Healthy
Conditions
Keywords
hepatitis C, chronic, pharmacokinetics, HIV, coinfection, concomitant therapy
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.
Interventions
DRUGNarlaprevir
100 mg, film-coated tablets, taken as 200 mg per os daily
DRUGRitonavir
100 mg, film-coated tablets, taken as 100 mg per os daily
DRUGTenofovir Disoproxil Fumarate
300 mg, film-coated tablets, taken as 300 mg per os daily
DRUGRaltegravir
400 mg, film-coated tablets, taken as 400 mg per os daily
Sponsors
Almedis
R-Pharm
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
21 Years to 55 Years
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cmax of Tenofovir | 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 |
| Cmax of Raltegravir | 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 | 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 |
| Cmax of Narlaprevir | 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 | 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 |
| AUCtau of Tenofovir | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Adverse Events | 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 | 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 ECG Changes | 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 |
| Number of Patients With Abnormal Laboratory Values | Up to 14 Days after the last dose of treatment in period 3 of each Part of the Study | — |
Countries
Russia
Participant flow
Recruitment details
Healthy adult volunteers were recruited for all Parts of the study in one clinical site (Bessalar clinic) in Moscow between April and June 2017. 36 subjects were randomized so that 18 subjects participated in each Part of the study (6 subjects in each treatment group of each Part).
Pre-assignment details
Subjects were to be screened within 28 days before dosing in this multi-part study. Subjects were to be admitted to the study center the evening before the first dose for baseline assessments to confirm eligibility.
Participants by arm
| Arm | Count |
|---|---|
| Sequence A/B/C All participants of Part 1 or 2 of the study randomized in this group received treatment combinations (according to the protocol allocation) in the following sequence:
Treatment period 1 - Treatment A Treatment period 2 - Treatment B Treatment period 3 - Treatment C | 12 |
| Sequence B/C/A All participants of Part 1 or 2 of the study randomized in this group received treatment combinations (according to the protocol allocation) in the following sequence:
Treatment period 1 - Treatment B Treatment period 2 - Treatment C Treatment period 3 - Treatment A | 12 |
| Sequence C/A/B All participants of Part 1 or 2 of the study randomized in this group received treatment combinations (according to the protocol allocation) in the following sequence:
Treatment period 1 - Treatment C Treatment period 2 - Treatment A Treatment period 3 - Treatment B | 12 |
| Total | 36 |
Baseline characteristics
| Characteristic | Sequence A/B/C | Sequence B/C/A | Sequence C/A/B | Total |
|---|---|---|---|---|
| Age, Continuous Part 1 | 24.3 years STANDARD_DEVIATION 1.75 | 38.3 years STANDARD_DEVIATION 8.26 | 29.7 years STANDARD_DEVIATION 1.86 | 30.8 years STANDARD_DEVIATION 7.57 |
| Age, Continuous Part 2 | 24.3 years STANDARD_DEVIATION 4.03 | 38.7 years STANDARD_DEVIATION 4.59 | 29.5 years STANDARD_DEVIATION 3.33 | 30.8 years STANDARD_DEVIATION 7.17 |
| Body Mass Index (BMI) Part 1 | 23.14 kg/m2 STANDARD_DEVIATION 1.287 | 24.73 kg/m2 STANDARD_DEVIATION 3.022 | 24.20 kg/m2 STANDARD_DEVIATION 3.134 | 24.02 kg/m2 STANDARD_DEVIATION 2.554 |
| Body Mass Index (BMI) Part 2 | 24.26 kg/m2 STANDARD_DEVIATION 4.132 | 25.40 kg/m2 STANDARD_DEVIATION 2.732 | 25.63 kg/m2 STANDARD_DEVIATION 3.408 | 25.10 kg/m2 STANDARD_DEVIATION 3.319 |
| Race/Ethnicity, Customized Part 1 Asian | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Part 1 Black | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Part 1 Other | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Part 1 White | 6 Participants | 6 Participants | 5 Participants | 17 Participants |
| Race/Ethnicity, Customized Part 2 Asian | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Part 2 Black | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Part 2 Other | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Part 2 White | 6 Participants | 5 Participants | 6 Participants | 17 Participants |
| Sex: Female, Male Part 1 Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Part 1 Male | 6 Participants | 6 Participants | 6 Participants | 18 Participants |
| Sex: Female, Male Part 2 Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Part 2 Male | 6 Participants | 6 Participants | 6 Participants | 18 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 | 0 / 18 | 0 / 18 | 0 / 18 | 0 / 18 | 0 / 18 | 0 / 18 |
| other Total, other adverse events | 1 / 18 | 0 / 18 | 4 / 18 | 0 / 18 | 0 / 18 | 1 / 18 |
| serious Total, serious adverse events | 0 / 18 | 0 / 18 | 0 / 18 | 0 / 18 | 0 / 18 | 0 / 18 |
Outcome results
Primary
AUCtau of Narlaprevir
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
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)
Population: All subjects randomized to study treatment and received at least one dose of study drug.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Treatment A (Part 1) | AUCtau of Narlaprevir | 20504.31 ng*h/ml |
| Treatment C (Part 1) | AUCtau of Narlaprevir | 21366.2 ng*h/ml |
| Treatment A (Part 2) | AUCtau of Narlaprevir | 26199.19 ng*h/ml |
| Treatment C (Part 2) | AUCtau of Narlaprevir | 24458.48 ng*h/ml |
90% CI: [-0.075, 0.157]
90% CI: [-0.201, 0.064]
Primary
AUCtau of Raltegravir
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
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)
