HIV-1 Infection
Conditions
Brief summary
This is a two part study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of MK-1972 in participants with HIV-1 infections. In Part 1, participants will be randomized to receive MK-1972 (at one of 5 different dose levels given once or twice per day) or placebo. Part II will begin after the results of Part I are known; participants will be randomized to receive MK-1972 (only one dose level, twice per day) or placebo. The primary hypotheses are that MK-1972 at the studied doses is safe and well tolerated in HIV-1 infected males; and that MK-1972 has superior antiretroviral activity compared to placebo.
Interventions
DRUGMK-1972
MK-1972 will be supplied as 25 and 100 mg capsules, and will be given orally, at a dose dependent on the treatment arm; participants will take ten capsules (active drug and/or placebo) once or twice per day for 10 days
DRUGPlacebo to MK-1972
Placebo will be supplied as matching 25 and 100 mg capsules, and will be given orally, at a dose dependent on the treatment arm; participants will take ten capsules (active drug and/or placebo) once or twice per day for 10 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
* Stable baseline health. * Appropriate use of contraception; condom protection with pregnant partners. * Documented HIV-1 positive * Anti-retroviral therapy (ART)-naïve, defined as having never received any antiretroviral agent or ≤30 consecutive days of an investigational antiretroviral agent, excluding an integrase inhibitor, or ≤60 consecutive days of combination ART excluding an integrase inhibitor. * No investigational agent or licensed ART within 30 days of study drug administration. * Diagnosis of HIV-1-infection ≥ 3 months prior to screening.
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. * Use of any immune therapy agents or immunosuppressive therapy within 1 month prior to treatment in this study. * Requirement for chronic daily prescription medications. * Current (active) diagnosis of acute hepatitis due to any cause. * History of chronic Hepatitis C unless there has been documented cure and/or participant with a positive serologic test for Hepatitis C virus (HCV) has a negative HCV viral load. * Positive Hepatitis B surface antigen. * Refusal to stop using 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 (including washout intervals), until the post-study visit. * Consumption of 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. * Consumption of 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. * Smoker of more than 10 cigarettes/day unwilling to restrict smoking to ≤10 cigarettes per day. * Major surgery, donation or loss of 1 unit of blood (approximately 500 mL) or participation in another investigational study within 4 weeks prior to screening. * History of significant multiple and/or severe allergies (including latex allergy), or an anaphylactic reaction or significant intolerability to prescription or non-prescription drugs or food. * Current regular user of any illicit drugs or has a history of drug (including alcohol) abuse within approximately 1 year. Participants with a positive cannabis test with no evidence of drug-dependency may be enrolled at the discretion of the investigator. * History of hepatic or gallbladder disease or history of clinically significant abnormalities in liver function tests, or history of Gilbert's Syndrome, or history of elevated unconjugated bilirubin.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Experiencing Clinical and Laboratory Adverse Events (AEs) | From consent to 14 days after the last dose (up to Day 24) | An adverse event is any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the SPONSOR's product, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the SPONSOR's product, is also an adverse event. |
| Change From Baseline to Day 10 in Plasma Human Immunodeficiency Virus (HIV)-1 Ribonucleic Acid (RNA) Due to Treatment With MK-1972 or Placebo | Baseline and Day 10 (24 hours post-dose) | Blood was collected at baseline and on Day 10, and the plasma concentration for HIV-1 RNA was determined using the Abbott RealTime HIV assay. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Area Under the Curve From 0-24 Hours (AUC0-24hrs) on Day 10 for Plasma Concentration of MK-1972 in Participants With HIV-1 Infection | Day 10: pre-dose, and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, and 24 hours post-dose | Plasma concentration of MK-1972 was determined from blood collected from HIV-1 infected participants on Day 10 : pre-dose up to 24 hours post-dose in order to determine the AUC0-24hrs. |
Participant flow
Recruitment details
Two treatment groups planned for Part II (800 mg MK-1972 twice daily, and Placebo twice daily) were not enrolled, and are therefore not included in these Results.
Participants by arm
| Arm | Count |
|---|---|
| MK-1972 50 mg Once Daily (Part I) Ten capsules containing a total daily dose of 50 mg MK-1972 or placebo were taken orally, once per day for 10 days (Part I) | 2 |
| MK-1972 200 mg Once Daily (Part I) Ten capsules containing a total daily dose of 200 mg MK-1972 or placebo were taken orally, once per day for 10 days (Part I) | 2 |
| MK-1972 800 mg Once Daily (Part I) Ten capsules containing a total daily dose of 800 mg MK-1972 or placebo were taken orally, once per day for 10 days (Part I) | 2 |
| MK-1972 25 mg Twice Daily (Part I) Ten capsules containing a total daily dose of 25 mg MK-1972 or placebo were taken orally, twice per day for 10 days (Part I) | 2 |
| MK-1972 100 mg Twice Daily (Part I) Ten capsules containing a total daily dose of 100 mg MK-1972 or placebo were taken orally, twice per day for 10 days (Part I) | 2 |
| Placebo Twice Daily (Part I) Ten capsules containing placebo were taken orally, twice per day for 10 days (Part I) | 2 |
| Total | 12 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Study site terminated | 0 | 0 | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | MK-1972 50 mg Once Daily (Part I) | MK-1972 200 mg Once Daily (Part I) | MK-1972 800 mg Once Daily (Part I) | MK-1972 25 mg Twice Daily (Part I) | MK-1972 100 mg Twice Daily (Part I) | Placebo Twice Daily (Part I) | Total |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 31.5 Years STANDARD_DEVIATION 14.8 | 24.0 Years STANDARD_DEVIATION 2.8 | 32.5 Years STANDARD_DEVIATION 0.7 | 47.5 Years STANDARD_DEVIATION 10.6 | 37.0 Years STANDARD_DEVIATION 1.4 | 37.0 Years STANDARD_DEVIATION 17 | 34.9 Years STANDARD_DEVIATION 10.6 |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 2 Participants | 2 Participants | 2 Participants | 2 Participants | 2 Participants | 2 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 2 / 2 | 1 / 2 | 2 / 2 | 2 / 2 | 1 / 2 | 1 / 2 |
| serious Total, serious adverse events | 0 / 2 | 0 / 2 | 0 / 2 | 0 / 2 | 0 / 2 | 0 / 2 |
Outcome results
Primary
Change From Baseline to Day 10 in Plasma Human Immunodeficiency Virus (HIV)-1 Ribonucleic Acid (RNA) Due to Treatment With MK-1972 or Placebo
Blood was collected at baseline and on Day 10, and the plasma concentration for HIV-1 RNA was determined using the Abbott RealTime HIV assay.
Time frame: Baseline and Day 10 (24 hours post-dose)
Population: All participants who comply with the protocol sufficiently to ensure that these data will be likely to exhibit the effects of treatment, according to the underlying scientific model.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MK-1972 50 mg Once Daily (Part I) | Change From Baseline to Day 10 in Plasma Human Immunodeficiency Virus (HIV)-1 Ribonucleic Acid (RNA) Due to Treatment With MK-1972 or Placebo | -0.97 log10 copies/mL | Standard Error 0.2 |
| MK-1972 200 mg Once Daily (Part I) | Change From Baseline to Day 10 in Plasma Human Immunodeficiency Virus (HIV)-1 Ribonucleic Acid (RNA) Due to Treatment With MK-1972 or Placebo | -0.60 log10 copies/mL | Standard Error 0.3 |
| MK-1972 800 mg Once Daily (Part I) | Change From Baseline to Day 10 in Plasma Human Immunodeficiency Virus (HIV)-1 Ribonucleic Acid (RNA) Due to Treatment With MK-1972 or Placebo | -1.06 log10 copies/mL | Standard Error 0.6 |
| MK-1972 25 mg Twice Daily (Part I) | Change From Baseline to Day 10 in Plasma Human Immunodeficiency Virus (HIV)-1 Ribonucleic Acid (RNA) Due to Treatment With MK-1972 or Placebo | -0.60 log10 copies/mL | Standard Error 0.42 |
| MK-1972 100 mg Twice Daily (Part I) | Change From Baseline to Day 10 in Plasma Human Immunodeficiency Virus (HIV)-1 Ribonucleic Acid (RNA) Due to Treatment With MK-1972 or Placebo | -1.90 log10 copies/mL | Standard Error 0.33 |
| Placebo Twice Daily (Part I) | Change From Baseline to Day 10 in Plasma Human Immunodeficiency Virus (HIV)-1 Ribonucleic Acid (RNA) Due to Treatment With MK-1972 or Placebo | -0.07 log10 copies/mL | Standard Error 0.05 |
Primary
Number of Participants Experiencing Clinical and Laboratory Adverse Events (AEs)
An adverse event is any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the SPONSOR's product, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the SPONSOR's product, is also an adverse event.
Time frame: From consent to 14 days after the last dose (up to Day 24)
Population: All participants who received at least one dose of the investigational drug, according to the treatment they actually received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MK-1972 50 mg Once Daily (Part I) | Number of Participants Experiencing Clinical and Laboratory Adverse Events (AEs) | 2 Participants |
| MK-1972 200 mg Once Daily (Part I) | Number of Participants Experiencing Clinical and Laboratory Adverse Events (AEs) | 1 Participants |
| MK-1972 800 mg Once Daily (Part I) | Number of Participants Experiencing Clinical and Laboratory Adverse Events (AEs) | 2 Participants |
| MK-1972 25 mg Twice Daily (Part I) | Number of Participants Experiencing Clinical and Laboratory Adverse Events (AEs) | 2 Participants |
| MK-1972 100 mg Twice Daily (Part I) | Number of Participants Experiencing Clinical and Laboratory Adverse Events (AEs) | 1 Participants |
| Placebo Twice Daily (Part I) | Number of Participants Experiencing Clinical and Laboratory Adverse Events (AEs) | 2 Participants |
Secondary
The Area Under the Curve From 0-24 Hours (AUC0-24hrs) on Day 10 for Plasma Concentration of MK-1972 in Participants With HIV-1 Infection
Plasma concentration of MK-1972 was determined from blood collected from HIV-1 infected participants on Day 10 : pre-dose up to 24 hours post-dose in order to determine the AUC0-24hrs.
Time frame: Day 10: pre-dose, and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, and 24 hours post-dose
Population: All participants who comply with the protocol sufficiently to ensure that these data will be likely to exhibit the effects of treatment, according to the underlying scientific model. MK-1972 was not measured for the placebo group since it did not receive any of this drug.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| MK-1972 50 mg Once Daily (Part I) | The Area Under the Curve From 0-24 Hours (AUC0-24hrs) on Day 10 for Plasma Concentration of MK-1972 in Participants With HIV-1 Infection | 1540 nM.hr | Geometric Coefficient of Variation 24.3 |
| MK-1972 200 mg Once Daily (Part I) | The Area Under the Curve From 0-24 Hours (AUC0-24hrs) on Day 10 for Plasma Concentration of MK-1972 in Participants With HIV-1 Infection | 3590 nM.hr | Geometric Coefficient of Variation 43.8 |
| MK-1972 800 mg Once Daily (Part I) | The Area Under the Curve From 0-24 Hours (AUC0-24hrs) on Day 10 for Plasma Concentration of MK-1972 in Participants With HIV-1 Infection | 12500 nM.hr | Geometric Coefficient of Variation 15.5 |
| MK-1972 25 mg Twice Daily (Part I) | The Area Under the Curve From 0-24 Hours (AUC0-24hrs) on Day 10 for Plasma Concentration of MK-1972 in Participants With HIV-1 Infection | 676 nM.hr | Geometric Coefficient of Variation 27.6 |
| MK-1972 100 mg Twice Daily (Part I) | The Area Under the Curve From 0-24 Hours (AUC0-24hrs) on Day 10 for Plasma Concentration of MK-1972 in Participants With HIV-1 Infection | 1800 nM.hr | Geometric Coefficient of Variation 114 |
Comparison: Compared to historical data for AUC0-24hrs measured on Day 7 for healthy participants treated with 200 mg MK-1972 once daily
Comparison: Compared to historical data for AUC0-24hrs measured on Day 7 for healthy participants treated with 800 mg MK-1972 once daily