Study to Evaluate Effect of Belatacept on Pharmacokinetics of Inje Cocktail in Healthy Volunteers

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Bristol-Myers Squibb
ClinicalTrials.gov Identifier:
NCT01766050
First received: January 10, 2013
Last updated: May 27, 2014
Last verified: May 2014
Results First Received: April 28, 2014  
Study Type: Interventional
Study Design: Endpoint Classification: Pharmacokinetics Study;   Intervention Model: Single Group Assignment;   Masking: Open Label;   Primary Purpose: Basic Science
Condition: Transplant Rejection
Interventions: Drug: Caffeine
Drug: Losartan
Drug: Omeprazole
Drug: Dextromethorphan
Drug: Midazolam
Biological: Belatacept

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
Study initiated January 2013 and completed April 2013. Participants (healthy volunteers) checked into a clinical pharmacology unit (CPU) on Day -1 for screening.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
45 were enrolled and 22 dosed with study drug. Reasons for not dosing: 5 withdrew consent, 1 lost to follow up, 1 poor/non-compliance, 15 no longer met study criteria, and 1 other.

Reporting Groups
  Description
Inje Cocktail Alone and Inje Cocktail Plus Belatacept Single oral doses of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) were administered on Days 1, 4, 7 and 11. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered on Day 4.

Participant Flow:   Overall Study
    Inje Cocktail Alone and Inje Cocktail Plus Belatacept  
STARTED     22  
COMPLETED     18  
NOT COMPLETED     4  
Adverse Event                 1  
Lost to Follow-up                 1  
Withdrawal by Subject                 2  



  Baseline Characteristics
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Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
All participants who received study drug.

Reporting Groups
  Description
Inje Cocktail Alone and Inje Cocktail Plus Belatacept Single oral doses of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) were administered on Days 1, 4, 7 and 11. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered on Day 4.

Baseline Measures
    Inje Cocktail Alone and Inje Cocktail Plus Belatacept  
Number of Participants  
[units: participants]
  22  
Age  
[units: years]
Mean ± Standard Deviation
  31.5  ± 5.96  
Gender  
[units: participants]
 
Female     1  
Male     21  
Race (NIH/OMB)  
[units: participants]
 
American Indian or Alaska Native     0  
Asian     0  
Native Hawaiian or Other Pacific Islander     0  
Black or African American     7  
White     15  
More than one race     0  
Unknown or Not Reported     0  
Region of Enrollment  
[units: participants]
 
United States     22  
Body Mass Index (kg/m^2) [1]
[units: kg/m^2]
Mean ± Standard Deviation
  24.62  ± 2.886  
[1] body mass index (BMI): weight in kilograms (kg)/[height in meters (m)]2



  Outcome Measures
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1.  Primary:   Adjusted Geometric Mean Maximum Drug Concentration (Cmax) of Midazolam With and Without the Coadministration of Belatacept - Pharmacokinetic (PK) Evaluable Population   [ Time Frame: Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 ]

2.  Primary:   Adjusted Geometric Mean Area Under the Concentration Time Curve (AUC) From Zero to Last Concentration (0-T) and AUC Extrapolated to Infinity (INF) of Midazolam With and Without the Coadministration of Belatacept - Pharmacokinetic (PK) Evaluable Population   [ Time Frame: Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7and 11 ]

3.  Primary:   Adjusted Geometric Mean Cmax of Losartan With and Without the Coadministration of Belatacept - PK Evaluable Population   [ Time Frame: Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 ]

4.  Primary:   Adjusted Geometric Mean AUC (0-T) and AUC (INF) of Losartan With and Without the Coadministration of Belatacept - Pharmacokinetic (PK) Evaluable Population   [ Time Frame: Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 ]

5.  Primary:   Adjusted Geometric Mean Cmax of Omeprazole With and Without the Coadministration of Belatacept - Pharmacokinetic (PK) Evaluable Population   [ Time Frame: Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 ]

6.  Primary:   Adjusted Geometric Mean AUC (0-T) and AUC (INF) of Omeprazole With and Without the Coadministration of Belatacept - Pharmacokinetic (PK) Evaluable Population   [ Time Frame: Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 ]

7.  Primary:   Adjusted Geometric Mean Cmax of Dextromethorphan With and Without the Coadministration of Belatacept - PK Evaluable Population   [ Time Frame: Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 ]

8.  Primary:   Adjusted Geometric Mean AUC (0-T) and AUC (INF) of Dextromethorphan With and Without the Coadministration of Belatacept - PK Evaluable Population   [ Time Frame: Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 ]

9.  Primary:   Adjusted Geometric Mean Cmax of Caffeine With and Without the Coadministration of Belatacept - PK Evaluable Population   [ Time Frame: Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 ]

10.  Primary:   Adjusted Geometric Mean AUC (0-T) and AUC (INF) of Caffeine With and Without the Coadministration of Belatacept - PK Evaluable Population   [ Time Frame: Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 ]

11.  Secondary:   Time of Maximum Observed Plasma Concentration (Tmax) of the Inje Cocktail Components (Midazolam, Losartan, Omeprazole, Dextromethorphan, and Caffeine) With and Without Coadministration of Belatacept - PK Evaluable Population   [ Time Frame: Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 ]

12.  Secondary:   Plasma Half-Life (T-HALF) of the Inje Cocktail Components (Midazolam, Losartan, Omeprazole, Dextromethorphan, and Caffeine) With and Without Coadministration of Belatacept - PK Evaluable Population   [ Time Frame: Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 ]

13.  Secondary:   Apparent Total Body Clearance (CLT/F) of the Inje Cocktail Components (Midazolam, Losartan, Omeprazole, Dextromethorphan and Caffeine) With and Without Coadministration of Belatacept - PK Evaluable Population   [ Time Frame: Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 ]

14.  Secondary:   Cmax of Inje Cocktail Metabolites (1’-Hydroxy-Midazolam, E-3174, 5-Hydroxyomeprazole, Dextrorphan, and Paraxanthine) With and Without Coadministration of Belatacept - PK Evaluable Population   [ Time Frame: Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 ]

15.  Secondary:   AUC(0-T) of Inje Cocktail Component Metabolites (1'-Hydroxy-Midazolam, E-3174, 5-Hydroxyomeprazole, Dextrorphan, and Paraxanthine) With and Without Coadministration of Belatacept - PK Evaluable Population   [ Time Frame: Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 ]

16.  Secondary:   AUC(INF) of Inje Cocktail Component Metabolites (1'-Hydroxy-Midazolam, E-3174, 5-Hydroxyomeprazole, Dextrorphan, and Paraxanthine) With and Without Coadministration of Belatacept - PK Evaluable Population   [ Time Frame: Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 ]

17.  Secondary:   Tmax of Inje Cocktail Component Metabolites (1'-Hydroxy-Midazolam, E-3174, 5-Hydroxyomeprazole, Dextrorphan, and Paraxanthine) With and Without the Coadministration of Belatacept - PK Evaluable Population   [ Time Frame: Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 ]

18.  Secondary:   T-HALF of Inje Cocktail Component Metabolites (1'-Hydroxy-Midazolam, E-3174, 5-Hydroxyomeprazole, Dextrorphan, and Paraxanthine) With and Without the Coadministration of Belatacept - PK Evaluable Population   [ Time Frame: Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 ]

19.  Secondary:   Ratio of Paraxanthine AUC(0-T) to Caffeine AUC(0-T) and Paraxanthine AUC (INF) to Caffeine AUC (INF), Corrected for Molecular Weight [MR_AUC(0-T) and MR_AUC (INF)] With and Without Coadministration of Belatacept - PK Evaluable Population   [ Time Frame: Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 ]

20.  Secondary:   Ratio of Paraxanthine (Cmax) to Caffeine (Cmax), Corrected for Molecular Weight (MR_Cmax) With and Without Coadministration of Belatacept - PK Evaluable Population   [ Time Frame: Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 ]

21.  Secondary:   Ratio of E-3174 AUC(0-T) to Losartan AUC(0-T) and E3174 AUC (INF) to Losartan AUC (INF) Corrected for Molecular Weight [MR_AUC(0-T), MR_AUC(INF)] With and Without Coadministration of Belatacept - PK Evaluable Population   [ Time Frame: Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 ]

22.  Secondary:   Ratio of E-3174 (Cmax) to Losartan (Cmax), Corrected for Molecular Weight (MR_Cmax) With and Without Coadministration of Belatacept - PK Evaluable Population   [ Time Frame: Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 ]

23.  Secondary:   Ratio of 5-Hydroxyomeprazole AUC(0-T) to Omeprazole AUC(0-T) and 5-Hydroxyomeprazole AUC(INF) to Omeprazole AUC(INF) , Corrected for Molecular Weight [MR_AUC(0-T), MR_AUC(INF)] With and Without Coadministration of Belatacept - PK Evaluable Population   [ Time Frame: Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 ]

24.  Secondary:   Ratio of 5-Hydroxyomeprazole (Cmax) to Omeprazole (Cmax), Corrected for Molecular Weight (MR_Cmax) With and Without Coadministration of Belatacept - PK Evaluable Population   [ Time Frame: Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 ]

25.  Secondary:   Ratio of 5-Dextrorphan AUC(0-T) to Dextromethorphan AUC(0-T) and 5-Dextrorphan AUC(INF) to Dextromethorphan AUC(INF), Corrected for Molecular Weight [MR_AUC(0-T), MR_AUC (INF)] With and Without Coadministration of Belatacept - PK Evaluable Population   [ Time Frame: Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 ]

26.  Secondary:   Ratio of 5-Dextrorphan (Cmax) to Dextromethorphan (Cmax), Corrected for Molecular Weight (MR_Cmax) With and Without Coadministration of Belatacept - PK Evaluable Population   [ Time Frame: Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 ]

27.  Secondary:   Ratio of 1’-Hydroxy-Midazolam AUC(0-T) to Midazolam AUC(0-T) and 1’-Hydroxy-Midazolam AUC(INF) to Midazolam AUC(INF), Corrected for Molecular Weight [MR_AUC(0-T), MR_AUC (INF)] With and Without Coadministration of Belatacept - PK Evaluable Population   [ Time Frame: Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 ]

28.  Secondary:   Ratio of 1'-Hydroxy-Midazolam (Cmax) to Midazolam (Cmax), Corrected for Molecular Weight (MR_Cmax) With and Without Coadministration of Belatacept - PK Evaluable Population   [ Time Frame: Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 ]

29.  Secondary:   Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Deaths, and AEs Leading to Discontinuation - All Treated Participants   [ Time Frame: Day 1 to Day of discharge (Day 46±2) ]

30.  Secondary:   Number of Participants With Marked Serum Chemistry Laboratory Abnormalities - All Treated Participants   [ Time Frame: Day -1 to Day 46 ±2 days or at early termination ]

31.  Secondary:   Number of Participants With Marked Hematology and Urinalysis Laboratory Abnormalities - All Treated Participants   [ Time Frame: Day -1 to Day 46 ±2 days or at early termination ]

32.  Secondary:   Number of Participants With Out-of-Range Electrocardiogram Intervals - All Treated Participants   [ Time Frame: Day 1 to Day 46 ±2 days or at early termination ]

33.  Secondary:   Mean Change From Baseline in Sitting Systolic and Diastolic Blood Pressure - All Treated Participants   [ Time Frame: Baseline and 0.5 and 2.0 hours Post Dose on Days 1, 4, 7, and 11 ]

34.  Secondary:   Mean Change From Baseline in Sitting Heart Rate - All Treated Participants   [ Time Frame: Baseline and 0.5 and 2.0 hours Post Dose on Days 1, 4, 7, and 11 ]

35.  Secondary:   Mean Change From Baseline in Systolic and Diastolic Blood Pressure at Study Discharge (Day 46±2 Days)   [ Time Frame: Baseline and Day 46 ±2 days ]

36.  Secondary:   Mean Change From Baseline in Heart Rate at Study Discharge (Day 46±2 Days)   [ Time Frame: Baseline and Day 46 ±2 days ]


  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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  More Information
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Certain Agreements:  
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The agreement is:
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.


Results Point of Contact:  
Name/Title: Bristol-Myers Squibb Study Director
Organization: Bristol-Myers Squibb
e-mail: Clinical.Trials@bms.com


No publications provided


Responsible Party: Bristol-Myers Squibb
ClinicalTrials.gov Identifier: NCT01766050     History of Changes
Other Study ID Numbers: IM103-151
Study First Received: January 10, 2013
Results First Received: April 28, 2014
Last Updated: May 27, 2014
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board