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A Study to Evaluate the Safety, Pharmacokinetics and Efficacy of the Combination of AL-335, Odalasvir, and Simeprevir

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ClinicalTrials.gov Identifier: NCT02569710
Recruitment Status : Completed
First Posted : October 7, 2015
Results First Posted : July 16, 2019
Last Update Posted : July 16, 2019
Sponsor:
Information provided by (Responsible Party):
Alios Biopharma Inc.

Brief Summary:
The purpose of this study is to evaluate the safety and tolerability of AL-335 in combination with odalasvir (ODV) with or without simeprevir (SMV) in participants with genotype (GT)1 or GT2 or GT3 chronic hepatitis C (CHC) infection.

Condition or disease Intervention/treatment Phase
Chronic Hepatitis C Drug: AL-335 Drug: Odalasvir (ODV) Drug: Simeprevir (SMV) Phase 2

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 161 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 2a, Open-Label Study to Evaluate the Safety, Pharmacokinetics and Efficacy of the Combination of AL-335 and Odalasvir, With or Without Simeprevir, in Treatment-Naïve Subjects With Genotype 1, 2 or 3 Chronic Hepatitis C Infection With or Without Compensated Child Pugh A Cirrhosis
Actual Study Start Date : October 31, 2015
Actual Primary Completion Date : May 11, 2018
Actual Study Completion Date : May 11, 2018

Resource links provided by the National Library of Medicine

Drug Information available for: Simeprevir

Arm Intervention/treatment
Experimental: Cohorts 1 and 2 (Without Cirrhosis) : AL-335+ODV+SMV
Treatment-naïve non-cirrhotic Hepatitis C virus (HCV)-infected participants will receive AL-335 and Odalasvir (ODV) with Simeprevir (SMV) for 8 weeks.
Drug: AL-335
AL-335 tablets will be administered in a dose range of 400 to 1200 mg once daily (QD).

Drug: Odalasvir (ODV)
ODV capsules will be administered in a dose range of 25 to 50 mg.
Other Name: ACH-3102

Drug: Simeprevir (SMV)
SMV tablets will be administered in a dose range of 75 to 150 mg QD or every other day (QOD).

Experimental: Cohort 1b (Without Cirrhosis) : AL-335+ODV
Treatment-naïve non-cirrhotic HCV-infected participants will receive AL-335 and ODV for 8 weeks.
Drug: AL-335
AL-335 tablets will be administered in a dose range of 400 to 1200 mg once daily (QD).

Drug: Odalasvir (ODV)
ODV capsules will be administered in a dose range of 25 to 50 mg.
Other Name: ACH-3102

Experimental: Cohort 3 (Without Cirrhosis) : AL-335+ODV+SMV
Treatment-naïve non-cirrhotic HCV-infected participants will receive AL-335 and ODV with SMV for 6 weeks.
Drug: AL-335
AL-335 tablets will be administered in a dose range of 400 to 1200 mg once daily (QD).

Drug: Odalasvir (ODV)
ODV capsules will be administered in a dose range of 25 to 50 mg.
Other Name: ACH-3102

Drug: Simeprevir (SMV)
SMV tablets will be administered in a dose range of 75 to 150 mg QD or every other day (QOD).

Experimental: Cohort 4 (Without Cirrhosis) : AL-335+ODV
Treatment-naïve non-cirrhotic HCV-infected participants will receive AL-335 and ODV up to 8 or 12 weeks.
Drug: AL-335
AL-335 tablets will be administered in a dose range of 400 to 1200 mg once daily (QD).

Drug: Odalasvir (ODV)
ODV capsules will be administered in a dose range of 25 to 50 mg.
Other Name: ACH-3102

Experimental: Cohort 5 (Without Cirrhosis) : AL-335+ODV + SMV
Treatment-naïve non-cirrhotic HCV-infected participants will receive AL-335 and ODV with SMV up to 8 or 12 weeks.
Drug: AL-335
AL-335 tablets will be administered in a dose range of 400 to 1200 mg once daily (QD).

Drug: Odalasvir (ODV)
ODV capsules will be administered in a dose range of 25 to 50 mg.
Other Name: ACH-3102

Drug: Simeprevir (SMV)
SMV tablets will be administered in a dose range of 75 to 150 mg QD or every other day (QOD).

Experimental: Cohorts 6, 7, 8 and 12 (With Cirrhosis) : AL-335+ODV+SMV
Treatment naïve or treatment experienced HCV-infected participants with compensated cirrhosis will receive AL-335 and ODV with SMV for 8 weeks.
Drug: AL-335
AL-335 tablets will be administered in a dose range of 400 to 1200 mg once daily (QD).

Drug: Odalasvir (ODV)
ODV capsules will be administered in a dose range of 25 to 50 mg.
Other Name: ACH-3102

Drug: Simeprevir (SMV)
SMV tablets will be administered in a dose range of 75 to 150 mg QD or every other day (QOD).

Experimental: Cohorts 9, 10 and 11 (With Cirrhosis) : AL-335+ODV+SMV
Treatment naïve or treatment experienced HCV-infected participants with compensated cirrhosis will receive AL-335 and ODV with SMV for 12 weeks.
Drug: AL-335
AL-335 tablets will be administered in a dose range of 400 to 1200 mg once daily (QD).

Drug: Odalasvir (ODV)
ODV capsules will be administered in a dose range of 25 to 50 mg.
Other Name: ACH-3102

Drug: Simeprevir (SMV)
SMV tablets will be administered in a dose range of 75 to 150 mg QD or every other day (QOD).

Experimental: Cohorts 12 to 15: AL-335+ODV With/without SMV
Based on safety, pharmacokinetic (PK), and viral load data, the treatment duration (4 to 12 weeks) and dose levels (AL-335: 400-1,200 milligram [mg], ODV: 25-50 mg with/without SMV: 75-150 mg) may be changed for ongoing and future cohorts (up to 15) after obtaining agreement from the Sponsor and the Principal Investigator.
Drug: AL-335
AL-335 tablets will be administered in a dose range of 400 to 1200 mg once daily (QD).

Drug: Odalasvir (ODV)
ODV capsules will be administered in a dose range of 25 to 50 mg.
Other Name: ACH-3102

Drug: Simeprevir (SMV)
SMV tablets will be administered in a dose range of 75 to 150 mg QD or every other day (QOD).




Primary Outcome Measures :
  1. Number of Participants With Treatment Emergent Adverse Event (TEAE) [ Time Frame: Up to 43 weeks ]
    An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Treatment-emergent were events between administration of study drug and up to 43 weeks that were absent before treatment or that worsened relative to pre-treatment state.

  2. Body Weight at End of Treatment [ Time Frame: End of treatment (Cohort 3: 6 weeks; Cohort 1, Cohort 1b+ Cohort 4, Cohort 2, Cohort 5a, and Cohort 6, 7, 8: 8 weeks; Cohort 4, Cohort 5b, Cohort 9 and Cohort 11: 12 weeks) ]
    Body weight (measured using a calibrated scale) at end of treatment was reported.

  3. Body Mass Index (BMI) at End of Treatment [ Time Frame: End of treatment (Cohort 3: 6 weeks; Cohort 1, Cohort 1b+ Cohort 4, Cohort 2, Cohort 5a, and Cohort 6, 7, 8: 8 weeks; Cohort 4, Cohort 5b, Cohort 9 and Cohort 11: 12 weeks) ]
    BMI was calculated by dividing the body weight (in kilogram) by the square of height (in meters). BMI at end of treatment was reported.

  4. Percentage of Participants With Worst Post-Baseline Values of Vital Signs [ Time Frame: Up to 43 weeks ]
    Percentage of participants with worst post-baseline values of vital signs (Systolic blood pressure [sBP], Diastolic blood pressure [dBP], and Heart rate) were reported. For sBP, abnormally low: less than or equal to [<=] 90 millimeters mercury [mmHg]; Grade 1 or mild: greater than [>] 140 to less than [<] 160 mmHg; Grade 2 or moderate: >=160 to <180 and Grade 3 or severe: >=180 mmHg. For dBP, abnormally low: <=50 mmHg; Grade 1 or mild: >90 to <100 mmHg; Grade 2 or moderate: >=100 to <110 mmHg and Grade 3 or severe: >=110 mmHg. For Heart Rate, abnormally low: <=50 beats per minute [bpm] and abnormally high: >=120 bpm.

  5. Percentage of Participants With Maximum Decrease From Baseline in Mean Ejection Fraction [ Time Frame: Baseline up to End of treatment (up to 43 weeks) ]
    Percentage of participants with maximum decrease from baseline in mean ejection fraction was reported. Percentages are based on the number of participants with available data.

  6. Percentage of Participants by Treatment Emergent Toxicity Grade - Hematology Parameters [ Time Frame: Up to 43 weeks ]
    Percentage of participants by treatment emergent toxicity grade (1, 2, 3, 4 and 3+4) for Hematology parameters (hemoglobin, lymphocytes, neutrophils, leukocytes, platelets) were reported. Toxicity grades were defined as Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe and Grade 4: potentially life-threatening. A toxicity is treatment-emergent if it is worse than the baseline or if baseline is missing.

  7. Percentage of Participants by Treatment Emergent Toxicity Grade - Blood Chemistry Parameters [ Time Frame: Up to 43 weeks ]
    Percentage of participants by treatment emergent toxicity grade (Grade 1,2,3,4,3+4) for Blood Chemistry (Calcium, Phosphate, Potassium, Sodium, Bicarbonate, Alanine aminotransferase, Alkaline phosphatase, Aspartate aminotransferase, Bilirubin, Direct bilirubin, Glucose, Cholesterol, Triglycerides, Urate, Triacylglycerol lipase, Creatinine, Creatinine clearance, Albumin and Creatine kinase) were reported. Toxicity grades were defined as Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe and Grade 4: potentially life-threatening. A toxicity is treatment-emergent if it is worse than the baseline or if baseline is missing.

  8. Percentage of Participants by Treatment Emergent Toxicity Grade - Prothrombin International Normalized Ratio (INR) [ Time Frame: Up to 43 weeks ]
    Percentage of participants by treatment emergent toxicity grade for coagulation parameter (Prothrombin International Normalized Ratio) were reported. Toxicity grades were defined as Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe and Grade 4: potentially life-threatening. A toxicity is treatment-emergent if it is worse than the baseline or if baseline is missing.

  9. Percentage of Participants by Treatment Emergent Toxicity Grade - Urinalysis Parameter (Protein) [ Time Frame: Up to 43 weeks ]
    Percentage of participants by treatment emergent toxicity grade (Grade 1, 2, 3, 4, 3+4) for urinalysis parameter (protein) was reported. Toxicity grades were defined as Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe and Grade 4: potentially life-threatening. A toxicity is treatment-emergent if it is worse than the baseline or if baseline is missing.

  10. Percentage of Participants With Worst Treatment Emergent Abnormalities of Electrocardiogram (ECG) Parameters [ Time Frame: Up to 43 weeks ]
    Percentage of participants with worst treatment emergent abnormalities of ECG parameters (Fridericia Corrected QT interval [QTcF], Bazett Corrected QT interval [QTcB], Heart rate, QRS and PR, was reported. For QTcF abnormality was defined as 30 milliseconds (ms) less than or equal to (<=) QTcF increase from baseline <= 60 ms; for QTcB abnormality was defined as 30 ms <= QTcB increase from baseline <= 60 ms; for heart rate - abnormal low: <= 50 beats per minute (bpm) and abnormal high: >= 120 bpm; for QRS - abnormal high: >120 ms; for PR - abnormally low: PR < 120 ms; abnormally high - 200 ms < PR <= 240 ms and 240 ms < PR <= 300 ms.


Secondary Outcome Measures :
  1. Percentage of Participants With Sustained Virologic Response (SVR) at Week 4, 12 and 24 After End of Treatment [ Time Frame: At Week 4, 12 and Week 24 after end of treatment (Cohort 3: 6 weeks; Cohort 1, Cohort 1b+ Cohort 4, Cohort 2, Cohort 5a, and Cohort 6, 7, 8: 8 weeks; Cohort 4, Cohort 5b, Cohort 9 and Cohort 11: 12 weeks) ]
    Participants were considered to have achieved SVR if the Hepatitis C virus (HCV) Ribonucleic acid (RNA) less than (<) Lower limit of quantification (LLOQ) (<15 international unit per milliliter [IU/mL]) detectable or undetectable at Week 4, 12 and 24 after the actual end of study drug treatment.

  2. Minimum Observed Plasma Concentration (Cmin) of AL-335 and Its Metabolites (ALS-022399 and ALS-022227) [ Time Frame: Predose, 0.5, 1, 2, 3, 4, 6, 9, and 24 hours postdose (Week 2), 2-4 hours postdose (Weeks 3 and 6), 6-8 hours postdose (Weeks 4 and 8) ]
    Cmin is the minimum observed plasma concentration of AL-335 and its metabolites (ALS-022399 and ALS-022227). For Pharmacokinetic (PK) analyses, cohorts were grouped by treatment dosage (not duration of treatment) for participants without cirrhosis (Cohort 1; Cohort 1b+4; Cohort 2+3+5) and for participants with cirrhosis (Cohort 6; Cohort 7+8+9+11).

  3. Maximum Observed Plasma Concentration (Cmax) of AL-335 and Its Metabolites (ALS-022399 and ALS-022227) [ Time Frame: Predose, 0.5, 1, 2, 3, 4, 6, 9, and 24 hours postdose (Week 2), 2-4 hours postdose (Weeks 3 and 6), 6-8 hours postdose (Weeks 4 and 8) ]
    Cmax is the maximum observed plasma concentration of AL-335 and its metabolites (ALS-022227). For PK analyses, cohorts were grouped by treatment dosage (not duration of treatment) for participants without cirrhosis (Cohort 1; Cohort 1b+4; Cohort 2+3+5) and for participants with cirrhosis (Cohort 6; Cohort 7+8+9+11).

  4. Trough Plasma Concentration (Ctrough) for AL-335 and Its Metabolites (ALS-022399 and ALS-022227) [ Time Frame: Predose, 0.5, 1, 2, 3, 4, 6, 9, and 24 hours postdose (Week 2), 2-4 hours postdose (Weeks 3 and 6), 6-8 hours postdose (Weeks 4 and 8) ]
    Ctrough is the trough plasma concentration for AL-335 and its metabolites (ALS-022399 and ALS-022227). For PK analyses, cohorts were grouped by treatment dosage (not duration of treatment) for participants without cirrhosis (Cohort 1; Cohort 1b+4; Cohort 2+3+5) and for participants with cirrhosis (Cohort 6; Cohort 7+8+9+11).

  5. Time to Reach the Maximum Plasma Concentration (Tmax) of AL-335 and Its Metabolites (ALS-022399 and ALS-022227) [ Time Frame: Predose, 0.5, 1, 2, 3, 4, 6, 9, and 24 hours postdose (Week 2), 2-4 hours postdose (Weeks 3 and 6), 6-8 hours postdose (Weeks 4 and 8) ]
    Tmax is the time to reach the maximum plasma concentration of AL-335, ALS-022399 and ALS-022227. For PK analyses, cohorts were grouped by treatment dosage (not duration of treatment) for participants without cirrhosis (Cohort 1; Cohort 1b+4; Cohort 2+3+5) and for participants with cirrhosis (Cohort 6; Cohort 7+8+9+11).

  6. Area Under the Plasma Concentration-Time Curve From Time 0 to Last Measurable Plasma Concentration (AUC [0-last]) of AL-335 and Its Metabolites (ALS-022399 and ALS-022227) [ Time Frame: Predose, 0.5, 1, 2, 3, 4, 6, 9, and 24 hours postdose (Week 2), 2-4 hours postdose (Weeks 3 and 6), 6-8 hours postdose (Weeks 4 and 8) ]
    AUC(0-last) is the area under the plasma concentration-time curve from time 0 to last measurable plasma concentration of AL-335, ALS-022399 and ALS-022227. For PK analyses, cohorts were grouped by treatment dosage (not duration of treatment) for participants without cirrhosis (Cohort 1; Cohort 1b+4; Cohort 2+3+5) and for participants with cirrhosis (Cohort 6; Cohort 7+8+9+11).

  7. Area Under the Plasma Concentration Time-Curve at 24 Hours (AUC0-24) for AL-335 and Its Metabolites (ALS-022399 and ALS-022227) [ Time Frame: Predose, 0.5, 1, 2, 3, 4, 6, 9, and 24 hours postdose ]
    AUC(0-24) is the area under the plasma concentration-time curve from time zero to time 24 hours for AL-335, ALS-022399 and ALS-022227. For PK analyses, cohorts were grouped by treatment dosage (not duration of treatment) for participants without cirrhosis (Cohort 1; Cohort 1b+4; Cohort 2+3+5) and for participants with cirrhosis (Cohort 6; Cohort 7+8+9+11).

  8. Last Measurable Plasma Concentration (Clast) of AL-335 and Its Metabolite (ALS-022399 and ALS-022227) [ Time Frame: Predose, 0.5, 1, 2, 3, 4, 6, 9, and 24 hours postdose (Week 2), 2-4 hours postdose (Weeks 3 and 6), 6-8 hours postdose (Weeks 4 and 8) ]
    Clast is the last measurable plasma concentration (Clast) of AL-335, ALS-022399 and ALS-022227. For PK analyses, cohorts were grouped by treatment dosage (not duration of treatment) for participants without cirrhosis (Cohort 1; Cohort 1b+4; Cohort 2+3+5) and for participants with cirrhosis (Cohort 6; Cohort 7+8+9+11).

  9. Time Corresponding to Last Measurable Plasma Concentration (Tlast) for AL-335 and Its Metabolites (ALS-022399 and ALS-022227) [ Time Frame: Predose, 0.5, 1, 2, 3, 4, 6, 9, and 24 hours postdose (Week 2), 2-4 hours postdose (Weeks 3 and 6), 6-8 hours postdose (Weeks 4 and 8) ]
    Tlast is the time corresponding to last measurable plasma concentration for AL-335, ALS-022399 and ALS-022227. For PK analyses, cohorts were grouped by treatment dosage (not duration of treatment) for participants without cirrhosis (Cohort 1; Cohort 1b+4; Cohort 2+3+5) and for participants with cirrhosis (Cohort 6; Cohort 7+8+9+11).

  10. Average Plasma Concentration at Steady State (Css,Avg) of ALS-022227 [ Time Frame: Predose, 0.5, 1, 2, 3, 4, 6, 9, and 24 hours postdose (Week 2), 2-4 hours postdose (Weeks 3 and 6), 6-8 hours postdose (Weeks 4 and 8) ]
    Css,avg is the average plasma concentration at steady state of ALS-022227. For PK analyses, cohorts were grouped by treatment dosage (not duration of treatment) for participants without cirrhosis (Cohort 1; Cohort 1b+4; Cohort 2+3+5) and for participants with cirrhosis (Cohort 6; Cohort 7+8+9+11).

  11. Cmin of Simeprevir [ Time Frame: Predose, 0.5, 1, 2, 3, 4, 6, 9, and 24 hours postdose (Week 2), 2-4 hours postdose (Weeks 3 and 6), 6-8 hours postdose (Weeks 4 and 8) ]
    Cmin is the minimum measured plasma concentration of simeprevir. For PK analyses, cohorts were grouped by treatment dosage (not duration of treatment) for participants without cirrhosis (Cohort 1; Cohort 1b+4; Cohort 2+3+5) and for participants with cirrhosis (Cohort 6; Cohort 7+8+9+11).

  12. Cmax of Simeprevir [ Time Frame: Predose, 0.5, 1, 2, 3, 4, 6, 9, and 24 hours postdose (Week 2), 2-4 hours postdose (Weeks 3 and 6), 6-8 hours postdose (Weeks 4 and 8) ]
    Cmax is the maximum measured plasma concentration of simeprevir. For PK analyses, cohorts were grouped by treatment dosage (not duration of treatment) for participants without cirrhosis (Cohort 1; Cohort 1b+4; Cohort 2+3+5) and for participants with cirrhosis (Cohort 6; Cohort 7+8+9+11).

  13. Ctrough of Simeprevir [ Time Frame: Predose, 0.5, 1, 2, 3, 4, 6, 9, and 24 hours postdose (Week 2), 2-4 hours postdose (Weeks 3 and 6), 6-8 hours postdose (Weeks 4 and 8) ]
    Ctrough is the trough plasma concentration of Simeprevir. For PK analyses, cohorts were grouped by treatment dosage (not duration of treatment) for participants without cirrhosis (Cohort 1; Cohort 1b+4; Cohort 2+3+5) and for participants with cirrhosis (Cohort 6; Cohort 7+8+9+11).

  14. Tmax of Simeprevir [ Time Frame: Predose, 0.5, 1, 2, 3, 4, 6, 9, and 24 hours postdose (Week 2), 2-4 hours postdose (Weeks 3 and 6), 6-8 hours postdose (Weeks 4 and 8) ]
    Tmax is the Time to reach the maximum plasma concentration of simeprevir. For PK analyses, cohorts were grouped by treatment dosage (not duration of treatment) for participants without cirrhosis (Cohort 1; Cohort 1b+4; Cohort 2+3+5) and for participants with cirrhosis (Cohort 6; Cohort 7+8+9+11).

  15. AUC (0-last) of Simeprevir [ Time Frame: Predose, 0.5, 1, 2, 3, 4, 6, 9, and 24 hours postdose (Week 2), 2-4 hours postdose (Weeks 3 and 6), 6-8 hours postdose (Weeks 4 and 8) ]
    AUC (0-last) is the area under the plasma concentration-time curve from time 0 to last measurable plasma concentration of simeprevir. For PK analyses, cohorts were grouped by treatment dosage (not duration of treatment) for participants without cirrhosis (Cohort 1; Cohort 1b+4; Cohort 2+3+5) and for participants with cirrhosis (Cohort 6; Cohort 7+8+9+11).

  16. AUC (0-24) of Simeprevir [ Time Frame: Predose, 0.5, 1, 2, 3, 4, 6, 9, and 24 hours postdose ]
    AUC (0-24) is the area under the plasma concentration-time curve from time 0 to 24 hours of simeprevir. For PK analyses, cohorts were grouped by treatment dosage (not duration of treatment) for participants without cirrhosis (Cohort 1; Cohort 1b+4; Cohort 2+3+5) and for participants with cirrhosis (Cohort 6; Cohort 7+8+9+11).

  17. Clast of Simeprevir [ Time Frame: Predose, 0.5, 1, 2, 3, 4, 6, 9, and 24 hours postdose (Week 2), 2-4 hours postdose (Weeks 3 and 6), 6-8 hours postdose (Weeks 4 and 8) ]
    Clast is the maximum measured plasma concentration of simeprevir. For PK analyses, cohorts were grouped by treatment dosage (not duration of treatment) for participants without cirrhosis (Cohort 1; Cohort 1b+4; Cohort 2+3+5) and for participants with cirrhosis (Cohort 6; Cohort 7+8+9+11).

  18. Tlast of Simeprevir [ Time Frame: Predose, 0.5, 1, 2, 3, 4, 6, 9, and 24 hours postdose (Week 2), 2-4 hours postdose (Weeks 3 and 6), 6-8 hours postdose (Weeks 4 and 8) ]
    Tlast is the time corresponding to last measurable plasma concentration of simeprevir. For PK analyses, cohorts were grouped by treatment dosage (not duration of treatment) for participants without cirrhosis (Cohort 1; Cohort 1b+4; Cohort 2+3+5) and for participants with cirrhosis (Cohort 6; Cohort 7+8+9+11).

  19. Average Plasma Concentration at Steady State (Css,Avg) of Simeprevir [ Time Frame: Predose, 0.5, 1, 2, 3, 4, 6, 9, and 24 hours postdose (Week 2), 2-4 hours postdose (Weeks 3 and 6), 6-8 hours postdose (Weeks 4 and 8) ]
    Css,avg is the average plasma concentration at steady state of simeprevir. For PK analyses, cohorts were grouped by treatment dosage (not duration of treatment) for participants without cirrhosis (Cohort 1; Cohort 1b+4; Cohort 2+3+5) and for participants with cirrhosis (Cohort 6; Cohort 7+8+9+11).

  20. Cmin of Odalasvir [ Time Frame: Predose, 0.5, 1, 2, 3, 4, 6, 9, and 24 hours postdose (Week 2), 2-4 hours postdose (Weeks 3 and 6), 6-8 hours postdose (Weeks 4 and 8) ]
    Cmin is the minimum observed plasma concentration of odalasvir. For PK analyses, cohorts were grouped by treatment dosage (not duration of treatment) for participants without cirrhosis (Cohort 1; Cohort 1b+4; Cohort 2+3+5) and for participants with cirrhosis (Cohort 6; Cohort 7+8+9+11).

  21. Cmax of Odalasvir [ Time Frame: Predose, 0.5, 1, 2, 3, 4, 6, 9, and 24 hours postdose (Week 2), 2-4 hours postdose (Weeks 3 and 6), 6-8 hours postdose (Weeks 4 and 8) ]
    Cmax is the maximum observed plasma concentration of odalasvir. For PK analyses, cohorts were grouped by treatment dosage (not duration of treatment) for participants without cirrhosis (Cohort 1; Cohort 1b+4; Cohort 2+3+5) and for participants with cirrhosis (Cohort 6; Cohort 7+8+9+11).

  22. Ctrough of Odalasvir [ Time Frame: Predose, 0.5, 1, 2, 3, 4, 6, 9, and 24 hours postdose (Week 2), 2-4 hours postdose (Weeks 3 and 6), 6-8 hours postdose (Weeks 4 and 8) ]
    Ctrough is the trough plasma concentration of odalasvir. For PK analyses, cohorts were grouped by treatment dosage (not duration of treatment) for participants without cirrhosis (Cohort 1; Cohort 1b+4; Cohort 2+3+5) and for participants with cirrhosis (Cohort 6; Cohort 7+8+9+11).

  23. Tmax of Odalasvir [ Time Frame: Predose, 0.5, 1, 2, 3, 4, 6, 9, and 24 hours postdose (Week 2), 2-4 hours postdose (Weeks 3 and 6), 6-8 hours postdose (Weeks 4 and 8) ]
    Tmax is the time to reach the maximum plasma concentration of odalasvir. For PK analyses, cohorts were grouped by treatment dosage (not duration of treatment) for participants without cirrhosis (Cohort 1; Cohort 1b+4; Cohort 2+3+5) and for participants with cirrhosis (Cohort 6; Cohort 7+8+9+11).

  24. AUC (0-last) of Odalasvir [ Time Frame: Predose, 0.5, 1, 2, 3, 4, 6, 9, and 24 hours postdose (Week 2), 2-4 hours postdose (Weeks 3 and 6), 6-8 hours postdose (Weeks 4 and 8) ]
    AUC(0-last) is the area under the plasma concentration-time curve from time 0 to last measurable plasma concentration of odalasvir. For PK analyses, cohorts were grouped by treatment dosage (not duration of treatment) for participants without cirrhosis (Cohort 1; Cohort 1b+4; Cohort 2+3+5) and for participants with cirrhosis (Cohort 6; Cohort 7+8+9+11).

  25. AUC (0-24) for Odalasvir [ Time Frame: Predose, 0.5, 1, 2, 3, 4, 6, 9, and 24 hours postdose ]
    AUC(0-24) is the area under the plasma concentration-time curve from time zero to time 24 hours for odalasvir. For PK analyses, cohorts were grouped by treatment dosage (not duration of treatment) for participants without cirrhosis (Cohort 1; Cohort 1b+4; Cohort 2+3+5) and for participants with cirrhosis (Cohort 6; Cohort 7+8+9+11).

  26. Clast of Odalasvir [ Time Frame: Predose, 0.5, 1, 2, 3, 4, 6, 9, and 24 hours postdose (Week 2), 2-4 hours postdose (Weeks 3 and 6), 6-8 hours postdose (Weeks 4 and 8) ]
    Clast is the last measurable plasma concentration (Clast) of odalasvir. For PK analyses, cohorts were grouped by treatment dosage (not duration of treatment) for participants without cirrhosis (Cohort 1; Cohort 1b+4; Cohort 2+3+5) and for participants with cirrhosis (Cohort 6; Cohort 7+8+9+11).

  27. Tlast of Odalasvir [ Time Frame: Predose, 0.5, 1, 2, 3, 4, 6, 9, and 24 hours postdose (Week 2), 2-4 hours postdose (Weeks 3 and 6), 6-8 hours postdose (Weeks 4 and 8) ]
    Tlast is the time corresponding to last measurable plasma concentration of odalasvir. For PK analyses, cohorts were grouped by treatment dosage (not duration of treatment) for participants without cirrhosis (Cohort 1; Cohort 1b+4; Cohort 2+3+5) and for participants with cirrhosis (Cohort 6; Cohort 7+8+9+11).

  28. Average Plasma Concentration at Steady State (Css,Avg) of Odalasvir [ Time Frame: Predose, 0.5, 1, 2, 3, 4, 6, 9, and 24 hours postdose (Week 2), 2-4 hours postdose (Weeks 3 and 6), 6-8 hours postdose (Weeks 4 and 8) ]
    Css,avg is the average plasma concentration at steady state of odalasvir. For PK analyses, cohorts were grouped by treatment dosage (not duration of treatment) for participants without cirrhosis (Cohort 1; Cohort 1b+4; Cohort 2+3+5) and for participants with cirrhosis (Cohort 6; Cohort 7+8+9+11).

  29. Percentage of Participants With Virologic Relapse During the Follow-up Period [ Time Frame: Follow up period (Up to Week 12 after end of treatment) ]
    Viral relapse is defined as participants SVR12, with HCV RNA <LLOQ at the actual end of study drug treatment and confirmed HCV RNA greater than or equal to (>=) LLOQ during follow up.

  30. Percentage of Participants With On-treatment Failure [ Time Frame: Up to 12 weeks ]
    On-treatment failure was defined by participants who did not achieve SVR12 and with confirmed HCV RNA >= LLOQ at the actual end of study drug treatment.

  31. Percentage of Participants Who Achieved HCV RNA Less Then (<) LLOQ Undetectable [ Time Frame: Day 2, 3, Week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 and End of treatment (Cohort 3: 6 weeks; Cohort 1, Cohort 1b+ Cohort 4, Cohort 2, Cohort 5a, and Cohort 6, 7, 8: 8 weeks; Cohort 4, Cohort 5b, Cohort 9 and Cohort 11: 12 weeks) ]
    Percentage of participants who achieved HCV RNA less then (<) LLOQ undetectable was reported.

  32. Percentage of Participants Who Achieved HCV RNA <LLOQ [ Time Frame: Day 2, 3, Week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 and End of treatment (Cohort 3: 6 weeks; Cohort 1, Cohort 1b+ Cohort 4, Cohort 2, Cohort 5a, and Cohort 6, 7, 8: 8 weeks; Cohort 4, Cohort 5b, Cohort 9 and Cohort 11: 12 weeks) ]
    Percentage of participants who achieved HCV RNA <LLOQ was reported.

  33. Time to Achieve Undetectable HCV RNA or < LLOQ HCV RNA [ Time Frame: Up to Week 24 (follow up visit) ]
    Time to achieve undetectable HCV RNA or < LLOQ HCV RNA was reported.

  34. Number of Participants With HCV Nonstructural Protein NS5A, NS5B, and NS3/4A Sequence in Participants With Virologic Failure [ Time Frame: Up to Week 24 (Follow up visit) ]
    Sequencing of the HCV nonstructural protein 3/4A (NS3/4A), nonstructural protein 5A (NS5A) and nonstructural protein 5B (NS5B) genes was done to identify pre-existing sequence polymorphisms and characterize emerging HCV viral variants in participants with virologic failure.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Participant has provided written consent
  2. In the Investigator's opinion, the participant is able to understand and comply with protocol requirements, instructions, and protocol stated restrictions and is likely to complete the study as planned
  3. Male or female, 18-70 years of age
  4. Body mass index (BMI) 18-35 kilogram per meter square (kg/m^2), inclusive
  5. A woman of childbearing potential must have a negative serum (beta-human chorionic gonadotropin) pregnancy test at screening
  6. Female participants must either:

    • not be of childbearing potential defined as: i. Postmenopausal for at least 12 months (that is [i.e.], 2 years of amenorrhea without an alternative medical cause) and a serum follicle stimulating hormone (FSH) level in the postmenopausal range (per reference laboratory), OR ii. Surgically sterile (example [e.g.], underwent total hysterectomy, bilateral oophorectomy, or bilateral tubal ligation/bilateral tubal clips without reversal operation), or otherwise incapable of becoming pregnant, OR
    • be of childbearing potential AND
    • not heterosexually active (e.g., abstinent or homosexual) from screening until 6 months after study drug administration (or longer, if dictated by local regulations), OR
    • if heterosexually active

      • have a vasectomized partner (confirmed sterile per verbal account of the participant), OR
      • using an acceptable method of birth control from screening and agree to continue to use the same method of contraception throughout the study and for 6 months after study drug administration (or longer, if dictated by local regulations). Oral hormone based contraceptives are not allowed from 14 days before the planned study drug administration until 6 months after the last dose of treatment due to the potential for drug-drug interactions which might undermine their efficacy. An intrauterine device (IUD), being either hormonal (i.e., Intra-Uterine System [IUS*]) or non-hormonal, is considered highly effective and reliable; therefore participants using an IUD/IUS are not required to use additional contraceptive methods (no double-barrier method is required). Other non-oral hormone-based contraception methods (e.g., injectable, implants, transdermal system, vaginal ring) may be continued, but as the interaction of the study drug with hormone-based contraception is unknown, these methods are not considered to be reliable and therefore participants should use a double-barrier method (e.g., male condom+either diaphragm or cervical cap with or without spermicide).

