A Study of Doravirine (MK-1439) in Human Immunodeficiency Virus Type 1 (HIV-1)-Infected Participants (MK-1439-005)

Study Overview
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Brief Summary
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This is a study to evaluate the safety, tolerability, pharmacokinetics, and antiretroviral activity of doravirine (MK-1439) as monotherapy in antiretroviral therapy (ART)-naïve, HIV-1-infected participants.

Official Title
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A Multiple Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Antiretroviral Activity of MK-1439 in HIV-1 Infected Patients

Conditions
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HIV-1 Infection

Intervention / Treatment
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* Drug: Doravirine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of HIV-1-infection ≥3 months prior to screening Participants with female partner(s) of child-bearing potential must agree to use a medically acceptable method of contraception during the study and for 90 days after the last dose of study drug Body Mass Index (BMI) ≤35 kg/m^2 Other than HIV infection, participant's baseline health is judged to be stable No clinically significant abnormality on electrocardiogram (ECG) Participant is ART-naïve (defined as having never received any antiretroviral agent or ≤30 consecutive days of an investigational antiretroviral agent (excluding an Non-Nucleoside Reverse Transcriptase Inhibitor [NNRTI]) or ≤60 consecutive days of combination ART not including an NNRTI) Participant is willing to receive no other ART for the duration of the treatment phase of this study. Exclusion Criteria: History of stroke, chronic seizures, or major neurological disorder History of clinically significant endocrine, gastrointestinal, cardiovascular, hematological, hepatic, immunological (outside of HIV-1 infection), renal, respiratory, or genitourinary abnormalities or diseases History of clinically significant neoplastic disease Participant has used any immune therapy agents or immunosuppressive therapy within 1 month prior to treatment in this study Participant has one or more pre-existing risk factors for Torsades de Pointes (New York Heart Association Functional Classification II through IV heart failure, familial long-QT-syndrome, uncorrected hypokalemia, QTcF >470 msec) Participant requires or is anticipated to require chronic daily prescription medications Current (active) diagnosis of acute hepatitis due to any cause History of chronic Hepatitis C virus (HCV) unless there has been documented cure and/or patient with a positive serologic test for HCV has a negative HCV viral load. Positive Hepatitis B surface antigen Participant is unable to refrain from or anticipates the use of any medication, including prescription and non-prescription drugs or herbal remedies (such as St. John's Wort [Hypericum perforatum]) beginning approximately 2 weeks (or 5 half-lives) prior to administration of the initial dose of study drug, throughout the study, until the post-study visit Participant consumes excessive amounts of alcohol, defined as greater than 3 glasses of alcoholic beverages (1 glass is approximately equivalent to: beer [284 mL/10 ounces], wine [125 mL/4 ounces], or distilled spirits [25 mL/1 ounce]) per day Participant consumes excessive amounts, defined as greater than 6 servings (1 serving is approximately equivalent to 120 mg of caffeine) of coffee, tea, cola, or other caffeinated beverages per day Participant is an excessive smoker (i.e., more than 10 cigarettes/day) and is unwilling to restrict smoking to ≤10 cigarettes per day Major surgery, donated or lost 1 unit of blood (approximately 500 mL) within 4 weeks prior to the prestudy (screening) visit Participation in another investigational study within 4 weeks prior to the prestudy (screening) visit History of significant multiple and/or severe allergies (including latex allergy), or has had an anaphylactic reaction or significant intolerability to prescription or non-prescription drugs or food Current regular user (including use of any illicit drugs) or has a history of drug (including alcohol) abuse within approximately 1 year

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Panel A: Doravirine 25 mg or Placebo<br>Participants will receive oral doses of doravirine 25 mg or placebo once daily for 7 days. | Drug: Doravirine<br>* Doravirine tablets, orally, once daily for 7 days at a dose of 25 mg in Panel A and 200 mg in Panel B; dose in Panel C to be determined (≤200 mg).<br>* Other names: MK-1439;Drug: Placebo<br>* Placebo tablets once daily for 7 days.<br>|
| Experimental: Panel B: Doravirine 200 mg or Placebo<br>Panel B (doravirine 200 mg or placebo once daily for 7 days) will initiate upon satisfactory review of safety and tolerability from Panel A, and all safety, tolerability and pharmacokinetic data from the study MK-1439-001. | Drug: Doravirine<br>* Doravirine tablets, orally, once daily for 7 days at a dose of 25 mg in Panel A and 200 mg in Panel B; dose in Panel C to be determined (≤200 mg).<br>* Other names: MK-1439;Drug: Placebo<br>* Placebo tablets once daily for 7 days.<br>|
| Experimental: Panel C: Doravirine or Placebo<br>Panel C is optional. If conducted, the dose will be confirmed after review of data from prior panels. | Drug: Doravirine<br>* Doravirine tablets, orally, once daily for 7 days at a dose of 25 mg in Panel A and 200 mg in Panel B; dose in Panel C to be determined (≤200 mg).<br>* Other names: MK-1439;Drug: Placebo<br>* Placebo tablets once daily for 7 days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage Change From Baseline in HIV-1 Ribonucleic Acid (RNA) Viral Load | The change from baseline to Day 7 in plasma HIV RNA viral load was determined for each arm. Results are expressed as change in HIV RNA log10 copies/mL after 7 daily doses of doravirine or placebo. It was hypothesized that at least 1 dose of doravirine would be superior to placebo as documented by the upper bound of the 90% confidence interval <-1. Plasma HIV RNA levels were determined using the Abbott RealTime HIV assay which has a linear range from 40 to 10 million copies/mL. | Baseline and Day 7 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Plasma Concentration Time Curve From Dosing to 24 Hours Postdose (AUC0-24hr) of Doravirine on Day 7 | The AUC0-24hr of doravirine on Day 7 was determined in the doravirine treatment arms. | Predose and 1, 2, 4, 6, 8, 10, 12 and 24 hours postdose on Day 7 | 
| Maximum Plasma Concentration (Cmax) of Doravirine on Day 7 | The Cmax of doravirine on Day 7 was determined in the doravirine treatment arms. | Predose and 1, 2, 4, 6, 8, 10, 12 and 24 hours postdose on Day 7 | 
| Plasma Concentration 24 Hours Postdose (C24hr) of Doravirine on Day 7 | The C24hr of doravirine on Day 7 was determined in the doravirine treatment arms. | 24 hours postdose on Day 7 (Day 8) | 
| Time to Maximum Plasma Concentration (Tmax) of Doravirine on Day 7 | The Tmax of doravirine on Day 7 was determined in the doravirine treatment arms. | Predose and 1, 2, 4, 6, 8, 10, 12 and 24 hours postdose on Day 7 |