Population: All subjects randomized to study treatment and received at least one dose of study drug.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Treatment A (Part 1) | AUCtau of Raltegravir | 2912.45 ng*h/ml |
| Treatment C (Part 1) | AUCtau of Raltegravir | 2653.65 ng*h/ml |
90% CI: [-0.354, 0.168]
Primary
AUCtau of Tenofovir
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
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)
Population: All subjects randomized to study treatment and received at least one dose of study drug.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Treatment A (Part 1) | AUCtau of Tenofovir | 2599.95 ng*h/ml |
| Treatment C (Part 1) | AUCtau of Tenofovir | 2799.72 ng*h/ml |
90% CI: [0.016, 0.132]
Primary
Cmax of Narlaprevir
Maximum observed Concentration of Narlaprevir at Day 5 of treatment A and C of Part 1 or 2 of the study
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)
Population: All subjects randomized to study treatment and received at least one dose of study drug.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Treatment A (Part 1) | Cmax of Narlaprevir | 2130.2742 ng/ml |
| Treatment C (Part 1) | Cmax of Narlaprevir | 2172.233 ng/ml |
| Treatment A (Part 2) | Cmax of Narlaprevir | 2946.131 ng/ml |
| Treatment C (Part 2) | Cmax of Narlaprevir | 2880.612 ng/ml |
90% CI: [-0.103, 0.142]
90% CI: [-0.22, 0.175]
Primary
Cmax of Raltegravir
Maximum observed Concentration of Raltegravir at Day 5 of treatment B and C of Part 2 of the study
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)
Population: All subjects randomized to study treatment and received at least one dose of study drug.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Treatment A (Part 1) | Cmax of Raltegravir | 830.204 ng/ml |
| Treatment C (Part 1) | Cmax of Raltegravir | 715.726 ng/ml |
90% CI: [-0.45, 0.153]
Primary
Cmax of Tenofovir
Maximum observed Concentration of Tenofovir at Day 5 of treatment B and C of Part 1 of the study
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)
Population: All subjects randomized to study treatment and received at least one dose of study drug.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Treatment A (Part 1) | Cmax of Tenofovir | 263.037 ng/ml |
| Treatment C (Part 1) | Cmax of Tenofovir | 344.796 ng/ml |
90% CI: [0.159, 0.383]
Secondary
Number of Patients With Abnormal ECG Changes
There were no subjects with abnormal ECG changes during the study
Time frame: Up to 14 Days after the last dose of treatment in period 3 of each Part of the Study
Population: All subjects randomized to study treatment and received at least one dose of study drug
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment A (Part 1) | Number of Patients With Abnormal ECG Changes | Part 1 | 0 Participants |
| Treatment A (Part 1) | Number of Patients With Abnormal ECG Changes | Part 2 | 0 Participants |
| Treatment C (Part 1) | Number of Patients With Abnormal ECG Changes | Part 1 | 0 Participants |
| Treatment C (Part 1) | Number of Patients With Abnormal ECG Changes | Part 2 | 0 Participants |
| Treatment A (Part 2) | Number of Patients With Abnormal ECG Changes | Part 1 | 0 Participants |
| Treatment A (Part 2) | Number of Patients With Abnormal ECG Changes | Part 2 | 0 Participants |
Secondary
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
Population: All subjects randomized to study treatment and received at least one dose of study drug separately for each Patr of the study
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment A (Part 1) | Number of Patients With Abnormal Laboratory Values | Part 1 | 0 Participants |
| Treatment A (Part 1) | Number of Patients With Abnormal Laboratory Values | Part 2 | 0 Participants |
| Treatment C (Part 1) | Number of Patients With Abnormal Laboratory Values | Part 1 | 0 Participants |
| Treatment C (Part 1) | Number of Patients With Abnormal Laboratory Values | Part 2 | 0 Participants |
| Treatment A (Part 2) | Number of Patients With Abnormal Laboratory Values | Part 1 | 2 Participants |
| Treatment A (Part 2) | Number of Patients With Abnormal Laboratory Values | Part 2 | 1 Participants |
Secondary
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
Population: All subjects randomized to study treatment and received at least one dose of study drug
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment A (Part 1) | Number of Patients With Adverse Events | 1 Participants |
| Treatment C (Part 1) | Number of Patients With Adverse Events | 0 Participants |
| Treatment A (Part 2) | Number of Patients With Adverse Events | 4 Participants |
| Treatment C (Part 2) | Number of Patients With Adverse Events | 0 Participants |
| Treatment B (Part 2) | Number of Patients With Adverse Events | 0 Participants |
| Treatment C (Part 2) | Number of Patients With Adverse Events | 1 Participants |
Secondary
Number of Patients With Changes in Vital Signs
There were no subjects with abnormal 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
Population: All subjects randomized to study treatment and received at least one dose of study drug
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment A (Part 1) | Number of Patients With Changes in Vital Signs | 0 Participants |
| Treatment C (Part 1) | Number of Patients With Changes in Vital Signs | 0 Participants |
| Treatment A (Part 2) | Number of Patients With Changes in Vital Signs | 0 Participants |
| Treatment C (Part 2) | Number of Patients With Changes in Vital Signs | 0 Participants |
| Treatment B (Part 2) | Number of Patients With Changes in Vital Signs | 0 Participants |
| Treatment C (Part 2) | Number of Patients With Changes in Vital Signs | 0 Participants |