An Open-Label, Randomised, Active Controlled, Multi-Centre Phase 3 Study to Evaluate the Safety and Efficacy of Danaparoid vs Argatroban in Treatment of Subjects With Acute HIT

Overview

An Open-Label, Randomised, Active Controlled, Multi-Centre Phase 3 Study to Evaluate the Safety and Efficacy of Danaparoid vs Argatroban in Treatment of Subjects with Acute HIT (HITSOVA study)

Full Title of Study: “An Open-Label, Randomised, Active Controlled, Multi-Centre Phase 3 Study to Evaluate the Safety and Efficacy of Danaparoid vs Argatroban in Treatment of Subjects With Acute HIT (HITSOVA Study)”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: Single (Outcomes Assessor)
  • Study Primary Completion Date: October 2020

Detailed Description

Objectives:

Primary:

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. 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

Secondary/Exploratory:

To collect additional efficacy data

- 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

To describe the safety of danaparoid in comparison to argatroban

- 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

Design: This is a Phase 3, open-label, randomized, active-controlled, multi-center study to evaluate the safety and efficacy of danaparoid versus argatroban in treatment of subjects with acute HIT. If available, a screening HIT test will be performed for subjects who may be eligible to participate in the study. Subjects who test negative using the in-house screening test will not be considered for study enrollment.

If the test is not available and for those that tested positive using the test, subjects who develop a reduction in platelet count (PC) greater than or equal to 30% compared with the higher of their pre-heparin treatment count or their highest platelet count after the start of heparin either

1. Between Days 4 and 14 of the start of heparin treatment with or without thrombosis OR

2. At Day 1 of heparin treatment and recent heparin exposure (within the last 30 days with or without thrombosis) and who have a score on the 4Ts test of >3 will be considered for study enrollment as a Suspected HIT.

- The following will occur for all subjects (regardless of whether they had a screening HIT test performed in the enrolling hospital or not): All heparin administration must immediately cease including the use of heparin-bonded vascular access catheters and circuits as well as heparin flushes.

- The subject will be randomized to receive 1 of the 2 study drugs after written informed consent has been obtained

- The subject will initiate the treatment based on clinical evaluation of the Investigator, at the same time a blood sample for HIT anti- antibodies and cross reactivity will be obtained

HIT diagnosis will be determined by clinical signs suggestive of HIT and confirmed serologically by the HIPA assay and a specific ELISA test for the HIT IgG.

Subjects with a positive HIPA assay and IgG antigen test with optical density (OD) > 0.5will be classified as Confirmed HIT and treatment with randomized study drug will continue.

Subjects with negative HIPA assay and a strongly positive HIT IgG antigen test with an optical density (OD) >1.5 and a 4Ts score >3 will be classified as suspected HIT and treatment with randomized study drug will continue. These subjects will be adjudicated retrospectively by the Adjudication Committee (AdjC) and then grouped into highly likely HIT or non-HIT.

All other subjects will be considered as non-HIT and the subjects will be removed from the protocol, study drug will be discontinued, and further procedures and treatment will be given at the discretion of the Investigator according to local standard practice. These subjects will be followed to Day 44 after their first dose of study drug for assessment of safety If it becomes necessary during the treatment period for an operation, invasive vascular procedure or acute kidney injury requiring the use of an extracorporeal circulation machine develops, then specific dosing instructions are available.

If the acute kidney injury does not recover during the treatment period and the use of an extracorporeal circulation machine is required longer, then the subject will not be eligible to be included in the per protocol set (PPS), but will still be eligible to be included in the full analysis set (FAS).

Study Population: All subjects who develop a reduction in platelet count (PC) ≥ 30% compared to the higher of their pre-heparin treatment count or their highest platelet count after the start of heparin at either a) between Days 4 and 14 of the start of heparin treatment with or without thrombosis or b) at Day 1 of heparin treatment (and recent heparin exposure within the last 30 days) with or without thrombosis and who have a score on the 4Ts test of >3 and who are later confirmed to have HIT or highly likely HIT by the HIPA assay or HIT IgG or by the AdjC If available, a screening HIT test will be performed on subjects by the laboratory of the enrolling hospital and subjects testing negative will not be enrolled . Clinical signs of HIT are:

- New thrombosis, especially on both sides of the circulation

- Acute systemic reaction when heparin bolus was given

- Transient global amnesia

- White clot syndrome

- Skin necrosis

- Occlusion of an extracorporeal circuit

Interventions

  • Drug: Danaparoid Sodium
    • inhibits thrombin generation by indirect anti-Xa inhibition and direct inhibition of factor IX activation
  • Drug: Argatroban
    • Synthetic direct thrombin inhibitor

Arms, Groups and Cohorts

  • Experimental: Danaparoid Sodium
    • Subjects will receive danaparoid via IV infusion for at least 7 days then transition to a VKA. IV loading bolus injection of 2250 U, followed by 400 U/h for 4 hours, then 300 U/h for 4 hours, then a maintenance infusion of 150-200 U/h.
  • Active Comparator: Argatroban
    • Subjects will receive argatroban 2 microgram/kg/min as a continuous infusion, titrated to an aPTT that is 1.5 to 3.0 x initial baseline value, but not exceeding 100 seconds.

Clinical Trial Outcome Measures

Primary Measures

  • Composite Efficacy Response
    • Time Frame: Day 44
    • A subject will be considered a treatment responder if none of the following occur: New or extended thrombosis, all-cause mortality, unplanned amputation

Secondary Measures

  • Consistent increases in platelet count
    • Time Frame: Days 3, 5, and 7
    • Consistent increases in platelets at days 3, 5, and 7
  • Death due to TE or bleeding
    • Time Frame: Day 44
    • Death due to TE or bleedin
  • Major Bleeding
    • Time Frame: Day 44
    • Fatal or non-fatal bleeding
  • New or extended thrombosis
    • Time Frame: Day 44
    • New of extended thrombosis, including gangrene/skin necrosis
  • Unplanned amputation
    • Time Frame: Day 44
    • Unplanned amputation, including ischemic gut resection
  • All-cause mortality
    • Time Frame: Day 44
    • All-cause mortality

Participating in This Clinical Trial

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:

1. Between Day 4 and 14 of the start of heparin exposure or

2. 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:

1. Not a woman of childbearing potential OR

2. 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

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 central nervous system (iii) Brain, spinal or ophthalmologic surgery are to be excluded if alternative antithrombotic treatments are available.

(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

Gender Eligibility: All

Minimum Age: N/A

Maximum Age: 100 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Aspen Global Incorporated
  • Provider of Information About this Clinical Study
    • Sponsor

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