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

Chronic Hepatitis C Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00663208
• Other study ID #: AI444-004
• Status: Completed
• Phase: Phase 2
• First received: April 18, 2008
• Last updated: September 16, 2015
• Start date: May 2008
• Est. completion date: June 2009

Study information

• Verified date: September 2015
• Source: Bristol-Myers Squibb
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 167
• Est. completion date: June 2009
• Est. primary completion date: June 2009
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 60 Years

Eligibility

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

Study Design

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

Related Conditions & MeSH terms

• Chronic Hepatitis C
• Hepatitis
• Hepatitis A
• Hepatitis C
• Hepatitis C, Chronic
• Hepatitis, Chronic

Intervention

Drug:
• Daclatasvir
Capsule, Oral, Approximately 182 days from initial dosing
• Placebo
Capsule, Oral, After 28 days from initial dosing and unblinding of the dose panel

Locations

Country	Name	City	State
Puerto Rico	Local Institution	Santurce
United States	Advanced Clinical Res Inst	Anaheim	California
United States	Parexel International Corporation	Baltimore	Maryland
United States	West Coast Clinical Trials, Llc	Cypress	California
United States	Elite Research Institute	Miami	Florida
United States	Yale University School of Medicine	New Haven	Connecticut
United States	Orlando Clinical Research Center	Orlando	Florida
United States	Alamo Medical Research	San Antonio	Texas

Sponsors (1)

Lead Sponsor	Collaborator
Bristol-Myers Squibb

Countries where clinical trial is conducted

United States,  Puerto Rico, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	Plasma Half-life (T-half) of Daclatasvir at Day 14	The absolute values of lamda (?) were used to evaluate apparent terminal half-life (T-half) was defined as T-half= ln 2/?. 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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	Yes
Secondary	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	Yes
Secondary	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	Yes
Secondary	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	Yes
Secondary	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	Yes
Secondary	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	Yes
Secondary	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	Screening, Day 2, 3, 5, 7, 9, 11, 13, 15, 21 and 28	Yes

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