Intracranial haemorrhagic bleed Circulatory System
Conditions
Interventions
A 2-part, randomised, double-blind, single ascending dose, placebo controlled alternating group, partial crossover study to assess the safety and tolerability, pharmacokinetics, and pharmacodynamics o
Sponsors
Alveron Pharma UK Ltd
Eligibility
Sex/Gender
Male
Inclusion criteria
Inclusion criteria: 1. Male 2. Aged 18–50 years, with a body mass index of 18.0–32.0 kg/m2 3. Deemed healthy on the basis of clinical history, physical examination, electrocardiogram (ECG), vital signs, and laboratory tests of blood, urine and faeces 4. Registered with a general practitioner 5. No contraindication for or sensitivity to dabigatran etexilate
Exclusion criteria
Exclusion criteria: 1. Clinically relevant abnormal history, physical findings, ECG, or laboratory values at the pre-trial screening assessment that could interfere with the objectives of the trial or the safety of the volunteer. 2. Aspartate aminotransferase (AST), alanine aminotransferase (ALT) or total bilirubin values which are above the upper limit of normal (ULN). 3. Presence of acute or chronic illness or history of chronic illness sufficient to invalidate the volunteer’s participation in the trial or make it unnecessarily hazardous. 4. Impaired endocrine, thyroid, hepatic, respiratory or renal function, diabetes mellitus, coronary heart disease, or history of any psychotic mental illness. 5. Surgery (eg stomach bypass) or medical condition that might affect absorption of medicines (Part B only). 6. Estimated glomerular filtration rate (eGFR) at screening < 80 mL/min/1.73 m2 (estimated using the method established by the Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI]). 7. Presence or history of severe adverse reaction to any drug (Parts A and B), or a history of sensitivity to dabigatran etexilate and/or major excipients (Part B only). 8. Presence or history of any contraindication for administration of dabigatran etexilate (Part B only). 9. Positive faecal occult blood sample at screening (Part B only). 10. Use of a prescription medicine during the 28 days before the first dose of trial medication or use of an over-the-counter medicine, with the exception of acetaminophen (paracetamol), during the 7 days before the first dose of trial medication. 11. Receipt of an investigational product (including prescription medicines) as part of another clinical trial within the 3 months before first admission to this study; in the follow-up period of another clinical trial at the time of screening for this study. 12. Presence or history of drug or alcohol abuse, or intake of more than 14 units of alcohol weekly. 13. Has not smoked or used nicotine-containing products for 6 months prior to screening for this study. 14. Mean blood pressure and mean pulse rate in supine position at the screening examination, or on Day –1 of Session 1 outside the ranges: blood pressure 90–140 mm Hg systolic, 40–90 mm Hg diastolic; pulse rate 40_100 beats/min. One set of repeats in triplicates is permitted if the mean values are borderline (ie values that are within 5 mm Hg for blood pressure or 5 beats/min for pulse rate) or if requested by the investigator. Subjects can be included if the repeat mean value is within range or still borderline, but deemed not clinically significant by the investigator. 15. QT value, measured at the screening visit or at baseline (predose on Day 1 of Session 1), outside the range 300–450 msec on 12-lead ECG, using Fridericia’s formula (QTcF) for correction. At screening and predose on Day 1 of Session 1, the mean of triplicate ECG recordings will be used for determining eligibility. 16. Possibility that the volunteer will not cooperate with the requirements of the protocol. 17. Evidence of drug abuse on urine testing. 18. Positive test for hepatitis B, hepatitis C or HIV. 19. Loss of more than 400 mL blood during the 3 months before the trial, eg as a blood donor. 20. Objection by GP to volunteer entering trial.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Safety as assessed by Adverse event monitoring, physical examination, regular vital signs and 12-lead ECG recording, injection site assessment of local tolerability, adverse events (AEs) and clinical laboratory assessments (haematology, coagulation (including thrombin-antithrombin III complexes (TAT) and the fibrin split product D-dimer), clinical chemistry, and urinalysis) until 24 h postdose and 9 days (± 2 days) after the last dose. Continuous monitoring of QT intervals corrected with Fridericia’s and Bazett’s formula (QTcF and QTcB) was performed with a Mortara Surveyor Telemetry System (Mortara Instrument, Inc, Milwaukee, WI, USA) during the first 24 h postdose, and in case of QTcF or QTcB = 500 ms, a 12-lead ECG was to be recorded. In addition, urinary markers of renal tissue injury were monitored: Vanin-1, neutrophil gelatinase associated lipocalin (NGAL) and N-acetyl-beta-D glucosaminidase (NAG) | — |
Secondary
| Measure | Time frame |
|---|---|
| PK plasma and urinary concentration time profiles were assessed and the following PK parameters were derived by non-compartmental analysis: Cmax, tmax, AUClast, AUCinf, AUC12, AUC24, %AUCextrap, ?Z, t½, CL, VZ, MRTinf Ae24, and CLR. PD coagulation markers were thrombin generation in clotting plasma, using the Calibrated Automated Thrombogram® (CAT) assays: [lag time, peak height, time to peak, endogenous thrombin potential and derived velocity index]; thrombin generation in presence of an ex vivo challenge with DOACs (Part A only); Ecarin Chromogenic Assay (STA-ECA-II); Direct Thrombin Inhibitor (DTI); activated partial thromboplastin time (aPTT); prothrombin time (PT), expressed as international normalised ratio (INR) thrombotic and thrombolytic status (occlusion time, thrombus stability, lysis time. | — |
Countries
England, United Kingdom
Outcome results
None listed