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

Sponsor
Bristol-Myers Squibb (Industry)
Overall Status
Completed
CT.gov ID
NCT01766050
Collaborator
(none)
45
Enrollment
1
Location
1
Arm
3
Duration (Months)
15.2
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to determine the effects of belatacept on the pharmacokinetics of caffeine, losartan, omeprazole, dextromethorphan and midazolam

Condition or Disease Intervention/Treatment Phase
Phase 4

Study Design

Study Type:
Interventional
Actual Enrollment :
45 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Basic Science
Official Title:
An Open-label, Single-sequence Study of the Effect of Belatacept on the Pharmacokinetics of Caffeine, Losartan, Omeprazole, Dextromethorphan, and Midazolam Administered as "Inje Cocktail" in Healthy Subjects
Study Start Date :
Jan 1, 2013
Actual Primary Completion Date :
Apr 1, 2013
Actual Study Completion Date :
Apr 1, 2013

Arms and Interventions

Arm Intervention/Treatment
Experimental: Arm: Inje Cocktail + Belatacept

Inje Cocktail consisting of (200 mg Caffeine, 50 mg losartan tablet, 40 mg Omeprazole capsule, 30 mg Dextromethorphan capsule and 5 mg Midazolam oral syrup) administered on Days 1, 4, 7 and 11 Belatacept 10 mg/kg Intravenous (IV) solution, administered on Day 4

Drug: Caffeine

Drug: Losartan

Drug: Omeprazole

Drug: Dextromethorphan

Drug: Midazolam

Biological: Belatacept
Other Names:
  • Nulojix
  • BMS-224818

    		•

    Outcome Measures

    Primary Outcome Measures

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

      Samples for the assessment of plasma concentrations of Inje cocktail components (midazolam, losartan, omeprazole, dextromethorphan and caffeine) and their metabolites (1'-hydroxy-midazolam, E-3174, 5-hydroxyomeprazole, dextrorphan, and paraxanthine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Adjusted geometric mean for midazolam with and without belatacept, along with adjusted geometric mean ratios for Days 4, 7, and 11 versus Day 1, respectively, are presented. Cmax measured in nanograms per milliliter (ng/mL). Inje cocktail components (Midazolam) measured using High Performance Liquid Chromatography (HPLC) with Tandem Mass Spectrometry (MS/MS) Detection.

    2. 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 [Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7and 11]

      AUC(0-T): area under the plasma concentration-time curve from zero to the last time of the last quantifiable concentration and AUC (INF): AUC from time zero extrapolated to infinite time were measured in ng*h/mL. Samples for the assessment of plasma concentrations of Inje cocktail components (midazolam, losartan, omeprazole, dextromethorphan and caffeine) and their metabolites (1'-hydroxy-midazolam, E-3174, 5-hydroxyomeprazole, dextrorphan, and paraxanthine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Adjusted geometric mean for midazolam with and without belatacept, along with adjusted geometric mean ratios for Days 4, 7, and 11 versus Day 1, respectively, are presented. Midazolam measured using HPLC with MS/MS Detection.

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

      Cmax measured in ng/mL. Samples for assessment of plasma concentrations of Inje cocktail components (midazolam, losartan, omeprazole, dextromethorphan and caffeine) and their metabolites (1'-hydroxy-midazolam, E-3174, 5-hydroxyomeprazole, dextrorphan, and paraxanthine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Adjusted geometric mean for losartan with and without belatacept, along with adjusted geometric mean ratios for Days 4, 7, and 11 versus Day 1, respectively, are presented. Inje cocktail components (losartan) measured using HPLC with MS/MS Detection.

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

      AUC (0-T): area under the concentration curve from time 0 to the time of the last quantifiable concentration and AUC (INF) extrapolated to infinity were measured in ng*h/mL. Samples for assessment of plasma concentrations of Inje cocktail components (midazolam, losartan, omeprazole, dextromethorphan and caffeine) and their metabolites (1'-hydroxy-midazolam, E-3174, 5-hydroxyomeprazole, dextrorphan, and paraxanthine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Adjusted geometric mean for losartan with and without belatacept, along with adjusted geometric mean ratios for Days 4, 7, and 11 versus Day 1, respectively, are presented. Inje cocktail components (losartan) measured using HPLC with MS/MS Detection.

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

      Cmax: Maximum observed plasma concentration was measured in ng/mL. Samples for assessment of plasma concentrations of Inje cocktail components (midazolam, losartan, omeprazole, dextromethorphan and caffeine) and their metabolites (1'-hydroxy-midazolam, E-3174, 5-hydroxyomeprazole, dextrorphan, and paraxanthine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Adjusted geometric mean for omeprazole with and without belatacept, along with adjusted geometric mean ratios for Days 4, 7, and 11 versus Day 1, respectively, are presented. Inje cocktail components (omeprazole) measured using HPLC with MS/MS Detection.

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

      AUC(0-T): Area under the plasma concentration-time curve from time zero zero to the time of the last quantifiable concentration and AUC (INF): AUC extrapolated to infinity were measured in ng*h/mL. Samples for assessment of plasma concentrations of Inje cocktail components (midazolam, losartan, omeprazole, dextromethorphan and caffeine) and their metabolites (1'-hydroxy-midazolam, E-3174, 5-hydroxyomeprazole, dextrorphan, and paraxanthine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Adjusted geometric mean for omeprazole with and without belatacept, along with adjusted geometric mean ratios for Days 4, 7, and 11 versus Day 1, respectively, are presented. Inje cocktail components (omeprazole) measured using HPLC with MS/MS Detection.

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

      Cmax was measured in ng/mL. Samples for assessment of plasma concentrations of Inje cocktail components (midazolam, losartan, omeprazole, dextromethorphan and caffeine) and their metabolites (1'-hydroxy-midazolam, E-3174, 5-hydroxyomeprazole, dextrorphan, and paraxanthine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Adjusted geometric mean for dextromethorphan with and without belatacept, along with adjusted geometric mean ratios for Days 4, 7, and 11 versus Day 1, respectively, are presented. The poor metabolizer of CYP2D6 was excluded from the statistical analysis. Inje cocktail components (dextromethorphan) measured using HPLC with MS/MS Detection.

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

      AUC(0-T): area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration and AUC (INF): AUC extrapolated to infinity, were measured as ng*h/mL. Samples for assessment of plasma concentrations of Inje cocktail components (midazolam, losartan, omeprazole, dextromethorphan and caffeine) and their metabolites (1'-hydroxy-midazolam, E-3174, 5-hydroxyomeprazole, dextrorphan, and paraxanthine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Adjusted geometric mean for dextromethorphan with and without belatacept, along with adjusted geometric mean ratios for Days 4, 7, and 11 versus Day 1, respectively, are presented. The poor metabolizer of CYP2D6 was excluded from the statistical analysis. Inje cocktail components (dextromethorphan) measured using HPLC with MS/MS Detection.

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

      Samples for assessment of plasma concentrations of Inje cocktail components (midazolam, losartan, omeprazole, dextromethorphan and caffeine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Inje cocktail components were each measured using HPLC with MS/MS detection. Cmax was measured in ng/mL.

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

      Samples for assessment of plasma concentrations of Inje cocktail components (midazolam, losartan, omeprazole, dextromethorphan and caffeine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Inje cocktail components were each measured using HPLC with MS/MS detection. AUC (0-T) and AUC (INF) were measured as ng*h/mL.

    Secondary Outcome Measures

    1. 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 [Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11]

      Samples for assessment of plasma concentrations of Inje cocktail components (midazolam, losartan, omeprazole, dextromethorphan and caffeine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. The poor metabolizer of CYP2D6 was excluded from summary of dextromethorphan parameters. Inje cocktail components were each measured using HPLC with MS/MS detection. Tmax was measured in hours (h).

    2. 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 [Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11]

      Samples for assessment of plasma concentrations of Inje cocktail components (midazolam, losartan, omeprazole, dextromethorphan and caffeine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. The poor metabolizer of CYP2D6 was excluded from summary of dextromethorphan parameters. Inje cocktail components were each measured using HPLC with MS/MS detection. T-HALF was measured in hours (h).

    3. 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 [Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11]

      Samples for assessment of plasma concentrations of Inje cocktail components (midazolam, losartan, omeprazole, dextromethorphan and caffeine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. The poor metabolizer of CYP2D6 was excluded from summary of dextromethorphan parameters. Inje cocktail components were each measured using HPLC with MS/MS detection. CLT/F was measured as liters/hour (L/h)

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

      Samples for assessment of plasma concentrations of Inje cocktail component metabolites (1'-hydroxy-midazolam, E-3174, 5-hydroxyomeprazole, dextrorphan, and paraxanthine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. The poor metabolizer of CYP2D6 was excluded from summary of Dextrorphan parameters. Inje cocktail component metabolites were each measured using HPLC with MS/MS detection. Cmax was measured in ng/mL.

    5. 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 [Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11]

      Area under the plasma concentration-time curve from zero to the last time of the last quantifiable concentration [AUC(0-T)] was measured in ng*h/mL. Samples for assessment of plasma concentrations of Inje cocktail components metabolites (1'-hydroxy-midazolam, E-3174, 5-hydroxyomeprazole, dextrorphan, and paraxanthine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. The poor metabolizer of CYP2D6 was excluded from summary of Dextrorphan parameters. Inje cocktail components were each measured using HPLC with MS/MS detection.

    6. 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 [Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11]

      Area under the plasma concentration-time curve from time zero extrapolated to infinite time [AUC(INF)] was measured in ng*h/mL. Samples for assessment of plasma concentrations of Inje cocktail components metabolites (1'-hydroxy-midazolam, E-3174, 5-hydroxyomeprazole, dextrorphan, and paraxanthine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. The poor metabolizer of CYP2D6 was excluded from summary of Dextrorphan parameters. Inje cocktail components were each measured using HPLC with MS/MS detection.

    7. 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 [Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11]

      Samples for assessment of plasma concentrations of Inje cocktail components metabolites (1'-hydroxy-midazolam, E-3174, 5-hydroxyomeprazole, dextrorphan, and paraxanthine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. The poor metabolizer of CYP2D6 was excluded from summary of Dextrorphan parameters. Inje cocktail components were each measured using HPLC with MS/MS detection. Time of maximum observed plasma concentration (Tmax) was measured in hours (h).

    8. 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 [Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11]

      Plasma half-life (T-HALF) was measured in hours (h). Samples for assessment of plasma concentrations of Inje cocktail components metabolites (1'-hydroxy-midazolam, E-3174, 5-hydroxyomeprazole, dextrorphan, and paraxanthine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. The poor metabolizer of CYP2D6 was excluded from summary of Dextrorphan parameters. Inje cocktail components were each measured using HPLC with MS/MS detection.

    9. 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 [Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11]

      Metabolite (paraxanthine) to parent (caffeine) ratio was corrected for molecular weight. AUC (0-T) and AUC (INF) measured in ng*h/mL. Samples for assessment of plasma concentrations of Inje cocktail components and the metabolites of those components were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Inje cocktail components were each measured using HPLC with MS/MS detection.

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

      Metabolite (paraxanthine) to parent (caffeine) ratio was corrected for molecular weight. Cmax measured in ng/mL. Samples for assessment of plasma concentrations of Inje cocktail components and their metabolites were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Inje cocktail components were each measured using HPLC with MS/MS detection.

