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

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.

Time frame: 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.

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

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.

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

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.

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

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.

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

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.

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

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).

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

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.

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

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).

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: Screening, Day 2, 3, 5, 7, 9, 11, 13, 15, 21 and 28