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A Drug Interaction Study to Assess the Pharmacokinetics of Narlaprevir and Antiretroviral Drugs

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ClinicalTrials.gov Identifier: NCT03537404
Recruitment Status : Completed
First Posted : May 25, 2018
Results First Posted : February 19, 2019
Last Update Posted : February 19, 2019
Sponsor:
Collaborator:
Almedis
Information provided by (Responsible Party):
R-Pharm

Tracking Information
First Submitted Date  ICMJE May 15, 2018
First Posted Date  ICMJE May 25, 2018
Results First Submitted Date  ICMJE August 31, 2018
Results First Posted Date  ICMJE February 19, 2019
Last Update Posted Date February 19, 2019
Actual Study Start Date  ICMJE April 24, 2017
Actual Primary Completion Date June 24, 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 31, 2018)
  • Cmax of Narlaprevir [ Time Frame: Day 5 Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16 and 24 hours post-dose on Day 5 of treatment A and C (Part 1/ Part 2) ]
    Maximum observed Concentration of Narlaprevir at Day 5 of treatment A and C of Part 1 or 2 of the study
  • AUCtau of Narlaprevir [ Time Frame: Day 5 Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16 and 24 hours post-dose on Day 5 of treatment A and C (Part 1/ Part 2) ]
    Area Under the Concentration-time curve during a dosing interval τ at steady state of Narlaprevir at Day 5 of treatment A and C of Part 1/ Part 2 of the study
  • Cmax of Tenofovir [ Time Frame: Day 5 Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 18 and 24 hrs post-dose on Day 5 of treatment B and C (Part 1) ]
    Maximum observed Concentration of Tenofovir at Day 5 of treatment B and C of Part 1 of the study
  • AUCtau of Tenofovir [ Time Frame: Day 5 Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 18 and 24 hrs post-dose on Day 5 of treatment B and C (Part 1) ]
    Area Under the Concentration-time curve during a dosing interval τ at steady state of Tenofovir at Day 5 of treatment B and C of Part 1 of the study
  • Cmax of Raltegravir [ Time Frame: Day 5 Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12 hrs post-dose of Day 5 of treatment B and C (Part 2) ]
    Maximum observed Concentration of Raltegravir at Day 5 of treatment B and C of Part 2 of the study
  • AUCtau of Raltegravir [ Time Frame: Day 5 Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12 hrs post-dose of Day 5 of treatment B and C (Part 2) ]
    Area Under the Concentration-time curve during a dosing interval τ at steady state of Tenofovir at Day 5 of treatment B and C of Part 2 of the study
Original Primary Outcome Measures  ICMJE
 (submitted: May 15, 2018)
  • Cmax of Narlaprevir [ Time Frame: Day 5 Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16 and 24 hrs post-dose on Day 5 of treatment A and C (Part 1/ Part 2) ]
    Maximum observed Concentration of Narlaprevir at Day 5 of treatment A and C of Part 1/ Part 2 of the study
  • AUCtau of Narlaprevir [ Time Frame: Day 5 Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16 and 24 hrs post-dose on Day 5 of treatment A and C (Part 1/ Part 2) ]
    Area Under the Concentration-time curve during a dosing interval τ at steady state of Narlaprevir at Day 5 of treatment A and C of Part 1/ Part 2 of the study
  • Cmax of Tenofovir [ Time Frame: Day 5 Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 18 and 24 hrs post-dose on Day 5 of treatment B and C (Part 1) ]
    Maximum observed Concentration of Tenofovir at Day 5 of treatment B and C of Part 1 of the study
  • AUCtau of Tenofovir [ Time Frame: Day 5 Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 18 and 24 hrs post-dose on Day 5 of treatment B and C (Part 1) ]
    Area Under the Concentration-time curve during a dosing interval τ at steady state of Tenofovir at Day 5 of treatment B and C of Part 1 of the study
  • Cmax of Raltegravir [ Time Frame: Day 5 Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12 hrs post-dose of Day 5 of treatment B and C (Part 2) ]
    Maximum observed Concentration of Raltegravir at Day 5 of treatment B and C of Part 2 of the study
  • AUCtau of Raltegravir [ Time Frame: Day 5 Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12 hrs post-dose of Day 5 of treatment B and C (Part 2) ]
    Area Under the Concentration-time curve during a dosing interval τ at steady state of Tenofovir at Day 5 of treatment B and C of Part 2 of the study
Change History Complete list of historical versions of study NCT03537404 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: August 31, 2018)
  • Number of Patients With Adverse Events [ Time Frame: Up to 14 Days after the last dose of treatment in period 3 of each Part of the Study ]
  • Number of Patients With Changes in Vital Signs [ Time Frame: Up to 14 Days after the last dose of treatment in period 3 of each Part of the Study ]
    There were no subjects with abnormal changes in vital signs
  • Number of Patients With Abnormal Laboratory Values [ Time Frame: Up to 14 Days after the last dose of treatment in period 3 of each Part of the Study ]
  • Number of Patients With Abnormal ECG Changes [ Time Frame: Up to 14 Days after the last dose of treatment in period 3 of each Part of the Study ]
    There were no subjects with abnormal ECG changes during the study
Original Secondary Outcome Measures  ICMJE
 (submitted: May 15, 2018)
  • Number of Patients With Adverse Events [ Time Frame: Up to Day 5 of Period 3 of each Part of the Study ]
  • Number of Patients With Changes in Vital Signs [ Time Frame: Up to Day 5 of Period 3 of each Part of the Study ]
  • Number of Patients With Abnormal Laboratory Values [ Time Frame: Up to Day 5 of Period 3 of each Part of the Study ]
  • Number of Patients With Abnormal ECG Changes [ Time Frame: Up to Day 5 of Period 3 of each Part of the Study ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Drug Interaction Study to Assess the Pharmacokinetics of Narlaprevir and Antiretroviral Drugs
Official Title  ICMJE A Drug Interaction Study to Assess the Pharmacokinetics of Narlaprevir and Antiretroviral Drugs
Brief Summary The study purpose is to evaluate the potential for a pharmacokinetic drug-drug interaction, safety and tolerability when Narlaprevir, Ritonavir (used as a metabolic inhibitor) and Tenofovir disoproxil fumarate (part 1) and Narlaprevir, Ritonavir and Raltegravir (part 2) are administered in combination to healthy volunteers.
Detailed Description

