Clinical trial NCT03537404: A Drug Interaction Study to Assess the Pharmacokinetics of Narlaprevir and Antiretroviral Drugs
Official title: A Drug Interaction Study to Assess the Pharmacokinetics of Narlaprevir and Antiretroviral Drugs
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy
Keywords: hepatitis C
chronic
pharmacokinetics
HIV
coinfection
concomitant therapy
Lead sponsor: R-Pharm
Sponsor class: INDUSTRY
Collaborators: name: Almedis
First posted: 2018-05-25
Enrollment: 36
Sex: ALL
Minimum age (years): 21
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Cmax of Narlaprevir
timeFrame: 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)
measure: AUCtau of Narlaprevir
timeFrame: 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)
measure: Cmax of Tenofovir
timeFrame: 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)
measure: AUCtau of Tenofovir
timeFrame: 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)
measure: Cmax of Raltegravir
timeFrame: 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)
measure: AUCtau of Raltegravir
timeFrame: 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)
Secondary outcomes:
measure: Number of Patients With Adverse Events
timeFrame: Up to 14 Days after the last dose of treatment in period 3 of each Part of the Study
measure: Number of Patients With Changes in Vital Signs
timeFrame: Up to 14 Days after the last dose of treatment in period 3 of each Part of the Study
measure: Number of Patients With Abnormal Laboratory Values
timeFrame: Up to 14 Days after the last dose of treatment in period 3 of each Part of the Study
measure: Number of Patients With Abnormal ECG Changes
timeFrame: Up to 14 Days after the last dose of treatment in period 3 of each Part of the Study
Other outcomes:
Locations:
city: Moscow
country: Russian Federation
facility: Clinic "Bessalar" JSC
Study officials:
affiliation: R-Pharm
name: Mikhail Samsonov
role: STUDY_DIRECTOR
References: