A Phase I, Double Blind, Placebo Controlled, Single Ascending Dose Study of Intravenously Administered Ir-CPI to Evaluate Pharmacokinetics, Pharmacodynamics, Safety and Tolerability in Healthy Male Volunteers
Overview
- Phase
- Phase 1
- Intervention
- Ir-CPI - Dose 1
- Conditions
- Healthy
- Sponsor
- Bioxodes S.A.
- Enrollment
- 32
- Locations
- 1
- Primary Endpoint
- Measurement of the Safety Lab Parameter Activated Partial Thromboplastin Time (aPTT)
- Status
- Completed
- Last Updated
- 3 years ago
Overview
Brief Summary
The purpose of this First-in-Human study is to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of Ir-CPI, a novel dual inhibitor of FXIIa and FXIa, following IV administration of single ascending doses in healthy male volunteers.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Participants must satisfy all of the following inclusion criteria before being allowed to enter the study:
- •Have given written informed consent approved by the relevant Ethics Committee (EC) governing the site, indicating that they understand the purpose of and procedures required for the study and are willing to participate in the study.
- •Male participants between 18 and 55 years of age, inclusive at screening.
- •Otherwise healthy with no clinically significant abnormalities as determined by medical history, physical examination, blood chemistry assessments, haematological assessments, coagulation and urinalysis, measurement of vital signs, and ECG. Isolated out-of-range values judged by the PI (or designated physician) to be of no clinical significance can be allowed. This determination must be recorded in the participant's source documents.
- •Have a body weight in the range of 50 to 90 kg inclusive at screening. Have a body mass index (BMI) of 19 to 28 kg/m2 inclusive at screening.
- •Agree to abstain from alcohol intake 24 hours before administration of study drug, during the in-patient period of the study and 24 hours prior to all other ambulatory visits, up until and including the discharge visit.
- •Agree not to use prescription medications within 14 days prior to study drug administration and through the duration of the study, unless approved by the PI and Sponsor medical monitor.
- •Non-smokers or abstinence from tobacco or nicotine-containing products for at least 3 months prior to screening.
- •Agree not to use over-the-counter (OTC) medications \[including decongestants, antihistamines, and herbal medication (including herbal tea and St. John's Wort)\], within 14 days prior to study drug administration through the discharge visit, unless approved by the PI and Sponsor medical monitor. Occasional use of paracetamol at recommended doses is allowed. Special rules apply for aspirin, corticosteroids and nonsteroidal anti-inflammatory drugs (NSAIDS (see exclusion criteria 6-7-8-9)
- •Venous access (both arms) sufficient to allow blood sampling and study drug administration as per protocol.
Exclusion Criteria
- •If any of the following exclusion criteria apply, the participant must not enter the study:
- •Currently have or have a history of any clinically significant medical illness or medical disorders the PI considers should exclude the participant, including (but not limited to) cardiovascular disease, neuromuscular, haematological disease, immune deficiency state, respiratory disease, hepatic or gastrointestinal disease, neurological or psychiatric disease, ophthalmological disorders, neoplastic disease, renal or urinary tract diseases, or dermatological disease.
- •History of personal or familial bleeding disorders; including prolonged or unusual bleeding.
- •History of deficiency in factor XII (FXII) or haemophilia type A (FVII) or type B (FIX) or type C (FXI).
- •History of cerebral bleeding (e.g. after a car accident), stroke and cerebrovascular accident (CVA).
- •Anamnestic history of Lyme disease or tick-borne encephalitis.
- •Use of Acetylsalicylic-Acid (ASA)-containing OTC medications within 1 month prior to screening.
- •Chronic administration of NSAIDs, chronic use of corticosteroids within 1 month prior to screening.
- •Chronic administration of clopidogrel, ticlopidin, dipyridamole, Coumadin-like anticoagulants, new oral anticoagulant dabigatran, rivaroxaban, apixaban or edoxaban within 3 months prior to screening.
- •Administration of unfractionated heparin, low molecular weight heparin, fibrinolytic agents and anti-FXa within 3 months prior to screening.
Arms & Interventions
Ir-CPI - Dose 1
Participants received a single intravenous dose of 1.5 mg/kg of Ir-CPI during 6 hours
Intervention: Ir-CPI - Dose 1
Ir-CPI - Dose 2
Participants received a single intravenous dose of 3.0 mg/kg of Ir-CPI during 6 hours
Intervention: Ir-CPI - Dose 2
Ir-CPI - Dose 3
Participants received a single intravenous dose of 6.0 mg/kg of Ir-CPI during 6 hours
Intervention: Ir-CPI - Dose 3
Ir-CPI - Dose 4
Participants received a single intravenous dose of 9.0 mg/kg of Ir-CPI during 6 hours
Intervention: Ir-CPI - Dose 4
Placebo
Participants received a single intravenous dose of placebo during 6 hours
Intervention: Placebo
Outcomes
Primary Outcomes
Measurement of the Safety Lab Parameter Activated Partial Thromboplastin Time (aPTT)
Time Frame: At pre-dose (baseline), 2, 4, 6, 8, 12, 24, 48, 72 hours post-dose and at the discharge visit (Day 10 ± 2 days)
These safety aPTT results were readily available to the PI for safety follow-up during and after the study drug administration. Safety aPTT was followed up "at the bedside" at regular time-points (as opposed to the PD biomarker aPTT, which was assessed by the central laboratory alongside the PK time-points). An aPTT ratio was calculated by dividing the aPTT value (in sec) of the specific time-point (aPTTt) by the baseline aPTT value (in sec) (aPTTbaseline) of the same participant (aPTT ratio = aPTTt/aPTTbaseline). The baseline time-point was considered as having an aPTT ratio of 1. Concerning the row titles, for example, Day 1 H02:00 corresponds to aPTT ratio results obtained on Day 1, 2 hours after the start of the infusion.
Secondary Outcomes
- Measurement of the Maximum Plasma Concentration (Cmax) of Ir-CPI(Pre-dose, 0.5, 1, 1.5, 2, 4, 6, 6.5, 7, 7.5, 8, 10, 12, 16, 24, 48, 72, 96, 144 hours (144 hours for Dose 4 only))
- Measurement of the Time to Reach Maximum Plasma Concentration (Tmax) of Ir-CPI(Pre-dose, 0.5, 1, 1.5, 2, 4, 6, 6.5, 7, 7.5, 8, 10, 12, 16, 24, 48, 72, 96, 144 hours (144 hours for Dose 4 only))
- Measurement of the Area Under the Plasma Concentration-time Curve From Time Zero to 6h (AUC0-6) and From Time Zero to Time of Infinity (AUCinf)(Pre-dose, 0.5, 1, 1.5, 2, 4, 6, 6.5, 7, 7.5, 8, 10, 12, 16, 24, 48, 72, 96, 144 hours (144 hours for Dose 4 only))
- Measurement of the Effect of Ir-CPI on the Activated Partial Thromboplastin Time (aPTT)(Pre-dose (baseline), 0.5, 1, 1.5, 2, 4, 6, 6.5, 7, 7.5, 8, 10, 12, 16, 24, 48, 72, 96 hours post-dose and at the discharge visit (Day 10 ± 2 days))
- Measurement of the Effect of Ir-CPI on Factor XI Activity(Pre-dose (baseline), 0.5, 1, 1.5, 2, 4, 6, 6.5, 7, 7.5, 8, 10, 12, 16, 24, 48, 72, 96 hours post-dose and at the discharge visit (Day 10 ± 2 days))
- Measurement of the Effect of Ir-CPI on Factor XII Activity(Pre-dose (baseline), 0.5, 1, 1.5, 2, 4, 6, 6.5, 7, 7.5, 8, 10, 12, 16, 24, 48, 72, 96 hours post-dose and at the discharge visit (Day 10 ± 2 days))