Pharmacokinetics, Pharmacodynamics, Safety and Tolerability of Dabigatran Etexilate in Patients With and Without Renal Impairment

Boehringer Ingelheim

Status and phase: Completed; Phase 1

Conditions: Renal Insufficiency

Treatments: Drug: Dabigatran etexilate high dose; Drug: Dabigatran etexilate low dose

Study type: Interventional

Funder types: Industry

Identifiers

NCT02182024

1160.23

Details and patient eligibility

About

To assess the effect of different degrees of renal impairment on the pharmacokinetics and pharmacodynamics of dabigatran etexilate administered orally.

Enrollment: 35 patients

Sex: All

Ages: 18 to 75 years old

Volunteers: Accepts Healthy Volunteers

Inclusion criteria

• Healthy male or female subjects determined by results of screening with a creatinine clearance >80 mL/min (group 1, control group)

• Renally impaired male or female subjects determined by results of screening with the following creatinine clearance results:

  • creatinine clearance >50 - ≤80 mL/min (group 2)
  • creatinine clearance >30 - ≤50 mL/min (group 3)
  • creatinine clearance ≤30 mL/min (group 4)
  • uraemia requiring maintenance dialysis (group 5)
  • Signed written informed consent in accordance with Good Clinical Practice (GCP) and local legislation

• Age >=18 and <=75 years

• BMI >=18.0 and <=32 kg/m2, at least 45 kg for females

Exclusion criteria

• Any finding of the medical examination (including blood pressure, pulse rate, and electrocardiogram) deviating from normal and of clinical relevance
• Clinically relevant gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunologic or hormonal disorders
• Surgery of gastrointestinal tract (except appendectomy, cholecystectomy or herniotomy)
• Clinically relevant diseases of the central nervous system
• Relevant history of orthostatic hypotension, fainting spells or blackouts
• Abnormal prothrombin time (PT), TT, aPTT (must be within the normal range after no more than one repeated test), thrombocytes <150000/μl (two repeats of the first test)
• Evidence of haematuria either macroscopically detectable or microscopic on urinalysis (normal microscopic results after no more than one repeated test)
• 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 or nephrolithiasis)
• Recent or contemplated diagnostic or therapeutic procedures with potential for uncontrollable bleeding (e.g. spinal puncture, lumbar block anaesthesia, surgery of CNS or eye or surgery resulting in large open surfaces) within 14 days before or after drug administration of this clinical trial
• Chronic or relevant acute infections
• History of allergy/hypersensitivity (including drug allergy) which is deemed relevant to the trial as judged by the investigator
• For women with childbearing potential: no reliable contraception (accepted methods are intra uterine device, hormonal contraceptives, bilateral tubal ligation, hysterectomy, condoms) or pregnancy (known or detected by a positive pregnancy test) or breast feeding period
• Intake of drugs with a long half-life (>24 hours) (<1 month prior to administration or during the trial)
• Use of any drugs, within 14 days prior to administration or during the trial
• Participation in another trial with an investigational drug (<2 months prior to drug administration or during trial)
• Drug abuse
• Blood donation or loss >400 mL, <1 month prior to administration or during the trial
• Excessive physical activities <5 days prior to administration of study drug or during trial
• Clinically relevant laboratory abnormalities

Renally impaired subjects (groups 2, 3, 4 and 5) who met any of the following criteria were not be entered into this trial:

• Moderate and severe concurrent liver function impairment (e.g. due to hepatorenal syndrome)
• Clinically relevant gastrointestinal, respiratory, cardiovascular, metabolic, immunologic or hormonal disorders
• Surgery of gastrointestinal tract (except appendectomy, cholecystectomy or herniotomy)
• Clinically relevant diseases of the central nervous system
• Relevant history of orthostatic hypotension, fainting spells or blackouts
• Abnormal values for PT, TT, aPTT and thrombocytes considered by the investigator or one of the co-investigators to be clinically relevant
• 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, CNS trauma, retinopathy, nephrolithiasis) considered by the investigator or one of the co-investigators to be clinically relevant
• Recent or contemplated diagnostic or therapeutic procedures with potential for uncontrollable bleeding (e.g. spinal puncture, lumbar block anaesthesia, surgery of CNS or eye or surgery resulting in large open surfaces) within 14 days before or after drug administration of this clinical trial
• Chronic or relevant acute infections
• History of allergy/hypersensitivity (including drug allergy) which is deemed relevant to the trial as judged by the investigator
• For women with childbearing potential: no reliable contraception (accepted methods are intra-uterine device, hormonal contraceptives, bilateral tubal ligation, hysterectomy or condoms) or pregnancy (known or detected by a positive pregnancy test) or breast-feeding period
• Participation in another trial with an investigational drug (<2 months prior to administration or during trial)
• Drug abuse
• Blood donation or loss >400 mL, <1 month prior to administration or during the trial
• Excessive physical activities < 5 days prior to administration of study drug or during trial
• Clinically relevant laboratory abnormalities except those values typical for renally impaired patients

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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35 participants in 5 patient groups

Dabigatran high dose in healthy subjects

Experimental group

Description:

healthy subjects with a creatinine clearance of \>80 mL/m

Treatment:

Drug: Dabigatran etexilate high dose

Dabigatran high dose in mild renal impairment

Experimental group

Description:

patients with a creatinine clearance of \>50 up to 80 mL/min

Treatment:

Drug: Dabigatran etexilate high dose

Dabigatran high dose in moderate renal impairment

Experimental group

Description:

patients with a creatinine clearance of \>30 up to 50 mL/min

Treatment:

Drug: Dabigatran etexilate high dose

Dabigatran high dose in severe renal impairment

Experimental group

Description:

patients with a creatinine clearance of up to 30 mL/min

Treatment:

Drug: Dabigatran etexilate high dose

Dabigatran low dose in haemodialysis patients

Experimental group

Description:

patients requiring haemodialysis

Treatment:

Drug: Dabigatran etexilate low dose