    11. 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 [Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11]

      Metabolite (E-3174) to parent (losartan) ratio was corrected for molecular weight. AUC (0-T) and AUC (INF) measured in ng*h/mL. Samples for assessment of plasma concentrations of Inje cocktail components and the metabolites of those components were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Inje cocktail components were each measured using HPLC with MS/MS detection.

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

      Metabolite (E-3174) to parent (losartan) ratio was corrected for molecular weight. Cmax measured in ng/mL. Samples for assessment of plasma concentrations of Inje cocktail components and the metabolites of those components were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Inje cocktail components were each measured using HPLC with MS/MS detection.

    13. 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 [Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11]

      Metabolite (5-Hydroxyomeprazole) to parent (omeprazole) ratio was corrected for molecular weight. AUC (0-T) and AUC (INF) measured in ng*h/mL. Samples for assessment of plasma concentrations of Inje cocktail components and the metabolites of those components were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Inje cocktail components were each measured using HPLC with MS/MS detection.

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

      Metabolite (5-hydroxyomeprazole) to parent (omeprazole) ratio was corrected for molecular weight. Cmax measured in ng/mL. Samples for assessment of plasma concentrations of Inje cocktail components and the metabolites of those components were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Inje cocktail components were each measured using HPLC with MS/MS detection.

    15. 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 [Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11]

      Metabolite (5-dextrorphan ) to parent (dextromethorphan) ratio was corrected for molecular weight. AUC (0-T) and AUC (INF) measured in ng*h/mL. Samples for assessment of plasma concentrations of Inje cocktail components and the metabolites of those components were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. The poor metabolizer of CYP2D6 was excluded from summary of Dextrorphan parameters. Inje cocktail components were each measured using HPLC with MS/MS detection.

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

      Metabolite (5-dextrorphan) to parent (dextromethorphan) ratio was corrected for molecular weight. Cmax measured in ng/mL. Samples for assessment of plasma concentrations of Inje cocktail components and the metabolites of those components were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. The poor metabolizer of CYP2D6 was excluded from summary of Dextrorphan parameters. Inje cocktail components were each measured using HPLC with MS/MS detection.

    17. 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 [Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11]

      Metabolite (1'-hydroxy-midazolam) to parent (midazolam) ratio was corrected for molecular weight. AUC (0-T) and AUC (INF) measured in ng*h/mL. Samples for assessment of plasma concentrations of Inje cocktail components and the metabolites of those components were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Inje cocktail components were each measured using HPLC with MS/MS detection.

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

      Metabolite (1'-hydroxy-midazolam) to parent (midazolam) ratio was corrected for molecular weight. Cmax measured in ng/mL. Samples for assessment of plasma concentrations of Inje cocktail components and the metabolites of those components were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Inje cocktail components were each measured using HPLC with MS/MS detection.

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

      Adverse events were coded according to the Medical Dictionary for Regulatory Activities (MedDRA), version 15.1. 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. Events captured from Day 1 (pre-dose) to last day prior to discharge (Day 46 ±2). In the total group, a participant with an AE is only counted once (ie, data reflected in Days 1, 4, 7, and 11 below could be the same participant with an AE on multiple days of the study).

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

      Samples for laboratory tests were obtained at Screening visit, Day -1 or prior to dosing on Day 1, Days 3, 6, 10, 46, and at early termination, after 10 hours fasting. Upper limits of normal (ULN); Lower limits of normal (LLN); Pre-therapy (Rx); micromoles per liter (µmol/L); millimoles per liter (mmol/L); grams per liter (g/L); Units per liter (U/L); Aspartate Aminotransferase (AST); Blood Urea Nitrogen (BUN) Total Bilirubin: >1.1*ULN if Pre-Rx<= ULN or Pre-Rx is missing, or >1.2*Pre-Rx if Pre-Rx >ULN. AST: >1.25*Pre-Rx if Pre-Rx >ULN or 1.25*ULN if Pre-Rx <= ULN or Pre-Rx is missing. BUN: >1.1*ULN if Pre-Rx<= ULN or Pre-Rx is missing, or >1.2*Pre-Rx if Pre-Rx >ULN. Phosphorus: <0.85*LLN if Pre-RX >= LLN or is missing or if Pre-Rx < LLN. total Protein: <0.9*LLN if Pre-Rx>= LLN or is missing or Pre-Rx > LLN. Creatine Kinase: >1.5*Pre-Rx if Pre-Rx > ULN or is missing or Pre-Rx is <= ULN. Lactate Dehydrogenase: >1.25*ULN if Pre-Rx <= ULN or missing, >1.5*Pre-Rx if Pre-Rx > ULN.

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

      Samples for laboratory tests were obtained at Screening visit, Day -1 or prior to dosing on Day 1, Days 3, 6, 10, 46 ±2, and at early termination, after 10 hours fasting. Leukocytes: *10^9 cells per liter (c/L) < 0.85*Pre-Rx if Pre-Rx < LLN or <0.9*LLN if LLN <= Pre-Rx or Pre-Rx is missing. Neutrophils (absolute): *10^12 c/L < 0.85* Pre-Rx if Pre-Rx < 1.5, <1.5 if Pre-Rx >= 1.5, < 1.5 if Pre-Rx missing. Urine blood from dipstick: >=2 if Pre-Rx <1 or was missing or if Pre-Rx >=1. Urinary microscopic white blood cells (WBC) and red blood cells (RBC) >= 2 if Pre-Rx <2 or if Pre-Rx was missing or >=4 if Pre-Rx >=2.

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

      Participants had 12-Lead electrocardiograms (ECGs) performed at Screening Visit, Day 1 prior to dosing, Day 46 ±2, and at early termination. Definition of out-of-range: PR Interval >210 milliseconds (msec); QRS > 120 msec, QT > 500 msec or > 30 msec change from baseline (Day 1); QT with Fridericia correction (QTcF) > 450 msec or change from baseline of > 30 msec to <= 60 msec or change from baseline > 60 msec.

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

      Systolic and Diastolic blood pressures were taken after the participant had been sitting quietly for at least 5 minutes and the pressures were measured in millimeters of mercury (mm Hg). Pressures were obtained at screening visit, Day -1, and at 0 hour (pre-dose), 0.5 hour (post dose), and 2 hours (post dose) on Days 1, 4, 7, 11. Baseline was defined as last non-missing result with a collection date-time less than the date-time of the first active dose of study drug.

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

      Heart Rate was taken after the participant had been sitting quietly for at least 5 minutes and the heart rate was measured in beats per minute (bpm). Heart Rates were obtained at screening visit, Day -1, and at 0 hour (pre-dose), 0.5 hour (post dose), and 2 hours (post dose) on Days 1, 4, 7, 11. Baseline was defined as last non-missing result with a collection date-time less than the date-time of the first active dose of study drug.

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

      Systolic and Diastolic blood pressures were taken after the participant had been sitting quietly for at least 5 minutes and the pressures were measured in millimeters of mercury (mm Hg). Systolic and Diastolic blood pressures were taken on Day 46 (day of discharge from the study). Baseline was defined as last non-missing result with a collection date-time less than the date-time of the first active dose of study drug.

    26. Mean Change From Baseline in Heart Rate at Study Discharge (Day 46±2 Days) [Baseline and Day 46 ±2 days]

      Heart Rate was taken after the participant had been sitting quietly for at least 5 minutes and was measured in beats per minute (bpm). Hear rate was taken on Day 46 (day of discharge) during the follow up period. Baseline was defined as last non-missing result with a collection date-time less than the date-time of the first active dose of study drug.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 45 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    Yes
    Inclusion Criteria:

    • BMI 18 to 30 kg/m2

    • Men and women ages 18 to 45

    Exclusion Criteria:

    • Active tuberculosis

    • Any recent infection requiring antibiotic treatment within 4 weeks of dosing

    • Positive urine screen for drugs of abuse

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Healthcare Discoveries, Llc D/B/A Icon Development Solutions San Antonio Texas United States 78209

    Sponsors and Collaborators

    • Bristol-Myers Squibb

    Investigators

    • Study Director: Bristol-Myers Squibb, Bristol-Myers Squibb

    Study Documents (Full-Text)

    None provided.

    More Information

    Additional Information:

    Publications

    None provided.
    Responsible Party:
    Bristol-Myers Squibb
    ClinicalTrials.gov Identifier:
    NCT01766050
    Other Study ID Numbers:
    • IM103-151
    First Posted:
    Jan 11, 2013
    Last Update Posted:
    Jun 27, 2014
    Last Verified:
    May 1, 2014
    Additional relevant MeSH terms:
    Abatacept
    Losartan
    Midazolam
    Dextromethorphan
    Caffeine
    Omeprazole

    Study Results

    Participant Flow

    Recruitment Details 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 Detail 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.
    Arm/Group Title Inje Cocktail Alone and Inje Cocktail Plus Belatacept
    Arm/Group Description 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.
    Period Title: Overall Study
    STARTED 22
    COMPLETED 18
    NOT COMPLETED 4

    Baseline Characteristics

    Arm/Group Title Inje Cocktail Alone and Inje Cocktail Plus Belatacept
    Arm/Group Description 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.
    Overall Participants 22
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    31.5
    (5.96)
    Sex: Female, Male (Count of Participants)
    Female
    1
    4.5%
    Male
    21
    95.5%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    Asian
    0
    0%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    Black or African American
    7
    31.8%
    White
    15
    68.2%
    More than one race
    0
    0%
    Unknown or Not Reported
    0
    0%
    Region of Enrollment (participants) [Number]
    United States
    22
    100%
    Body Mass Index (kg/m^2) (kg/m^2) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [kg/m^2]
    24.62
    (2.886)

    Outcome Measures

    1. Primary Outcome
    Title Adjusted Geometric Mean Maximum Drug Concentration (Cmax) of Midazolam With and Without the Coadministration of Belatacept - Pharmacokinetic (PK) Evaluable Population
    Description Samples for the assessment of plasma concentrations of Inje cocktail components (midazolam, losartan, omeprazole, dextromethorphan and caffeine) and their metabolites (1'-hydroxy-midazolam, E-3174, 5-hydroxyomeprazole, dextrorphan, and paraxanthine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Adjusted geometric mean for midazolam with and without belatacept, along with adjusted geometric mean ratios for Days 4, 7, and 11 versus Day 1, respectively, are presented. Cmax measured in nanograms per milliliter (ng/mL). Inje cocktail components (Midazolam) measured using High Performance Liquid Chromatography (HPLC) with Tandem Mass Spectrometry (MS/MS) Detection.
    Time Frame Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11

    Outcome Measure Data

    Analysis Population Description
    Participants who received any study drug and had at least 1 adequate Pharmacokinetic (PK) profile for any Inje cocktail analytes (parent or metabolite).
    Arm/Group Title Day 1 Inje Cocktail Day 4 Inje Cocktail Plus Belatacept Day 7 Inje Cocktail Day 11 Inje Cocktail
    Arm/Group Description Single oral dose 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) was administered on Day 1. Single oral dose 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) was administered on Day 4. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered only on Day 4. Single oral dose 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) was administered on Day 7. Single oral dose 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) was administered on Day 11.
    Measure Participants 22 21 21 20
    Geometric Mean (90% Confidence Interval) [ng/mL]
    24.376
    (42)
    24.152
    22.211
    24.220
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Day 1 Inje Cocktail, Day 4 Inje Cocktail Plus Belatacept
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Adjusted geometric mean ratio
    Estimated Value 0.991
    Confidence Interval (2-Sided) 90%
    0.898 to 1.093
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Day 1 Inje Cocktail, Day 7 Inje Cocktail
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Adjusted geometric mean ratio
    Estimated Value 0.911
    Confidence Interval (2-Sided) 90%
    0.830 to 1.000
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Day 1 Inje Cocktail, Day 11 Inje Cocktail
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Adjusted geometric mean ratio
    Estimated Value 0.994
    Confidence Interval (2-Sided) 90%
    0.885 to 1.116
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    2. Secondary Outcome
    Title 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
    Description Samples for assessment of plasma concentrations of Inje cocktail components (midazolam, losartan, omeprazole, dextromethorphan and caffeine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. The poor metabolizer of CYP2D6 was excluded from summary of dextromethorphan parameters. Inje cocktail components were each measured using HPLC with MS/MS detection. Tmax was measured in hours (h).
    Time Frame Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Day 1 Inje Cocktail Day 4 Inje Cocktail Plus Belatacept Day 7 Inje Cocktail Day 11 Inje Cocktail
    Arm/Group Description Single oral dose 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) was administered on Day 1. Single oral dose 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) was administered on Day 4. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered only on Day 4. Single oral dose 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) was administered on Day 7. Single oral dose 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) was administered on Day 11.
    Measure Participants 22 21 21 20
    Midazolam (N=22,21,21,20)
    0.50
    0.50
    0.50
    1.0
    Losartan (N= 22, 21, 21, 20)
    1.52
    2.00
    1.50
    1.50
    Omeprazole (N=22,21,21,20)
    2.00
    3.00
    3.00
    3.00
    Dextromethorphan (N=21, 19, 19, 19)
    3.00
    3.00
    3.00
    3.00
    Caffeine (N= 22,21,21,18)
    1.00
    1.00
    1.50
    1.50
    3. Secondary Outcome
    Title 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
    Description Samples for assessment of plasma concentrations of Inje cocktail components (midazolam, losartan, omeprazole, dextromethorphan and caffeine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. The poor metabolizer of CYP2D6 was excluded from summary of dextromethorphan parameters. Inje cocktail components were each measured using HPLC with MS/MS detection. T-HALF was measured in hours (h).
    Time Frame Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11

    Outcome Measure Data

    Analysis Population Description
    Evaluable PK population: Participants who received any study drug and had at least 1 adequate PK profile for any Inje cocktail analytes (parent or metabolite).
    Arm/Group Title Day 1 Inje Cocktail Day 4 Inje Cocktail Plus Belatacept Day 7 Inje Cocktail Day 11 Inje Cocktail
    Arm/Group Description Single oral dose 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) was administered on Day 1. Single oral dose 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) was administered on Day 4. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered only on Day 4. Single oral dose 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) was administered on Day 7. Single oral dose 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) was administered on Day 11.
    Measure Participants 22 21 21 20
    Midazolam (N=22, 21, 21, 20)
    4.01
    (1.86)
    4.43
    (1.89)
    4.27
    (1.88)
    4.05
    (1.61)
    Losartan (N=22, 21, 21, 20)
    2.96
    (1.29)
    2.56
    (1.31)
    3.30
    (1.49)
    2.87
    (1.52)
    Omeprazole (N= 22, 19, 21, 18)
    1.19
    (0.497)
    1.39
    (0.569)
    1.28
    (0.470)
    1.36
    (0.907)
    Dextromethorphan (N=18, 17, 18, 15)
    6.76
    (2.09)
    6.98
    (2.67)
    6.33
    (1.69)
    6.70
    (2.29)
    Caffeine (N=22, 21, 21, 18)
    5.61
    (1.87)
    5.71
    (2.01)
    6.17
    (2.29)
    6.03
    (2.13)
    4. Secondary Outcome
    Title 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
    Description Samples for assessment of plasma concentrations of Inje cocktail components (midazolam, losartan, omeprazole, dextromethorphan and caffeine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. The poor metabolizer of CYP2D6 was excluded from summary of dextromethorphan parameters. Inje cocktail components were each measured using HPLC with MS/MS detection. CLT/F was measured as liters/hour (L/h)
    Time Frame Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Day 1 Inje Cocktail Day 4 Inje Cocktail Plus Belatacept Day 7 Inje Cocktail Day 11 Inje Cocktail
    Arm/Group Description Single oral dose 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) was administered on Day 1. Single oral dose 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) was administered on Day 4. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered only on Day 4. Single oral dose 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) was administered on Day 7. Single oral dose 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) was administered on Day 11.
    Measure Participants 22 21 21 20
    Midazolam (N=22, 21, 21, 20)
    73.8
    (49)
    71.3
    (48)
    77.3
    (50)
    71.4
    (51)
    Losartan (N=22, 21, 21, 20)
    148
    (37)
    146
    (36)
    146
    (34)
    151
    (44)
    Omeprazole (N=22, 19, 21, 18)
    29.2
    (66)
    23.7
    (72)
    24.7
    (79)
    25.3
    (69)
    Dextromethorphan (N=18,17,18,18)
    3916
    (85)
    4247
    (84)
    4264
    (126)
    3968
    (107)
    Caffeine (N=22, 21, 21, 18)
    4.99
    (34)
    5.30
    (32)
    4.97
    (36)
    4.83
    (36)
    5. Secondary Outcome
    Title Cmax of Inje Cocktail Metabolites (1'-Hydroxy-Midazolam, E-3174, 5-Hydroxyomeprazole, Dextrorphan, and Paraxanthine) With and Without Coadministration of Belatacept - PK Evaluable Population
    Description Samples for assessment of plasma concentrations of Inje cocktail component metabolites (1'-hydroxy-midazolam, E-3174, 5-hydroxyomeprazole, dextrorphan, and paraxanthine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. The poor metabolizer of CYP2D6 was excluded from summary of Dextrorphan parameters. Inje cocktail component metabolites were each measured using HPLC with MS/MS detection. Cmax was measured in ng/mL.
    Time Frame Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11

    Outcome Measure Data

    Analysis Population Description
    Evaluable PK population: Participants who received any study drug and had at least 1 adequate PK profile for any Inje cocktail analytes (parent or metabolite).
    Arm/Group Title Day 1 Inje Cocktail Day 4 Inje Cocktail Plus Belatacept Day 7 Inje Cocktail Day 11 Inje Cocktail
    Arm/Group Description Single oral dose 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) was administered on Day 1. Single oral dose 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) was administered on Days 4. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered only on Day 4. Single oral dose 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) was administered on Day 7. Single oral dose 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) was administered on Day 11.
    Measure Participants 22 21 21 20
    1'-Hydroxy-Midazolam (N=22, 21, 21, 20)
    11.1
    (40)
    11.9
    (40)
    11.4
    (38)
    12.3
    (36)
    E-3174 (N=22, 21, 21, 20)
    262
    (37)
    276
    (33)
    300
    (33)
    291
    (41)
    5-Hydroxyomeprazole (N=22, 21, 21, 20)
    335
    (41)
    360
    (40)
    332
    (38)
    337
    (38)
    Dextrorphan (N=21,20,20,19)
    342
    (30)
    324
    (32)
    312
    (31)
    331
    (35)
    Paraxanthine (N=17,19,18,18)
    1291
    (15)
    1367
    (12)
    1320
    (13)
    1358
    (15)
    6. Secondary Outcome
    Title 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
    Description Area under the plasma concentration-time curve from zero to the last time of the last quantifiable concentration [AUC(0-T)] was measured in ng*h/mL. Samples for assessment of plasma concentrations of Inje cocktail components metabolites (1'-hydroxy-midazolam, E-3174, 5-hydroxyomeprazole, dextrorphan, and paraxanthine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. The poor metabolizer of CYP2D6 was excluded from summary of Dextrorphan parameters. Inje cocktail components were each measured using HPLC with MS/MS detection.
    Time Frame Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11

    Outcome Measure Data

    Analysis Population Description
    Evaluable PK population: Participants who received any study drug and had at least 1 adequate PK profile for any Inje cocktail analytes (parent or metabolite).
    Arm/Group Title Day 1 Inje Cocktail Day 4 Inje Cocktail Plus Belatacept Day 7 Inje Cocktail Day 11 Inje Cocktail
    Arm/Group Description Single oral dose 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) was administered on Day 1. Single oral dose 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) was administered on Day 4. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered only on Day 4. Single oral dose 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) was administered on Day 7. Single oral dose 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) was administered on Day 11.
    Measure Participants 22 21 21 20
    1'-hydroxy-midazolam (N=22, 21, 21, 20)
    28.9
    (39)
    31.8
    (30)
    32.5
    (32)
    33.6
    (27)
    E-3174 (N= 22,21,21,20)
    1995
    (32)
    1999
    (29)
    2089
    (30)
    2072
    (37)
    5-hydroxyomeprazole (N=22,21,21,20)
    997
    (36)
    967
    (33)
    929
    (35)
    995
    (35)
    dextrorphan (N=21,20,20,19)
    1636
    (27)
    1570
    (26)
    1519
    (27)
    1644
    (26)
    paraxanthine (N=17,19,18,18)
    20592
    (15)
    21077
    (16)
    20680
    (18)
    21353
    (20)
    7. Secondary Outcome
    Title 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
    Description Area under the plasma concentration-time curve from time zero extrapolated to infinite time [AUC(INF)] was measured in ng*h/mL. Samples for assessment of plasma concentrations of Inje cocktail components metabolites (1'-hydroxy-midazolam, E-3174, 5-hydroxyomeprazole, dextrorphan, and paraxanthine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. The poor metabolizer of CYP2D6 was excluded from summary of Dextrorphan parameters. Inje cocktail components were each measured using HPLC with MS/MS detection.
    Time Frame Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Day 1 Inje Cocktail Day 4 Inje Cocktail Plus Belatacept Day 7 Inje Cocktail Day 11 Inje Cocktail
    Arm/Group Description Single oral dose 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) was administered on Day 1. Single oral dose 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) was administered on Days 4. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered only on Day 4. Single oral dose 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) was administered on Day 7. Single oral dose 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) was administered on Day 11.
    Measure Participants 22 21 21 20
    1'-hydroxy-midazolam (N=22,21,20,20)
    30.5
    (38)
    33.8
    (32)
    32.9
    (27)
    35.1
    (27)
    E-3174 (N=22,20,21,20)
    2103
    (32)
    2060
    (29)
    2187
    (31)
    2182
    (38)
    5-hydroxyomeprazole (N=22,20,21,17
    1010
    (36)
    990
    (34)
    938
    (35)
    1063
    (32)
    dextrorphan (N=21,20,20,19)
    1679
    (25)
    1610
    (25)
    1562
    (26)
    1682
    (25)
    paraxanthine (N=7,8,6,6)
    22401
    (18)
    22905
    (24)
    22063
    (12)
    21874
    (20)
    8. Secondary Outcome
    Title 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
    Description Samples for assessment of plasma concentrations of Inje cocktail components metabolites (1'-hydroxy-midazolam, E-3174, 5-hydroxyomeprazole, dextrorphan, and paraxanthine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. The poor metabolizer of CYP2D6 was excluded from summary of Dextrorphan parameters. Inje cocktail components were each measured using HPLC with MS/MS detection. Time of maximum observed plasma concentration (Tmax) was measured in hours (h).
    Time Frame Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11

    Outcome Measure Data

    Analysis Population Description
    Evaluable PK population: Participants who received any study drug and had at least 1 adequate PK profile for any Inje cocktail analytes (parent or metabolite).
    Arm/Group Title Day 1 Inje Cocktail Day 4 Inje Cocktail Plus Belatacept Day 7 Inje Cocktail Day 11 Inje Cocktail
    Arm/Group Description Single oral dose 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) was administered on Day 1. Single oral dose 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) was administered on Day 4. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered only on Day 4. Single oral dose 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) was administered on Day 7. Single oral dose 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) was administered on Day 11.
    Measure Participants 22 21 21 20
    1'-Hydroxy-Midazolam (N=22,21,21,20)
    1.00
    1.00
    1.00
    1.00
    E-3174 (N=22, 21, 21, 20)
    4.00
    4.00
    4.00
    4.00
    5-Hydroxyomeprazole (N=22,21,21,20)
    2.00
    3.00
    3.00
    2.53
    Dextrorphan (N=21,20,20,19)
    2.00
    2.00
    2.00
    2.00
    Paraxanthine (N=17, 19, 18, 18)
    8.00
    8.00
    8.00
    8.00
    9. Secondary Outcome
    Title 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
    Description Plasma half-life (T-HALF) was measured in hours (h). Samples for assessment of plasma concentrations of Inje cocktail components metabolites (1'-hydroxy-midazolam, E-3174, 5-hydroxyomeprazole, dextrorphan, and paraxanthine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. The poor metabolizer of CYP2D6 was excluded from summary of Dextrorphan parameters. Inje cocktail components were each measured using HPLC with MS/MS detection.
    Time Frame Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11

    Outcome Measure Data

    Analysis Population Description
    Evaluable PK population: Participants who received any study drug and had at least 1 adequate PK profile for any Inje cocktail analytes (parent or metabolite).
    Arm/Group Title Day 1 Inje Cocktail Day 4 Inje Cocktail Plus Belatacept Day 7 Inje Cocktail Day 11 Inje Cocktail
    Arm/Group Description Single oral dose 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) was administered on Day 1. Single oral dose 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) was administered on Days 4. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered only on Day 4. Single oral dose 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) was administered on Day 7. Single oral dose 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) was administered on Day 11.
    Measure Participants 22 21 21 20
    1'-Hydroxy-Midazolam (N=22,21,20,20)
    5.29
    (2.98)
    6.35
    (3.60)
    5.61
    (3.47)
    5.31
    (2.65)
    E-3174 (N=22, 20, 21, 20)
    4.86
    (0.749)
    4.57
    (0.757)
    4.75
    (0.757)
    4.88
    (0.690)
    5-Hydroxyomeprazole (N=22,20,21,17)
    1.43
    (0.308)
    1.55
    (0.397)
    1.52
    (0.371)
    1.54
    (0.624)
    Dextrorphan (N=21,20,20,19)
    4.26
    (1.60)
    4.36
    (1.46)
    4.23
    (1.13)
    4.08
    (0.999)
    Paraxanthine (N=7,8,6,6)
    7.33
    (1.91)
    6.86
    (1.71)
    7.33
    (1.55)
    7.44
    (2.67)
    10. Secondary Outcome
    Title 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
    Description Metabolite (paraxanthine) to parent (caffeine) ratio was corrected for molecular weight. AUC (0-T) and AUC (INF) measured in ng*h/mL. Samples for assessment of plasma concentrations of Inje cocktail components and the metabolites of those components were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Inje cocktail components were each measured using HPLC with MS/MS detection.
    Time Frame Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11

    Outcome Measure Data

    Analysis Population Description
    Evaluable PK population: Participants who received any study drug and had at least 1 adequate PK profile for any Inje cocktail analytes (parent or metabolite).
    Arm/Group Title Day 1 Inje Cocktail Day 4 Inje Cocktail Plus Belatacept Day 7 Inje Cocktail Day 11 Inje Cocktail
    Arm/Group Description Single oral dose 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) was administered on Day 1. Single oral dose 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) was administered on Day 4. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered only on Day 4. Single oral dose 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) was administered on Day 7. Single oral dose 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) was administered on Day 11.
    Measure Participants 17 19 18 18
    MR_AUC(0-T) ratio; N=17,19,18,18
    0.627
    (24)
    0.677
    (17)
    0.635
    (20)
    0.603
    (21)
    MR_AUC(INF) ratio; N=7, 8, 6, 6
    0.827
    (15)
    0.827
    (8)
    0.799
    (14)
    0.781
    (12)
    11. Secondary Outcome
    Title Ratio of Paraxanthine (Cmax) to Caffeine (Cmax), Corrected for Molecular Weight (MR_Cmax) With and Without Coadministration of Belatacept - PK Evaluable Population
    Description Metabolite (paraxanthine) to parent (caffeine) ratio was corrected for molecular weight. Cmax measured in ng/mL. Samples for assessment of plasma concentrations of Inje cocktail components and their metabolites were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Inje cocktail components were each measured using HPLC with MS/MS detection.
    Time Frame Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11

    Outcome Measure Data

    Analysis Population Description
    Evaluable PK population: Participants who received any study drug and had at least 1 adequate PK profile for any Inje cocktail analytes (parent or metabolite).
    Arm/Group Title Day 1 Inje Cocktail Day 4 Inje Cocktail Plus Belatacept Day 7 Inje Cocktail Day 11 Inje Cocktail
    Arm/Group Description Single oral dose 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) was administered on Day 1. Single oral dose 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) was administered on Day 4. A single 10 mg/kg IV infusion of belatacept over 30 minutes was administered only on Day 4. Single oral dose 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) was administered on Day 7. Single oral dose 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) was administered on Day 11.
    Measure Participants 17 19 18 18
    Geometric Mean (Geometric Coefficient of Variation) [ratio]
    0.303
    (22)
    0.337
    (15)
    0.333
    (23)
    0.323
    (20)
    12. Secondary Outcome
    Title 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
    Description Metabolite (E-3174) to parent (losartan) ratio was corrected for molecular weight. AUC (0-T) and AUC (INF) measured in ng*h/mL. Samples for assessment of plasma concentrations of Inje cocktail components and the metabolites of those components were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Inje cocktail components were each measured using HPLC with MS/MS detection.
    Time Frame Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11

    Outcome Measure Data

    Analysis Population Description
    Evaluable PK population: Participants who received any study drug and had at least 1 adequate PK profile for any Inje cocktail analytes (parent or metabolite).
    Arm/Group Title Day 1 Inje Cocktail Day 4 Inje Cocktail Plus Belatacept Day 7 Inje Cocktail Day 11 Inje Cocktail
    Arm/Group Description Single oral dose 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) was administered on Day 1. Single oral dose 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) was administered on Day 4. A single 10 mg/kg IV infusion of belatacept over 30 minutes was administered only on Day 4. Single oral dose 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) was administered on Day 7. Single oral dose 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) was administered on Day 11.
    Measure Participants 22 21 21 20
    MR_AUC (0-T) ratio; N=22,21,21,20
    5.81
    (32)
    5.75
    (33)
    5.99
    (33)
    6.17
    (33)
    MR_AUC (INF) ratio; N=22,20,21,20
    6.02
    (30)
    5.99
    (32)
    6.16
    (32)
    6.37
    (31)
    13. Secondary Outcome
    Title Ratio of E-3174 (Cmax) to Losartan (Cmax), Corrected for Molecular Weight (MR_Cmax) With and Without Coadministration of Belatacept - PK Evaluable Population
    Description Metabolite (E-3174) to parent (losartan) ratio was corrected for molecular weight. Cmax measured in ng/mL. Samples for assessment of plasma concentrations of Inje cocktail components and the metabolites of those components were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Inje cocktail components were each measured using HPLC with MS/MS detection.
    Time Frame Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11

    Outcome Measure Data

    Analysis Population Description
    Evaluable PK population: Participants who received any study drug and had at least 1 adequate PK profile for any Inje cocktail analytes (parent or metabolite).
    Arm/Group Title Day 1 Inje Cocktail Day 4 Inje Cocktail Plus Belatacept Day 7 Inje Cocktail Day 11 Inje Cocktail
    Arm/Group Description Single oral dose 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) was administered on Day 1. Single oral dose 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) was administered on Day 4. A single 10 mg/kg IV infusion of belatacept over 30 minutes was administered only on Day 4. Single oral dose 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) was administered on Day 7. Single oral dose 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) was administered on Day 11.
    Measure Participants 22 21 21 20
    Geometric Mean (Geometric Coefficient of Variation) [ratio]
    2.31
    (39)
    2.24
    (45)
    2.26
    (43)
    2.26
    (45)
    14. Secondary Outcome
    Title 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
    Description Metabolite (5-Hydroxyomeprazole) to parent (omeprazole) ratio was corrected for molecular weight. AUC (0-T) and AUC (INF) measured in ng*h/mL. Samples for assessment of plasma concentrations of Inje cocktail components and the metabolites of those components were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Inje cocktail components were each measured using HPLC with MS/MS detection.
    Time Frame Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11

    Outcome Measure Data

    Analysis Population Description
    Evaluable PK population: Participants who received any study drug and had at least 1 adequate PK profile for any Inje cocktail analytes (parent or metabolite).
    Arm/Group Title Day 1 Inje Cocktail Day 4 Inje Cocktail Plus Belatacept Day 7 Inje Cocktail Day 11 Inje Cocktail
    Arm/Group Description Single oral dose 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) was administered on Day 1. Single oral dose 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) was administered on Day 4. A single 10 mg/kg IV infusion of belatacept over 30 minutes was administered only on Day 4. Single oral dose 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) was administered on Day 7. Single oral dose 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) was administered on Day 11.
    Measure Participants 22 21 21 20
    MR_AUC (0-T) ratio; N=22,21,21,20
    0.700
    (57)
    0.609
    (66)
    0.551
    (70)
    0.610
    (66)
    MR_AUC (INF) ratio; N=22,19,21,17
    0.705
    (56)
    0.558
    (61)
    0.553
    (69)
    0.679
    (62)
    15. Secondary Outcome
    Title Ratio of 5-Hydroxyomeprazole (Cmax) to Omeprazole (Cmax), Corrected for Molecular Weight (MR_Cmax) With and Without Coadministration of Belatacept - PK Evaluable Population
    Description Metabolite (5-hydroxyomeprazole) to parent (omeprazole) ratio was corrected for molecular weight. Cmax measured in ng/mL. Samples for assessment of plasma concentrations of Inje cocktail components and the metabolites of those components were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Inje cocktail components were each measured using HPLC with MS/MS detection.
    Time Frame Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11

    Outcome Measure Data

    Analysis Population Description
    Evaluable PK population: Participants who received any study drug and had at least 1 adequate PK profile for any Inje cocktail analytes (parent or metabolite).
    Arm/Group Title Day 1 Inje Cocktail Day 4 Inje Cocktail Plus Belatacept Day 7 Inje Cocktail Day 11 Inje Cocktail
    Arm/Group Description Single oral dose 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) was administered on Day 1. Single oral dose 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) was administered on Day 4. A single 10 mg/kg IV infusion of belatacept over 30 minutes was administered only on Day 4. Single oral dose 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) was administered on Day 7. Single oral dose 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) was administered on Day 11.
    Measure Participants 22 21 21 20
    Geometric Mean (Geometric Coefficient of Variation) [ratio]
    0.548
    (54)
    0.471
    (60)
    0.424
    (65)
    0.478
    (59)
    16. Secondary Outcome
    Title 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
    Description Metabolite (5-dextrorphan ) to parent (dextromethorphan) ratio was corrected for molecular weight. AUC (0-T) and AUC (INF) measured in ng*h/mL. Samples for assessment of plasma concentrations of Inje cocktail components and the metabolites of those components were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. The poor metabolizer of CYP2D6 was excluded from summary of Dextrorphan parameters. Inje cocktail components were each measured using HPLC with MS/MS detection.
    Time Frame Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11

    Outcome Measure Data

    Analysis Population Description
    Evaluable PK population: Participants who received any study drug and had at least 1 adequate PK profile for any Inje cocktail analytes (parent or metabolite).
    Arm/Group Title Day 1 Inje Cocktail Day 4 Inje Cocktail Plus Belatacept Day 7 Inje Cocktail Day 11 Inje Cocktail
    Arm/Group Description Single oral dose 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) was administered on Day 1. Single oral dose 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) was administered on Day 4. A single 10 mg/kg IV infusion of belatacept over 30 minutes was administered only on Day 4. Single oral dose 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) was administered on Day 7. Single oral dose 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) was administered on Day 11.
    Measure Participants 21 20 20 19
    MR_AUC (0-T) ratio; N=21,20,20,19
    201
    (103)
    200
    (94)
    177
    (124)
    193
    (99)
    MR_AUC (INF) ratio; N=18,17,18,15
    173
    (95)
    177
    (90)
    170
    (122)
    173
    (102)
    17. Secondary Outcome
    Title Ratio of 5-Dextrorphan (Cmax) to Dextromethorphan (Cmax), Corrected for Molecular Weight (MR_Cmax) With and Without Coadministration of Belatacept - PK Evaluable Population
    Description Metabolite (5-dextrorphan) to parent (dextromethorphan) ratio was corrected for molecular weight. Cmax measured in ng/mL. Samples for assessment of plasma concentrations of Inje cocktail components and the metabolites of those components were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. The poor metabolizer of CYP2D6 was excluded from summary of Dextrorphan parameters. Inje cocktail components were each measured using HPLC with MS/MS detection.
    Time Frame Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11

    Outcome Measure Data

    Analysis Population Description
    Evaluable PK population: Participants who received any study drug and had at least 1 adequate PK profile for any Inje cocktail analytes (parent or metabolite).
    Arm/Group Title Day 1 Inje Cocktail Day 4 Inje Cocktail Plus Belatacept Day 7 Inje Cocktail Day 11 Inje Cocktail
    Arm/Group Description Single oral dose 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) was administered on Day 1. Single oral dose 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) was administered on Day 4. A single 10 mg/kg IV infusion of belatacept over 30 minutes was administered only on Day 4. Single oral dose 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) was administered on Day 7. Single oral dose 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) was administered on Day 11.
    Measure Participants 21 20 20 19
    Geometric Mean (Geometric Coefficient of Variation) [ratio]
    280
    (107)
    303
    (99)
    275
    (88)
    303
    (84)
    18. Secondary Outcome
    Title 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
    Description Metabolite (1'-hydroxy-midazolam) to parent (midazolam) ratio was corrected for molecular weight. AUC (0-T) and AUC (INF) measured in ng*h/mL. Samples for assessment of plasma concentrations of Inje cocktail components and the metabolites of those components were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Inje cocktail components were each measured using HPLC with MS/MS detection.
    Time Frame Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11

    Outcome Measure Data

    Analysis Population Description
    Evaluable PK population: Participants who received any study drug and had at least 1 adequate PK profile for any Inje cocktail analytes (parent or metabolite).
    Arm/Group Title Day 1 Inje Cocktail Day 4 Inje Cocktail Plus Belatacept Day 7 Inje Cocktail Day 11 Inje Cocktail
    Arm/Group Description Single oral dose 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) was administered on Day 1. Single oral dose 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) was administered on Day 4. A single 10 mg/kg IV infusion of belatacept over 30 minutes was administered only on Day 4. Single oral dose 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) was administered on Day 7. Single oral dose 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) was administered on Day 11.
    Measure Participants 22 21 21 20
    MR_AUC (0-T) ratio; N=22, 21, 21, 20
    0.421
    (56)
    0.447
    (46)
    0.495
    (55)
    0.472
    (55)
    MR_(INF) ratio; N=22, 21, 20, 20
    0.428
    (57)
    0.460
    (47)
    0.479
    (52)
    0.478
    (55)
    19. Primary Outcome
    Title 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
    Description AUC(0-T): area under the plasma concentration-time curve from zero to the last time of the last quantifiable concentration and AUC (INF): AUC from time zero extrapolated to infinite time were measured in ng*h/mL. Samples for the assessment of plasma concentrations of Inje cocktail components (midazolam, losartan, omeprazole, dextromethorphan and caffeine) and their metabolites (1'-hydroxy-midazolam, E-3174, 5-hydroxyomeprazole, dextrorphan, and paraxanthine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Adjusted geometric mean for midazolam with and without belatacept, along with adjusted geometric mean ratios for Days 4, 7, and 11 versus Day 1, respectively, are presented. Midazolam measured using HPLC with MS/MS Detection.
    Time Frame Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7and 11

    Outcome Measure Data

    Analysis Population Description
    Evaluable PK population: Participants who received any study drug and had at least 1 adequate PK profile for any Inje cocktail analytes (parent or metabolite).
    Arm/Group Title Day 1 Inje Cocktail Day 4 Inje Cocktail Plus Belatacept Day 7 Inje Cocktail Day 11 Inje Cocktail
    Arm/Group Description Single oral dose 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) was administered on Day 1. Single oral dose 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) was administered on Day 4. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered only on Day 4. Single oral dose 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) was administered on Day 7. Single oral dose 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) was administered on Day 11.
    Measure Participants 22 21 21 20
    AUC (0-T);N=22, 21, 21, 20)
    65.548
    68.833
    63.303
    67.717
    AUC (INF);N=22, 21, 21, 20)
    67.743
    71.039
    65.555
    69.841
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Day 1 Inje Cocktail, Day 4 Inje Cocktail Plus Belatacept
    Comments AUC (0-T)
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Adjusted geometric mean ratio
    Estimated Value 1.050
    Confidence Interval (2-Sided) 90%
    0.976 to 1.130
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Day 1 Inje Cocktail, Day 7 Inje Cocktail
    Comments AUC (0-T)
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Adjusted geometric mean ratio
    Estimated Value 0.966
    Confidence Interval (2-Sided) 90%
    0.889 to 1.049
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Day 1 Inje Cocktail, Day 11 Inje Cocktail
    Comments AUC (0-T)
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Adjusted geometric mean ratio
    Estimated Value 1.033
    Confidence Interval (2-Sided) 90%
    0.950 to 1.123
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Day 1 Inje Cocktail, Day 4 Inje Cocktail Plus Belatacept
    Comments AUC (INF)
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Adjusted geometric mean ratio
    Estimated Value 1.049
    Confidence Interval (2-Sided) 90%
    0.975 to 1.127
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection Day 1 Inje Cocktail, Day 7 Inje Cocktail
    Comments AUC (INF)
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Adjusted geometric mean ratio
    Estimated Value 0.968
    Confidence Interval (2-Sided) 90%
    0.892 to 1.049
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection Day 1 Inje Cocktail, Day 11 Inje Cocktail
    Comments AUC(INF)
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Adjusted geometric mean ratio
    Estimated Value 1.031
    Confidence Interval (2-Sided) 90%
    0.948 to 1.121
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    20. Primary Outcome
    Title Adjusted Geometric Mean Cmax of Losartan With and Without the Coadministration of Belatacept - PK Evaluable Population
    Description Cmax measured in ng/mL. Samples for assessment of plasma concentrations of Inje cocktail components (midazolam, losartan, omeprazole, dextromethorphan and caffeine) and their metabolites (1'-hydroxy-midazolam, E-3174, 5-hydroxyomeprazole, dextrorphan, and paraxanthine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Adjusted geometric mean for losartan with and without belatacept, along with adjusted geometric mean ratios for Days 4, 7, and 11 versus Day 1, respectively, are presented. Inje cocktail components (losartan) measured using HPLC with MS/MS Detection.
    Time Frame Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11

    Outcome Measure Data

    Analysis Population Description
    Evaluable PK population: Participants who received any study drug and had at least 1 adequate PK profile for any Inje cocktail analytes (parent or metabolite).
    Arm/Group Title Day 1 Inje Cocktail Day 4 Inje Cocktail Plus Belatacept Day 7 Inje Cocktail Day 11 Inje Cocktail
    Arm/Group Description Single oral dose 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) was administered on Day 1. Single oral dose 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) was administered on Day 4. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered on Day 4. Single oral dose 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) was administered on Day 7. Single oral dose 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) was administered on Day 1, 4, 7 and 11.
    Measure Participants 22 21 21 20
    Geometric Mean (90% Confidence Interval) [ng/mL]
    119.789
    118.663
    127.184
    126.461
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Day 1 Inje Cocktail, Day 4 Inje Cocktail Plus Belatacept
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Adjusted geometric mean ratio
    Estimated Value 0.991
    Confidence Interval (2-Sided) 90%
    0.898 to 1.093
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Day 1 Inje Cocktail, Day 7 Inje Cocktail
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Adjusted geometric mean ratio
    Estimated Value 0.911
    Confidence Interval (2-Sided) 90%
    0.830 to 1.000
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Day 1 Inje Cocktail, Day 11 Inje Cocktail
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Adjusted geometric mean ratio
    Estimated Value 0.994
    Confidence Interval (2-Sided) 90%
    0.885 to 1.116
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    21. Primary Outcome
    Title Adjusted Geometric Mean AUC (0-T) and AUC (INF) of Losartan With and Without the Coadministration of Belatacept - Pharmacokinetic (PK) Evaluable Population
    Description AUC (0-T): area under the concentration curve from time 0 to the time of the last quantifiable concentration and AUC (INF) extrapolated to infinity were measured in ng*h/mL. Samples for assessment of plasma concentrations of Inje cocktail components (midazolam, losartan, omeprazole, dextromethorphan and caffeine) and their metabolites (1'-hydroxy-midazolam, E-3174, 5-hydroxyomeprazole, dextrorphan, and paraxanthine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Adjusted geometric mean for losartan with and without belatacept, along with adjusted geometric mean ratios for Days 4, 7, and 11 versus Day 1, respectively, are presented. Inje cocktail components (losartan) measured using HPLC with MS/MS Detection.
    Time Frame Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11

    Outcome Measure Data

    Analysis Population Description
    Evaluable PK population: Participants who received any study drug and had at least 1 adequate PK profile for any Inje cocktail analytes (parent or metabolite).
    Arm/Group Title Day 1 Inje Cocktail Day 4 Inje Cocktail Plus Belatacept Day 7 Inje Cocktail Day 11 Inje Cocktail
    Arm/Group Description Single oral dose 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) was administered on Day 1. Single oral dose 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) was administered on Day 4. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered on Day 4. Single oral dose 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) was administered on Day 7. Single oral dose 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) was administered on Day 11.
    Measure Participants 22 21 21 20
    AUC (0-T) N=22, 21, 21, 20)
    332.191
    336.531
    337.487
    332.400
    AUC (INF) N=22, 21, 21, 20)
    338.033
    341.644
    343.508
    338.646
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Day 1 Inje Cocktail, Day 4 Inje Cocktail Plus Belatacept
    Comments AUC (0-T)
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Adjusted geometric mean ratio
    Estimated Value 1.013
    Confidence Interval (2-Sided) 90%
    0.944 to 1.088
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Day 1 Inje Cocktail, Day 7 Inje Cocktail
    Comments AUC (0-T)
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Adjusted geometric mean ratio
    Estimated Value 1.016
    Confidence Interval (2-Sided) 90%
    0.936 to 1.103
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Day 1 Inje Cocktail, Day 11 Inje Cocktail
    Comments AUC (0-T)
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Adjusted geometric mean ratio
    Estimated Value 1.001
    Confidence Interval (2-Sided) 90%
    0.893 to 1.121
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Day 1 Inje Cocktail, Day 4 Inje Cocktail Plus Belatacept
    Comments AUC (INF)
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Adjusted geometric mean ratio
    Estimated Value 1.011
    Confidence Interval (2-Sided) 90%
    0.942 to 1.085
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection Day 1 Inje Cocktail, Day 7 Inje Cocktail
    Comments AUC (INF)
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Adjusted geometric mean ratio
    Estimated Value 1.016
    Confidence Interval (2-Sided) 90%
    0.938 to 1.101
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection Day 1 Inje Cocktail, Day 11 Inje Cocktail
    Comments AUC (INF)
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Adjusted geometric mean ratio
    Estimated Value 1.002
    Confidence Interval (2-Sided) 90%
    0.896 to 1.121
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    22. Primary Outcome
    Title Adjusted Geometric Mean Cmax of Omeprazole With and Without the Coadministration of Belatacept - Pharmacokinetic (PK) Evaluable Population
    Description Cmax: Maximum observed plasma concentration was measured in ng/mL. Samples for assessment of plasma concentrations of Inje cocktail components (midazolam, losartan, omeprazole, dextromethorphan and caffeine) and their metabolites (1'-hydroxy-midazolam, E-3174, 5-hydroxyomeprazole, dextrorphan, and paraxanthine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Adjusted geometric mean for omeprazole with and without belatacept, along with adjusted geometric mean ratios for Days 4, 7, and 11 versus Day 1, respectively, are presented. Inje cocktail components (omeprazole) measured using HPLC with MS/MS Detection.
    Time Frame Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11

    Outcome Measure Data

    Analysis Population Description
    Evaluable PK population: Participants who received any study drug and had at least 1 adequate PK profile for any Inje cocktail analytes (parent or metabolite).
    Arm/Group Title Day 1 Inje Cocktail Day 4 Inje Cocktail Plus Belatacept Day 7 Inje Cocktail Day 11 Inje Cocktail
    Arm/Group Description Single oral dose 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) was administered on Day 1. Single oral dose 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) was administered on Day 4. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered on Day 4. Single oral dose 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) was administered on Day 7. Single oral dose 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) was administered on Day 11.
    Measure Participants 22 21 21 20
    Geometric Mean (90% Confidence Interval) [ng/mL]
    583.047
    734.776
    753.126
    686.929
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Day 1 Inje Cocktail, Day 4 Inje Cocktail Plus Belatacept
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Adjusted geometric mean ratio
    Estimated Value 1.260
    Confidence Interval (2-Sided) 90%
    1.118 to 1.421
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Day 1 Inje Cocktail, Day 7 Inje Cocktail
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Adjusted geometric mean ratio
    Estimated Value 1.292
    Confidence Interval (2-Sided) 90%
    1.090 to 1.531
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Day 1 Inje Cocktail, Day 11 Inje Cocktail
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Adjusted geometric mean ratio
    Estimated Value 1.178
    Confidence Interval (2-Sided) 90%
    0.971 to 1.429
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    23. Primary Outcome
    Title Adjusted Geometric Mean AUC (0-T) and AUC (INF) of Omeprazole With and Without the Coadministration of Belatacept - Pharmacokinetic (PK) Evaluable Population
    Description AUC(0-T): Area under the plasma concentration-time curve from time zero zero to the time of the last quantifiable concentration and AUC (INF): AUC extrapolated to infinity were measured in ng*h/mL. Samples for assessment of plasma concentrations of Inje cocktail components (midazolam, losartan, omeprazole, dextromethorphan and caffeine) and their metabolites (1'-hydroxy-midazolam, E-3174, 5-hydroxyomeprazole, dextrorphan, and paraxanthine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Adjusted geometric mean for omeprazole with and without belatacept, along with adjusted geometric mean ratios for Days 4, 7, and 11 versus Day 1, respectively, are presented. Inje cocktail components (omeprazole) measured using HPLC with MS/MS Detection.
    Time Frame Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11

    Outcome Measure Data

    Analysis Population Description
    Evaluable PK population: Participants who received any study drug and had at least 1 adequate PK profile for any Inje cocktail analytes (parent or metabolite).
    Arm/Group Title Day 1 Inje Cocktail Day 4 Inje Cocktail Plus Belatacept Day 7 Inje Cocktail Day 11 Inje Cocktail
    Arm/Group Description Single oral dose 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) was administered on Days 1. Single oral dose 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) was administered on Day 4. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered on Day 4. Single oral dose 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) was administered on Day 7. Single oral dose 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) was administered on Day11.
    Measure Participants 22 21 21 20
    AUC (0-T); (N= 22, 21, 21, 20)
    1361.024
    1577.017
    1671.173
    1653.491
    AUC (INF); (N= 22, 19, 21, 18)
    1368.593
    1632.455
    1679.693
    1779.717
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Day 1 Inje Cocktail, Day 4 Inje Cocktail Plus Belatacept
    Comments AUC (0-T)
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Adjusted geometric mean ratio
    Estimated Value 1.159
    Confidence Interval (2-Sided) 90%
    1.056 to 1.272
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Day 1 Inje Cocktail, Day 7 Inje Cocktail
    Comments AUC (0-T)
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Adjusted geometric mean ratio
    Estimated Value 1.228
    Confidence Interval (2-Sided) 90%
    1.092 to 1.381
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Day 1 Inje Cocktail, Day 11 Inje Cocktail
    Comments AUC (0-T)
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Adjusted geometric mean ratio
    Estimated Value 1.215
    Confidence Interval (2-Sided) 90%
    1.047 to 1.410
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Day 1 Inje Cocktail, Day 4 Inje Cocktail Plus Belatacept
    Comments AUC (INF)
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Adjusted geometric mean ratio
    Estimated Value 1.193
    Confidence Interval (2-Sided) 90%
    1.091 to 1.304
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection Day 1 Inje Cocktail, Day 7 Inje Cocktail
    Comments AUC (INF)
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Adjusted geometric mean ratio
    Estimated Value 1.227
    Confidence Interval (2-Sided) 90%
    1.093 to 1.379
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection Day 1 Inje Cocktail, Day 11 Inje Cocktail
    Comments AUC (INF)
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Adjusted geometric mean ratio
    Estimated Value 1.300
    Confidence Interval (2-Sided) 90%
    1.141 to 1.482
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    24. Primary Outcome
    Title Adjusted Geometric Mean Cmax of Dextromethorphan With and Without the Coadministration of Belatacept - PK Evaluable Population
    Description Cmax was measured in ng/mL. Samples for assessment of plasma concentrations of Inje cocktail components (midazolam, losartan, omeprazole, dextromethorphan and caffeine) and their metabolites (1'-hydroxy-midazolam, E-3174, 5-hydroxyomeprazole, dextrorphan, and paraxanthine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Adjusted geometric mean for dextromethorphan with and without belatacept, along with adjusted geometric mean ratios for Days 4, 7, and 11 versus Day 1, respectively, are presented. The poor metabolizer of CYP2D6 was excluded from the statistical analysis. Inje cocktail components (dextromethorphan) measured using HPLC with MS/MS Detection.
    Time Frame Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11

    Outcome Measure Data

    Analysis Population Description
    Evaluable PK population: Participants who received any study drug and had at least 1 adequate PK profile for any Inje cocktail analytes (parent or metabolite).
    Arm/Group Title Day 1 Inje Cocktail Day 4 Inje Cocktail Plus Belatacept Day 7 Inje Cocktail Day 11 Inje Cocktail
    Arm/Group Description Single oral dose 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) was administered on Day 1. Single oral dose 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) was administered on Day 4. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered on Day 4. Single oral dose 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) was administered on Day 7. Single oral dose 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) was administered on Day 11.
    Measure Participants 21 19 19 19
    Geometric Mean (90% Confidence Interval) [ng/mL]
    0.927
    0.800
    0.855
    0.794
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Day 1 Inje Cocktail, Day 4 Inje Cocktail Plus Belatacept
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Adjusted geometric mean ratio
    Estimated Value 0.863
    Confidence Interval (2-Sided) 90%
    0.746 to 0.997
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Day 1 Inje Cocktail, Day 7 Inje Cocktail
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Adjusted geometric mean ratio
    Estimated Value 0.922
    Confidence Interval (2-Sided) 90%
    0.793 to 1.071
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Day 1 Inje Cocktail, Day 11 Inje Cocktail
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Adjusted geometric mean ratio
    Estimated Value 0.856
    Confidence Interval (2-Sided) 90%
    0.709 to 1.034
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    25. Primary Outcome
    Title Adjusted Geometric Mean AUC (0-T) and AUC (INF) of Dextromethorphan With and Without the Coadministration of Belatacept - PK Evaluable Population
    Description AUC(0-T): area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration and AUC (INF): AUC extrapolated to infinity, were measured as ng*h/mL. Samples for assessment of plasma concentrations of Inje cocktail components (midazolam, losartan, omeprazole, dextromethorphan and caffeine) and their metabolites (1'-hydroxy-midazolam, E-3174, 5-hydroxyomeprazole, dextrorphan, and paraxanthine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Adjusted geometric mean for dextromethorphan with and without belatacept, along with adjusted geometric mean ratios for Days 4, 7, and 11 versus Day 1, respectively, are presented. The poor metabolizer of CYP2D6 was excluded from the statistical analysis. Inje cocktail components (dextromethorphan) measured using HPLC with MS/MS Detection.
    Time Frame Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11

