NCT04233216

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

Completed Phase 3 Results posted Last updated 27 December 2024

What this trial tests

Phase 3 trial testing ISL in HIV-1 Infection in 35 participants. Completed in 1 November 2023.

Timeline

18 March 2020

Primary endpoint
21 November 2022

1 November 2023

Quick facts

Lead sponsor	Merck Sharp & Dohme LLC
Phase	Phase 3
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	double
Primary purpose	treatment
Enrollment	35
Start date	18 March 2020
Primary completion	21 November 2022
Estimated completion	1 November 2023
Sites	98 locations across France, Colombia, Italy, Japan, Russia, South Africa, Peru, Ukraine

Drugs / interventions tested

• ISL — full drug profile →
• DOR — full drug profile →
• DOR/ISL — full drug profile →
• Placebo to ISL — full drug profile →
• Placebo to DOR — full drug profile →

Conditions studied

• HIV-1 Infection — all drugs for HIV-1 Infection →

Sponsor

Merck Sharp & Dohme LLC — full company profile →

Who can join

Eligibility, any sex, with HIV-1 Infection. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

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 Primary · 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.

Group	Value	95% CI
DOR/ISL + ART	85.7	42.1 – 99.6
Placebo + ART	0.0	0.0 – 41.0

Percentage of Participants With ≥1 AEs Through Week 49 Primary · 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.

Group	Value	95% CI
ISL + ART	71.4
DOR + ART	85.7
DOR/ISL + ART	85.7
Placebo + ART	85.7

Percentage of Participants Withdrawing From Study Treatment Due to AE(s) Through Week 25 Primary · 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.

Group	Value	95% CI
ISL + ART	0.0
DOR + ART	7.1
DOR/ISL + ART	14.3
Placebo + ART	0.0

Percentage of Participants With ≥1 Adverse Events (AEs) Through Week 25 Primary · 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.

Group	Value	95% CI
ISL + ART	42.9
DOR + ART	85.7
DOR/ISL + ART	85.7
Placebo + ART	85.7

Percentage of Participants Withdrawing From Study Treatment Due to AE(s) Through Week 49 Primary · 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.

Group	Value	95% CI
ISL + ART	0.0
DOR + ART	14.3
DOR/ISL + ART	14.3
Placebo + ART	0.0

Percentage of Participants With ≥1 Adverse Events (AEs) Through Week 97 Secondary · 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.

Group	Value	95% CI
ISL + ART	85.7
DOR + ART	100.0
DOR/ISL + ART	85.7
Placebo + ART	100.0

Percentage of Participants Discontinuing From Study Therapy Due to AE(s) Through Week 97 Secondary · 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.

Group	Value	95% CI
ISL + ART	0.0
DOR + ART	21.4
DOR/ISL + ART	28.6
Placebo + ART	14.3

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 Secondary · 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 PCR assay which has a LLOD of 40 copies/mL Only participants treated with either DOR or ISL or placebo (given with ART) were analyzed in this outcome measure. Participants treated with DOR/ISL FDC were not analyzed in this outcome measure.

Group	Value	95% CI
ISL + ART	28.6	3.7 – 71.0
DOR + ART	78.6	49.2 – 95.3
Placebo + ART	0.0	0.0 – 41.0

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 Secondary · Day 1 (baseline) and Day 8

The change from baseline Day to Day 8 in HIV-1 RNA was determined by the central laboratory using an Abbott Real Time PCR assay with a LLOD of 40 copies/mL. The within-group 95% confidence intervals (CIs) were calculated based on the t-distribution.

