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Effects of BI 44370 TA Orally Applied as Tablets on the Pharmacokinetics of Orally Administered Midazolam Solution in Healthy Volunteers

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ClinicalTrials.gov Identifier: NCT02217514
Recruitment Status : Completed
First Posted : August 15, 2014
Last Update Posted : August 15, 2014
Sponsor:
Information provided by (Responsible Party):
Boehringer Ingelheim

Brief Summary:
Evaluation of the long-term (48 h) and short-term (1 h) effects of BI 44370 BS on the pharmacokinetics of midazolam as marker of a possible inhibition of CYP 3A4; safety and tolerability.

Condition or disease Intervention/treatment Phase
Healthy Drug: Midazolam Drug: BI 44370 low dose Drug: BI 44370 medium dose Drug: BI 44370 high dose Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 48 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Effects of 100 mg and 500 mg BI 44370 TA Orally Applied as 50 mg Tablets on the Pharmacokinetics of 2 mg Orally Administered Midazolam Solution. An Open-label, Randomised, Parallel Group, Fixed-sequence Study With Intraindividual Comparison of Midazolam Pharmacokinetics With and Without BI 44370 TA
Study Start Date : February 2008
Actual Primary Completion Date : March 2008

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Treatment sequence 1 in male subjects
Midazolam alone and 1 h after low dose BI44370BS in male subjects
Drug: Midazolam
Other Name: Dormicum®

Drug: BI 44370 low dose
Experimental: Treatment sequence 1 in female subjects
Midazolam alone and 1 h after low dose BI44370BS followed by medium dose BI 44370 in an additional visit in female subjects
Drug: Midazolam
Other Name: Dormicum®

Drug: BI 44370 low dose
Drug: BI 44370 medium dose
Experimental: Treatment sequence 2
Midazolam before and 48 h after high dose BI44370BS
Drug: Midazolam
Other Name: Dormicum®

Drug: BI 44370 high dose
Experimental: Treatment sequence 3
Midazolam before and 24 h after high dose BI44370BS
Drug: Midazolam
Other Name: Dormicum®

Drug: BI 44370 high dose
Experimental: Treatment sequence 4
Midazolam before and 1 h after high dose BI44370BS
Drug: Midazolam
Other Name: Dormicum®

Drug: BI 44370 high dose



Primary Outcome Measures :
  1. Cmax (maximum concentration of midazolam in plasma) [ Time Frame: up to 24 hours after drug administration ]
  2. AUC0-tz (area under the concentration-time curve of midazolam in plasma over the time interval from 0 to the time of the last quantifiable data point) [ Time Frame: up to 24 hours after drug administration ]
  3. AUC0-infinity (area under the concentration-time curve of midazolam in plasma over the time interval from 0 extrapolated to infinity) [ Time Frame: up to 24 hours after drug administration ]

Secondary Outcome Measures :
  1. Cmax (maximum measured concentration of the analyte in plasma) [ Time Frame: Up to 48 hours after drug administration ]
  2. tmax (time from dosing to maximum measured concentration) [ Time Frame: up to 48 hours after drug administration ]
  3. AUC0-∞ (area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity) [ Time Frame: up to 48 hours after drug administration ]
  4. %AUCtz-∞ (the percentage of the AUC0-∞ that is obtained by extrapolation) [ Time Frame: up to 48 hours after drug administration ]
  5. AUC0-tz (area under the concentration-time curve of the analyte in plasma in plasma over the time interval from 0 to the time of the last quantifiable data point) [ Time Frame: up to 48 hours after drug administration ]
  6. AUCt1-t2 (Area under the concentration-time curve of the analyte in plasma over the time interval t1 to t2) [ Time Frame: up to 48 hours after drug administration ]
  7. λz (terminal rate constant in plasma) [ Time Frame: up to 48 hours after drug administration ]
  8. t1/2 (terminal half-life of the analyte in plasma) [ Time Frame: up to 48 hours after drug administration ]
  9. MRTp.o. (mean residence time of the analyte in the body after oral administration) [ Time Frame: up to 48 hours after drug administration ]
  10. CL/F (total/apparent clearance of the analyte in plasma after extravascular administration) [ Time Frame: up to 48 hours after drug administration ]
  11. Vz/F (apparent volume of distribution during the terminal phase λz following an extravascular dose) [ Time Frame: up to 48 hours after drug administration ]
  12. ratio of AUC0-∞ 1-OH-midazolam / AUC0-∞ midazolam [ Time Frame: up to 48 hours after drug administration ]
  13. Aet1-t2 (amount of BI 44370 BS eliminated in urine from the time point t1 to time point t2) [ Time Frame: up to 24 hours after drug administration ]
  14. fet1-t2 (fraction of BI 44370 BS eliminated in urine from time point t1 to time point t2) [ Time Frame: up to 24 hours after drug administration ]
  15. CLR,t1-t2 (renal clearance of BI 44370 BS from the time point t1 until the time point t2) [ Time Frame: up to 24 hours after drug administration ]
  16. Number of patients with adverse events [ Time Frame: up to 8 days after last drug administration ]
  17. Assessment of tolerability by investigator on a 4-point scale [ Time Frame: up to 8 days after last drug administration ]


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Ages Eligible for Study:   21 Years to 50 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Healthy males and females according to the following criteria: Based upon a complete medical history, including the physical examination, vital signs (BP, PR), 12-lead ECG, clinical laboratory tests
  • Age ≥21 and Age ≤50 years
  • BMI ≥18.5 and BMI ≤29.9 kg/m2 (Body Mass Index)
  • Signed and dated written informed consent prior to admission to the study in accordance with Good clinical practice (GCP) and the local legislation.

Exclusion Criteria:

  • Any finding of the medical examination (including Blood Pressure (BP), Pulse Rate (PR) and Electrocardiogram (ECG)) deviating from normal and of clinical relevance
  • Any evidence of a clinically relevant concomitant disease
  • Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders
  • Surgery of the gastrointestinal tract (except appendectomy)
  • Diseases of the central nervous system (such as epilepsy) or psychiatric disorders or neurological disorders
  • History of relevant orthostatic hypotension, fainting spells or blackouts
  • Chronic or relevant acute infections
  • History of relevant allergy/hypersensitivity (including allergy to drug or its excipients)
  • Intake of drugs with a long half-life (> 24 hours) within at least one month or less than 10 half-lives of the respective drug prior to administration or during the trial
  • Use of drugs which might reasonably influence the results of the trial or that prolong the QT/QTc interval based on the knowledge at the time of protocol preparation within 10 days prior to administration or during the trial
  • Participation in another trial with an investigational drug within 30 days prior to administration or during the trial
  • Smoker (> 10 cigarettes or > 3 cigars or > 3 pipes/day)
  • Inability to refrain from smoking on trial days
  • Alcohol abuse (more than 60 g/day)
  • Drug abuse
  • Blood donation (more than 100 mL within four weeks prior to administration or during the trial)
  • Excessive physical activities (within one week prior to administration or during the trial)
  • Any laboratory value outside the reference range that is of clinical relevance
  • Inability to comply with dietary regimen of trial site
  • A marked baseline prolongation of QT/QTc interval (e.g., repeated demonstration of a QTc interval >470 ms);
  • A history of additional risk factors for Torsade de Pointes (TdP) (e.g., heart failure, hypokalemia, family history of Long QT Syndrome)

For Male Subjects:

  • Not willing to use adequate contraception (condom use plus another form of contraception e.g. spermicide, oral contraceptive taken by female partner, sterilisation, intrauterine device (IUD)) during the whole study period from the time of the first intake of study drug until three months after the last intake

For Female Subjects:

  • Pregnancy
  • Positive pregnancy test
  • No adequate contraception (adequate contraception e.g. sterilisation, intrauterine pessary (IUP), oral contraceptives)
  • Inability to maintain this adequate contraception during the whole study period during the whole study period from the time of the first intake of study drug until one month after the last intake

Additional Information:
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Responsible Party: Boehringer Ingelheim
ClinicalTrials.gov Identifier: NCT02217514     History of Changes
Other Study ID Numbers: 1246.3
First Posted: August 15, 2014    Key Record Dates
Last Update Posted: August 15, 2014
Last Verified: August 2014
Additional relevant MeSH terms:
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Midazolam
Adjuvants, Anesthesia
Hypnotics and Sedatives
Central Nervous System Depressants
Physiological Effects of Drugs
Anti-Anxiety Agents
Tranquilizing Agents
Psychotropic Drugs
Anesthetics, Intravenous
Anesthetics, General
Anesthetics
GABA Modulators
GABA Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action