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    Summary
    EudraCT Number:2014-004416-11
    Sponsor's Protocol Code Number:TVOC01
    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:2015-04-15
    Trial results View 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 number2014-004416-11
    A.3Full title of the trial
    A Multi-Centre, Phase II, Randomized, Double-Blind, Placebo-Controlled Study to Investigate Efficacy and Safety of Sevuparin Infusion for the Management of Acute Vaso-Occlusive Crisis (VOC) in Subjects with Sickle-Cell Disease (SCD)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Study to Explore Sevuparin Infusion for the Management of Acute Vaso-Occlusive Crisis (VOC) in Subjects with Sickle-Cell Disease (SCD)
    A.4.1Sponsor's protocol code numberTVOC01
    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 SponsorModus Therapeutics AB
    B.1.3.4CountrySweden
    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 supportModus Therapeutics AB
    B.4.2CountrySweden
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationModus Therapeutics AB
    B.5.2Functional name of contact pointMaria Klockare
    B.5.3 Address:
    B.5.3.1Street AddressSankt Eriksgatan 117
    B.5.3.2Town/ city Stockholm
    B.5.3.3Post codeSE-113 43
    B.5.3.4CountrySweden
    B.5.4Telephone number+46 706232505
    B.5.6E-mailmaria.klockare@modustx.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 No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEMA/OD/210/14, EMA/COMP/716539/2014
    D.3 Description of the IMP
    D.3.1Product nameSevuparin
    D.3.2Product code DF02
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous bolus use (Noncurrent)
    Intravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNsevuparin sodium
    D.3.9.2Current sponsor codeDF02
    D.3.9.3Other descriptive nameSEVUPARIN
    D.3.9.4EV Substance CodeSUB171360
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number150
    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 No
    D.3.11.8Extractive medicinal product Yes
    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
    Acute Vaso-Occlusive Crisis (VOC) in Subjects with Sickle-Cell Disease
    E.1.1.1Medical condition in easily understood language
    Acute Vaso-Occlusive Crisis in Subjects with Sickle-Cell Disease
    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 10040644
    E.1.2Term Sickle cell disease
    E.1.2System Organ Class 100000004850
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of this study is to assess the time to painful VOC resolution, measured from first dose given to achievement of crises resolution, as compared to placebo.
    E.2.2Secondary objectives of the trial
    1. Safety+tolerability
    2. Time to discharge (between 1. study drug dose and discharge)
    3. Time to readiness for discharge, as judged by the subject/investigator
    4. Time to discontinuation of IV opioids
    5. Time from start of infusion to 25%, 50% +75% of subjects achieving VOC resolution
    6. Proportion of subjects with VOC resolution achieved at 24, 48, 72, 96 and 120h
    7. Clinical+subject global impression of change
    8. Pain intensity assessment on VAS
    9. Duration of severest pain, defined as time to a >30% reduction in VAS pain score from baseline (maintained during 8h)
    10. Use of parenteral opioids (accumulated opioid consumption)
    11. Use of parenteral opioids (accumulated opioid consumption as average per 24h after first dose of study drug) until VOC resolution/readiness of discharge
    12. Re-occurrence of hospitalisation for VOC within 3 or 28 days from resolution of 1.VOC
    13. PK of sevuparin during and after administration of sevuparin as continuous IV infusion (subgroup)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Sign a written informed consent (adults, parents) and assent (adolescents).
    2. Male or female, age 12-50 years.
    3. Diagnosis of Sickle cell disease, types HbSS, HbSC, Hb O Arab, HbSβ0-thalassemia or HbSβ+-thalassemia (SCD type to be confirmed by liquid chromatography or other method of comparable reliability during the study, if confirmation is not available at time of inclusion)
    4. Subjects admitted for an acute, painful VOC to be treated/or treated with parenteral opioid analgesia at the time of admission. VOC is defined as an episode of pain that led to a clinic or emergency department visit, and cannot be explained except by SCD. Please note: Study treatment should start as soon as possible and at latest within 24 hours from the time of the decision to hospitalize the subject.
    5. Expectancy of need for hospitalization during at least 48 hours.
    6. Be at least 1 year postmenopausal, surgically sterile, or if WOCBP, e.g. following menarche practicing an effective method of birth control (e.g. oral contraception, intrauterine device, or diaphragm with spermicide; or double barrier method) during study drug administration and one month following treatment completion.
    E.4Principal exclusion criteria
    1. Severe hepatic failure/disease or liver enzyme tests (AST and ALT) above 2 times the upper limit of normal (ULN) range, or clinically significant impairment of liver function due to HBV, HCV or other liver diseases.
    2. Conjugated (direct) bilirubin 3 fold above ULN.
    3. History of clinically significant bleeding in vital organs (not due to relevant trauma), or pathological bleeding.
    4. Current clinically significant bleeding, as judged by the investigator.
    5. Current use of ASA, anti-platelet therapy, anticoagulant therapy and prophylactic and therapeutic LMWH or un-fractioned heparin.
    6. APTT above normal range , and INR above 1.4.
    7. A platelet count < 75,000/µL.
    8. BMI >35
    9. Subjects with more than 5 hospitalizations for VOC during the last 6 months (to exclude subjects with exacerbations of chronic pain rather than true vaso-occlusion).
    10. Evidence of acute SCD complications other than VOC at screening (CVA, ACS, multi-organ failure).
    11. The use of strong opioids for > 3 consecutive days during the last 15 days before presenting to hospital.
    12. History of chronic drug abuse.
    13. Renal dysfunction (GFR< 60 ml/min), calculated per Cockcroft-Gault formula
    14. Known infection with HIV, and active infection with HBV or HCV.
    15. Significant ECG abnormality including QTcf > 450 msec
    16. History of a clinically significant drug allergy to heparin, LMWH’s or sevuparin.
    17. Use of any investigational agent during the 30 days prior to the first dose.
    18. For females: pregnancy, lactating or intention of becoming pregnant within the next 40 days.
    19. Evidence of clinically significant disorders that might interfere with the study aim or safety of the subject, as judged by the Investigator: e.g. neurological, psychiatric (depression, psychosis or schizophrenia), cardiovascular (including arrhythmia), pulmonary, metabolic, gastrointestinal, endocrine diseases, coagulation or malignancies.
    20. Any condition that, in the view of the Investigator, places the subject at high risk of poor treatment compliance or of not completing the study
    E.5 End points
    E.5.1Primary end point(s)
    Time from start of infusion until resolution of crisis/episode is defined as fulfillment of the two following criteria:
    a) freedom from parenteral opioid use (in preceding 8 hours)
    b) readiness for discharge as judged by the subject or physician
    E.5.1.1Timepoint(s) of evaluation of this end point
    at each study visit
    E.5.2Secondary end point(s)
    1. Frequency and pattern of treatment emergent adverse events (TEAEs)
    2. Time to discharge (number of hours between the first study drug dose given and discharge).
    3. Time to readiness for discharge, as judged by the subject or investigator (number of hours between the first study drug dose given and time point at which subjects feels readiness or investigator judges readiness for discharge from the hospital). The assessment will be done every 4 hours during time awake, starting from the time when the subject has been without parenteral opioids for 8 hours
    4. Time to discontinuation of IV opioids (number of hours between the first study drug dose given and discontinuation of parenteral opioids)
    5. Time from start of infusion to 25%, 50% and 75% of subjects achieving VOC resolution
    6. Proportion of subjects with VOC resolution achieved at 24, 48, 72, 96 and 120 hours.
    7. Clinical Global Impression of Change, measured once daily starting on day 3 until VOC resolution
    8. Patient Global Impression of Change, measured once daily starting on day 3 until VOC resolution
    9. Pain intensity assessment on VAS from the start of study treatment (first assessment within 30 minutes prior to infusion treatment) and thereafter every 4 hours during time awake, until VOC resolution
    10. Duration of severest pain, defined as time to a 30% reduction in VAS pain score from baseline (maintained for 8 hours)
    11. Amount of parenteral opioids (accumulated opioid consumption) until VOC resolution/readiness for discharge.
    12. Amount of parenteral opioids (accumulated opioid consumption as average per 24h after first dose of study drug) until VOC resolution/readiness for discharge.
    13. Re-occurrence of hospitalisation for VOC within 3 days, or 28 days from resolution of first VOC.
    14. PK characteristics of sevuparin during and after administration of sevuparin as a continuous IV infusion (subgroup).
    E.5.2.1Timepoint(s) of evaluation of this end point
    at each study visit
    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 Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    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) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    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 No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    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 trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA6
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Bahrain
    Belgium
    Jamaica
    Lebanon
    Netherlands
    Oman
    Saudi Arabia
    Turkey
    E.8.7Trial has a data monitoring committee Yes
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months9
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months9
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 40
    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) Yes
    F.1.1.6.1Number of subjects for this age range: 40
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 93
    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 No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation Yes
    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 state30
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 30
    F.4.2.2In the whole clinical trial 133
    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)
    Standard of Care
    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 Decision2015-04-15
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-08-25
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2019-02-10
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