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| Name | Class |
|---|---|
| Almedis | INDUSTRY |
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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.
The current study includes 2 parts, as the following drugs may be used concomitantly to treat hepatitis C virus (HCV)/HIV coinfection:
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Treatment A (Part 1/ Part 2) | Active Comparator | Narlaprevir 200 mg once daily with Ritonavir 100 mg once daily for 5 days |
|
| Treatment B (Part 1) | Active Comparator | Tenofovir disoproxil fumarate 300 mg once daily for 5 days |
|
| Treatment B (Part 2) | Active Comparator | Raltegravir 400 mg twice daily for 5 days |
|
| Treatment C (Part 1) | Experimental | Narlaprevir 200 mg once daily coadministered with ritonavir 100 mg once daily and Tenofovir disoproxil fumarate 300 mg once daily for 5 days |
|
| Treatment C (Part 2) | Experimental | Narlaprevir 200 mg once daily coadministered with ritonavir 100 mg once daily and 400 mg raltegravir twice daily for 5 days |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Narlaprevir | Drug | 100 mg, film-coated tablets, taken as 200 mg per os daily |
|
| Measure | Description | Time Frame |
|---|---|---|
| Cmax of Narlaprevir | Maximum observed Concentration of Narlaprevir at Day 5 of treatment A and C of Part 1 or 2 of the study | 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) |
| 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 | 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) |
| Cmax of Tenofovir | Maximum observed Concentration of Tenofovir at Day 5 of treatment B and C of Part 1 of the study | 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) |
| 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 | 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) |
| Cmax of Raltegravir | Maximum observed Concentration of Raltegravir at Day 5 of treatment B and C of Part 2 of the study | 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) |
| 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 |
| Measure | Description | Time Frame |
|---|---|---|
| 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 | There were no subjects with abnormal changes in vital signs |
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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:
Female subjects must be:
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):
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| Name | Affiliation | Role |
|---|---|---|
| Mikhail Samsonov | R-Pharm | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Clinic "Bessalar" JSC | Moscow | Russia |
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.
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).
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| ID | Title | Description |
|---|---|---|
| FG000 | Part 1 | All patients of Part 1 of the study were randomized in 1:1:1 ratio to receive one of the treatment sequences (A/B/C, B/C/A or C/A/B). Every subject received only one drug combination (A or B or C) in one treatment period. Each period was followed by 8 washout days. Treatments include: Narlaprevir (100 mg, film-coated tablets, taken as 200 mg per os once daily); Ritonavir (100 mg, film-coated tablets, taken as 100 mg per os once daily); Tenofovir Disoproxil Fumarate (300 mg, film-coated tablets, taken as 300 mg per os once daily) in different combinations assigned to the subjects in accordance with protocol considerations for Part 1 of the study. |
| FG001 | Part 2 | All patients of Part 2 of the study were randomized in 1:1:1 ratio to receive one of the treatment sequences (A/B/C, B/C/A or C/A/B). Every subject received only one drug combination (A or B or C) in one treatment period. Each period was followed by 8 washout days. Treatments include: Narlaprevir (100 mg, film-coated tablets, taken as 200 mg per os once daily); Ritonavir (100 mg, film-coated tablets, taken as 100 mg per os once daily); Raltegravir (400 mg, film-coated tablets, taken as 400 mg per os once daily) in different combinations assigned to the subjects in accordance with protocol considerations for Part 2 of the study. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| First Intervention (A or B or C) |
| |||||||||||||
| First Washout Period (8 Days) |
| |||||||||||||
| Second Intervention (A or B or C) |
| |||||||||||||
| Second Washout Period (8 Days) |
| |||||||||||||
| Third Intervention (A or B or C) |
|
All 36 subjects randomized to study treatment and received at least one dose of study drug (Safety Population).
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| ID | Title | Description |
|---|---|---|
| BG000 | 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 |
| BG001 |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Baseline characteristics analisys was performed separately for Part 1 and 2 of the study (18 subjects in each Part were randomized in 1:1:1 ratio for each treatment sequence - 6 participants in each). |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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 | All subjects randomized to study treatment and received at least one dose of study drug. | Posted | Geometric Mean | 90% Confidence Interval | ng/ml | 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) |
|
Up to 14 Days after the last dose of treatment in period 3 of each Part of the Study
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Treatment A (Part 1) | Narlaprevir, 100 mg, film-coated tablets, taken as 200 mg per os daily in combination with Ritonavir, 100 mg, film-coated tablets, taken as 100 mg per os daily for 5 days |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Alanine Aminotransferase Increased | Investigations | MedRA 19.0 | Systematic Assessment |
Not provided
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Emiliya Krasavina, Medical Adviser | R-Pharm | 0074959567937 | krasavina@rpharm.ru |
Not provided
| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Feb 20, 2017 | Aug 28, 2018 | Prot_SAP_000.pdf |
Not provided
| ID | Term |
|---|---|
| D006526 | Hepatitis C |
| D000092122 | Bronchiolitis Obliterans Syndrome |
| D060085 | Coinfection |
| ID | Term |
|---|---|
| D000086982 | Blood-Borne Infections |
| D003141 | Communicable Diseases |
| D007239 | Infections |
| D006525 | Hepatitis, Viral, Human |
Not provided
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| ID | Term |
|---|---|
| C552043 | narlaprevir |
| D019438 | Ritonavir |
| D000068698 | Tenofovir |
| D000068898 | Raltegravir Potassium |
| ID | Term |
|---|---|
| D013844 | Thiazoles |
| D013457 | Sulfur Compounds |
| D009930 | Organic Chemicals |
| D001393 | Azoles |
Not provided
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Not provided
Not provided
Not provided
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Not provided
|
| Ritonavir | Drug | 100 mg, film-coated tablets, taken as 100 mg per os daily |
|
|
| Tenofovir Disoproxil Fumarate | Drug | 300 mg, film-coated tablets, taken as 300 mg per os daily |
|
|
| Raltegravir | Drug | 400 mg, film-coated tablets, taken as 400 mg per os daily |
|
|
| 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) |
| Up to 14 Days after the last dose of treatment in period 3 of each Part of 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 |
| Number of Patients With Abnormal ECG Changes | There were no subjects with abnormal ECG changes during the study | Up to 14 Days after the last dose of treatment in period 3 of each Part of the Study |
| NOT COMPLETED |
|
| NOT COMPLETED |
|
| NOT COMPLETED |
|
| NOT COMPLETED |
|
| 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 |
| BG002 | 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 |
| BG003 | Total | Total of all reporting groups |
| Mean |
| Standard Deviation |
| years |
|
| Sex: Female, Male | Baseline characteristics analisys was performed separately for Part 1 and 2 of the study (18 subjects in each Part were randomized in 1:1:1 ratio for each treatment sequence - 6 participants in each). | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Baseline characteristics analisys was performed separately for Part 1 and 2 of the study (18 subjects in each Part were randomized in 1:1:1 ratio for each treatment sequence - 6 participants in each). | Count of Participants | Participants |
|
| Body Mass Index (BMI) | Calculated as weight(kg)/height(m^2) | Baseline characteristics analisys was performed separately for Part 1 and 2 of the study (18 subjects in each Part were randomized in 1:1:1 ratio for each treatment sequence - 6 participants in each). | Mean | Standard Deviation | kg/m2 |
|
Subjects recieved as Treatment C for 5 days (in respective treatment period): Narlaprevir (100 mg, film-coated tablets, taken as 200 mg per os once daily) coadministered with Ritonavir (100 mg, film-coated tablets, taken as 100 mg per os once daily) and Tenofovir Disoproxil Fumarate (300 mg, film-coated tablets, taken as 300 mg per os once daily). |
| OG002 | Treatment A (Part 2) | Subjects in both Parts of the study recieved as Treatment A for 5 days (in respective treatment period): Narlaprevir (100 mg, film-coated tablets, taken as 200 mg per os once daily) and Ritonavir (100 mg, film-coated tablets, taken as 100 mg per os once daily). |
| OG003 | Treatment C (Part 2) | Subjects recieved as Treatment C for 5 days (in respective treatment period): Narlaprevir (100 mg, film-coated tablets, taken as 200 mg per os once daily) coadministered with Ritonavir (100 mg, film-coated tablets, taken as 100 mg per os once daily and Raltegravir (400 mg, film-coated tablets, taken as 400 mg per os twice daily). |
|
|
|
| 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 | All subjects randomized to study treatment and received at least one dose of study drug. | Posted | Geometric Mean | 90% Confidence Interval | ng*h/ml | 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) |
|
|
|
|