    Outcome Measure Data

    Analysis Population Description
    Evaluable PK population: Participants who received any study drug and had at least 1 adequate PK profile for any Inje cocktail analytes (parent or metabolite).
    Arm/Group Title Day 1 Inje Cocktail Day 4 Inje Cocktail Plus Belatacept Day 7 Inje Cocktail Day 11 Inje Cocktail
    Arm/Group Description Single oral dose 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) was administered on Day1. Single oral dose 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) was administered on Day 4. A single 10 mg/kg IV infusion of belatacept over 30 minutes was administered on Day 4. Single oral dose 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) was administered on Day 7. Single oral dose 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) was administered on Day 11.
    Measure Participants 21 19 19 19
    AUC (0-T); N= 21, 19, 19, 19
    6.176
    5.651
    6.195
    5.949
    AUC (INF); N= 18, 17, 18, 15
    6.220
    5.455
    6.412
    6.359
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Day 1 Inje Cocktail, Day 4 Inje Cocktail Plus Belatacept
    Comments AUC (0-T)
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Adjusted geometric mean ratio
    Estimated Value 0.915
    Confidence Interval (2-Sided) 90%
    0.817 to 1.024
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Day 1 Inje Cocktail, Day 7 Inje Cocktail
    Comments AUC (0-T)
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Adjusted geometric mean ratio
    Estimated Value 1.003
    Confidence Interval (2-Sided) 90%
    0.856 to 1.175
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Day 1 Inje Cocktail, Day 11 Inje Cocktail
    Comments AUC (0-T)
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Adjusted geometric mean ratio
    Estimated Value 0.963
    Confidence Interval (2-Sided) 90%
    0.821 to 1.130
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Day 1 Inje Cocktail, Day 4 Inje Cocktail Plus Belatacept
    Comments AUC (INF)
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Adjusted geometric mean ratio
    Estimated Value 0.877
    Confidence Interval (2-Sided) 90%
    0.783 to 0.982
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection Day 1 Inje Cocktail, Day 7 Inje Cocktail
    Comments AUC (INF)
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Adjusted geometric mean ratio
    Estimated Value 1.031
    Confidence Interval (2-Sided) 90%
    0.885 to 1.200
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection Day 1 Inje Cocktail, Day 11 Inje Cocktail
    Comments AUC (INF)
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Adjusted geometric mean ratio
    Estimated Value 1.022
    Confidence Interval (2-Sided) 90%
    0.839 to 1.245
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    26. Primary Outcome
    Title Adjusted Geometric Mean Cmax of Caffeine With and Without the Coadministration of Belatacept - PK Evaluable Population
    Description Samples for assessment of plasma concentrations of Inje cocktail components (midazolam, losartan, omeprazole, dextromethorphan and caffeine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Inje cocktail components were each measured using HPLC with MS/MS detection. Cmax was measured in ng/mL.
    Time Frame Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11

    Outcome Measure Data

    Analysis Population Description
    Evaluable PK population: Participants who received any study drug and had at least 1 adequate PK profile for any Inje cocktail analytes (parent or metabolite).
    Arm/Group Title Day 1 Inje Cocktail Day 4 Inje Cocktail Plus Belatacept Day 7 Inje Cocktail Day 11 Inje Cocktail
    Arm/Group Description Single oral dose 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) was administered on Day 1. Single oral dose 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) was administered on Day 4. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered only on Day 4. Single oral dose 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) was administered on Day 7. Single oral dose 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) was administered on Day 11.
    Measure Participants 22 21 21 18
    Geometric Mean (90% Confidence Interval) [ng/mL]
    4696.505
    4450.019
    4332.326
    4479.687
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Day 1 Inje Cocktail, Day 4 Inje Cocktail Plus Belatacept
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Adjusted geometric mean ratio
    Estimated Value 0.948
    Confidence Interval (2-Sided) 90%
    0.880 to 1.021
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Day 1 Inje Cocktail, Day 7 Inje Cocktail
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Adjusted geometric mean ratio
    Estimated Value 0.922
    Confidence Interval (2-Sided) 90%
    0.857 to 0.993
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Day 1 Inje Cocktail, Day 11 Inje Cocktail
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Adjusted geometric mean ratio
    Estimated Value 0.954
    Confidence Interval (2-Sided) 90%
    0.885 to 1.028
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    27. Primary Outcome
    Title Adjusted Geometric Mean AUC (0-T) and AUC (INF) of Caffeine With and Without the Coadministration of Belatacept - PK Evaluable Population
    Description Samples for assessment of plasma concentrations of Inje cocktail components (midazolam, losartan, omeprazole, dextromethorphan and caffeine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Inje cocktail components were each measured using HPLC with MS/MS detection. AUC (0-T) and AUC (INF) were measured as ng*h/mL.
    Time Frame Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11

    Outcome Measure Data

    Analysis Population Description
    Evaluable PK population: Participants who received any study drug and had at least 1 adequate PK profile for any Inje cocktail analytes (parent or metabolite).
    Arm/Group Title Day 1 Inje Cocktail Day 4 Inje Cocktail Plus Belatacept Day 7 Inje Cocktail Day 11 Inje Cocktail
    Arm/Group Description Single oral dose 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) was administered on Day 1. Single oral dose 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) was administered on Day 4. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered only on Day 4. Single oral dose 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) was administered on Day 7. Single oral dose 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) was administered on Day 11.
    Measure Participants 22 21 21 18
    AUC (0-T); N= 22, 21, 21, 18
    37394.5
    35200.3
    36853.4
    38407.0
    AUC (INF); N= 22, 21, 21, 18
    40084.1
    37647.8
    40149.9
    41537.6
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Day 1 Inje Cocktail, Day 4 Inje Cocktail Plus Belatacept
    Comments AUC (0-T)
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Adjusted geometric mean ratio
    Estimated Value 0.941
    Confidence Interval (2-Sided) 90%
    0.874 to 1.013
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Day 1 Inje Cocktail, Day 7 Inje Cocktail
    Comments AUC (0-T)
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Adjusted geometric mean ratio
    Estimated Value 0.986
    Confidence Interval (2-Sided) 90%
    0.902 to 1.076
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Day 1 Inje Cocktail, Day 11 Inje Cocktail
    Comments AUC (0-T)
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Adjusted geometric mean ratio
    Estimated Value 1.027
    Confidence Interval (2-Sided) 90%
    0.942 to 1.120
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Day 1 Inje Cocktail, Day 4 Inje Cocktail Plus Belatacept
    Comments AUC (INF)
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Adjusted geometric mean ratio
    Estimated Value 0.939
    Confidence Interval (2-Sided) 90%
    0.868 to 1.017
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection Day 1 Inje Cocktail, Day 7 Inje Cocktail
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Adjusted geometric mean ratio
    Estimated Value 1.002
    Confidence Interval (2-Sided) 90%
    0.914 to 1.098
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection Day 1 Inje Cocktail, Day 11 Inje Cocktail
    Comments AUC (INF)
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Adjusted geometric mean ratio
    Estimated Value 1.036
    Confidence Interval (2-Sided) 90%
    0.940 to 1.142
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    28. Secondary Outcome
    Title Ratio of 1'-Hydroxy-Midazolam (Cmax) to Midazolam (Cmax), Corrected for Molecular Weight (MR_Cmax) With and Without Coadministration of Belatacept - PK Evaluable Population
    Description Metabolite (1'-hydroxy-midazolam) to parent (midazolam) ratio was corrected for molecular weight. Cmax measured in ng/mL. Samples for assessment of plasma concentrations of Inje cocktail components and the metabolites of those components were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Inje cocktail components were each measured using HPLC with MS/MS detection.
    Time Frame Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11

    Outcome Measure Data

    Analysis Population Description
    Evaluable PK population: Participants who received any study drug and had at least 1 adequate PK profile for any Inje cocktail analytes (parent or metabolite).
    Arm/Group Title Day 1 Inje Cocktail Day 4 Inje Cocktail Plus Belatacept Day 7 Inje Cocktail Day 11 Inje Cocktail
    Arm/Group Description Single oral dose 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) was administered on Day 1. Single oral dose 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) was administered on Day 4. A single 10 mg/kg IV infusion of belatacept over 30 minutes was administered only on Day 4. Single oral dose 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) was administered on Day 7. Single oral dose 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) was administered on Day 11.
    Measure Participants 22 21 21 20
    Geometric Mean (Geometric Coefficient of Variation) [ratio]
    0.432
    (45)
    0.476
    (44)
    0.497
    (46)
    0.490
    (46)
    29. Secondary Outcome
    Title Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Deaths, and AEs Leading to Discontinuation - All Treated Participants
    Description Adverse events were coded according to the Medical Dictionary for Regulatory Activities (MedDRA), version 15.1. 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. Events captured from Day 1 (pre-dose) to last day prior to discharge (Day 46 ±2). In the total group, a participant with an AE is only counted once (ie, data reflected in Days 1, 4, 7, and 11 below could be the same participant with an AE on multiple days of the study).
    Time Frame Day 1 to Day of discharge (Day 46±2)

    Outcome Measure Data

    Analysis Population Description
    All participants who received any study medication.
    Arm/Group Title Day 1 Inje Cocktail Day 4 Inje Cocktail Plus Belatacept Day 7 Inje Cocktail Day 11 Inje Cocktail All Participants
    Arm/Group Description Single oral dose 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) was administered on Day 1. Single oral dose 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) was administered on Day 4. A single 10 mg/kg IV infusion of belatacept over 30 minutes was administered only on Day 4. Single oral dose 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) was administered on Day 7. Single oral dose 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) was administered on Day 11. 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.
    Measure Participants 22 21 21 20 22
    Adverse Events
    4
    18.2%
    2
    NaN
    1
    NaN
    1
    NaN
    5
    NaN
    SAEs
    0
    0%
    0
    NaN
    0
    NaN
    0
    NaN
    0
    NaN
    Deaths
    0
    0%
    0
    NaN
    0
    NaN
    0
    NaN
    0
    NaN
    AEs leading to discontinuation
    0
    0%
    0
    NaN
    1
    NaN
    0
    NaN
    1
    NaN
    30. Secondary Outcome
    Title Number of Participants With Marked Serum Chemistry Laboratory Abnormalities - All Treated Participants
    Description Samples for laboratory tests were obtained at Screening visit, Day -1 or prior to dosing on Day 1, Days 3, 6, 10, 46, and at early termination, after 10 hours fasting. Upper limits of normal (ULN); Lower limits of normal (LLN); Pre-therapy (Rx); micromoles per liter (µmol/L); millimoles per liter (mmol/L); grams per liter (g/L); Units per liter (U/L); Aspartate Aminotransferase (AST); Blood Urea Nitrogen (BUN) Total Bilirubin: >1.1*ULN if Pre-Rx<= ULN or Pre-Rx is missing, or >1.2*Pre-Rx if Pre-Rx >ULN. AST: >1.25*Pre-Rx if Pre-Rx >ULN or 1.25*ULN if Pre-Rx <= ULN or Pre-Rx is missing. BUN: >1.1*ULN if Pre-Rx<= ULN or Pre-Rx is missing, or >1.2*Pre-Rx if Pre-Rx >ULN. Phosphorus: <0.85*LLN if Pre-RX >= LLN or is missing or if Pre-Rx < LLN. total Protein: <0.9*LLN if Pre-Rx>= LLN or is missing or Pre-Rx > LLN. Creatine Kinase: >1.5*Pre-Rx if Pre-Rx > ULN or is missing or Pre-Rx is <= ULN. Lactate Dehydrogenase: >1.25*ULN if Pre-Rx <= ULN or missing, >1.5*Pre-Rx if Pre-Rx > ULN.
    Time Frame Day -1 to Day 46 ±2 days or at early termination

    Outcome Measure Data

    Analysis Population Description
    Participants who received any study medication and had laboratory test results.
    Arm/Group Title Inje Cocktail Alone and Inje Cocktail Plus Belatacept
    Arm/Group Description 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.
    Measure Participants 22
    Total bilirubin >1.1*ULN µmol/L (N=22)
    1
    4.5%
    AST >1.25*Pre-Rx U/L (N=22)
    1
    4.5%
    BUN >1.1*ULN mmol/L (N=22)
    1
    4.5%
    Inorganic Phosphorus <0.85*LLN mmol/L (N=22)
    1
    4.5%
    Total Protein <0.9*LLN g/L (N=22)
    1
    4.5%
    Creatine Kinase > 1.5* Pre-Rx U/L (N=22)
    2
    9.1%
    Lactate Dehydrogenase >1.25*ULN U/L (N=22)
    1
    4.5%
    31. Secondary Outcome
    Title Number of Participants With Marked Hematology and Urinalysis Laboratory Abnormalities - All Treated Participants
    Description Samples for laboratory tests were obtained at Screening visit, Day -1 or prior to dosing on Day 1, Days 3, 6, 10, 46 ±2, and at early termination, after 10 hours fasting. Leukocytes: *10^9 cells per liter (c/L) < 0.85*Pre-Rx if Pre-Rx < LLN or <0.9*LLN if LLN <= Pre-Rx or Pre-Rx is missing. Neutrophils (absolute): *10^12 c/L < 0.85* Pre-Rx if Pre-Rx < 1.5, <1.5 if Pre-Rx >= 1.5, < 1.5 if Pre-Rx missing. Urine blood from dipstick: >=2 if Pre-Rx <1 or was missing or if Pre-Rx >=1. Urinary microscopic white blood cells (WBC) and red blood cells (RBC) >= 2 if Pre-Rx <2 or if Pre-Rx was missing or >=4 if Pre-Rx >=2.
    Time Frame Day -1 to Day 46 ±2 days or at early termination

    Outcome Measure Data

    Analysis Population Description
    Participants who received any study medication and had laboratory test results.
    Arm/Group Title Inje Cocktail Alone and Inje Cocktail Plus Belatacept
    Arm/Group Description 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.
    Measure Participants 22
    Leukocytes <0.85*Pre-Rx *10^9 c/L (N=22)
    1
    4.5%
    Neutrophils <0.85*Pre-Rx *10^12 c/L (N=22)
    4
    18.2%
    Urine Blood >= 2 (N=22)
    2
    9.1%
    Urinary RBC microscopic >= 2 (N=8)
    1
    4.5%
    Urinary WBC microscopic >= 2 (N=8)
    1
    4.5%
    32. Secondary Outcome
    Title Number of Participants With Out-of-Range Electrocardiogram Intervals - All Treated Participants
    Description Participants had 12-Lead electrocardiograms (ECGs) performed at Screening Visit, Day 1 prior to dosing, Day 46 ±2, and at early termination. Definition of out-of-range: PR Interval >210 milliseconds (msec); QRS > 120 msec, QT > 500 msec or > 30 msec change from baseline (Day 1); QT with Fridericia correction (QTcF) > 450 msec or change from baseline of > 30 msec to <= 60 msec or change from baseline > 60 msec.
    Time Frame Day 1 to Day 46 ±2 days or at early termination

    Outcome Measure Data

    Analysis Population Description
    All participants who received any study medication and had an ECG performed on Day 1, Day 46 or early termination.
    Arm/Group Title Inje Cocktail Alone and Inje Cocktail Plus Belatacept
    Arm/Group Description 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.
    Measure Participants 18
    Day 46 (N=18)
    0
    0%
    Early Termination (N=2)
    0
    0%
    33. Secondary Outcome
    Title Mean Change From Baseline in Sitting Systolic and Diastolic Blood Pressure - All Treated Participants
    Description Systolic and Diastolic blood pressures were taken after the participant had been sitting quietly for at least 5 minutes and the pressures were measured in millimeters of mercury (mm Hg). Pressures were obtained at screening visit, Day -1, and at 0 hour (pre-dose), 0.5 hour (post dose), and 2 hours (post dose) on Days 1, 4, 7, 11. Baseline was defined as last non-missing result with a collection date-time less than the date-time of the first active dose of study drug.
    Time Frame Baseline and 0.5 and 2.0 hours Post Dose on Days 1, 4, 7, and 11

    Outcome Measure Data

    Analysis Population Description
    All participants who received any study medication and had a baseline and specific day blood pressure measurement available.
    Arm/Group Title Day 1 Inje Cocktail Day 4 Inje Cocktail Plus Belatacept Day 7 Inje Cocktail Day 11 Inje Cocktail
    Arm/Group Description Single oral dose 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) was administered on Day 1. Single oral dose 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) was administered on Day 4. A single 10 mg/kg IV infusion of belatacept over 30 minutes was administered only on Day 4. Single oral dose 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) was administered on Day 7. Single oral dose 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) was administered on Day 11.
    Measure Participants 22 21 21 20
    Systolic 0.5 hour post dose (N=22,21,21,20)
    -0.6
    (10.15)
    0.1
    (12.81)
    -4.9
    (9.05)
    -4.7
    (10.13)
    Systolic 2.0 hour post dose (N=22,21,21,20)
    0.2
    (10.09)
    2.0
    (11.79)
    -2.7
    (9.85)
    -2.9
    (11.73)
    Diastolic 0.5 hour post dose (N=22,21,21,20)
    -1.7
    (6.52)
    -0.2
    (6.03)
    -2.2
    (7.54)
    -2.2
    (5.38)
    Diastolic 2.0 hour post dose (N=22,21,21,20)
    0.9
    (4.67)
    -2.0
    (4.53)
    -3.4
    (5.22)
    -1.0
    (5.83)
    34. Secondary Outcome
    Title Mean Change From Baseline in Sitting Heart Rate - All Treated Participants
    Description Heart Rate was taken after the participant had been sitting quietly for at least 5 minutes and the heart rate was measured in beats per minute (bpm). Heart Rates were obtained at screening visit, Day -1, and at 0 hour (pre-dose), 0.5 hour (post dose), and 2 hours (post dose) on Days 1, 4, 7, 11. Baseline was defined as last non-missing result with a collection date-time less than the date-time of the first active dose of study drug.
    Time Frame Baseline and 0.5 and 2.0 hours Post Dose on Days 1, 4, 7, and 11

    Outcome Measure Data

    Analysis Population Description
    All participants who received study medication and had baseline and specific day measurement.
    Arm/Group Title Day 1 Inje Cocktail Day 4 Inje Cocktail Plus Belatacept Day 7 Inje Cocktail Day 11 Inje Cocktail
    Arm/Group Description Single oral dose 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) was administered on Day 1. Single oral dose 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) was administered on Day 4. A single 10 mg/kg IV infusion of belatacept over 30 minutes was administered only on Day 4. Single oral dose 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) was administered on Day 7. Single oral dose 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) was administered on Day 11.
    Measure Participants 22 21 21 20
    Heart Rate 0.5 hour post dose (N=22, 21, 21, 20)
    -3.3
    (12.38)
    -4.2
    (13.15)
    -1.8
    (12.58)
    -1.6
    (10.03)
    Heart Rate 2.0 hour post dose (N=22, 21, 21, 20)
    -3.5
    (10.61)
    0.2
    (13.86)
    0.5
    (11.95)
    3.1
    (11.91)
    35. Secondary Outcome
    Title Mean Change From Baseline in Systolic and Diastolic Blood Pressure at Study Discharge (Day 46±2 Days)
    Description Systolic and Diastolic blood pressures were taken after the participant had been sitting quietly for at least 5 minutes and the pressures were measured in millimeters of mercury (mm Hg). Systolic and Diastolic blood pressures were taken on Day 46 (day of discharge from the study). Baseline was defined as last non-missing result with a collection date-time less than the date-time of the first active dose of study drug.
    Time Frame Baseline and Day 46 ±2 days

    Outcome Measure Data

    Analysis Population Description
    All participants who had received study drug during the treatment period and had measurements at baseline and at discharge.
    Arm/Group Title Post Treatment
    Arm/Group Description Days 12 through 46 (Day of Discharge from Study). No study drug was administered during this time.
    Measure Participants 18
    Systolic (N=18)
    -5.9
    (11.25)
    Diastolic (N=18)
    -5.7
    (8.87)
    36. Secondary Outcome
    Title Mean Change From Baseline in Heart Rate at Study Discharge (Day 46±2 Days)
    Description Heart Rate was taken after the participant had been sitting quietly for at least 5 minutes and was measured in beats per minute (bpm). Hear rate was taken on Day 46 (day of discharge) during the follow up period. Baseline was defined as last non-missing result with a collection date-time less than the date-time of the first active dose of study drug.
    Time Frame Baseline and Day 46 ±2 days

    Outcome Measure Data

    Analysis Population Description
    All participants who received study drug during the treatment period and had measurements at baseline and discharge.
    Arm/Group Title Post Treatment
    Arm/Group Description Days 12 through 46 (Day of Discharge from Study). No study drug was administered during this time.
    Measure Participants 18
    Mean (Standard Deviation) [bpm]
    1.0
    (15.86)

    Adverse Events

    Time Frame Day 1 to Day of discharge (Day 46 ±2 days)
    Adverse Event Reporting Description
    Arm/Group Title Inje Cocktail Alone and Inje Cocktail Plus Belatacept
    Arm/Group Description 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.
    All Cause Mortality
    Inje Cocktail Alone and Inje Cocktail Plus Belatacept
    Affected / at Risk (%) # Events
    Total / (NaN)
    Serious Adverse Events
    Inje Cocktail Alone and Inje Cocktail Plus Belatacept
    Affected / at Risk (%) # Events
    Total 0/22 (0%)
    Other (Not Including Serious) Adverse Events
    Inje Cocktail Alone and Inje Cocktail Plus Belatacept
    Affected / at Risk (%) # Events
    Total 3/22 (13.6%)
    Nervous system disorders
    Headache 3/22 (13.6%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    Bristol-Myers Squibb Co. agreements with investigators vary; constant is our right to embargo communications regarding trial results prior to public release for a period ≤60 days from submittal for review. We will not prohibit investigators from publishing, but will prohibit the disclosure of previously undisclosed confidential information other than study results, and request postponement of single-center publications until after disclosure of the clinical trial's primary publication.

    Results Point of Contact

    Name/Title Bristol-Myers Squibb Study Director
    Organization Bristol-Myers Squibb
    Phone
    Email Clinical.Trials@bms.com
    Responsible Party:
    Bristol-Myers Squibb
    ClinicalTrials.gov Identifier:
    NCT01766050
    Other Study ID Numbers:
    • IM103-151
    First Posted:
    Jan 11, 2013
    Last Update Posted:
    Jun 27, 2014
    Last Verified:
    May 1, 2014