E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Acute Heparin-induced Thrombocytopenia (HIT) |
|
E.1.1.1 | Medical condition in easily understood language |
Acute Heparin-induced Thrombocytopenia (HIT) |
|
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 | PT |
E.1.2 | Classification code | 10062506 |
E.1.2 | Term | Heparin-induced thrombocytopenia |
E.1.2 | System Organ Class | 10005329 - Blood and lymphatic system disorders |
|
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To show that for the treatment of subjects with acute heparin-induced thrombocytopenia (HIT) danaparoid use is not inferior to argatroban in terms of efficacy. |
|
E.2.2 | Secondary objectives of the trial |
To collect additional efficacy data To describe the safety of danaparoid in comparison to argatroban |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
At the time of enrolment subjects are eligible to be included in the study only if all of the following criteria apply: 1. Signed written informed consent by the subject, or if the subject is temporarily unable to do so, then consent will be sought from a family member, or a legally accepted representative as per local regulations 2. Males or females aged ≥2 weeks 3. Subjects with suspected HIT by 4Ts of >3 and with reduction of platelet count of >30% at either: a) between day 4 and 14 of the start of heparin exposure or b) at Day 1 of heparin exposure with pre-treatment with heparin within the last 30 days, with or without thrombosis. 4. Have adequate renal function: Glomerular filtration rate ≥ 15 mL/min/1.73 m2 5. Male participants: A male participant must agree to use contraception during the treatment period and for at least 5 days after the last dose of study intervention and refrain from donating sperm during this period. 6. Female participants: A female participant is eligible to participate if 1 of the following conditions applies: a. Not a woman of childbearing potential OR b. A woman of childbearing potential who agrees to follow the contraceptive guidance during the treatment period and for at least 5 days corresponding to time needed to eliminate study intervention. (Subjects taking oral contraceptives or hormone replacement therapy must have a stable dose and regimen for ≥ 3 months prior to entry into the study.) 7. Understanding/willingness by the subject or his/her legally accepted representative to participate in the clinical study and ability to comply with study procedures and the study visit schedule
|
|
E.4 | Principal exclusion criteria |
At the time of enrolment subjects are excluded from the study if any of the following criteria apply: 1. Premature infants (corrected age <37 weeks gestational age) 2. Expectation of cardiac surgery within the next 44 days 3. Life expectancy clearly less than the 44 days 4. Fibrinolytic therapy <24 hours before enrolment 5. Lumbar puncture or spinal/epidural catheter placement within the past 48 hours 6. Severe hepatic impairment (Child-Pugh Class C) 7. Active bleeding 8. Subjects with the following conditions to be excluded if alternative antithrombotic treatments are available: (i) severe hemorrhagic diathesis (ii) damage to the CNS (iii) brain, spinal or ophthalmologic surgery (iv) active stomach/duodenal ulcers or active peptic ulcer unless this ulcer is the cause of the surgical procedure 9. An unexplained activated partial thromboplastin time (aPTT) > 2 x the normal range 10. A hemorrhagic cerebrovascular accident within the previous 3 months 11. Severe, uncontrolled hypertension defined as blood pressure >180/110 mmHg 12. Diabetic retinopathy 13. Acute bacterial endocarditis 14. Expectation of a long-term (> 3 weeks) hemodialysis requirement before the end of the acute treatment 15. Hypersensitivity to the active substances or to any of the excipients 16. Hypersensitivity to sulphite 17. Any investigational drug(s) use within 4 weeks preceding Screening or anticipated use during the course of the study 18. Pregnant or breastfeeding woman 19. Use of intra-aortic balloon pump, or ventricular assist device
|
|
E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint (composite endpoint) is defined as treatment response at Day 44. A subject will be considered a treatment responder, if none of the following events occur by Day 44: • New or extended venous and/or arterial thrombosis, including gangrene/skin necrosis Note: ‘thrombosis’ denotes venous and/or arterial here and throughout the protocol • All-cause mortality • Unplanned amputation, including ischemic gut resection
|
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
E.5.2 | Secondary end point(s) |
Secondary • Percentage of subjects with consistent increases in platelets at days 3, 5, and 7 (evidence of early response), defined as monotonically increasing platelet counts, measured 2 days apart on days 3 (±1 day), 5 (±1 day) and 7 (±1 day). • Deaths due to TE or bleeding up until Day 44 • Incidence of fatal or non-fatal major bleeding up until Day 44 Note: As outlined by the Control of Anticoagulation Subcommittee major bleeding in non-surgical subjects is defined as: 1. Fatal bleeding, and/or 2. Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intra-articular or pericardial, or intramuscular with compartment syndrome, and/or 3. Bleeding causing a fall in hemoglobin level of 20 g/L (1.24 mmol/ L) or more, or leading to transfusion of two or more units of whole blood or red cells • New or extended thrombosis, including gangrene/skin necrosis • Unplanned amputation, including ischemic gut resection • All-cause mortality Exploratory • Time to first event (new/extended thrombosis, all cause mortality, unplanned amputation) • Time to reach consistent increase in 3 consecutive alternate day platelet count measurements during acute treatment • Incidence of new or extended TE events, including gangrene/skin necrosis up until Day 14 • Incidence of all-cause mortality up until Day 14 • Incidence of unplanned amputation up until Day 14 • Incidence of fatal or non-fatal major bleeding up until Day 14 • All-cause mortality • Incidence of fatal and non-fatal major bleeding events (as defined above) during the acute treatment and then the entire follow-up period (until Day 44) • Incidence of serious adverse events (SAEs) • Incidence of adverse events (AEs) • Changes in vital parameters (heart rate, blood pressure, and respiratory rate) and 12-lead electrocardiogram (ECG) • Incidence of positive pre-danaparoid cross reactivity in the Heparin-induced Platelet Activation (HIPA) assay (Greinacher, 1991) • Safety laboratory parameters
|
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Increases in platelets at days 3,5,7 Death until Day 44 Bleeding at Day 44 Time to first bleeding Time to reach consistent increase in 3 consecutive alternate day platelet count measurements during acute treatment Incidence of new event until Day 14 |
|
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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
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 | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
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) | Yes |
E.8.2.2 | Placebo | No |
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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 54 |
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 |
Bosnia and Herzegovina |
Bulgaria |
Canada |
Croatia |
Czech Republic |
France |
Germany |
Hungary |
Italy |
Poland |
Russian Federation |
Serbia |
Spain |
United States |
|
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
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |