A Multiple Ascending Dose Study of Daclatasvir (BMS-790052) in Hepatitis C Virus Genotype 1 Infected Subjects

Study Overview
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Brief Summary
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The primary purpose of this study is to assess the change in Hepatitis C Virus RNA during dosing with daclatasvir and during the follow-up period in subjects with chronic hepatitis C infection

Official Title
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Double-Blind, Placebo-Controlled, Multiple Ascending Dose Study to Evaluate the Antiviral Activity and Safety, Tolerability, and Pharmacokinetics of Daclatasvir in Subjects Infected With Hepatitis C Virus Genotype 1

Conditions
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Chronic Hepatitis C

Intervention / Treatment
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* Drug: Daclatasvir
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Chronically infected with Hepatitis C Virus (HCV) genotype 1 Treatment naive or treatment non-responders or treatment intolerant; and not co-infected with HIV or Hepatitis B Virus HCV RNA viral load of ≥10*5 IU/mL BMI 18 to 35kg/m² Exclusion Criteria: Any significant acute or chronic medical illness which is not stable or is not controlled with medication and not consistent with Hepatitis C Virus infection HIV and/or HBV positive Major surgery within 4 weeks of study drug administration and any gastrointestinal surgery that could impact the absorption of study drug WOCBP will be enrolled as in-patient for 16 days

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Group 1<br>Daclatasvir (1 mg), once daily or Matching Placebo, once daily | Drug: Daclatasvir<br>* Capsule, Oral, Approximately 182 days from initial dosing<br>Drug: Placebo<br>* Capsule, Oral, After 28 days from initial dosing and unblinding of the dose panel<br>|
| Active Comparator: Group 2<br>Daclatasvir (10 mg), once daily or Matching Placebo, once daily | Drug: Daclatasvir<br>* Capsule, Oral, Approximately 182 days from initial dosing<br>Drug: Placebo<br>* Capsule, Oral, After 28 days from initial dosing and unblinding of the dose panel<br>|
| Active Comparator: Group 3<br>Daclatasvir (1-100 mg), once or twice daily or Matching Placebo, once or twice daily | Drug: Daclatasvir<br>* Capsule, Oral, Approximately 182 days from initial dosing<br>Drug: Placebo<br>* Capsule, Oral, After 28 days from initial dosing and unblinding of the dose panel<br>|
| Active Comparator: Group 4<br>Daclatasvir (1-100 mg), once or twice daily or Matching Placebo, once or twice daily | Drug: Daclatasvir<br>* Capsule, Oral, Approximately 182 days from initial dosing<br>Drug: Placebo<br>* Capsule, Oral, After 28 days from initial dosing and unblinding of the dose panel<br>|
| Active Comparator: Group 5<br>Group 5: Active Comparator Daclatasvir (1-100 mg), once or twice daily or Matching Placebo, once or twice daily | Drug: Daclatasvir<br>* Capsule, Oral, Approximately 182 days from initial dosing<br>Drug: Placebo<br>* Capsule, Oral, After 28 days from initial dosing and unblinding of the dose panel<br>|
| Active Comparator: Group 6<br>Group 6: Active Comparator Daclatasvir (1-100 mg), once or twice daily or Matching Placebo, once or twice daily | Drug: Daclatasvir<br>* Capsule, Oral, Approximately 182 days from initial dosing<br>Drug: Placebo<br>* Capsule, Oral, After 28 days from initial dosing and unblinding of the dose panel<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline at Day 7 in log10 Hepatitis C Virus (HCV) RNA of All Participants | The Roche TaqMan HCV quantitative assay was used for analysis with detection limit of 10 IU/mL. Baseline was Day -1. | Baseline, Day 7 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline at Day 7 in log10 Hepatitis C Virus (HCV) RNA Levels of Participants Without Baseline Drug Resistance | The Roche TaqMan HCV quantitative assay was used for analysis with detection limit of 10 international units/ millilitre (IU/mL). Baseline was Day -1 | Baseline, Day 7 | 
| Change From Baseline at 24 h Post Dose on Day 1 in log10 Hepatitis C Virus (HCV) RNA of Participants Without Baseline Drug Resistance | The Roche TaqMan HCV quantitative assay was used for analysis with detection limit of 10 IU/mL. Baseline was Day -1. | Baseline, 2, 4, 6, 8, 12, 16, 20, and 24 hours post dose on Day 1 | 
| Change From Baseline to Day 4 in log10 Hepatitis C Virus (HCV) RNA in Participants Without Baseline Drug Resistance | The Roche TaqMan HCV quantitative assay was used for analysis with detection limit of 10 IU/mL. Baseline was Day -1. | Baseline to Day 4 | 
| Change From Baseline to Day 14 in Log10 Hepatitis C Virus (HCV) RNA in Participants Without Baseline Drug Resistance | The Roche TaqMan HCV quantitative assay was used for analysis with detection limit of 10 IU/mL. Baseline was Day -1. | Baseline to Day 14 | 
| Time to Maximum Decline From Baseline in Hepatitis C Virus (HCV) RNA in Participants Without Baseline Drug Resistance | Participants without baseline drug resistance were assessed for time to reach maximum decrease in log10 HCV RNA level. | Day 1 up to Day 14 | 
| Maximum Decline From Baseline in Log10 Hepatitis C Virus (HCV) RNA in Participants Without Baseline Drug Resistance | The Roche TaqMan HCV quantitative assay was used for analysis with detection limit of 10 IU/mL. | Day 1 up to Day 14 | 
| Maximum Observed Plasma Concentration (Cmax) and Minimum Observed Plasma Concentration (Cmin) of Daclatasvir on Days 1 and 14 | The peak concentrations in plasma (Cmax) and minimum observed plasma concentration (Cmin) were defined as the peak maximum and minimum plasma level of daclatasvir, derived from plasma concentration-time data analyzed by non-compartmental methods. Cmax and Cmin of daclatasvir in plasma was assayed using a validated liquid chromatography tandem mass spectrometry method. | 0 hour (pre-dose) 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 hours (post morning dose) at Day1 and Day 14, 0 hour (pre-dose) at Days 2, 3, 4, 5, 7, 9, 11, 13 and 24, 48 and 72 hours (post morning dose) at Day 14 | 
| Area Under the Concentration-time Curve (AUC) in 1 Dosing Interval of Daclatasvir at Days 1 and 14 | The area under the concentration-time curve in 1 Dosing Interval AUC(TAU) was used to measure the drug exposure over 1 dosing interval., derived from plasma concentration-time data analyzed by non-compartmental methods. AUC(TAU) of daclatasvir in plasma was assayed using a validated liquid chromatography tandem mass spectrometry method. | 0 hour (pre-dose) 0.5, 1,1.5, 2, 3, 4, 6, 8 and 12 hours (post morning dose) at Day1 and Day 14, 0 hr (pre-dose) at Days 2, 3, 4, 5, 7, 9, 11, 13, and 24, 48 and 72 hours (post morning dose) at Day 14 | 
| Plasma Half-life (T-half) of Daclatasvir at Day 14 | The absolute values of lamda (λ) were used to evaluate apparent terminal half-life (T-half) was defined as T-half= ln 2/λ. T-half was derived from plasma concentration-time data analyzed by non-compartmental methods. T-half of daclatasvir in plasma was assayed using a validated liquid chromatography tandem mass spectrometry method. | 0 hour (pre-dose) 0.5, 1,1.5, 2, 3, 4, 6, 8 and 12 hours (post morning dose) at Day1 and Day 14, 0 hr (pre-dose) at Days 2, 3, 4, 5, 7, 9, 11, 13, and 24, 48 and 72 hours (post morning dose) at Day 14 | 
| Apparent Total Body Clearance (CLT/F) of Daclatasvir on Day 14 | The apparent total body clearance at steady state (CLT/F) was defined as the apparent body clearance of canakinumab from the serum when the systemic availability was unknown. CLT/F was derived from plasma concentration-time data analyzed by non-compartmental methods. CLT/F of daclatasvir in plasma was assayed using a validated liquid chromatography tandem mass spectrometry method. | 0 hour (pre-dose) 0.5, 1,1.5, 2, 3, 4, 6, 8 and 12 hours (post morning dose) at Day1 and Day 14, 0 hour (pre-dose) at Days 2, 3, 4, 5, 7, 9, 11, 13, and 24, 48 and 72 hours (post morning dose) at Day 14 | 
| Average Observed Plasma Concentration (Css-av) at Steady State of Daclatasvir at Days 1 and 14 | The average observed plasma concentration at steady state (Css-av) was calculated as ratio of AUC(TAU) by TAU, where TAU = 24 h for QD dosing and 12 h for BID dosing. Css-av was derived from plasma concentration-time data analyzed by non-compartmental methods. Css-av of daclatasvir in plasma was assayed using a validated liquid chromatography tandem mass spectrometry method. | 0 hour (pre-dose) 0.5, 1,1.5, 2, 3, 4, 6, 8 and 12 hours (post morning dose) at Day1 and Day 14, 0 hr (pre-dose) at Days 2, 3, 4, 5, 7, 9, 11,13, and 24, 48 and 72 hours (post morning dose) at Day 14 | 
| Accumulation Index (AI) AUC(TAU), AI Cmax, and Degree of Fluctuation (DF) of Daclatasvir on Day 14 | Accumulation index area under the concentration-time curve of daclatasvir to the end of the dosing period [AI AUC(TAU)] was defined as the ratio of AUC(TAU) at steady-state to AUC(TAU) after the first dose.Accumulation index maximum observed concentration of daclatasvir in plasma (AI Cmax) was defined as the ratio of Cmax at steady-state to Cmax after the first dose. Degree of Fluctuation (DF) was defined as the ratio of difference between Cmax and Cmin at steady state by Css-av. The parameters were analyzed using non-compartmental methods, assayed by validated liquid chromatography tandem mass spectrometry (LC-MS/MS). | 0 hour (pre-dose) 0.5, 1,1.5, 2, 3, 4, 6, 8 and 12 hours (post morning dose) at Day1 and Day 14, 0 hour (pre-dose) at Days 2, 3, 4, 5, 7, 9, 11, 13, and 24, 48 and 72 hours (post morning dose) at Day 14 | 
| Time of Maximum Observed Plasma Concentration (Tmax) of Daclatasvir on Days 1 and 14 | Tmax was defined as the time to reach maximum observed plasma concentration of daclatasvir in plasma. Tmax was derived from plasma concentration-time data analyzed by non-compartmental methods. Tmax of daclatasvir in plasma was assayed using a validated liquid chromatography tandem mass spectrometry method. | 0 hour (pre-dose) 0.5, 1,1.5, 2, 3, 4, 6, 8 and 12 hours (post morning dose) at Day1 and Day 14, 0 hour (pre-dose) at Days 2, 3, 4, 5, 7, 9, 11, 13, and 24, 48 and 72 hours (post morning dose) at Day 14 | 
| Correlation Coefficients Between Measures of Decline in log10 Hepatitis C Virus (HCV) RNA and Daclatasvir PK Parameters Cmax, AUC(TAU), and Cmin on Day 14 in Participants Without Baseline Drug Resistance | Correlation between decline of log10 hepatitis C virus (HCV) RNA and exposure to study drug was measured by Pearson Correlation Coefficients. The change from baseline at Day 4 in log10 HCV RNA and the maximum decline in log10 HCV RNA were evaluated against the PK parameters Cmax, Cmin and AUC(TAU). | Day 4, Day 14 | 
| Number of Participants With Serious Adverse Events (SAEs), Discontinuation Due to Adverse Events (AEs), and Who Died | AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. | Day 1 to Day 182 or Day of Discharge | 
| Number of Participants With Marked Laboratory Abnormalities in Hematology | Hematology marked laboratory abnormalities were defined as Hemoglobin (g/dL) Low as < 0.85*Pre-therapy (PreRx), Hematocrit (%) Low as < 0.85*PreRx, Platelet Count *10^9 c/L Low as < 0.85*Lower Limits of Normal (LLN) if PreRx = Missing/< 0.85*LLN if PreRx >= LLN/< 0.85*PreRx if PreRx < LLN, Eosinophils (absolute) *10^3 c/µL High as > 0.75*count, Leukocytes White Blood Cell (WBC) *10^3 c/µL High as > 1.2*ULN if LLN <= PreRx <= Upper Limits of Normal (ULN) > 1.2*ULN if PreRx = Missing/> 1.5*PreRx if PreRx > ULN/> ULN if PreRx < LLN. | Screening, Day 3, Day 7, Day 11, Day 14, and Day 28 | 
| Number of Participants With Marked Abnormalities in Liver and Kidney Function Laboratory Tests and Electrolytes | Liver and kidney function marked laboratory abnormalities were defined as Alanine Aminotransferase (ALT) units per liter (U/L) High as > 1.25*PreRx if PreRx > ULN/> 1.25*ULN if PreRx <= ULN/> 1.25*ULN if PreRx = Missing, Aspartate Aminotransferase (AST) U/L High as > 1.25* PreRx if PreRx > ULN/> 1.25*ULN if PreRx <= ULN/> 1.25*ULN if PreRx = Missing, Alkaline Phosphatase(ALP)U/L High as > 1.25*PreRx if PreRx > ULN/> 1.25*ULN if PreRx <= ULN/> 1.25*ULN if PreRx = Missing, G-Glutamyl Transferase (GGT) in U/L High as >1.15*ULN if PreRx<=ULN/>1.15* if PreRx missing/>1.2* PreRx if PreRx>ULN, Phosphorus Inorganic (mg/dL) Low as < 0.85*LLN if LLN <= PreRx <= ULN/< 0.85*LLN if PreRx = Missing/< 0.85*PreRx if PreRx < LLN/< LLN if PreRx > ULN, and Potassium serum milliequivalents per liter (mEq/L) High as > 1.1*PreRx if PreRx > ULN/> 1.1*ULN if LLN <= PreRx <= ULN/> 1.1*ULN if PreRx = Missing/> ULN if PreRx < LLN. | Screening, Day 3, Day 7, Day 11, Day 14, and Day 28 | 
| Number of Participants With Marked Laboratory Abnormalities in Lipase and Glucose | Marked abnormalities were defined as Lipase (U/L) High as >1.5*ULN, Glucose fasting serum (mg/dL) High as > 1.3*ULN if LLN <= PreRx <= ULN/> 1.3*ULN if PreRx = Missing/>2*PreRx; if PreRx > ULN/> ULN if PreRx < LLN. | Screening, Day 3, Day 7, Day 11, Day 14, and Day 28 | 
| Number of Participants With Marked Laboratory Abnormalities in Urinalysis | Marked laboratory abnormalities in urinalysis were defined as, Blood Urine High as >= 2*PreRx if PreRx >= 1/>= 2 if PreRx < 1/>= 2 if PreRx = Missing. Glucose Urine High as >= 1 if PreRx < 1/>= 1 if PreRx = Missing/>= 2*PreRx if PreRx >= 1. | Screening, Day 3, Day 7, Day 11, Day 14, and Day 28 | 
| Number of Participants With Clinically Relevant Change From Baseline in Vital Signs | Vital signs included: body temperature, respiratory rate, blood pressure (systolic and diastolic) and heart rate. Blood pressure and heart rate were measured after the participant had been supine, semi-supine, or seated quietly for at least 5 minutes. Baseline was defined as the last observation prior to dosing on Day 1. | Screening, Day -1 and prior to morning dose on Day 1, 2, 14, and 28 | 
| Number of Participants Meeting Pre-Specified Criteria in Electrocardiogram Parameters | Pre-specified criteria were defined as, Heart rate (HR) minimum as <=50 bpm/change from baseline <-20 bpm/maximum HR >100 bpm, QT interval corrected using Fridericia's formula (QTcF) maximum as QTcF<=450 msec/450 msec <maximum QTcF and <=480 msec/480 msec <maximum QTcF <= 500 msec/maximum QTcF>500 msec, QRS interval as <=120 msec/>120 msec, and PR interval maximum as <= 200 msec/>200 msec. | Screening, Day 2, 3, 5, 7, 9, 11, 13, 15, 21 and 28 |