        • An IUS does not rely on systemic plasma concentrations and is therefore not expected to be impacted by a potential drug-drug interaction (DDI)

    Note 1: Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study drug. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of the participant.

    Note 2: A male and female condom should not be used together due to risk of breakage or damage caused by latex friction

  7. A post-menopausal female who is receiving hormone replacement therapy and is willing to discontinue hormone therapy 30 days before study drug dosing and agrees to remain off hormone replacement therapy for the duration of the study may be eligible for study participation.

    • Male participants must either:
    • be surgically sterile (had a vasectomy), or otherwise incapable of fathering a child, OR
    • not be heterosexually active (e.g., abstinent or homosexual) from enrollment (Day 1) in the study until at least 6 months after study drug administration, OR
    • if heterosexually active:

      • have a partner who is postmenopausal (2 years amenorrhea), surgically sterile (e.g., has had a total hysterectomy, bilateral oophorectomy, or bilateral tubal ligation/bilateral tubal clips without reversal operation), or otherwise incapable of becoming pregnant OR
      • be practicing an acceptable method of birth control from enrollment in the study (Day 1) and agree to continue to use the same method of contraception throughout the study and for at least 6 months after study drug administration (or longer, if dictated by local regulations). An acceptable method of birth control for male participants is a double-barrier method (e.g., male condom+either diaphragm or cervical cap with or without spermicide).

    Note: Male participants with a female partner who uses hormonal contraceptives (oral, injectable, implants) or a hormonal (IUS) or non-hormonal IUD and male participants who are vasectomized or otherwise incapable of fathering a child are not required to use additional contraceptive methods.

    Note 1: Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study drug. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of the participant.

    Note 2: A male and female condom should not be used together due to risk of breakage or damage caused by latex friction.

    NOTE: Contraceptive use by men and women should be consistent with local regulations regarding the use of contraceptive methods for participants participating in clinical studies if these are stricter than what is proposed in these inclusion criteria

  8. Participants must agree to refrain from sperm/egg donation from start of dosing through 6 months after the completion of study drug administration
  9. Genotype (GT) 1a or 1b or GT2 or 3 chronic hepatitis C (CHC), depending on cohort, with positive Hepatitis C virus (HCV) antibody and a positive HCV ribonucleic acid (RNA) at screening including documentation of CHC infection for at least 6 months. Genotype testing must occur at a screening visit. NOTE: GT1 patients are eligible for inclusion even if they cannot be successfully subtyped unless a specific subtype is required for a cohort
  10. Screening HCV RNA viral load greater than or equal to (>=) 50,000 International Units per milliliter (IU/mL), except for participants with compensated cirrhosis (Child Pugh Class A) who may have HCV RNA viral load >=10^4 IU/mL
  11. No prior treatment for CHC (defined as no prior exposure to any approved or investigational drug including direct-acting antivirals, and interferon-based treatments)
  12. Fibroscan, collected within 6 months of baseline visit, with liver stiffness score less than or equal to (<=) 12.5 kilo Pascal (kPa) to be eligible (except for participants with cirrhosis, see below).

    • participants with compensated cirrhosis must meet the Child-Pugh Class A definition (see Appendix G) and at least one of the following criteria: i. Liver biopsy result indicating the presence of cirrhosis (e.g., Metavir F4; Ishak >5) or ii. Fibroscan evaluation with a liver stiffness score >12.5 kPa
  13. Participant is otherwise in good health as deemed by the investigator, based on the findings of a medical evaluation including medical history, physical examination, laboratory tests and electrocardiogram (ECG)
  14. Willing to avoid prolonged sun exposure and use of tanning devices while taking Simeprevir (SMV) and through 4 weeks of follow up. Participant should also be advised to use a broad-spectrum sunscreen and lip balm of at least sun protection factor >30 to help protect against potential sunburn

Exclusion Criteria:

  1. Pregnant, planning on becoming pregnant (during treatment and up to 6 months after the end of treatment [EOT]), or breast-feeding female participant, or male participant whose female partner is pregnant or planning on becoming pregnant (during treatment and up to 6 months after the EOT)
  2. Other than CHC with or without compensated cirrhosis, clinically significant cardiovascular, respiratory, renal, gastrointestinal, hematologic, neurologic, thyroid or any other medical illness or psychiatric disorder, as determined by the Investigator and/or Sponsor's Medical Monitor
  3. History or other clinical evidence of significant or unstable cardiac disease (e.g., angina, congestive heart failure, myocardial infarction, diastolic dysfunction, significant arrhythmia, coronary heart disease, and/or clinically significant ECG abnormalities), moderate to severe valvular disease or uncontrolled hypertension at screening
  4. Screening echocardiogram ejection fraction <55 percentage (%) or any other echocardiographic finding suggestive of clinically relevant cardiomyopathy
  5. Creatinine clearance of <60 mL/min (Cockcroft-Gault)
  6. Positive test for Hepatitis A virus immunoglobulin (HAV) Immunoglobulin M (IgM), Hepatitis B surface antigen (HBsAg), or Human Immunodeficiency Virus (HIV) Ab
  7. Abnormal screening laboratory results that are considered clinically significant by the investigator
  8. History of clinical hepatic decompensation, e.g., variceal bleeding, spontaneous bacterial peritonitis, ascites, hepatic encephalopathy or active jaundice (within last year)
  9. Any condition that, in the opinion of the investigator, would compromise the study's objectives or the well-being of the participant or prevent the participant from meeting the study requirements
  10. Participation in an investigational drug trial or having received an investigational vaccine within 30 days or 5 half lives (whichever is longer) prior to study medication
  11. Clinically significant abnormal screening ECG findings (e.g., PR >200 msec, QRS interval >120 millisecond (msec) or corrected QT interval (QTc) >450 msec for male participants and >470 msec for female participants), based on an average of triplicate ECGs. Any evidence of heart block or bundle branch block is also exclusionary
  12. History or family history of abnormal ECG intervals, for example prolonged QT syndrome (torsade de pointes) or sudden cardiac death
  13. The participant has a positive prestudy drug screen, including methadone unless the drug is prescribed by the participant's physician. The list of drugs that should be screened for includes amphetamines, barbiturates, cocaine, opiates, phencyclidine (PCP), and benzodiazepines
  14. Laboratory abnormalities including:

    • Hematocrit <0.34
    • White blood cell counts <3,500/millimeter (mm)^3 (<1,000/mm^3 for participants with compensated cirrhosis)
    • Absolute neutrophil count <1,000/mm^3 (<750/mm^3 for participants with compensated cirrhosis)
    • Platelets <=120,000/mm^3 (platelets ≤90,000/mm^3 for participants with compensated cirrhosis)
    • Glycosylated hemoglobin (HbA1C) >55 mmol/mol
    • Prothrombin time >=1.5 * upper limit of normal (ULN)
    • Albumin <=32 gram per liter (g/L), bilirubin >=1.5 milligram per deciliter (mg/dL) at screening (participants with documented Gilbert's disease allowed)
    • Serum ALT concentration >=5* ULN
    • CK >1.5* ULN A single repeat laboratory evaluation under appropriate conditions (e.g., fasted, no antecedent exercise) is allowed for eligibility determination
  15. Any condition possibly affecting drug absorption (e.g., gastrectomy or other significant gastrointestinal tract surgery, such as gastroenterostomy, small bowel resection, or active enterostomy)
  16. Clinically significant blood loss or elective blood donation of significant volume (i.e., >500 mL) within 60 days of first dose of study drug; >1 unit of plasma within 7 days of first dose of study drug
  17. Evidence of clinically relevant active infection that would interfere with study conduct or its interpretation
  18. History of regular alcohol intake >10 standard drinks per week of alcohol for females and >15 standard drinks per week for males (one unit is defined as 10 g alcohol) within 3 months of the screening visit
  19. The use of prohibited medications, including prescription, over the counter (OTC) medications, herbal medications, inducers or inhibitors of Cytochrome P450 (CYP450) enzymes or drug transporters (including P-gp) within 14 days prior to the first dose of study medication is excluded, unless previously approved by the Sponsor's Medical Monitor. NOTE: Chronic medication use is permitted so long as they are medically necessary, deemed acceptable by the Principal Investigator and Medical Monitor, and not Prohibited Medications (see Section 5.12)
  20. Hypersensitivity to the active substances (including sulfa allergy) or to any of the excipients of AL-335, Odalasvir (ODV) or SMV
  21. Evidence on recent (within 6 months) liver ultrasound of hepatic mass or lesion concerning for malignancy (participants with cirrhosis only)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02569710


Locations
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Mauritius
CAP Research Ltd
Phoenix, Mauritius
Moldova, Republic of
Republican Clinical Hospital
Chisinau, Moldova, Republic of
New Zealand
Auckland Clinical Studies
Auckland, New Zealand, 1150
Christchurch Clinical Studies Trust
Christchurch, New Zealand, 8011
Waikato Hospital
Hamilton, New Zealand
P3 Research Ltd - Hawkes Bay
Havelock North, New Zealand
P3 Research Ltd - Wellington
Wellington, New Zealand
Wellington Hospital
Wellington, New Zealand
United Kingdom
King's College Hospital
Brixton, United Kingdom
NHS Greater Glasgow and Clyde Glasgow Royal Infirmary
Glasgow, United Kingdom
Pennine Acute Hospitals Trust
Oldham, United Kingdom
Sponsors and Collaborators
Alios Biopharma Inc.
Investigators
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Study Director: Alios Biopharma Inc. Clinical Trial Alios Biopharma Inc.
  Study Documents (Full-Text)

Documents provided by Alios Biopharma Inc.:
Study Protocol  [PDF] May 3, 2017
Statistical Analysis Plan  [PDF] May 17, 2017


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Responsible Party: Alios Biopharma Inc.
ClinicalTrials.gov Identifier: NCT02569710     History of Changes
Other Study ID Numbers: AL-335-604
First Posted: October 7, 2015    Key Record Dates
Results First Posted: July 16, 2019
Last Update Posted: July 16, 2019
Last Verified: June 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes

Additional relevant MeSH terms:
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Hepatitis
Hepatitis C
Hepatitis, Chronic
Hepatitis C, Chronic
Hepatitis, Viral, Human
Liver Diseases
Digestive System Diseases
Virus Diseases
Flaviviridae Infections
RNA Virus Infections
Simeprevir
Odalasvir
Antiviral Agents
Anti-Infective Agents
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action