Group	Value	95% CI
ISL + ART	-0.44	-0.96 – 0.07
DOR + ART	-0.96	-1.38 – -0.54
DOR/ISL + ART	-1.23	-1.72 – -0.75
Placebo + ART	0.03	-0.15 – 0.21

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 Secondary · Day 1 (baseline) and Day 8

Participants with a ≥1.0 log10 decrease from baseline (Day 1) to Day 8 in HIV-1 RNA were identified by at the central laboratory with an Abbott Real Time Polymerase Chain Reaction (PCR) assay which has a LLOD of 40 copies/mL

Group	Value	95% CI
ISL + ART	14.3	0.4 – 57.9
DOR + ART	50.0	23.0 – 77.0
DOR/ISL + ART	85.7	42.1 – 99.6
Placebo + ART	0.0	0.0 – 41.0

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 Secondary · Day 1 (baseline) and Day 8

Participants with a ≥0.5 log10 decrease from baseline (Day 1) to Day 8 in HIV-1 RNA were identified by at the central laboratory with an Abbott Real Time PCR assay which has a lower limit of detection (LLOD) of 40 copies/mL Only participants treated with DOR/ISL or DOR alone or ISL alone were analyzed in this outcome measure. Participants treated with placebo were not analyzed in this outcome measure.

Group	Value	95% CI
ISL + ART	28.6	3.7 – 71.0
DOR + ART	78.6	49.2 – 95.3
DOR/ISL + ART	85.7	42.1 – 99.6

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 Secondary · Day 1 (baseline) and Day 8

The change from baseline Day 1 to Day 8in HIV-1 RNA was determined by the central laboratory using an Abbott Real Time PCR assay with a LLOD of 40 copies/mL. The within-group 95% CIs were calculated based on the t-distribution. The group treated with placebo were not analyzed in this outcome measure.

Group	Value	95% CI
ISL + ART	-0.44	-0.96 – 0.07
DOR + ART	-0.96	-1.38 – -0.54
DOR/ISL + ART	-1.23	-1.72 – -0.75

Adverse events — posted to ClinicalTrials.gov

Time frame: All-Cause Mortality (ACM): from randomization up to Week 49; Adverse Events (AE): from treatment ( Day 1) Up to Week 97. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

ISL+ART

Serious: 2/7 (29%)

Deaths: 0/7

DOR+ART

Serious: 2/14 (14%)

Deaths: 0/14

DOR/ISL+ART

Serious: 0/7 (0%)

Deaths: 0/7

Placebo+ART

Serious: 2/7 (29%)

Deaths: 0/7

Serious adverse events (9 terms)

Reaction	System	ISL+ART	DOR+ART	DOR/ISL+ART	Placebo+ART
Angina pectoris	Cardiac disorders	—	—	—	—
Colitis ulcerative	Gastrointestinal disorders	—	—	—	—
COVID-19	Infections and infestations	—	—	—	—
COVID-19 pneumonia	Infections and infestations	—	—	—	—
Postoperative wound infection	Infections and infestations	—	—	—	—
SARS-CoV-2 sepsis	Infections and infestations	—	—	—	—
Lower limb fracture	Injury, poisoning and procedural complications	—	—	—	—
Reactive gastropathy	Injury, poisoning and procedural complications	—	—	—	—
Castleman's disease	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—	—	—

Other adverse events (119 terms — click to expand)

Reaction	System	ISL+ART	DOR+ART	DOR/ISL+ART	Placebo+ART
Lymphocyte count decreased	Investigations	—	—	—	—
Diarrhoea	Gastrointestinal disorders	—	—	—	—
COVID-19	Infections and infestations	—	—	—	—
Creatinine renal clearance decreased	Investigations	—	—	—	—
Nausea	Gastrointestinal disorders	—	—	—	—
Chest pain	General disorders	—	—	—	—
Fatigue	General disorders	—	—	—	—
Upper respiratory tract infection	Infections and infestations	—	—	—	—
Accidental overdose	Injury, poisoning and procedural complications	—	—	—	—
Blood creatine phosphokinase increased	Investigations	—	—	—	—
Arthralgia	Musculoskeletal and connective tissue disorders	—	—	—	—
Myalgia	Musculoskeletal and connective tissue disorders	—	—	—	—
Headache	Nervous system disorders	—	—	—	—
Cough	Respiratory, thoracic and mediastinal disorders	—	—	—	—
Rash	Skin and subcutaneous tissue disorders	—	—	—	—
Anaemia	Blood and lymphatic system disorders	—	—	—	—
Pancytopenia	Blood and lymphatic system disorders	—	—	—	—
Mitral valve incompetence	Cardiac disorders	—	—	—	—
Ear pain	Ear and labyrinth disorders	—	—	—	—
Cataract	Eye disorders	—	—	—	—
Dry eye	Eye disorders	—	—	—	—
Eye allergy	Eye disorders	—	—	—	—
Eye irritation	Eye disorders	—	—	—	—
Retinal haemorrhage	Eye disorders	—	—	—	—
Abdominal pain	Gastrointestinal disorders	—	—	—	—
Abdominal pain lower	Gastrointestinal disorders	—	—	—	—
Anal rash	Gastrointestinal disorders	—	—	—	—
Constipation	Gastrointestinal disorders	—	—	—	—
Dental caries	Gastrointestinal disorders	—	—	—	—
Diverticulum	Gastrointestinal disorders	—	—	—	—
Dyspepsia	Gastrointestinal disorders	—	—	—	—
Haemorrhoids	Gastrointestinal disorders	—	—	—	—
Salivary hypersecretion	Gastrointestinal disorders	—	—	—	—
Toothache	Gastrointestinal disorders	—	—	—	—
Exercise tolerance decreased	General disorders	—	—	—	—
Feeling hot	General disorders	—	—	—	—
Injection site nodule	General disorders	—	—	—	—
Pyrexia	General disorders	—	—	—	—
Amoebiasis	Infections and infestations	—	—	—	—
Bronchitis	Infections and infestations	—	—	—	—

Most-reported serious reactions: Angina pectoris, Colitis ulcerative, COVID-19, COVID-19 pneumonia, Postoperative wound infection, SARS-CoV-2 sepsis, Lower limb fracture, Reactive gastropathy.

Data from ClinicalTrials.gov NCT04233216 adverse events section.

Sponsor's own description

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).

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Approved HIV reverse transcriptase inhibitors in the past decade.
   Li G, Wang Y, De Clercq E. · · 2022 · cited 71× · PMID 35847492 · DOI 10.1016/j.apsb.2021.11.009
2. Safety, tolerability, and pharmacokinetics of single- and multiple-dose administration of islatravir (MK-8591) in adults without HIV.
   Matthews RP, Ankrom W, Friedman E, Jackson Rudd D, et al · · 2021 · cited 37× · PMID 34463432 · DOI 10.1111/cts.13048
3. Islatravir Is Not Expected to Be a Victim or Perpetrator of Drug-Drug Interactions via Major Drug-Metabolizing Enzymes or Transporters.
   Bleasby K, Houle R, Hafey M, Lin M, et al · · 2021 · cited 21× · PMID 34452431 · DOI 10.3390/v13081566
4. In vitro cross-resistance to doravirine in a panel of HIV-1 clones harbouring multiple NNRTI resistance mutations.
   Saladini F, Giammarino F, Hosseini BA, Giannini A, et al · · 2021 · cited 17× · PMID 32974670 · DOI 10.1093/jac/dkaa401
5. HIV: how to manage heavily treatment-experienced patients.
   Spivack S, Pagkalinawan S, Samuel R, Koren DE. · · 2022 · cited 13× · PMID 35310298 · DOI 10.7573/dic.2021-9-1
6. A Phase 1 Study to Evaluate the Drug Interaction Between Islatravir (MK-8591) and Doravirine in Adults Without HIV.
   Matthews RP, Jackson Rudd D, Fillgrove KL, Zhang S, et al · · 2021 · cited 9× · PMID 34151413 · DOI 10.1007/s40261-021-01046-1
7. Lack of a Clinically Meaningful Drug Interaction Between the HIV-1 Antiretroviral Agents Islatravir, Dolutegravir, and Tenofovir Disoproxil Fumarate.
   Rudd DJ, Zhang S, Fillgrove KL, Fox-Bosetti S, et al · · 2021 · cited 6× · PMID 34676683 · DOI 10.1002/cpdd.1026
8. Optimising Paediatric HIV Treatment: Recent Developments and Future Directions.
   Kamphuis AEM, Bamford A, Tagarro A, Cressey TR, et al · · 2024 · cited 3× · PMID 39436531 · DOI 10.1007/s40272-024-00656-4