HIV-1 Infection
Conditions
Brief summary
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.
Interventions
DRUGDoravirine
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).
DRUGPlacebo
Placebo tablets once daily for 7 days.
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
MALE
Age
18 Years to 55 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage Change From Baseline in HIV-1 Ribonucleic Acid (RNA) Viral Load | Baseline and Day 7 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Plasma Concentration Time Curve From Dosing to 24 Hours Postdose (AUC0-24hr) of Doravirine on Day 7 | Predose and 1, 2, 4, 6, 8, 10, 12 and 24 hours postdose on Day 7 | The AUC0-24hr of doravirine on Day 7 was determined in the doravirine treatment arms. |
| Maximum Plasma Concentration (Cmax) of Doravirine on Day 7 | Predose and 1, 2, 4, 6, 8, 10, 12 and 24 hours postdose on Day 7 | The Cmax of doravirine on Day 7 was determined in the doravirine treatment arms. |
| Plasma Concentration 24 Hours Postdose (C24hr) of Doravirine on Day 7 | 24 hours postdose on Day 7 (Day 8) | The C24hr of doravirine on Day 7 was determined in the doravirine treatment arms. |
| Time to Maximum Plasma Concentration (Tmax) of Doravirine on Day 7 | Predose and 1, 2, 4, 6, 8, 10, 12 and 24 hours postdose on Day 7 | The Tmax of doravirine on Day 7 was determined in the doravirine treatment arms. |
Participant flow
Recruitment details
Participants with human immunodeficiency virus type 1 (HIV-1) who were antiretroviral therapy (ART)-naïve were enrolled at a single study center in Germany.
Pre-assignment details
Participants were allocated into panels, then randomized to doravirine 25 mg or placebo (Panel A) or doravirine 200 mg or placebo (Panel B). The protocol planned for a possible Panel C but Panel C was not enrolled. Study results are presented according to actual treatment received.
Participants by arm
| Arm | Count |
|---|---|
| Doravirine 25 mg Participants with HIV-1 infection received doravirine 25 mg q.d. for 7 days. | 6 |
| Doravirine 200 mg Participants with HIV-1 infection received doravirine 200 mg q.d. for 7 days. | 6 |
| Placebo Participants with HIV-1 infection received placebo q.d. by mouth for 7 days. | 6 |
| Total | 18 |
Baseline characteristics
| Characteristic | Doravirine 25 mg | Doravirine 200 mg | Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 36.7 Years STANDARD_DEVIATION 5.8 | 34.8 Years STANDARD_DEVIATION 8.4 | 26.8 Years STANDARD_DEVIATION 1 | 32.8 Years STANDARD_DEVIATION 7.1 |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 6 Participants | 6 Participants | 6 Participants | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 18 |
| other Total, other adverse events | 3 / 6 | 5 / 6 | 3 / 6 | 1 / 18 |
| serious Total, serious adverse events | 0 / 6 | 0 / 6 | 0 / 6 | 1 / 18 |
Outcome results
Primary
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.
Time frame: Baseline and Day 7
Population: All participants who received ≥1 dose of study drug are included (results are presented according to actual treatment received).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Doravirine 25 mg | Percentage Change From Baseline in HIV-1 Ribonucleic Acid (RNA) Viral Load | -1.52 Percentage change |
| Doravirine 200 mg | Percentage Change From Baseline in HIV-1 Ribonucleic Acid (RNA) Viral Load | -1.41 Percentage change |
| Placebo | Percentage Change From Baseline in HIV-1 Ribonucleic Acid (RNA) Viral Load | -0.15 Percentage change |
p-value: <0.00190% CI: [-1.6, -1.02]ANCOVA
p-value: <0.00190% CI: [-1.51, -1.02]ANCOVA
Secondary
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.
Time frame: Predose and 1, 2, 4, 6, 8, 10, 12 and 24 hours postdose on Day 7
Population: All participants who received ≥1 dose of doravirine are included.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Doravirine 25 mg | Area Under the Plasma Concentration Time Curve From Dosing to 24 Hours Postdose (AUC0-24hr) of Doravirine on Day 7 | 11.2 uM*hr |
| Doravirine 200 mg | Area Under the Plasma Concentration Time Curve From Dosing to 24 Hours Postdose (AUC0-24hr) of Doravirine on Day 7 | 62.2 uM*hr |
Secondary
Maximum Plasma Concentration (Cmax) of Doravirine on Day 7
The Cmax of doravirine on Day 7 was determined in the doravirine treatment arms.
Time frame: Predose and 1, 2, 4, 6, 8, 10, 12 and 24 hours postdose on Day 7
Population: All participants who received ≥1 dose of doravirine are included.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Doravirine 25 mg | Maximum Plasma Concentration (Cmax) of Doravirine on Day 7 | 826 nM |
| Doravirine 200 mg | Maximum Plasma Concentration (Cmax) of Doravirine on Day 7 | 4300 nM |
Secondary
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.
Time frame: 24 hours postdose on Day 7 (Day 8)
Population: All participants who received ≥1 dose of doravirine are included.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Doravirine 25 mg | Plasma Concentration 24 Hours Postdose (C24hr) of Doravirine on Day 7 | 251 nM |
| Doravirine 200 mg | Plasma Concentration 24 Hours Postdose (C24hr) of Doravirine on Day 7 | 1540 nM |
Secondary
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.
Time frame: Predose and 1, 2, 4, 6, 8, 10, 12 and 24 hours postdose on Day 7
Population: All participants who received ≥1 dose of doravirine are included.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Doravirine 25 mg | Time to Maximum Plasma Concentration (Tmax) of Doravirine on Day 7 | 1.00 Hours |
| Doravirine 200 mg | Time to Maximum Plasma Concentration (Tmax) of Doravirine on Day 7 | 2.00 Hours |