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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Bristol-Myers Squibb
ClinicalTrials.gov Identifier:
NCT00663208
First received: April 18, 2008
Last updated: September 16, 2015
Last verified: September 2015
  Purpose
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

Condition Intervention Phase
Chronic Hepatitis C
Drug: Daclatasvir
Drug: Placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacodynamics Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by Bristol-Myers Squibb:

Primary Outcome Measures:
  • Change From Baseline at Day 7 in log10 Hepatitis C Virus (HCV) RNA of All Participants [ Time Frame: Baseline, Day 7 ] [ Designated as safety issue: No ]
    The Roche TaqMan HCV quantitative assay was used for analysis with detection limit of 10 IU/mL. Baseline was Day -1.


Secondary Outcome Measures:
  • 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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: Yes ]
    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.


Enrollment: 167
Study Start Date: May 2008
Study Completion Date: June 2009
Primary Completion Date: June 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Group 1

Daclatasvir (1 mg), once daily

or

Matching Placebo, once daily

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
Active Comparator: Group 2

Daclatasvir (10 mg), once daily

or

Matching Placebo, once daily

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
Active Comparator: Group 3

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

or

Matching Placebo, once or twice daily

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
Active Comparator: Group 4

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

or

Matching Placebo, once or twice daily

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
Active Comparator: Group 5

Group 5: Active Comparator

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

or

Matching Placebo, once or twice daily

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
Active Comparator: Group 6

Group 6: Active Comparator

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

or

Matching Placebo, once or twice daily

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

  Eligibility

Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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

  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00663208

Locations
United States, California
Advanced Clinical Res Inst
Anaheim, California, United States, 92801
West Coast Clinical Trials, Llc
Cypress, California, United States, 90630
United States, Connecticut
Yale University School of Medicine
New Haven, Connecticut, United States, 06510
United States, Florida
Elite Research Institute
Miami, Florida, United States, 33169
Orlando Clinical Research Center
Orlando, Florida, United States, 32809
United States, Maryland
Parexel International Corporation
Baltimore, Maryland, United States, 21225
United States, Texas
Alamo Medical Research
San Antonio, Texas, United States, 78215
Puerto Rico
Local Institution
Santurce, Puerto Rico, 00909
Sponsors and Collaborators
Bristol-Myers Squibb
Investigators
Study Director: Bristol-Myers Squibb Bristol-Myers Squibb
  More Information

Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Bristol-Myers Squibb
ClinicalTrials.gov Identifier: NCT00663208     History of Changes
Other Study ID Numbers: AI444-004 
Study First Received: April 18, 2008
Results First Received: August 14, 2015
Last Updated: September 16, 2015
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Hepatitis
Hepatitis A
Hepatitis C
Hepatitis, Chronic
Hepatitis C, Chronic
Liver Diseases
Digestive System Diseases
Hepatitis, Viral, Human
Virus Diseases
Enterovirus Infections
Picornaviridae Infections
RNA Virus Infections
Flaviviridae Infections

ClinicalTrials.gov processed this record on July 28, 2016