MK-8583 Single Dose Study in Human Immunodeficiency Virus Type 1 (HIV-1) Infected Participants (MK-8583-002)

• ClinicalTrials.gov Identifier: NCT03552536
• Recruitment Status: Completed
• First Posted: June 12, 2018
• Results First Posted: March 4, 2020
• Last Update Posted: March 4, 2020
• Sponsor: Merck Sharp & Dohme Corp.
• Information provided by (Responsible Party): Merck Sharp & Dohme Corp.

Study Description

Brief Summary:

This study aims to evaluate the safety, tolerability, pharmacokinetics (PK), and anti-retroviral therapy (ART) activity of the tenofovir prodrug, MK-8583 monotherapy in ART-naïve, HIV-1 infected participants. The primary hypothesis is that at a dose that is sufficiently safe and generally well tolerated, MK-8583 has superior anti-retroviral activity compared to historical placebo, as measured by change from baseline in plasma HIV-1 ribonucleic acid (RNA) (log10 copies/mL) at 168 hours post-dose.

Condition or disease	Intervention/treatment	Phase
HIV-1 Infection	Drug: MK-8583	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 5 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Single-Dose Clinical Trial to Study the Safety, Tolerability, Pharmacokinetics, and Anti- Retroviral Activity of MK-8583 Monotherapy in Anti-Retroviral Therapy (ART)-Naïve, HIV-1 Infected Patients
• Actual Study Start Date: October 7, 2018
• Actual Primary Completion Date: March 11, 2019
• Actual Study Completion Date: March 11, 2019

Arms and Interventions

Arm	Intervention/treatment
Experimental: A: MK-8583 100mg; After fasting, a single oral dose of 100 mg MK-8583 in capsule form.	Drug: MK-8583; A single oral dose of MK-8583 in capsule form
Experimental: B: MK-8583 ≤ 150 mg; After fasting, a single oral dose of ≤ 150 mg MK-8583 in capsule form, with the dose based on the results from earlier treatments	Drug: MK-8583; A single oral dose of MK-8583 in capsule form
Experimental: C: MK-8583 ≤ 150 mg; After fasting, a single oral dose of ≤ 150 mg MK-8583 in capsule form, with the dose based on the results from earlier treatments	Drug: MK-8583; A single oral dose of MK-8583 in capsule form

Outcome Measures

Primary Outcome Measures :

1. Number of Participants With at Least One Adverse Event (AE) [ Time Frame: Up to Day 29 ]
   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. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an AE.
2. Number of Participants Who Discontinued Study Due to an AE [ Time Frame: Day 1 ]
   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. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an AE.
3. Change From Baseline in Plasma Human Immunodeficiency Virus Type 1 (HIV-1) Ribonucleic Acid (RNA) at 168 Hours Post-dose. [ Time Frame: Baseline (pre-dose) and 168 hours post-dose. ]
   Plasma HIV-1 RNA was measured at baseline and 168 hours after dosing. Change from baseline for MK-8583 at 168 hours post-baseline was estimated from longitudinal data analysis (LDA) model containing fixed effects for time (predose, 168 hours postdose) and a random effect for participant. The change from baseline in plasma HIV-1 RNA in participants administered MK-8583 was compared with historical placebo data.

Secondary Outcome Measures :

1. Area Under the Concentration Time Curve From Time 0-168 Hours Postdose (AUC0-168hr) of Tenofovir Diphosphate (TFV-DP) [ Time Frame: Pre-dose, 4, 12, 24, 48, 72, 96, and 168 hours postdose ]
   Values of TFV-DP in peripheral blood mononuclear cells (PBMCs) were natural-log transformed and analyzed based on a linear model containing a fixed effect for the MK-8583 100-mg dose. The area under the concentration time curve from time 0-168 hours post-dose (AUC0-168hr) for intracellular TFV-DP is presented.
2. Time to Achieve Maximum Concentration (Tmax) of TFV-DP [ Time Frame: Pre-dose, 4, 12, 24, 48, 72, 96, 168, 240, 312 and 672 hours postdose ]
   Values of TFV-DP in PBMCs were natural-log transformed and analyzed based on a linear model containing a fixed effect for the MK-8583 100-mg dose. The time to achieve maximum concentration (Tmax) of intracellular TFV-DP is presented.
3. Maximum Concentration (Cmax) of TFV-DP [ Time Frame: Pre-dose, 4, 12, 24, 48, 72, 96, 168, 240, 312 and 672 hours postdose ]
   Values of TFV-DP in PBMCs were natural-log transformed and analyzed based on a linear model containing a fixed effect for the MK-8583 100-mg dose. The maximum concentration (Cmax) of intracellular TFV-DP is presented.
4. Concentration at 168 Hours Postdose (C168hr) of TFV-DP [ Time Frame: 168 hr postdose ]
   Values of TFV-DP in PBMCs were natural-log transformed and analyzed based on a linear model containing a fixed effect for the MK-8583 100-mg dose. The concentration at 168 hours postdose (C168hr) of TFV-DP is presented. It is hypothesized that the true geometric mean (GM) of TFV-DP in PBMC is ≥ 0.1 μM (100 nmol/L).
5. Apparent Terminal Half-life (t1/2) of TFV-DP [ Time Frame: Pre-dose, 4, 12, 24, 48, 72, 96, 168, 240, 312 and 672 hours postdose ]
   Values of TFV-DP in PBMCs were natural-log transformed and analyzed based on a linear model containing a fixed effect for the MK-8583 100-mg dose. The apparent terminal half-life (t1/2) of intracellular TFV-DP is presented.
6. Area Under the Concentration Time Curve From Time 0-last Measurement (AUC0-last) of MK-8583 [ Time Frame: Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 12, 24, 36, 48, and 72 hours postdose ]
   Values of plasma MK-8583 were natural-log transformed and analyzed based on a linear model containing a fixed effect for the MK-8583 100-mg dose. The area under the concentration time curve from time 0-last measurement (AUC0-last) of plasma MK-8583 is presented. The last quantified concentration value occurred at 2 hours (n=4) and 4 hours (n=1).
7. Area Under the Concentration Time Curve From Time 0-infinity (AUC0-inf) of MK-8583 [ Time Frame: Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 12, 24, 36, 48, and 72 hours postdose ]
   Values of plasma MK-8583 were natural-log transformed and analyzed based on a linear model containing a fixed effect for the MK-8583 100-mg dose.
8. Tmax of Plasma MK-8583. [ Time Frame: Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 12, 24, 36, 48, and 72 hours postdose ]
   Values of plasma MK-8583 were natural-log transformed and analyzed based on a linear model containing a fixed effect for the MK-8583 100-mg dose. The time to achieve maximum concentration (Tmax) of plasma MK-8583 is presented.
9. Cmax of MK-8583 [ Time Frame: Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 12, 24, 36, 48, and 72 hours postdose ]
   Values of plasma MK-8583 were natural-log transformed and analyzed based on a linear model containing a fixed effect for the MK-8583 100-mg dose. The maximum concentration (Cmax) of plasma MK-8583 is presented.
10. t1/2 of MK-8583 [ Time Frame: Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 12, 24, 36, 48, and 72 hours postdose ]
    Values of plasma MK-8583 were natural-log transformed and analyzed based on a linear model containing a fixed effect for the MK-8583 100-mg dose.
11. Apparent Total Clearance (CL/F) of MK-8583 [ Time Frame: Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 12, 24, 36, 48, and 72 hours postdose ]
    Values of plasma MK-8583 were natural-log transformed and analyzed based on a linear model containing a fixed effect for the MK-8583 100-mg dose. The apparent total clearance (CL/F) of plasma MK-8583 is presented.
12. Apparent Volume of Distribution (Vz/F) of MK-8583 [ Time Frame: Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 12, 24, 36, 48, and 72 hours postdose ]
    Values of plasma MK-8583 were natural-log transformed and analyzed based on a linear model containing a fixed effect for the MK-8583 100-mg dose.
13. AUC0-last of Tenofovir (TFV) [ Time Frame: Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 12, 24, 36, 48, and 72 hours postdose ]
    Values of plasma TFV were natural-log transformed and analyzed based on a linear model containing a fixed effect for the MK-8583 100-mg dose. The area under the concentration time curve from time 0-last measurement (AUC0-last) of plasma TFV is presented.
14. AUC0-inf of TFV [ Time Frame: Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 12, 24, 36, 48, and 72 hours postdose ]
    Values of plasma TFV were natural-log transformed and analyzed based on a linear model containing a fixed effect for the MK-8583 100-mg dose. The area under the concentration time curve from time 0-infinity (AUC0-inf) of plasma TFV is presented.
15. Tmax of TFV [ Time Frame: Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 12, 24, 36, 48, and 72 hours postdose ]
    Values of plasma TFV were natural-log transformed and analyzed based on a linear model containing a fixed effect for the MK-8583 100-mg dose. The time to achieve maximum concentration (Tmax) of plasma TFV is presented.
16. Cmax of TFV [ Time Frame: Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 12, 24, 36, 48, and 72 hours postdose ]
    Values of plasma TFV were natural-log transformed and analyzed based on a linear model containing a fixed effect for the MK-8583 100-mg dose. The maximum concentration (Cmax) of plasma TFV is presented.
17. t1/2 of TFV [ Time Frame: Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 12, 24, 36, 48, and 72 hours postdose ]
    Values of plasma TFV were natural-log transformed and analyzed based on a linear model containing a fixed effect for the MK-8583 100-mg dose. The apparent terminal half-life (t1/2) of plasma TFV is presented.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 60 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Male with female partner(s) of child-bearing potential use required methods of birth control.
• Female of reproductive potential must demonstrate a nongravid state at the pretrial (screening) visit and agree to use acceptable methods of birth control beginning at the pretrial (screening) visit, throughout the trial and until 30 days following cessation of treatment.
• Postmenopausal female, defined as without menses for at least 1 year and have a documented follicle stimulating hormone (FSH) level in the postmenopausal range at pretrial (screening).
• Surgically sterile female's status is post hysterectomy or oophorectomy.
• Is documented HIV-1 positive
• Is diagnosed with HIV-1 infection ≥ 3 months prior to screening.
• Is ART-naïve, defined as having never received any anti-retroviral agent; or ≤ 30 consecutive days of an investigational anti-retroviral agent, excluding a nucleoside reverse transcriptase inhibitor (NRTI), or ≤ 60 consecutive days of combination ART not including a NRTI.

Exclusion Criteria:

• Is mentally or legally institutionalized/incapacitated, has significant emotional problems at the time of pretrial (screening) visit or expected during the conduct of the trial or has a history of clinically significant psychiatric disorder over the last 5 years.
• Has a history of clinically significant endocrine, gastrointestinal, cardiovascular, hematological, hepatic, immunological (outside of HIV-1 infection), renal, respiratory, genitourinary or major neurological (including stroke and chronic seizures) abnormalities or diseases.
• Has a history of cancer (malignancy).
• Has a history of significant multiple and/or severe allergies (e.g. food, drug, latex allergy), or has had an anaphylactic reaction or significant intolerability (i.e. systemic allergic reaction) to prescription or non-prescription drugs or food.
• Is positive for Hepatitis B surface antigen.
• Has a history of chronic Hepatitis C unless there has been documented cure.
• Had major surgery, donated or lost 1 unit of blood (approximately 500 mL) within 4 weeks prior to the pretrial (screening) visit.
• Has participated in another investigational trial within 4 weeks or 5 half-lives, whichever is greater, prior to the pre-trial (screening) visit.
• Uses or anticipates using any medication, including prescription and non-prescription drugs or herbal remedies beginning approximately 2 weeks (or 5 half-lives) prior to administration of the initial dose of trial drug, throughout the trial, until the post-trial visit.
• Consumes greater than 3 glasses of alcoholic beverages, wine or distilled spirits per day.
• Consumes excessive amounts of caffeinated beverages per day.
• Is an excessive smoker (i.e., more than 10 cigarettes/day) and is unwilling to restrict smoking to ≤10 cigarettes per day.
• Has a positive urine drug screen (except for cannabis) at screening and/or pre-dose.
• Has received any investigational agent or any anti-retroviral agent within 60 days of study drug administration; or intends to receive any ART during this study.

Contacts and Locations

Locations

Germany

Charite Research Organisation GmbH ( Site 0001)

Berlin, Germany, 10117

Sponsors and Collaborators

Merck Sharp & Dohme Corp.

Investigators

• Study Director: Medical Director; Merck Sharp & Dohme Corp.

  Study Documents (Full-Text)

Documents provided by Merck Sharp & Dohme Corp.:

Study Protocol and Statistical Analysis Plan  [PDF] March 9, 2018

More Information

• Responsible Party: Merck Sharp & Dohme Corp.
• ClinicalTrials.gov Identifier: NCT03552536
• Other Study ID Numbers: 8583-002; 2017-004017-92 ( EudraCT Number ); MK-8583-002 ( Other Identifier: Merck Protocol Number )
• First Posted: June 12, 2018
• Results First Posted: March 4, 2020
• Last Update Posted: March 4, 2020
• Last Verified: February 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
• URL: http://engagezone.msd.com/ds_documentation.php

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes