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NCT02217904

A Study of Islatravir (MK-8591) in Anti-Retroviral Therapy-Naive, Human Immunodeficiency Virus-1 Infected Participants (MK-8591-003)

Completed Phase 1 Results posted Last updated 12 August 2019
What this trial tests

Phase 1 trial testing 1 mg islatravir in HIV-1 in 30 participants. Completed in 11 May 2017.

Timeline
17 September 2015
Primary endpoint
11 May 2017
11 May 2017

Quick facts

Lead sponsorMerck Sharp & Dohme LLC
PhasePhase 1
StatusCompleted
Study typeINTERVENTIONAL
Allocationrandomized
Designparallel
Maskingnone
Primary purposetreatment
Enrollment30
Start date17 September 2015
Primary completion11 May 2017
Estimated completion11 May 2017

Drugs / interventions tested

Conditions studied

Sponsor

Merck Sharp & Dohme LLC — full company profile →

Who can join

Adults 18 to 60, any sex, with HIV-1. 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.

Change From Baseline in Plasma HIV-1 RNA at 168 Hours Post-Dose Primary · Baseline and 168 hours (7 days) post-dose

Plasma HIV-1 RNA was measured using the Roche COBAS Ampliprep/COBAS TaqMan HIV-1 test v.2.0, which has a linear range from 20 to 10,000,000 copies/mL. The lower limit of detection has 100% specificity at 20 copies/mL. Additionally, the test increases the probability of detection and expands coverage by targeting two highly conserved regions of the HIV-1 genome to compensate for the possibility of mutations or mismatches.

GroupValue95% CI
Panel A: 10 mg Islatravir-1.67-1.92 – -1.42
Panel B: 2 mg Islatravir-1.35-1.60 – -1.10
Panel C: 30 mg Islatravir-1.60-1.85 – -1.34
Panel D: 1 mg Islatravir-1.30-1.55 – -1.05
Panel E: 0.5 mg Islatravir-1.20-1.46 – -0.95
Number of Participants With One or More Adverse Events Primary · Up to 21 days post-dose

An adverse event (AE) is any untoward medical occurrence in a study participant administered a pharmaceutical product that does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not related to the medicinal product.

GroupValue95% CI
Panel A: 10 mg Islatravir5
Panel B: 2 mg Islatravir5
Panel C: 30 mg Islatravir6
Panel D: 1 mg Islatravir5
Panel E: 0.5 mg Islatravir6
Area Under the Concentration-Time Curve of Islatravir Triphosphate in Peripheral Blood Mononuclear Cells From Time 0 to 168 Hours (AUC0-168hr) Secondary · 4, 12, 24, 96, 120, 144, and 168 hours after islatravir administration. Value at predose was inferred from plasma predose sample.

Blood was collected to measure intracellular islatravir triphosphate concentration in peripheral blood mononuclear cells and determine AUC0-168hr.

GroupValue95% CI
Panel A: 10 mg Islatravir227± 33.3
Panel B: 2 mg Islatravir46.9± 38.1
Panel C: 30 mg Islatravir926± 47.7
Panel D: 1 mg Islatravir35.9± 27.6
Panel E: 0.5 mg Islatravir23.1± 83.0
Maximum Concentration (Cmax) of Islatravir Triphosphate in Peripheral Blood Mononuclear Cells Secondary · 4, 12, 24, 96, 120, 144, and 168 hours after islatravir administration. Value at predose was inferred from plasma predose sample.

Blood was collected to measure intracellular islatravir triphosphate concentration in peripheral blood mononuclear cells and determine Cmax.

GroupValue95% CI
Panel A: 10 mg Islatravir2.81± 49.9
Panel B: 2 mg Islatravir0.495± 62.9
Panel C: 30 mg Islatravir8.9± 60.3
Panel D: 1 mg Islatravir0.408± 49.3
Panel E: 0.5 mg Islatravir0.263± 54.5
Concentration of Islatravir Triphosphate in Peripheral Blood Mononuclear Cells at 168 Hours Post-Dose (C168hr) Secondary · 168 hours after islatravir administration

Blood was collected to measure intracellular islatravir triphosphate concentration in peripheral blood mononuclear cells and determine C168hr.

GroupValue95% CI
Panel A: 10 mg Islatravir0.983± 26
Panel B: 2 mg Islatravir0.188± 39.2
Panel C: 30 mg Islatravir4.83± 85.9
Panel D: 1 mg Islatravir0.164± 31.4
Panel E: 0.5 mg Islatravir0.116± 85.6
Time to Maximum Concentration (Tmax) of Islatravir Triphosphate in Peripheral Blood Mononuclear Cells Secondary · 4, 12, 24, 96, 120, 144, and 168 hours after islatravir administration. Value at predose was inferred from plasma predose sample.

Blood was collected to measure intracellular islatravir triphosphate concentration in peripheral blood mononuclear cells and determine TMax.

GroupValue95% CI
Panel A: 10 mg Islatravir1212 – 240
Panel B: 2 mg Islatravir84 – 144
Panel C: 30 mg Islatravir244 – 96
Panel D: 1 mg Islatravir84 – 24
Panel E: 0.5 mg Islatravir124 – 24
Apparent Terminal Half-Life (t1/2) of Islatravir Triphosphate in Peripheral Blood Mononuclear Cells Secondary · 4, 12, 24, 96, 120, 144, and 168 hours after islatravir administration. Value at predose was inferred from plasma predose sample.

Blood was collected to measure intracellular islatravir triphosphate concentration in peripheral blood mononuclear cells and determine apparent terminal t1/2.

GroupValue95% CI
Panel A: 10 mg Islatravir128± 42.2
Panel B: 2 mg Islatravir120± 14.7
Panel C: 30 mg Islatravir78.5± 31.4
Panel D: 1 mg Islatravir118± 16.1
Panel E: 0.5 mg Islatravir95.3± 38.2
Area Under the Plasma Concentration-Time Curve of Islatravir From Time 0 to 168 Hours (AUC0-168hr) Secondary · Predose and at 0.25, 0.5, 1, 2, 4, 8, 12, 24, 48, and 96 hours after islatravir administration. Value at 168 hours was extrapolated.

Blood was collected for the determination of AUC0-168hr of islatravir in plasma.

GroupValue95% CI
Panel A: 10 mg Islatravir1020± 16.8
Panel B: 2 mg Islatravir143± 39.6
Panel C: 30 mg Islatravir3020± 24.6
Panel D: 1 mg Islatravir88.3± 33.8
Panel E: 0.5 mg Islatravir38.3± 25.8
Maximum Plasma Concentration (Cmax) of Islatravir Secondary · Predose and at 0.25, 0.5, 1, 2, 4, 8, 12, 24, 48, and 96 hours after islatravir administration

Blood was collected for the determination of Cmax of islatravir in plasma.

GroupValue95% CI
Panel A: 10 mg Islatravir235± 32.1
Panel B: 2 mg Islatravir43.8± 51.2
Panel C: 30 mg Islatravir678± 29.6
Panel D: 1 mg Islatravir38.8± 31.3
Panel E: 0.5 mg Islatravir20.3± 36.4
Time to Maximum Plasma Concentration (Tmax) of Islatravir Secondary · Predose and at 0.25, 0.5, 1, 2, 4, 8, 12, 24, 48, and 96 hours after islatravir administration

Blood was collected for the determination of Tmax of islatravir in plasma.

GroupValue95% CI
Panel A: 10 mg Islatravir10.5 – 1
Panel B: 2 mg Islatravir0.50.5 – 1
Panel C: 30 mg Islatravir0.750.5 – 1
Panel D: 1 mg Islatravir0.50.5 – 1
Panel E: 0.5 mg Islatravir0.50.25 – 0.5
Apparent Terminal Half-Life (t1/2) of Islatravir in Plasma Secondary · Predose and at 0.25, 0.5, 1, 2, 4, 8, 12, 24, 48, and 96 hours after islatravir administration

Blood was collected for the determination of apparent terminal t1/2 of islatravir in plasma.

GroupValue95% CI
Panel A: 10 mg Islatravir59.7± 15.4
Panel B: 2 mg Islatravir47.4± 74.6
Panel C: 30 mg Islatravir56.8± 11.2
Panel D: 1 mg Islatravir10.4± 144
Panel E: 0.5 mg Islatravir2.31± 16.7

Adverse events — posted to ClinicalTrials.gov

Time frame: Up to 21 days following administration of investigational drug. Reporting threshold: 0%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Panel A: 10 mg Islatravir
Serious: 0/6 (0%)
Deaths: 0/6
Panel B: 2 mg Islatravir
Serious: 0/6 (0%)
Deaths: 0/6
Panel C: 30 mg Islatravir
Serious: 0/6 (0%)
Deaths: 0/6
Panel D: 1 mg Islatravir
Serious: 0/6 (0%)
Deaths: 0/6
Panel E: 0.5 mg Islatravir
Serious: 0/6 (0%)
Deaths: 0/6
Other adverse events (30 terms — click to expand)

ReactionSystemPanel A: 10 mg IslatravirPanel B: 2 mg IslatravirPanel C: 30 mg IslatravirPanel D: 1 mg IslatravirPanel E: 0.5 mg Islatravir
HeadacheNervous system disorders—————
Viral upper respiratory tract infectionInfections and infestations—————
DiarrhoeaGastrointestinal disorders—————
VomitingGastrointestinal disorders—————
HyperhidrosisSkin and subcutaneous tissue disorders—————
Angina pectorisCardiac disorders—————
Abdominal painGastrointestinal disorders—————
Abdominal pain upperGastrointestinal disorders—————
NauseaGastrointestinal disorders—————
Oral mucosa erosionGastrointestinal disorders—————
FatigueGeneral disorders—————
PyrexiaGeneral disorders—————
Gastrointestinal infectionInfections and infestations—————
Herpes zosterInfections and infestations—————
Otitis externaInfections and infestations—————
Rash pustularInfections and infestations—————
RhinitisInfections and infestations—————
ArthralgiaMusculoskeletal and connective tissue disorders—————
Back painMusculoskeletal and connective tissue disorders—————
MyalgiaMusculoskeletal and connective tissue disorders—————
Anogenital wartsNeoplasms benign, malignant and unspecified (incl cysts and polyps)—————
DizzinessNervous system disorders—————
SciaticaNervous system disorders—————
Sensory disturbanceNervous system disorders—————
ApathyPsychiatric disorders—————
Oropharyngeal painRespiratory, thoracic and mediastinal disorders—————
RhinorrhoeaRespiratory, thoracic and mediastinal disorders—————
AcneSkin and subcutaneous tissue disorders—————
EczemaSkin and subcutaneous tissue disorders—————
RashSkin and subcutaneous tissue disorders—————

Data from ClinicalTrials.gov NCT02217904 adverse events section.

Sponsor's own description

This study will evaluate the safety, tolerability, pharmacokinetics, and anti-retroviral therapy (ART) activity of islatravir (MK-8591) monotherapy in ART-naive, human immunodeficiency virus-1 (HIV-1) infected participants. The primary hypothesis is that at a safe and tolerable dose of islatravir, the true mean difference in the plasma HIV-1 ribonucleic acid (RNA) reduction from baseline between islatravir and placebo is at least 0.5 log (base10) copies/mL.

Publications & conference data

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

  1. The evolution of antiviral nucleoside analogues: A review for chemists and non-chemists. Part II: Complex modifications to the nucleoside scaffold.
    Yates MK, Seley-Radtke KL. · · 2019 · cited 160× · PMID 30529089 · DOI 10.1016/j.antiviral.2018.11.016
  2. 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
  3. Safety, pharmacokinetics, and antiretroviral activity of islatravir (ISL, MK-8591), a novel nucleoside reverse transcriptase translocation inhibitor, following single-dose administration to treatment-naive adults infected with HIV-1: an open-label, phase 1b, consecutive-panel tri
    Schürmann D, Rudd DJ, Zhang S, De Lepeleire I, et al · · 2020 · cited 64× · PMID 31911147 · DOI 10.1016/s2352-3018(19)30372-8
  4. Emerging reverse transcriptase inhibitors for HIV-1 infection.
    Rai MA, Pannek S, Fichtenbaum CJ. · · 2018 · cited 29× · PMID 29737220 · DOI 10.1080/14728214.2018.1474202
  5. Viral load Reduction in SHIV-Positive Nonhuman Primates via Long-Acting Subcutaneous Tenofovir Alafenamide Fumarate Release from a Nanofluidic Implant.
    Pons-Faudoa FP, Trani ND, Sizovs A, Shelton KA, et al · · 2020 · cited 13× · PMID 33080776 · DOI 10.3390/pharmaceutics12100981

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Primary sources · FDA · ClinicalTrials.gov · EMA · SEC EDGAR · ChEMBL · Wikidata · full sourcing