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    Summary
    EudraCT Number:2021-004009-37
    Sponsor's Protocol Code Number:MD2021.01
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2021-09-30
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedNetherlands - Competent Authority
    A.2EudraCT number2021-004009-37
    A.3Full title of the trial
    A Phase 1/2 study of the dose-response in pharmacodynamics and safety of prothrombin complex concentrate Cofact in healthy subjects under vitamin K antagonist anticoagulation
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study investigating the efficacy and safety of a new version of the existing compound Cofact, in the treatment of blood clotting problems.
    A.4.1Sponsor's protocol code numberMD2021.01
    A.5.4Other Identifiers
    Name:CRO codeNumber:SQN21298-21298X
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorProthya Biosolutions BV
    B.1.3.4CountryNetherlands
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportProthya Biosolutions BV
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationProthya Biosolutions BV
    B.5.2Functional name of contact pointIlona Kleine Budde
    B.5.3 Address:
    B.5.3.1Street AddressPlesmanlaan 125
    B.5.3.2Town/ cityAmsterdam
    B.5.3.3Post code1066 CX
    B.5.3.4CountryNetherlands
    B.5.6E-maililona.kleinebudde@prothya.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Human prothrombin complex concentrate (PCC) (Cofact)
    D.2.1.1.2Name of the Marketing Authorisation holderSanquin Plasma Products
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameCofact
    D.3.2Product code N/A
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNN/A
    D.3.9.1CAS number 37224-63-8
    D.3.9.2Current sponsor codeCofact
    D.3.9.3Other descriptive namePROTHROMBIN COMPLEX CONCENTRATES
    D.3.9.4EV Substance CodeSUB33011
    D.3.10 Strength
    D.3.10.1Concentration unit IU international unit(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product Yes
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Treatment of bleeding and perioperative prophylaxis
    E.1.1.1Medical condition in easily understood language
    treatment of blood clotting problems
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10005103
    E.1.2Term Bleeding
    E.1.2System Organ Class 100000004866
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level PT
    E.1.2Classification code 10036898
    E.1.2Term Prophylaxis
    E.1.2System Organ Class 10042613 - Surgical and medical procedures
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Establish dose-response relationship for Cofact in vitamine K antagonist (VKA) reversal with respect to thrombin generation in subjects anticoagulated with warfarin therapy
    E.2.2Secondary objectives of the trial
    Kinetics of thrombin generation

    Assessment of global parameters of coagulation over 14 days

    To evaluate the effects of Cofact in healthy subjects receiving warfarin on biomarkers reflective of coagulation activation

    To assess the safety and tolerability of Cofact in healthy subjects receiving warfarin
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Sex : Male or female of nonchildbearing potential.
    2. Age : 18 to 55 years, inclusive, at screening.
    3. Body mass index (BMI) : 18.0 to 30.0 kg/m2, inclusive, at screening. Body weight is not less than 50 kg and not more than 100 kg.
    4. Status : Healthy subjects.
    5. Female subjects will be included if they are of nonchildbearing potential. Female subjects should have a documented history of tubal ligation more than 6 months prior to the onset of the study, or with a documented hysterectomy. Postmenopausal women will be included in the study if the postmenopausal status is confirmed with a history of 12 months uninterrupted spontaneous amenorrhea, or 6 months of spontaneous amenorrhea with serum follicle stimulating hormone (FSH) levels >40 mIU/ml, or 6 weeks postsurgical bilateral oophorectomy with or without hysterectomy.
    6. Male subjects, if not surgically sterilized, must agree to use adequate contraception and not donate sperm from first admission to the clinical research center until 90 days after the EOS visit. Adequate contraception for the male subject (and his female partner, if she is of childbearing potential) is defined as using hormonal contraceptives or an intrauterine device combined with at least 1 of the following forms of contraception: a diaphragm, a cervical cap, or a condom. Total abstinence from heterosexual intercourse, in accordance with the lifestyle of the subject, is also acceptable.
    7. Subjects should not be taking any prescribed medication for at least 14 days prior to first admission to the clinical research center.
    8. All over-the-counter medication, vitamin preparations and other food supplements, or herbal medications (eg, St. John’s wort) must have been stopped at least 5 days prior to first admission to the clinical research center.
    9. Ability and willingness to abstain from alcohol from 48 hours (2 days) prior to each admission into the clinical research center.
    10. Ability and willingness to consume no more than a total of 4 cups of methylxanthine-containing beverages or food (coffee, tea, cola, chocolate, energy drinks) and grapefruit (juice) from 48 hours (2 days) prior to the first admission to the clinical research center on Day -11, and from 48 hours (2 days) prior to Day -1.
    11. Good physical and mental health on the basis of medical history, physical examination, clinical laboratory, electrocardiogram (ECG), and vital signs, as judged by the Investigator.
    12. Computerized 12-lead ECG recording without signs of clinically relevant pathology or showing no clinically relevant deviations as judged by the Investigator. The ECG may be repeated if in the judgment of the Investigator there is a reason to believe the initial result is inaccurate.
    13. All values for clinical laboratory tests of blood and urine within the normal range or showing no clinically relevant deviations as judged by the Investigator. Clinical laboratory tests may be repeated if they are just out of range, or there is a reason to believe the initial results are inaccurate (eg, clumped platelets).
    14. Willing and able to sign the ICF.
    15. The INR is 2.0 to 3.0 ± 10% (ie, 1.8 to 3.3, inclusive) at least in one of the two INR measurements taken on Day 1 after acenocoumarol has been administered for 10 days. The INR is measured twice predose on Day 1, one via the blood draw and the other via the INR device.
    E.4Principal exclusion criteria
    1. Employee of PRA or the Sponsor.
    2. History of relevant drug and/or food allergies.
    3. Any of the following laboratory results outside of the ranges, at screening: lupus anticoagulants (LA screen) and/or anti-beta2-glycoprotein I, low levels of protein C (activity), low levels of protein S (activity), or low levels of antithrombin.
    4. Abnormal aPTT or PT levels, or Fe or ferritin levels.
    5. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamyl transferase (GGT), lactate dehydrogenase (LDH), alkaline phosphatase (ALP), and total bilirubin are not more than about 1.2 times the upper limit of normal at screening (per the Investigator’s discretion).
    6. Participants with thyroid disorders as evidenced by assessment of thyroid stimulating hormone (TSH) levels outside the normal reference range at screening.
    7. Prior history of thromboembolic complications including those in first degree relatives.
    8. Glomerular filtration rate (GFR) is lower than estimated GFR 62 mL/min/1.73 m2 using the Modification of Diet in Renal Disease Study equation.
    9. Anaphylactic or systemic reactions to human plasma, plasma products, or blood products.
    10. History of hypersensitivity to active or inactive excipients of acenocoumarol or drugs with a similar chemical structure or class.
    11. Gastrointestinal disease that may impair acenocoumarol absorption..
    12. On medication that may affect acenocoumarol activity, such as aspirin, acetaminophen (with prolonged use [longer than 4 days] and in high doses (4 g per day), antibiotics, antifungals, or allergy medication.
    13. Any regular medication involving hepatic metabolism, increasing risk for thrombosis, or otherwise affecting hemostasis.
    14. Significant psychiatric illness that could interfere with the ability to comprehend and comply with study procedures and ability to tolerate treatment as outlined in the protocol.
    15. Participation in another clinical study <30 days prior to study entry.
    16. Any clinically significant history of or current clinically significant other disease or disorder – gastrointestinal (including gastrointestinal bleeding of any origin), cardiovascular, respiratory, renal, hepatic, neurological, dermatological, psychiatric, or metabolic - as judged by the Investigator.
    17. Any clinically significant abnormality following the Investigator’s review of physical examination findings, and clinical laboratory tests obtained at screening.
    18. An abnormal pulse rate and/or blood pressure measurements at the screening visit: pulse rate <40 or >100 beats per minute (bpm); systolic blood pressure <90 or >140 mmHg; diastolic blood pressure <50 or >90 mmHg (to be confirmed by a second measurement, after subject has been resting in supine position for 5 min). If initial results do not meet these criteria, blood pressure and/or pulse may be repeated if in the judgment of the Investigator there is a reason to believe the initial result is inaccurate (eg, white coat hypertension).
    19. Whole blood or plasma donation of more than 100 mL within 30 days prior to administration of study medication or intended donation during the study.
    20. Judgment by the Investigator that the subject should not participate in the study because the subject is unlikely to comply with all study procedures and treatment.
    21. Unsuitable veins for infusion or blood sampling.
    22. Subjects who have not reached an INR of 2.0 to 3.0 ± 10% (ie, 1.8 to 3.3, inclusive) on at least 1 of the measurements on Day 1, after receiving acenocoumarol for 10 days.
    23. Positive nasopharyngeal PCR test for SARS-CoV-2 on Day -11, or at entry into the research center.
    24. Positive pregnancy test at screening, Day -11, or at entry into the research center.
    E.5 End points
    E.5.1Primary end point(s)
    Peak thrombin generation at 30 minutes after the end of the Cofact infusion (EOI)
    E.5.1.1Timepoint(s) of evaluation of this end point
    Throughout the study
    E.5.2Secondary end point(s)
    Change in ETP over 24 hours after the EOI (ETP measured at predose, at the EOI, and at 30 minutes, 1, 3, 6, 12, and 24 hours after the EOI), including lag time, time to peak thrombin, peak thrombin

    Changes in global assays of the blood coagulation markers: activated partial thromboplastin time (aPTT), prothrombin time (PT), and international normalized ratio (INR)

    Concentration over time of clotting factors: Factor II, Factor VII, Factor IX, Factor X, Protein C and Protein S

    Activation of blood coagulation, as indicated by markers prothrombin fragment 1+2, D-Dimer, and thrombin–antithrombin complexes (TATs)

    Changes in safety laboratory parameters

    Incidence of clinical adverse events (AEs) particularly related to thrombic complications
    E.5.2.1Timepoint(s) of evaluation of this end point
    Throughout the study
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy No
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    PD
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial4
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA2
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    Last subject last visit or last contact, whichever occurs last.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days3
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days3
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 120
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers Yes
    F.3.2Patients No
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state85
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 120
    F.4.2.2In the whole clinical trial 120
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    None
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2021-09-30
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-11-05
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2022-09-09
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