with a ≥0.5 log10 decrease from Day 1 baseline to Day 8 in HIV-1 RNA were identified by the central laboratory with an Abbott Real Time Polymerase Chain Reaction (PCR) assay which has a lower limit of detection (LLOD) of 40 copies/mL Only participants treated with DOR/ISL FDC or placebo were analyzed in this outcome measure.
Percentage of Participants With ≥1 AEs Through Week 49
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.
Percentage of Participants Withdrawing From Study Treatment Due to AE(s) Through Week 25
Time Frame: Up to 25 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.
Percentage of Participants With ≥1 Adverse Events (AEs) Through Week 25
Time Frame: Up to 25 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.
Percentage of Participants Withdrawing From Study Treatment Due to AE(s) Through Week 49
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 Outcomes
- Percentage of Participants With ≥1 Adverse Events (AEs) Through Week 97(Up to 97 weeks)
- Percentage of Participants Discontinuing From Study Therapy Due to AE(s) Through Week 97(Up to 97 weeks)
- Percentage of Participants Receiving DOR or ISL (Given With Antiretroviral Therapy [ART]) With ≥0.5 log10 Change From Day 1 Baseline to Day 8 HIV-1 RNA Compared to Placebo Treatment(Day 1 (baseline) and Day 8)
- Percentage of Participants From the Pooled Treatment Group With ≥0.5 log10 Change From Day 1 Baseline to Week 97 in HIV-1 RNA(Day 1 (baseline) and Week 97)
- Percentage of Participants From the Pooled Treatment Group With ≥0.5 log10 Change From Day 8 Baseline to Week 49 in HIV-1 RNA(Day 8 (baseline) and Week 49)
- Percentage of Participants From the Pooled Treatment Group With ≥1.0 log10 Change From Day 8 Baseline to Week 49 in HIV-1 RNA(Day 8 (baseline) and Week 49)
- Percentage of Participants From the Pooled Treatment Group With ≥1.0 log10 Change From Day 8 Baseline to Week 97 in HIV-1 RNA(Day 8 (baseline) and Week 97)
- Mean Change From Baseline Day 1 to Day 8 in HIV-1 RNA Following Treatment With DOR/ISL (Given With ART), DOR, or ISL Compared to Placebo Treatment(Day 1 (baseline) and Day 8)
- Percentage of Participants Receiving DOR/ISL (Given With ART), DOR, or ISL With ≥1.0 log10 Change From Day 1 Baseline to Day 8 HIV-1 RNA Compared to Placebo Treatment(Day 1 (baseline) and Day 8)
- Percentage of Participants Receiving DOR/ISL (Given With ART) With ≥0.5 log10 Change From Day 1 Baseline to Day 8 in HIV-1 RNA Compared to DOR or ISL Treatment(Day 1 (baseline) and Day 8)
- Percentage of Participants Receiving DOR/ISL (Given With ART) With ≥1.0 log10 Change From Day 1 Baseline to Day 8 in HIV-1 RNA Compared to DOR or ISL Treatment(Day 1 (baseline) and Day 8)
- Percentage of Participants From the Pooled Treatment Group With ≥0.5 log10 Change From Day 1 Baseline to Week 25 in HIV-1 RNA(Day 1 (baseline) and Week 25)
- Percentage of Participants From the Pooled Treatment Group With ≥1.0 log10 Change From Day 1 Baseline to Week 49 in HIV-1 RNA(Day 1 (baseline) and Week 49)
- Percentage of Participants From the Pooled Treatment Group With ≥1.0 log10 Change From Day 1 Baseline to Week 97 in HIV-1 RNA(Day 1 (baseline) and Week 97)
- Percentage of Participants From the Pooled Treatment Group With ≥1.0 log10 Change From Day 8 Baseline to Week 25 in HIV-1 RNA(Day 8 (baseline) and Week 25)
- Mean Change From Baseline Day 8 to Week 49 in HIV-1 RNA From the Pooled Treatment Group(Day 8 (baseline) and Week 49)
- Mean Change From Baseline Day 1 to Day 8 in HIV-1 RNA Following Treatment With DOR/ISL (Given With ART) Compared to DOR or ISL Treatment(Day 1 (baseline) and Day 8)
- Percentage of Participants From the Pooled Treatment Group With ≥0.5 log10 Change From Day 1 Baseline to Week 49 in HIV-1 RNA(Day 1 (baseline) and Week 49)
- Percentage of Participants From Day 1 Baseline to Day 8 With HIV-1 RNA <40 Copies mL(Day 1 (baseline) and Day 8)
- Percentage of Participants From the Pooled Treatment Group With ≥0.5 log10 Change From Day 8 Baseline to Week 25 in HIV-1 RNA(Day 8 (baseline) and Week 25)
- Percentage of Participants From the Pooled Treatment Group With ≥0.5 log10 Change From Day 8 Baseline to Week 97 in HIV-1 RNA(Day 8 (baseline) and Week 97)
- Percentage of Participants From the Pooled Treatment Group With ≥1.0 log10 Change From Day 1 Baseline to Week 25 in HIV-1 RNA(Day 1 (baseline) and Week 25)
- Mean Change From Baseline Day 1 to Week 49 in HIV-1 RNA From the Pooled Treatment Group(Day 1 (baseline) and Week 49)
- Mean Change From Baseline Day 8 to Week 25 in HIV-1 RNA From the Pooled Treatment Group(Day 8 (baseline) and Week 25)
- Percentage of Participants From Day 1 Baseline to Day 8 With HIV-1 RNA <200 Copies mL(Day 1 (baseline) and Day 8)
- Percentage of Participants From the Pooled Treatment Group With HIV-1 RNA <40 Copies/mL at Week 25(Week 25)
- Percentage of Participants From the Pooled Treatment Group With HIV-1 RNA <40 Copies/mL at Week 49(Week 49)
- Mean Change From Baseline Day 1 to Week 25 in HIV-1 RNA From the Pooled Treatment Group(Day 1 (baseline) and Week 25)
- Mean Change From Baseline Day 1 to Week 97 in HIV-1 RNA From the Pooled Treatment Group(Day 1 (baseline) and Week 97)
- Mean Change From Baseline Day 8 to Week 97 in HIV-1 RNA From the Pooled Treatment Group(Day 8 (baseline) and Week 97)
- Percentage of Participants From Day 1 Baseline to Day 8 With HIV-1 RNA <50 Copies mL(Day 1 (baseline) and Day 8)
- Percentage of Participants From the Pooled Treatment Group With HIV-1 RNA <200 Copies/mL at Week 25(Week 25)
- Percentage of Participants From the Pooled Treatment Group With HIV-1 RNA <200 Copies/mL at Week 49(Week 49)
- Percentage of Participants From the Pooled Treatment Group With HIV-1 RNA <200 Copies/mL at Week 97(Week 97)
- Percentage of Participants From the Pooled Treatment Group With HIV-1 RNA <50 Copies/mL at Week 49(Week 49)
- Change From Baseline Day 8 to Week 49 in CD4+ T-cell Counts From the Pooled Treatment Group(Day 8 (baseline) and Week 49)
- Change From Baseline Day 8 to Week 97 in CD4+ T-cell Counts From the Pooled Treatment Group(Day 8 (baseline) and Week 97)
- Percentage of Participants From the Pooled Treatment Group With HIV-1 RNA <50 Copies/mL at Week 25(Week 25)
- Percentage of Participants From the Pooled Treatment Group With HIV-1 RNA <50 Copies/mL at Week 97(Week 97)
- Percentage of Participants From the Pooled Treatment Group With Treatment-emergent Resistance-associated Substitutions to ISL at Week 25(Week 25)
- Percentage of Participants From the Pooled Treatment Group With Treatment-emergent Resistance-associated Substitutions to ISL at Week 49(Week 49)
- Percentage of Participants From the Pooled Treatment Group With Treatment-emergent Resistance-associated Substitutions to Optimized Background Therapy (OBT) Components at Week 25(Week 25)
- Percentage of Participants From the Pooled Treatment Group With Treatment-emergent Resistance-associated Substitutions to OBT Components at Week 49(Week 49)
- Number of Participants From the Pooled Treatment Group With Viral Resistance-associated Substitutions (RASs) at Week 25(Week 25)
- Number of Participants From the Pooled Treatment Group With Viral RASs at Week 49(Week 49)
- Percentage of Participants From the Pooled Treatment Group With HIV-1 RNA <40 Copies/mL at Week 97(Week 97)
- Percentage of Participants From the Pooled Treatment Group With Treatment-emergent Resistance-associated Substitutions to DOR at Week 25(Week 25)
- Percentage of Participants From the Pooled Treatment Group With Treatment-emergent Resistance-associated Substitutions to DOR at Week 49(Week 49)
- Number of Participants From the Pooled Treatment Group Exhibiting Antiviral Resistance of HIV-1 RNA ≥200 Copies/mL at Week 97(Week 97)
- Change From Baseline Day 1 to Week 25 in Cluster of Differentiation 4+ (CD4+) T-cell Counts From the Pooled Treatment Group(Day 1 (baseline) and Week 25)
- Change From Baseline Day 1 to Week 49 in CD4+ T-cell Counts From the Pooled Treatment Group(Day 1 (baseline) and Week 49)
- Change From Baseline Day 1 to Week 97 in CD4+ T-cell Counts From the Pooled Treatment Group(Day 1 (baseline) and Week 97)
- Change From Baseline Day 8 to Week 25 in CD4+ T-cell Counts From the Pooled Treatment Group(Day 8 (baseline) and Week 25)
- Number of Participants From the Pooled Treatment Group With Viral RASs at Week 97(Week 97)
- Number of Participants From the Pooled Treatment Group Exhibiting Antiviral Resistance of HIV-1 RNA ≥200 Copies/mL at Week 25(Week 25)
- Number of Participants From the Pooled Treatment Group Exhibiting Antiviral Resistance of HIV-1 RNA ≥200 Copies/mL at Week 49(Week 49)