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Effects of Doravirine (MK-1439) on Methadone Pharmacokinetics in Methadone-Maintained Participants (MK-1439-045)

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ClinicalTrials.gov Identifier: NCT02715700
Recruitment Status : Completed
First Posted : March 22, 2016
Results First Posted : June 3, 2019
Last Update Posted : June 25, 2019
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.

Tracking Information
First Submitted Date  ICMJE March 17, 2016
First Posted Date  ICMJE March 22, 2016
Results First Submitted Date  ICMJE September 24, 2018
Results First Posted Date  ICMJE June 3, 2019
Last Update Posted Date June 25, 2019
Actual Study Start Date  ICMJE September 28, 2015
Actual Primary Completion Date June 13, 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 25, 2019)
  • Area Under the Concentration-Time Curve From Zero to 24 Hours After Dosing (AUC0-24) of R-Methadone [ Time Frame: Predose and 0.5, 1, 1.5, 2, 3, 4, 6, 12, 16, and 24 hours postdose on Day 1 and Day 6 ]
    The AUC0-24 of the R- methadone enantiomer was determined on Day 1 (methadone alone) and on Day 6 (methadone + doravirine). Plasma samples collected for methadone assay were analyzed for R- and S-methadone concentrations by Pharma Medica Research Inc. (Ontario, Canada). The analytical method used liquid-liquid extraction for analyte isolation followed by liquid chromatographic-tandem mass spectrometric (LC-MS/MS) detection. The lower limit of quantification (LLoQ) was 0.0250 ng/mL for each enantiomer. The analytical range was 0.0250 - 15.0 ng/mL.
  • Plasma Concentration at 24 Hours After Dosing (C24) of R-Methadone [ Time Frame: 24 hours postdose on Day 1 and Day 6 ]
    The C24 of the R- methadone enantiomer was determined on Day 1 (methadone alone) and on Day 6 (methadone + doravirine). Plasma samples collected for methadone assay were analyzed for R- and S-methadone concentrations by Pharma Medica Research Inc. (Ontario, Canada). The analytical method used liquid-liquid extraction for analyte isolation followed by LC-MS/MS detection. The LLoQ was 0.0250 ng/mL for each enantiomer. The analytical range was 0.0250 - 15.0 ng/mL.
  • Maximum Plasma Concentration (Cmax) of R-Methadone [ Time Frame: Predose and 0.5, 1, 1.5, 2, 3, 4, 6, 12, 16, and 24 hours postdose on Day 1 and Day 6 ]
    The Cmax of the R- methadone enantiomer was determined on Day 1 (methadone alone) and on Day 6 (methadone + doravirine). Plasma samples collected for methadone assay were analyzed for R- and S-methadone concentrations by Pharma Medica Research Inc. (Ontario, Canada). The analytical method used liquid-liquid extraction for analyte isolation followed by LC-MS/MS detection. The LLoQ was 0.0250 ng/mL for each enantiomer. The analytical range was 0.0250 - 15.0 ng/mL.
  • Time to Maximum Plasma Concentration (Tmax) of R-Methadone [ Time Frame: Predose and 0.5, 1, 1.5, 2, 3, 4, 6, 12, 16, and 24 hours postdose on Day 1 and Day 6 ]
    The Tmax of the R- methadone enantiomer was determined on Day 1 (methadone alone) and on Day 6 (methadone + doravirine). Plasma samples collected for methadone assay were analyzed for R- and S-methadone concentrations by Pharma Medica Research Inc. (Ontario, Canada). The analytical method used liquid-liquid extraction for analyte isolation followed by LC-MS/MS detection. The LLoQ was 0.0250 ng/mL for each enantiomer. The analytical range was 0.0250 - 15.0 ng/mL.
