A Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Ir-CPI in Healthy Male Subjects

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Healthy

Intervention / Treatment
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* Drug: Ir-CPI - Dose 1
* Drug: Ir-CPI - Dose 2
* Drug: Ir-CPI - Dose 3
* Drug: Ir-CPI - Dose 4
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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. Participants and their partners of childbearing potential [meaning who are not surgically sterile (tubal ligation/obstruction or removal of ovaries or uterus) or post-menopausal (absence of menstrual periods for at least 12 consecutive months)] must be willing to use 2 methods of contraception: - a highly effective method of birth control starting at screening. Highly effective methods of birth control are defined as those that result in a low failure rate (i.e. Pearl Index less than 1% per year) when used consistently and correctly, such as implants, rings, patches, injectable or combined oral contraceptives, intrauterine devices (IUDs), or sexual abstinence (periodic abstinence e.g. calendar, ovulation, symptothermal, postovulation methods, declaration of abstinence for the duration of the trial, and withdrawal are not acceptable methods of contraception) . - and a local barrier form of contraception. Acceptable barrier methods are either the participant's use of a condom or the partner's use of an occlusive cap or diaphragm, or spermicides. Participants will not donate sperm from the selection visit and up to 90 days after the infusion. In case of sterile or vasectomised participants, no contraception will be required for their partners of childbearing potential. Willing/able to adhere to the study visit schedule and other requirements, prohibitions and restrictions specified in this 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. Have an active acute or chronic infection or diagnosed latent infection. Systolic blood pressure (SBP) greater than 150 or less than 90 mmHg, diastolic blood pressure (DBP) greater than 90 or less than 50 mmHg, and heart rate (HR) greater than 100 or less than 40 bpm. Acute clinically relevant illness within 7 days prior to study drug administration or have had a major illness or hospitalisation within 1 month prior to study drug administration. Major or traumatic surgery within 12 weeks of screening. Any participant who plans to undergo elective surgery within 4 weeks prior to study drug administration and through the discharge visit. Positive serology test for HIV antibodies, hepatitis B surface antigen (HBsAg), or hepatitis C virus (HCV) antibodies at screening. Recent history (within previous 6 months) of alcohol or drug abuse. Have positive urine toxicology screen at screening or D -1 for substances of abuse including amphetamines, benzodiazepine, cocaine, opiates, barbiturate and cannabinoids. Have a positive alcohol breath test at screening or D-1. Consumes, on average, more than approximately 500 mg/day of caffeine (as contained in 5 cups of tea or coffee or 8 cans of caffeine-containing soda or other caffeinated products per day). Donated blood (i.e. 500 mL) within 3 months before D1. Have a history of active drug and/or food allergy or other active allergic disease requiring the constant use of medications, or a history of severe allergic reaction, angioedema or anaphylaxis. Received any other experimental therapy or new investigational drug within 30 days or 5 half-lives (whichever is longer) of study drug administration.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ir-CPI - Dose 1<br>Participants received a single intravenous dose of 1.5 mg/kg of Ir-CPI during 6 hours | Drug: Ir-CPI - Dose 1<br>* 6 participants received a single intravenous dose of 1.5 mg/kg of Ir-CPI during 6 hours<br>|
| Experimental: Ir-CPI - Dose 2<br>Participants received a single intravenous dose of 3.0 mg/kg of Ir-CPI during 6 hours | Drug: Ir-CPI - Dose 2<br>* 6 participants received a single intravenous dose of 3.0 mg/kg of Ir-CPI during 6 hours<br>|
| Experimental: Ir-CPI - Dose 3<br>Participants received a single intravenous dose of 6.0 mg/kg of Ir-CPI during 6 hours | Drug: Ir-CPI - Dose 3<br>* 6 participants received a single intravenous dose of 6.0 mg/kg of Ir-CPI during 6 hours<br>|
| Experimental: Ir-CPI - Dose 4<br>Participants received a single intravenous dose of 9.0 mg/kg of Ir-CPI during 6 hours | Drug: Ir-CPI - Dose 4<br>* 6 participants received a single intravenous dose of 9.0 mg/kg of Ir-CPI during 6 hours<br>|
| Placebo Comparator: Placebo<br>Participants received a single intravenous dose of placebo during 6 hours | Drug: Placebo<br>* For each dose group, 2 additional participants received a single intravenous dose of placebo during 6 hours (8 in total).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measurement of the Safety Lab Parameter Activated Partial Thromboplastin Time (aPTT) | 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. | At pre-dose (baseline), 2, 4, 6, 8, 12, 24, 48, 72 hours post-dose and at the discharge visit (Day 10 ± 2 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | The activated partial thromboplastin time (aPTT) is used as a pharmacodynamic marker. No data were available for the Ir-CPI 1.5 mg/kg group because the results were not usable due to plasma preparation and method repeatability problems. 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 (Day 1 H00:00) 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. | 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 | The method is a clotting assay where all the clotting factors are present (constant and in excess, brought by the deficient plasma), excepted for FXI, which is brought by the diluted tested plasma, and clotting is triggered with cephalin, activator and calcium (aPTT). FXI is the limiting factor and clotting time is inversely proportional to the concentration of FXI. There is an inverse linear relationship between the percentage of FXI activity and the corresponding clotting time. Central laboratory normal ranges for Factor XI activity are between 65 and 150 %. Concerning the row titles, for example, Day 1 H02:00 corresponds to the percentage of FXI activity obtained on Day 1, 2 hours after the start of the infusion. | 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 | The method is a clotting assay where all the clotting factors are present (constant and in excess, brought by the deficient plasma), excepted for FXII, which is brought by the diluted tested plasma, and clotting is triggered with cephalin, activator and calcium (aPTT). FXII is the limiting factor and clotting time is inversely proportional to the concentration of FXII. There is an inverse linear relationship between the percentage of FXII activity and the corresponding clotting time. Central laboratory normal ranges for Factor XII activity are between 50 and 150 %. Concerning the row titles, for example, Day 1 H02:00 corresponds to the percentage of FXII activity obtained on Day 1, 2 hours after the start of the infusion. | 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) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Antithrombotic, Intrinsic coagulation pathway