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

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ClinicalTrials.gov Identifier: NCT00663208
Recruitment Status : Completed
First Posted : April 22, 2008
Results First Posted : October 14, 2015
Last Update Posted : October 14, 2015
Sponsor:
Information provided by (Responsible Party):
Bristol-Myers Squibb

Tracking Information
First Submitted Date  ICMJE April 18, 2008
First Posted Date  ICMJE April 22, 2008
Results First Submitted Date  ICMJE August 14, 2015
Results First Posted Date  ICMJE October 14, 2015
Last Update Posted Date October 14, 2015
Study Start Date  ICMJE May 2008
Actual Primary Completion Date June 2009   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 16, 2015)
Change From Baseline at Day 7 in log10 Hepatitis C Virus (HCV) RNA of All Participants [ Time Frame: Baseline, Day 7 ]
The Roche TaqMan HCV quantitative assay was used for analysis with detection limit of 10 IU/mL. Baseline was Day -1.
Original Primary Outcome Measures  ICMJE
 (submitted: April 21, 2008)
Pharmacodynamic Measures: Antiviral activity will be assessed by the magnitude and rate of change in plasma HCV RNA levels from baseline [ Time Frame: The primary endpoint for antiviral activity is decrease from baseline in plasma HCV RNA levels to Day 7 ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 16, 2015)
  • Change From Baseline at Day 7 in log10 Hepatitis C Virus (HCV) RNA Levels of Participants Without Baseline Drug Resistance [ Time Frame: Baseline, Day 7 ]
    The Roche TaqMan HCV quantitative assay was used for analysis with detection limit of 10 international units/ millilitre (IU/mL). Baseline was Day -1
  • Change From Baseline at 24 h Post Dose on Day 1 in log10 Hepatitis C Virus (HCV) RNA of Participants Without Baseline Drug Resistance [ Time Frame: Baseline, 2, 4, 6, 8, 12, 16, 20, and 24 hours post dose on Day 1 ]
    The Roche TaqMan HCV quantitative assay was used for analysis with detection limit of 10 IU/mL. Baseline was Day -1.
  • Change From Baseline to Day 4 in log10 Hepatitis C Virus (HCV) RNA in Participants Without Baseline Drug Resistance [ Time Frame: Baseline to Day 4 ]
    The Roche TaqMan HCV quantitative assay was used for analysis with detection limit of 10 IU/mL. Baseline was Day -1.
  • Change From Baseline to Day 14 in Log10 Hepatitis C Virus (HCV) RNA in Participants Without Baseline Drug Resistance [ Time Frame: Baseline to Day 14 ]
    The Roche TaqMan HCV quantitative assay was used for analysis with detection limit of 10 IU/mL. Baseline was Day -1.
  • Time to Maximum Decline From Baseline in Hepatitis C Virus (HCV) RNA in Participants Without Baseline Drug Resistance [ Time Frame: Day 1 up to Day 14 ]
    Participants without baseline drug resistance were assessed for time to reach maximum decrease in log10 HCV RNA level.
  • Maximum Decline From Baseline in Log10 Hepatitis C Virus (HCV) RNA in Participants Without Baseline Drug Resistance [ Time Frame: Day 1 up to Day 14 ]
    The Roche TaqMan HCV quantitative assay was used for analysis with detection limit of 10 IU/mL.
  • Maximum Observed Plasma Concentration (Cmax) and Minimum Observed Plasma Concentration (Cmin) of Daclatasvir on Days 1 and 14 [ Time Frame: 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 ]
    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.
  • Area Under the Concentration-time Curve (AUC) in 1 Dosing Interval of Daclatasvir at Days 1 and 14 [ Time Frame: 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 ]
    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.
  • Plasma Half-life (T-half) of Daclatasvir at Day 14 [ Time Frame: 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 ]
    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.
  • Apparent Total Body Clearance (CLT/F) of Daclatasvir on Day 14 [ Time Frame: 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 ]
    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.
  • Average Observed Plasma Concentration (Css-av) at Steady State of Daclatasvir at Days 1 and 14 [ Time Frame: 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 ]
    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.
  • Accumulation Index (AI) AUC(TAU), AI Cmax, and Degree of Fluctuation (DF) of Daclatasvir on Day 14 [ Time Frame: 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 ]
    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).
  • Time of Maximum Observed Plasma Concentration (Tmax) of Daclatasvir on Days 1 and 14 [ Time Frame: 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 ]
    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.
  • 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 [ Time Frame: Day 4, Day 14 ]
    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).
  • Number of Participants With Serious Adverse Events (SAEs), Discontinuation Due to Adverse Events (AEs), and Who Died [ Time Frame: Day 1 to Day 182 or Day of Discharge ]
    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.
  • Number of Participants With Marked Laboratory Abnormalities in Hematology [ Time Frame: Screening, Day 3, Day 7, Day 11, Day 14, and Day 28 ]
    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.
  • Number of Participants With Marked Abnormalities in Liver and Kidney Function Laboratory Tests and Electrolytes [ Time Frame: Screening, Day 3, Day 7, Day 11, Day 14, and Day 28 ]
    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.
  • Number of Participants With Marked Laboratory Abnormalities in Lipase and Glucose [ Time Frame: Screening, Day 3, Day 7, Day 11, Day 14, and Day 28 ]
    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.
  • Number of Participants With Marked Laboratory Abnormalities in Urinalysis [ Time Frame: Screening, Day 3, Day 7, Day 11, Day 14, and Day 28 ]
    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.
  • Number of Participants With Clinically Relevant Change From Baseline in Vital Signs [ Time Frame: Screening, Day -1 and prior to morning dose on Day 1, 2, 14, and 28 ]
    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.
  • Number of Participants Meeting Pre-Specified Criteria in Electrocardiogram Parameters [ Time Frame: Screening, Day 2, 3, 5, 7, 9, 11, 13, 15, 21 and 28 ]
    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.
Original Secondary Outcome Measures  ICMJE
 (submitted: April 21, 2008)
  • PD-PK Relationship Measures: Assess relationship between antiviral activity and measures of exposure to BMS-790052 [ Time Frame: Upon occurrence ]
  • Safety Outcome Measures [ Time Frame: Safety and tolerability assessments will be performed for a period of 28 days after administration of multiple doses of BMS-790052 for 14 days ]
  • Pharmacokinetic Measures [ Time Frame: Pharmacokinetic assessments will be done for a period of 5 days from Day 1, 72 hours after the last morning dose and at steady state ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Multiple Ascending Dose Study of Daclatasvir (BMS-790052) in Hepatitis C Virus Genotype 1 Infected Subjects
Official Title  ICMJE 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
Brief Summary 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
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Chronic Hepatitis C
Intervention  ICMJE
  • Drug: Daclatasvir
    Capsule, Oral, Approximately 182 days from initial dosing
  • Drug: Placebo
    Capsule, Oral, After 28 days from initial dosing and unblinding of the dose panel
Study Arms  ICMJE
  • Active Comparator: Group 1

