Study to Investigate the Pharmacokinetics (PK) and Pharmacodynamics (PD) of Idarucizumab in Chinese Healthy Male and Female Volunteers Who Had Taken Dabigatran Etexilate and Whose Plasma Concentrations of Dabigatran Were at or Close to Steady State

Study Overview
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Brief Summary
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The primary objective of the trial is to investigate the pharmacokinetics and pharmacodynamics of idarucizumab in Chinese healthy male and female subjects following intravenous administration of idarucizumab followed by idarucizumab with 15 minutes interval when administered at or close to the steady state of dabigatran. Another objective of this trial is to explore the effect idarucizumab on the PK (pharmacokinetic(s)) and PD (pharmacodynamic) parameters of dabigatran.

Official Title
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Open Label Phase I Trial in Healthy Chinese Male and Female Volunteers to Investigate Pharmacokinetics and Pharmacodynamics of Idarucizumab to Reverse Dabigatran Anticoagulant Activity

Conditions
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Healthy Volunteers

Intervention / Treatment
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* Drug: Dabigatran etexilate
* Drug: Idarucizumab


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Age >= 18 and Age <= 45 years at screening Healthy male and female based upon a complete medical history, including vital signs (Blood Pressure, Pulse Rate, and Body Temperature), 12-lead Electrocardiogram and clinical laboratory tests. Women of childbearing potential must be ready and able to use highly effective methods of birth control per International Committee on Harmonisation M3 (R2) that result in a low failure rate of less than 1% per year when used consistently and correctly. A list of contraception methods meeting these criteria is provided in the patient information. Body weight >=50 kg with body mass index range >=19.0 and <24.0 kg/m2 at Visit 1. Signed and dated written informed consent in accordance with Good Clinical Practice and local legislation prior to admission to the trial. Exclusion criteria: Any finding of the medical examination (including Blood Pressure, Pulse Rate, Body Temperature and Electrocardiogram) is deviating from normal and judged as clinically relevant by the investigator Any evidence of a clinically relevant concomitant disease according to investigator's clinical judgement Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders Surgery of the gastrointestinal tract that could interfere with kinetics of the trial medication (except appendectomy) Diseases of the central nervous system (including but not limited to any kind of seizures or stroke), and other relevant neurological or psychiatric 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) or immune system disease Intake of drugs with a long half-life (> 24 hours) within at least 30 days or less than 10 half-lives of the respective drug prior to first trial drug administration Within 10 days prior to administration of trial medication, use of drugs that might reasonably influence the results of the trial or that might prolong the QT/corrected QT (QTc) interval. Participation in another trial with investigational drug administration within 60 days prior to first trial drug administration Smoker (> 10 cigarettes or > 3 cigars or > 3 pipes/day) Inability to refrain from smoking during hospitalization Alcohol abuse (consumption of more than 20 g per day: e.g., 1 middle-sized bottles of beer, 1 gou [equivalent to 180 mL] of sake)) Drug abuse or positive drug screening Blood donation (400 mL whole blood donation within 12 weeks, 200 mL whole blood donation or blood component donation within 4 weeks) prior to first trial drug administration Intention to perform excessive physical activities within one week prior to first trial drug administration or during the trial Any laboratory values outside the reference range that are of clinical relevance according to investigator's clinical judgement Inability to comply with dietary regimen of trial site A marked baseline prolongation of QT/QTc interval (e.g., repeated demonstration of a QTcF interval >450 ms) A history of additional risk factors for torsades de points (TdP) (e.g., heart failure, hypokalemia, family history of Long QT Syndrome) Positive HIV (human immunodeficiency virus) test result at screening examination Positive testing for Hepatitis B Antigen and/or a positive Hepatitis C antibody test result at screening examination Subjects considered unsuitable for inclusion by the investigator, e.g. are unable to understand and comply with trial requirements, or have any condition which in the opinion of the investigator would not allow safe participation in the trial. Subjects who do not agree to minimize the risk of female partners becoming pregnant from the first dosing day until 12 weeks after the trial completion. Acceptable methods of contraception comprises barrier contraception and a medically accepted contraceptive method for the female (intra-uterine device with spermicide. hormonal contraceptive since at least 8 weeks) History or evidence of blood dyscrasia, haemorrhagic diathesis, severe thrombocytopenia, cerebrovascular haemorrhage, bleeding tendencies associated with active ulceration or overt bleeding of gastrointestinal, respiratory or genitourinary tract or any disease or condition with haemorrhagic tendencies (e.g. cerebral aneurysm, dissecting aorta, central nervous system (CNS) trauma, retinopathy, nephrolithiasis) Abnormal values for prothrombin time (PT), activated partial thromboplastin time (aPTT) and thrombocytes considered by the investigator or one of the co-investigators to be clinically relevant Creatinine and estimated glomerular filtration rate (GFR) outside the normal range Evidence of proteinuria Women who are pregnant, nursing, or who plan to become pregnant while in the trial

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: All Subjects<br>Dabigatran etexilate alone (days 1-4) and (days 8-10) and with Idarucizumab (day 11) | Drug: Dabigatran etexilate<br>* Days 1-4 and Day 8-11<br>* Other names: PRADAXA, PRAZAXA;Drug: Idarucizumab<br>* Day 11<br>* Other names: PRAXBIND, Praxbind, Prizbind;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Measured Concentration of Idarucizumab in Plasma (Cmax) | Cmax, maximum measured concentration of idarucizumab in plasma | -0.017, 0.083, 0.167, 0.317, 0.417, 0.45, 0.583, 0.917, 1.417, 2.083, 3.083, 4.083, 6.083, 10.083, 12.083, 24.083, 48.083, 72.083 hours (h) | 
| For Diluted Thrombin Time: Area After Subtraction of Baseline Area From Area Under the Effect Curve Over the Time Interval From 2 - 12 Hours (AUEC Above,2-12) on Day 4 and Day 11 | For diluted thrombin time: AUEC above,2-12 (area after subtraction of baseline area from area under the effect curve over the time interval from 2 - 12) on day 4 and day 11. The standard deviation (SD) presented is actually the percentage coefficient of variation (CV %) | Day 4 and day 11 | 
| Area Under the Concentration-time Curve of Idarucizumab in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | AUC0-∞, area under the concentration-time curve of idarucizumab in plasma over the time interval from 0 extrapolated to infinity | -0.017, 0.083, 0.167, 0.317, 0.417, 0.45, 0.583, 0.917, 1.417, 2.083, 3.083, 4.083, 6.083, 10.083, 12.083, 24.083, 48.083, 72.083 hours (h) | 
| Amount of Idarucizumab Eliminated in Urine Over the Time Interval From 0 to 72 Hours (h) (Ae0-72) | Ae0-72, amount of idarucizumab eliminated in urine over the time interval from 0 to 72 h. As per the protocol, day is counted as Day 1 = 0:00 | 0-2 h, 2-6 h, 6-10 h, 10-12 h,12-14h, 14-26 h, 26-50 h, 50-74 h after drug administration of dabigatran etexilate on Day 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| For Sum Dabigatran: Amount of the Analyte Excreted in Urine at Steady State Over the Time Interval 0-74 Hours (Ae0-74,ss ) on Day 4 and Day 11 | For sum dabigatran: Ae0-74,ss (amount of the analyte excreted in urine at steady state over the time interval 0-74) on day 4 and day 11 if feasible. As per the protocol, day is counted as Day 1 = 0:00 | 0-2 h, 2-6 h, 6-10 h, 10-12 h,12-14h, 14-26 h, 26-50 h, 50-74 h after drug administration of dabigatran etexilate on Day 4 and Day 11. | 
| For Unbound Sum Dabigatran: Area Under the Concentration-time Curve of the Dabigatran in Plasma at Steady State Over the Time Interval 2 Hours-12 Hours | For unbound sum dabigatran: AUC 2-12,ss (Area under the concentration-time curve of the dabigatran in plasma at steady state over the time interval 2 hours-12 hours). As per the protocol, day is counted as Day 1 = 0:00. | Day 4: 74h, 74.5h, 75h, 76h, 78h, 80h, 84h; Day 11: 242h, 242.083h, 242.25h, 242.333h 243.333h, 244h, 246h, 248h, 252h |