The current study includes 2 parts, as the following drugs may be used concomitantly to treat hepatitis C virus (HCV)/HIV coinfection:

  • Part 1 of the study is being conducted to evaluate the pharmacokinetic effect of coadministration of narlaprevir with ritonavir and tenofovir disoproxil fumarate.
  • Part 2 of the study is being conducted to evaluate the pharmacokinetic effect of coadministration of narlaprevir/ritonavir and raltegravir.

Each part of the study is designed as a randomized 3-period crossover study and will assess if there is any effect of tenofovir disoproxil fumarate or raltegravir on the pharmacokinetics of narlaprevir and vice versa.

Subjects will be screened within 28 days before dosing in this multi-part study. All subjects eligible for protocol criteria will be randomized 1:1:1 to receive one of the following treatment sequences: A/B/C, or B/C/A, or C/A/B. Every subject will receive only one treatment (A or B or C) in one Period. Subjects will be confined to the study center throughout treatment in each period. Following completion of study procedures for each treatment period, subjects will be released from the clinic. After a 7-14 (maximum) days interval between dosing, subjects will return to start hospitalization for the next treatment period. Subjects will be discharged from the study upon completion of all study related procedures in Period 3. Phone call will be conducted after 5-7 days of follow-up period to assess safety data.

This drug interaction study is designed to investigate pharmacokinetic drug-drug interactions between Narlaprevir coadministered with Ritonavir and antiretroviral drugs (Tenofovir disoproxil fumarate and Raltegravir) for labeling and clinical dosing guidance purposes.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Healthy
Intervention  ICMJE
  • Drug: Narlaprevir
    100 mg, film-coated tablets, taken as 200 mg per os daily
    Other Name: Arlansa
  • Drug: Ritonavir
    100 mg, film-coated tablets, taken as 100 mg per os daily
    Other Name: Norvir
  • Drug: Tenofovir Disoproxil Fumarate
    300 mg, film-coated tablets, taken as 300 mg per os daily
    Other Names:
    • Tenofovir-TL
    • Viread
  • Drug: Raltegravir
    400 mg, film-coated tablets, taken as 400 mg per os daily
    Other Name: Isentress
Study Arms  ICMJE
  • Active Comparator: Treatment A (Part 1/ Part 2)
    Narlaprevir 200 mg once daily with Ritonavir 100 mg once daily for 5 days
    Interventions:
    • Drug: Narlaprevir
    • Drug: Ritonavir
  • Active Comparator: Treatment B (Part 1)
    Tenofovir disoproxil fumarate 300 mg once daily for 5 days
    Intervention: Drug: Tenofovir Disoproxil Fumarate
  • Active Comparator: Treatment B (Part 2)
    Raltegravir 400 mg twice daily for 5 days
    Intervention: Drug: Raltegravir
  • Experimental: Treatment C (Part 1)
    Narlaprevir 200 mg once daily coadministered with ritonavir 100 mg once daily and Tenofovir disoproxil fumarate 300 mg once daily for 5 days
    Interventions:
    • Drug: Narlaprevir
    • Drug: Ritonavir
    • Drug: Tenofovir Disoproxil Fumarate
  • Experimental: Treatment C (Part 2)
    Narlaprevir 200 mg once daily coadministered with ritonavir 100 mg once daily and 400 mg raltegravir twice daily for 5 days
    Interventions:
    • Drug: Narlaprevir
    • Drug: Ritonavir
    • Drug: Raltegravir
Publications * Not Provided