  • AUC0-24 of S-Methadone [ Time Frame: Predose and 0.5, 1, 1.5, 2, 3, 4, 6, 12, 16, and 24 hours postdose on Day 1 and Day 6 ]
    The AUC0-24 of the S- methadone enantiomer was determined on Day 1 (methadone alone) and on Day 6 (methadone + doravirine). Plasma samples collected for methadone assay were analyzed for R- and S-methadone concentrations by Pharma Medica Research Inc. (Ontario, Canada). The analytical method used liquid-liquid extraction for analyte isolation followed by LC-MS/MS detection. The LLoQ was 0.0250 ng/mL for each enantiomer. The analytical range was 0.0250 - 15.0 ng/mL.
  • C24 of S-Methadone [ Time Frame: 24 hours postdose on Day 1 and Day 6 ]
    The C24 of the S- methadone enantiomer was determined on Day 1 (methadone alone) and on Day 6 (methadone + doravirine). Plasma samples collected for methadone assay were analyzed for R- and S-methadone concentrations by Pharma Medica Research Inc. (Ontario, Canada). The analytical method used liquid-liquid extraction for analyte isolation followed by LC-MS/MS detection. The LLoQ was 0.0250 ng/mL for each enantiomer. The analytical range was 0.0250 - 15.0 ng/mL.
  • Cmax of S-Methadone [ Time Frame: Predose and 0.5, 1, 1.5, 2, 3, 4, 6, 12, 16, and 24 hours postdose on Day 1 and Day 6 ]
    The Cmax of the S- methadone enantiomer was determined on Day 1 (methadone alone) and on Day 6 (methadone + doravirine). Plasma samples collected for methadone assay were analyzed for R- and S-methadone concentrations by Pharma Medica Research Inc. (Ontario, Canada). The analytical method used liquid-liquid extraction for analyte isolation followed by LC-MS/MS detection. The LLoQ was 0.0250 ng/mL for each enantiomer. The analytical range was 0.0250 - 15.0 ng/mL.
  • Tmax of S-Methadone [ Time Frame: Predose and 0.5, 1, 1.5, 2, 3, 4, 6, 12, 16, and 24 hours postdose on Day 1 and Day 6 ]
    The Tmax of the S- methadone enantiomer was determined on Day 1 (methadone alone) and on Day 6 (methadone + doravirine). Plasma samples collected for methadone assay were analyzed for R- and S-methadone concentrations by Pharma Medica Research Inc. (Ontario, Canada). The analytical method used liquid-liquid extraction for analyte isolation followed by LC-MS/MS detection. The LLoQ was 0.0250 ng/mL for each enantiomer. The analytical range was 0.0250 - 15.0 ng/mL.
  • AUC0-24 of Total Methadone [ Time Frame: Predose and 0.5, 1, 1.5, 2, 3, 4, 6, 12, 16, and 24 hours postdose on Day 1 and Day 6 ]
    The AUC0-24 of total methadone was determined on Day 1 (methadone alone) and on Day 6 (methadone + doravirine). Plasma samples collected for methadone assay were analyzed for R- and S-methadone concentrations by Pharma Medica Research Inc. (Ontario, Canada). The analytical method used liquid-liquid extraction for analyte isolation followed by LC-MS/MS detection. The LLoQ was 0.0250 ng/mL for each enantiomer. The analytical range was 0.0250 - 15.0 ng/mL.
  • C24 of Total Methadone [ Time Frame: 24 hours postdose on Day 1 and Day 6 ]
    The C24 of total methadone was determined on Day 1 (methadone alone) and on Day 6 (methadone + doravirine). Plasma samples collected for methadone assay were analyzed for R- and S-methadone concentrations by Pharma Medica Research Inc. (Ontario, Canada). The analytical method used liquid-liquid extraction for analyte isolation followed by LC-MS/MS detection. The LLoQ was 0.0250 ng/mL for each enantiomer. The analytical range was 0.0250 - 15.0 ng/mL.
  • Cmax of Total Methadone [ Time Frame: Predose and 0.5, 1, 1.5, 2, 3, 4, 6, 12, 16, and 24 hours postdose on Day 1 and Day 6 ]
    The Cmax of total methadone was determined on Day 1 (methadone alone) and on Day 6 (methadone + doravirine). Plasma samples collected for methadone assay were analyzed for R- and S-methadone concentrations by Pharma Medica Research Inc. (Ontario, Canada). The analytical method used liquid-liquid extraction for analyte isolation followed by LC-MS/MS detection. The LLoQ was 0.0250 ng/mL for each enantiomer. The analytical range was 0.0250 - 15.0 ng/mL.
  • Tmax of Total Methadone [ Time Frame: Predose and 0.5, 1, 1.5, 2, 3, 4, 6, 12, 16, and 24 hours postdose on Day 1 and Day 6 ]
    The Tmax of total methadone was determined on Day 1 (methadone alone) and on Day 6 (methadone + doravirine). Plasma samples collected for methadone assay were analyzed for R- and S-methadone concentrations by Pharma Medica Research Inc. (Ontario, Canada). The analytical method used liquid-liquid extraction for analyte isolation followed by LC-MS/MS detection. The LLoQ was 0.0250 ng/mL for each enantiomer. The analytical range was 0.0250 - 15.0 ng/mL.
Original Primary Outcome Measures  ICMJE
 (submitted: March 21, 2016)
  • Area Under the Concentration-Time Curve from Time Zero to 24 Hours (AUC0-24) of Methadone [ Time Frame: Predose and 0.5, 1, 1.5, 2, 3, 4, 6, 12, 16, and 24 hours postdose on Day 1 and Day 6 ]
  • Concentration at 24-Hours After Dosing (C24) of Methadone [ Time Frame: Predose and 24 hours postdose on Day 1 and Day 6 ]
  • Maximum Concentration (Cmax) of Methadone [ Time Frame: Predose and 0.5, 1, 1.5, 2, 3, 4, 6, 12, 16, and 24 hours postdose on Day 1 and Day 6 ]
Change History
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Effects of Doravirine (MK-1439) on Methadone Pharmacokinetics in Methadone-Maintained Participants (MK-1439-045)
Official Title  ICMJE A Multiple-Dose Clinical Trial to Study the Effect of MK-1439 (Doravirine) on Methadone Pharmacokinetics
Brief Summary This study will evaluate the effects of multiple doses of doravirine (MK-1439) on the pharmacokinetics of methadone in participants requiring methadone maintenance therapy. The primary hypothesis is that area under the plasma concentration-time curve to 24 hours postdose (AUC0-24) of (R)-methadone is similar when a maintenance regimen of methadone is administered with or without multiple daily doses of doravirine.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Human Immunodeficiency Virus (HIV) Infection
Intervention  ICMJE
  • Drug: Methadone
    Methadone 20 to 200 mg (10 mg/mL if oral solution concentrate) oral tablet once per day.
  • Drug: Doravirine
    Doravirine 100 mg oral tablet once per day.
    Other Name: MK-1439
Study Arms  ICMJE Experimental: Maintenance Methadone and MK-1439
Participants maintained on a stable methadone regimen (20 to 200 mg once daily) for ≥14 days prior to Day 1 will continue to receive methadone maintenance once per day on Days 1 to 7. From Day 2 to 6, participants will also receive doravirine 100 mg once daily.
Interventions:
  • Drug: Methadone
  • Drug: Doravirine
Publications * Khalilieh S, Yee KL, Sanchez RI, Vaynshteyn K, Fan L, Searle S, Bouhajib M, Iwamoto M. Evaluation of the Pharmacokinetic Interaction Between Doravirine and Methadone. Clin Pharmacol Drug Dev. 2020 Feb;9(2):151-161. doi: 10.1002/cpdd.699. Epub 2019 May 23.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: March 21, 2016)
14
Original Estimated Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE August 15, 2016
Actual Primary Completion Date June 13, 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • If female with reproductive potential: must demonstrate a serum β-human chorionic gonadotropin (β -hCG) level consistent with the nongravid state and agree to use (and/or have their partner use) two acceptable methods of birth control throughout the trial and until 2 weeks after the last dose of trial drug.
  • If postmenopausal female: must be without menses for at least 1 year.
  • If surgically sterile female: must have a status of post hysterectomy, oophorectomy or tubal ligation.
  • Body Mass Index (BMI) of 18-35 kg/m^2 (inclusive).
  • Able to comply with the smoking restrictions, including <=10 cigarettes per day while in the Clinical Research Unit, and no smoking from 2 hours predose to 2 hours postdose on Days 1 and 6.
  • Reliably participating in a methadone maintenance program for at least two months prior to Day 1. Required to be on a documented stable dose of methadone for at least 14 days prior to Day 1.
  • Agree not to change current maintenance methadone dose of 20-200 mg once daily (unless for safety reasons) from screening until the end of the study. Must agree to observation and documentation of daily methadone dose administration during the period of the study during which they are domiciled.

Exclusion Criteria:

  • Mentally or legally incapacitated, have significant emotional problems at the time of pretrial (screening) visit or expected during the conduct of the trial or have a history of clinically significant psychiatric disorder of the last 5 years. Participants who have had situational depression may be enrolled in the trial at the discretion of the investigator.
  • History of clinically significant endocrine, gastrointestinal, cardiovascular, hematological, hepatic, immunological, renal, respiratory, genitourinary or major neurological (including stroke and chronic seizures) abnormalities or diseases. Participants with a history of uncomplicated kidney stones or childhood asthma may be enrolled in the trial at the discretion of the investigator.
  • History of cancer (malignancy) - exceptions apply.
  • History of significant multiple and/or severe allergies (e.g. food, drug, latex allergy), or has had an anaphylactic reaction or significant intolerability to prescription or non-prescription drugs or food.
  • Positive for Human Immunodeficiency Virus (HIV).
  • Major surgery, donated or lost 1 unit of blood (approximately 500 mL) within 4 weeks prior to the pretrial (screening) visit.
  • Participated in another investigational trial within 4 weeks prior to the pretrial (screening) visit.
  • Nursing mother.
  • Unable to refrain from or anticipates the use of any medication, including prescription and non-prescription drugs or herbal remedies beginning approximately 2 weeks prior to the first dose of the 14 day methadone maintenance phase prior to Day 1, throughout the trial, until the post-trial visit - exceptions apply.
  • Consumes greater than 3 glasses of alcoholic beverages (1 glass is approximately equivalent to: beer [354 mL/12 ounces], wine [118 mL/4 ounces], or distilled spirits [29.5 mL/1 ounce]) per day - exceptions apply.
  • Consumes excessive amounts of caffeine, defined as greater than 6 servings (1 serving is approximately equivalent to 120 mg of caffeine) of coffee, tea, cola, energy-drinks, or other caffeinated beverages per day.
  • Has a positive screen for drugs with a high potential for abuse such as cocaine, amphetamines, methylenedioxymethamphetamine (MDMA), barbiturates, benzodiazepines (exceptions apply), or opiates/opioids (apart from methadone as assigned maintenance therapy) on Day 1 that cannot be explained by concomitant medications, unless at the discretion of the principal investigator and the sponsor. Must have a negative Urine Drug Screen prior to randomization, with the exception of tetrahydrocannabinol (THC) and prescription benzodiazepines.
  • Clinical Opiate Withdrawal Scale (COWS) score of >=5 prior to randomization.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Not Provided
Removed Location Countries United States
 
Administrative Information
NCT Number  ICMJE NCT02715700
Other Study ID Numbers  ICMJE 1439-045
MK-1439-045 ( Other Identifier: Merck Protocol Number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
URL: http://engagezone.msd.com/ds_documentation.php
Responsible Party Merck Sharp & Dohme Corp.
Study Sponsor  ICMJE Merck Sharp & Dohme Corp.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Medical Director Merck Sharp & Dohme Corp.
PRS Account Merck Sharp & Dohme Corp.
Verification Date June 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP