Study to Determine the Potential DDIs When the Daclatasvir/Asunaprevir/BMS-791325 Three Drug Antiviral Combination Tablet (FDC) is Coadministered With a Cocktail of Cytochrome P450 (CYP) Probe Substrates and Transporter Probe Substrates (Digoxin and Pravastatin) in Healthy Subjects

Hepatitis C Clinical Trial

Official title:

Effect of a Fixed Dose Combination Formulation of Daclatasvir/Asunaprevir/BMS-791325 on the Pharmacokinetics of a Cocktail of CYP Probe Substrates (Caffeine, Metoprolol, Montelukast, Flurbiprofen, Omeprazole, and Midazolam) and Transporter Probe Substrates (Digoxin and Pravastatin) in Healthy Subjects

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02045966
• Other study ID #: AI443-021
• Status: Completed
• Phase: Phase 1
• First received: January 23, 2014
• Last updated: June 16, 2014
• Start date: February 2014
• Est. completion date: April 2014

Study information

• Verified date: June 2014
• Source: Bristol-Myers Squibb
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationUnited States: Institutional Review Board
• Study type: Interventional

Clinical Trial Summary

The primary purpose of this study is to assess the effect of the Daclatasvir/Asunaprevir/BMS-791325 fixed dose combination (FDC) tablet on the pharmacokinetics of the cocktail CYP and transporter probe substrates and to assess the effect of the DCV 3DAA FDC [DCV 3DAA FDC = fixed dose combination formulation of 3 direct-acting antivirals (3DAA) (DCV 30 mg, ASV 200 mg, and BMS-791325 75 mg)] + BMS-791325 75-mg single-agent tablet on the Pharmacokinetic (PK) of the cocktail CYP and transporter probe substrates.

Description:

IND number: 79,599 and 101,943

Primary purpose: Other: study is being conducted to investigate the potential drug-drug interactions (DDIs) when the Daclatasvir/Asunaprevir/BMS-791325 FDC formulation is coadministered with a cocktail of cytochrome P450 (CYP) probe substrates (Caffeine, Metoprolol, Montelukast, Flurbiprofen, Omeprazole, and Midazolam) and transporter probe substrates (Digoxin and Pravastatin) in healthy subjects. It is also intended to characterize the PK of Daclatasvir (DCV), Asunaprevir (ASV), BMS-791325, and its major metabolite, BMS-794712, at steady state.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 16
• Est. completion date: April 2014
• Est. primary completion date: April 2014
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 18 Years to 45 Years

Eligibility

For more information regarding BMS clinical trial participation, please visit www.BMSStudyConnect.com

Inclusion Criteria:

• Healthy subjects as determined by no clinically significant deviation from normal in medical history, physical examinations, vital sign measurements, 12-lead ECG measurements, and clinical laboratory test results

• Body mass index (BMI) of 18.0 to 32.0 kg/m2, inclusive. BMI = weight (kg)/[height (m)]2

• Men and women, ages 18 to 45 years, inclusive

• Women must not be of childbearing potential, must not be breastfeeding

Exclusion Criteria:

• Any significant acute or chronic medical illness

• History of important arrhythmias including, but not limited to, ventricular fibrillation, ventricular tachycardia, complete atrioventricular (A-V) block, Wolff-Parkinson-White syndrome

• History of cardiac arrhythmias or palpitations associated with presyncope or syncope, or history of unexplained syncope

• History of heart disease

• History of prolonged QT interval or torsades de pointes (TdP)

• History of hypokalemia

• Family history of sudden cardiac death at a young age, TdP, or Long QT syndrome

• History of asthma, bronchospasm, or sleep apnea

• History of rhabdomyolysis

• History of a bleeding disorder

• History of Raynaud's disease

• History of peptic ulcer disease or significant gastrointestinal bleed

• History of biliary disorders, including Gilbert's disease or Dubin-Johnson disease

• Current or recent (within 3 months of study drug administration) gastrointestinal disease

• Any major surgery within 4 weeks of study drug administration

• Any gastrointestinal surgery (including cholecystectomy) that could impact upon the absorption of study drug

Study Design

Endpoint Classification: Pharmacokinetics Study, Intervention Model: Single Group Assignment, Masking: Open Label

Related Conditions & MeSH terms

• Hepatitis C

Intervention

Drug:
• Cocktail
Cocktail = Caffeine 200 mg, Metoprolol 50 mg, Montelukast 10 mg, Flurbiprofen 50 mg, Omeprazole 40 mg, Midazolam 5 mg, Digoxin 0.25 mg, and Pravastatin 40 mg
• DCV 3DAA FDC
DCV 30 mg + ASV 200 mg + BMS-791325 75 mg
• BMS-791325

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Bristol-Myers Squibb

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Area under the concentration-time curve from time zero extrapolated to infinite time [AUC(INF)] for each cocktail CYP and transporter probe substrate		51 time points up to day 36	No
Secondary	Maximum observed concentration (Cmax) for each cocktail CYP and transporter probe substrate		51 time points up to day 36	No
Secondary	Area under the concentration-time curve from time zero to the time of the last quantifiable concentration [AUC(0-T)] for each cocktail CYP and transporter probe substrate		51 time points up to day 36	No
Secondary	Cmax for the measured metabolites of the cocktail CYP and transporter probe substrates		51 time points up to day 36	No
Secondary	AUC(0-T) for the measured metabolites of the cocktail CYP and transporter probe substrates		51 time points up to day 36	No
Secondary	AUC(INF) for the measured metabolites of the cocktail CYP and transporter probe substrates		51 time points up to day 36	No
Secondary	Time of maximum observed concentration (Tmax) for each cocktail CYP and transporter probe substrate and their metabolites		51 time points up to day 36	No
Secondary	Half life (T-HALF) for each cocktail CYP and transporter probe substrate and their metabolites		51 time points up to day 36	No
Secondary	Ratio of metabolite Cmax to parent Cmax, corrected for molecular weight (MR_Cmax) for each cocktail CYP and transporter probe substrate and their metabolites		51 time points up to day 36	No
Secondary	Ratio of metabolite AUC(0-T) to parent AUC(0-T), corrected for molecular weight [MR_AUC(0-T)] for each cocktail CYP and transporter probe substrate and their metabolites		51 time points up to day 36	No
Secondary	Ratio of metabolite AUC(INF) to parent AUC(INF), corrected for molecular weight [MR_AUC(INF)] for each cocktail CYP and transporter probe substrate and their metabolites		51 time points up to day 36	No
Secondary	Apparent total body clearance (CLT/F) for each cocktail CYP and transporter probe substrate		51 time points up to day 36	No
Secondary	Cmax for Daclatasvir, Asunaprevir, BMS-791325, and the metabolite, BMS- 794712 at steady state		24 time points up to day 31	No
Secondary	Tmax for Daclatasvir, Asunaprevir, BMS-791325, and the metabolite, BMS- 794712 at steady state		24 time points up to day 31	No
Secondary	Concentration at 12 hours (C12) for Daclatasvir, Asunaprevir, BMS-791325, and the metabolite, BMS- 794712 at steady state		24 time points up to day 31	No
Secondary	Area under the concentration-time curve in one dosing interval [AUC(TAU)] for Daclatasvir, Asunaprevir, BMS-791325, and the metabolite, BMS- 794712 at steady state		24 time points up to day 31	No
Secondary	MR_Cmax for BMS-791325 and the metabolite, BMS-794712		24 time points up to day 31	No
Secondary	Ratio of metabolite AUC(TAU) to parent AUC(TAU), corrected for molecular weight [MR_AUC(TAU)] for BMS-791325 and the metabolite, BMS-794712		24 time points up to day 31	No
Secondary	Trough observed plasma concentration (Ctrough) for Daclatasvir, Asunaprevir, BMS-791325, and the metabolite, BMS-794712		24 time points up to day 31	No
Secondary	Safety measured by the occurrence of AEs and SAEs, abnormalities in vital sign measurements exceeding pre-defined thresholds, findings on ECG measurements and physical examinations, and marked abnormalities in clinical laboratory test results	AEs = Adverse events; SAEs = Serious Adverse events; ECG = Electrocardiogram	Up to day 36	Yes