*   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: May 15, 2018)
36
Original Actual Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE June 30, 2017
Actual Primary Completion Date June 24, 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria (the subject must meet all the criteria listed below for entry at baseline and at Days -1 and 1 before each treatment Period):

  • Subjects must be willing to give written informed consent for the trial and able to adhere to dose and visit schedules.
  • Subjects having a Body Mass Index (BMI) between 18,5 and 30 kg/m^2, inclusive.
  • Subjects should diagnosed as "healthy": no pathology of the gastrointestinal tract, liver, kidneys, cardiovascular system, central nervous system (previously carried out by standard clinical and lab tests which did not reveal the presence of any diseases. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) must not exceed the normal range; QT interval calculated by Bazett's formula (QTcB) for men should be ≤ 450 ms and ≤ 470 ms for women, the interval PR should be ≤ 200 ms).
  • Vital sign measurements (taken after ~3 minutes in a supine or sitting position) must be within the following ranges:

    1. systolic blood pressure, 100 - 130 mm Hg;
    2. diastolic blood pressure, 60 -90 mm Hg;
    3. pulse rate, 60-80 bpm.
  • Female subjects must be:

    1. postmenopausal (defined as 12 months with no menses; age > 40 years and with a follicle-stimulating hormone (FSH) level of >40 u/mL);
    2. surgically sterilized at least 3 months prior to baseline (e.g., documented hysterectomy or tubal ligation).
  • Men must agree to use a medically accepted method of contraception (condom and spermicide) during the trial and for 3 months after stopping the medication.

Exclusion Criteria (the subject will be excluded from entry if any of the criteria listed below are met at baseline):

  • Females with childbearing potential.
  • Subjects who, in the opinion of the investigator, will not be able to participate optimally in the study.
  • Positive results for hepatitis B surface antigen, hepatitis C antibodies or HIV, positive RW results.
  • Allergic reactions in history.
  • Intolerance to medication.
  • Chronic disease of cardiovascular, bronchopulmonary, and/or neuroendocrine systems, gastrointestinal, liver, pancreas, kidney and/or blood disease.
  • History or presence of impaired renal function, lactase deficiency, lactose intolerance, glucose-galactose malabsorption.
  • History of urinary obstruction or difficulty in voiding.
  • Gastrointestinal surgery in history (except of appendectomy).
  • Acute infections less than 4 weeks before participation in the study.
  • Subjects with a medical history of osteopenia and/or osteoporosis.
  • Regular administration of any medicines less than 4 weeks before participation in the study.
  • Administration of medicines with marked influence on hemodynamics, liver function et al (barbiturates, omeprazole, cimetidine et al) less than 30 days before participation in the study.
  • Blood donation (450 ml or more of blood or plasma) less than 2 months before participation in the study.
  • Intake of more than 10 units of alcohol in a week (1 unit of alcohol is equal to 0.5 L of beer, 200 mL of wine or 50 mL of spirits) or history of drug abuse or alcoholism.
  • Smoking of more than 10 cigarettes or equivalent tobacco use per day.
  • Participation in phase 1 clinical trial less than 3 months before participation in the study.
  • Positive screen for drugs abuse and drugs use.
  • Subjects with a medical history of psychiatric or personality disorders that in the opinion of the investigator and sponsor, affects the subject's ability to participate in the trial.
  • Subjects who are part of the study staff personnel or family members of the study staff personnel.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 21 Years to 55 Years   (Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Russian Federation
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03537404
Other Study ID Numbers  ICMJE CJ05013019
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party R-Pharm
Study Sponsor  ICMJE R-Pharm
Collaborators  ICMJE Almedis
Investigators  ICMJE
Study Director: Mikhail Samsonov R-Pharm
PRS Account R-Pharm
Verification Date August 2018

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