E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Acute Vaso-Occlusive Crisis (VOC) in Subjects with Sickle-Cell Disease |
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E.1.1.1 | Medical condition in easily understood language |
Acute Vaso-Occlusive Crisis in Subjects with Sickle-Cell Disease |
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E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10040644 |
E.1.2 | Term | Sickle cell disease |
E.1.2 | System Organ Class | 100000004850 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main 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. |
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E.2.2 | Secondary 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) |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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. |
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E.4 | Principal 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
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E.5 End points |
E.5.1 | Primary 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
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary 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).
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 6 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If 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 |
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E.8.7 | Trial 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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 9 |
E.8.9.2 | In all countries concerned by the trial days | 0 |