| Primary | Cmax of Tenofovir | Maximum observed Concentration of Tenofovir at Day 5 of treatment B and C of Part 1 of the study | All subjects randomized to study treatment and received at least one dose of study drug. | Posted | Geometric Mean | 90% Confidence Interval | ng/ml | 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) |
|
|
|
|
| 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 | All subjects randomized to study treatment and received at least one dose of study drug. | Posted | Geometric Mean | 90% Confidence Interval | ng*h/ml | 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) |
|
|
|
|
| Primary | Cmax of Raltegravir | Maximum observed Concentration of Raltegravir at Day 5 of treatment B and C of Part 2 of the study | All subjects randomized to study treatment and received at least one dose of study drug. | Posted | Geometric Mean | 90% Confidence Interval | ng/ml | 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) |
|
|
|
|
| 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 | All subjects randomized to study treatment and received at least one dose of study drug. | Posted | Geometric Mean | 90% Confidence Interval | ng*h/ml | 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 | Number of Patients With Adverse Events | All subjects randomized to study treatment and received at least one dose of study drug | Posted | Count of Participants | Participants | Up to 14 Days after the last dose of treatment in period 3 of each Part of the Study |
|
|
|
| Secondary | Number of Patients With Changes in Vital Signs | There were no subjects with abnormal changes in vital signs | All subjects randomized to study treatment and received at least one dose of study drug | Posted | Count of Participants | Participants | Up to 14 Days after the last dose of treatment in period 3 of each Part of the Study |
|
|
|
| Secondary | Number of Patients With Abnormal Laboratory Values | All subjects randomized to study treatment and received at least one dose of study drug separately for each Patr of the study | Posted | Count of Participants | Participants | Up to 14 Days after the last dose of treatment in period 3 of each Part of the Study |
|
|
|
| Secondary | Number of Patients With Abnormal ECG Changes | There were no subjects with abnormal ECG changes during the study | All subjects randomized to study treatment and received at least one dose of study drug | Posted | Count of Participants | Participants | Up to 14 Days after the last dose of treatment in period 3 of each Part of the Study |
|
|
|
| 0 |
| 18 |
| 0 |
| 18 |
| 1 |
| 18 |
| EG001 | Treatment B (Part 1) | Tenofovir Disoproxil Fumarate, 300 mg, film-coated tablets, taken as 300 mg per os daily for 5 days | 0 | 18 | 0 | 18 | 0 | 18 |
| EG002 | Treatment C (Part 1) | Narlaprevir, 100 mg, film-coated tablets, taken as 200 mg per os daily coadministered with Ritonavir, 100 mg, film-coated tablets, taken as 100 mg per os daily and Tenofovir Disoproxil Fumarate, 300 mg, film-coated tablets, taken as 300 mg per os daily for 5 days | 0 | 18 | 0 | 18 | 4 | 18 |
| EG003 | Treatment A (Part 2) | Narlaprevir, 100 mg, film-coated tablets, taken as 200 mg per os daily in combination with Ritonavir, 100 mg, film-coated tablets, taken as 100 mg per os daily for 5 days | 0 | 18 | 0 | 18 | 0 | 18 |
| EG004 | Treatment B (Part 2) | Raltegravir, 400 mg, film-coated tablets, taken as 400 mg per os daily for 5 days | 0 | 18 | 0 | 18 | 0 | 18 |
| EG005 | Treatment C (Part 2) | Narlaprevir, 100 mg, film-coated tablets, taken as 200 mg per os daily coadministered with Ritonavir, 100 mg, film-coated tablets, taken as 100 mg per os daily and Raltegravir, 400 mg, film-coated tablets, taken as 400 mg per os daily for 5 days | 0 | 18 | 0 | 18 | 1 | 18 |
| Blood Lactate Dehydrogenase Decreased | Investigations | MedRA 19.0 | Systematic Assessment |
|
| Headache | Nervous system disorders | MedRA 19.0 | Systematic Assessment |
|
| Diarrhoea | Gastrointestinal disorders | MedRA 19.0 | Systematic Assessment |
|
| Gamma-Glutamyltransferase Increased | Investigations | MedRA 19.0 | Systematic Assessment |
|
Any study related information could be made public availiable only after Sponsors written permission.
| D014777 |
| Virus Diseases |
| D018178 | Flaviviridae Infections |
| D012327 | RNA Virus Infections |
| D006505 | Hepatitis |
| D008107 | Liver Diseases |
| D004066 | Digestive System Diseases |
| D000092124 | Organizing Pneumonia |
| D001989 | Bronchiolitis Obliterans |
| D001988 | Bronchiolitis |
| D001991 | Bronchitis |
| D001982 | Bronchial Diseases |
| D012140 | Respiratory Tract Diseases |
| D008173 | Lung Diseases, Obstructive |
| D008171 | Lung Diseases |
| D006086 | Graft vs Host Disease |
| D007154 | Immune System Diseases |
| D006573 |
| Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D063065 | Organophosphonates |
| D009943 | Organophosphorus Compounds |
| D000225 | Adenine |
| D011687 | Purines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D011760 | Pyrrolidinones |
| D011759 | Pyrrolidines |
| Title | Measurements |
|---|---|
|
| Male |
|
| Title | Measurements |
|---|---|
| Female |
|
| Male |
|
| Asian |
|
| Black |
|
| Other |
|
| Title | Measurements |
|---|---|
| White |
|
| Asian |
|
| Black |
|
| Other |
|
| Title | Measurements |
|---|---|
|
| Geometric Mean Ratio |
| -0.069 |
| 2-Sided |
| 90 |
| -0.201 |
| 0.064 |
AUCtau parameters were logarithmically transformed |
| Other |
| Title | Measurements |
|---|---|
|
| Title | Measurements |
|---|---|
|