    Daclatasvir (1 mg), once daily

    or

    Matching Placebo, once daily

    Interventions:
    • Drug: Daclatasvir
    • Drug: Placebo
  • Active Comparator: Group 2

    Daclatasvir (10 mg), once daily

    or

    Matching Placebo, once daily

    Interventions:
    • Drug: Daclatasvir
    • Drug: Placebo
  • Active Comparator: Group 3

    Daclatasvir (1-100 mg), once or twice daily

    or

    Matching Placebo, once or twice daily

    Interventions:
    • Drug: Daclatasvir
    • Drug: Placebo
  • Active Comparator: Group 4

    Daclatasvir (1-100 mg), once or twice daily

    or

    Matching Placebo, once or twice daily

    Interventions:
    • Drug: Daclatasvir
    • Drug: Placebo
  • Active Comparator: Group 5

    Group 5: Active Comparator

    Daclatasvir (1-100 mg), once or twice daily

    or

    Matching Placebo, once or twice daily

    Interventions:
    • Drug: Daclatasvir
    • Drug: Placebo
  • Active Comparator: Group 6

    Group 6: Active Comparator

    Daclatasvir (1-100 mg), once or twice daily

    or

    Matching Placebo, once or twice daily

    Interventions:
    • Drug: Daclatasvir
    • Drug: Placebo
Publications * Nettles RE, Gao M, Bifano M, Chung E, Persson A, Marbury TC, Goldwater R, DeMicco MP, Rodriguez-Torres M, Vutikullird A, Fuentes E, Lawitz E, Lopez-Talavera JC, Grasela DM. Multiple ascending dose study of BMS-790052, a nonstructural protein 5A replication complex inhibitor, in patients infected with hepatitis C virus genotype 1. Hepatology. 2011 Dec;54(6):1956-65. doi: 10.1002/hep.24609.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: September 16, 2015)
167
Original Estimated Enrollment  ICMJE
 (submitted: April 21, 2008)
40
Actual Study Completion Date  ICMJE June 2009
Actual Primary Completion Date June 2009   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 60 Years   (Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Puerto Rico,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00663208
Other Study ID Numbers  ICMJE AI444-004
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Bristol-Myers Squibb
Study Sponsor  ICMJE Bristol-Myers Squibb
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Bristol-Myers Squibb Bristol-Myers Squibb
PRS Account Bristol-Myers Squibb
Verification Date September 2015

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP