Open-Label, Randomised, Active Controlled, Multi-Centre Phase 3 Study Safety and Efficacy of Danaparoid vs Argatroban
- Conditions
- Heparin-induced Thrombocytopenia
- Interventions
- Registration Number
- NCT03809481
- Lead Sponsor
- Aspen Global Incorporated
- Brief Summary
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)
- 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 increase in platelet count to values ≥ 100,000/ μL at day 14
* 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 acuteHIT.
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.
Subjects who have tested negative in available screening tests for HIT within the last 48 hours before enrollment will not be considered for study enrollment, unless new clinical symptoms occurred.The following will occur for all subjects (regardless of whether they had a screening HIT test performed in the enrolling hospital or not):
1. All heparin administration must be ceased after strong clinical suspicion of HIT, based on clinical evaluation of the subject, including the use of heparin-bonded vascular access catheters and circuits as well as heparin flushes.
2. Subject must be randomized into the study and treated with the study drug or transferred to alternative non-heparin anticoagulant in situations where study drug cannot be started within 2 hours after stop of heparin.
3. A blood sample may be taken at the same time for HIT testing according to local practice.
4. The investigator will assess the subject for eligibility for the HITSOVA study by clinical criteria (4T score \>3) and inclusion and exclusion criteria.
5. If eligible, written informed consent will be obtained from the subject or a legal guardian and the subject will be randomized to receive study drug. .
6. A new blood sample for HIPA/ PF4/heparin IgG ELISA and anti-danaparoid antibodies and cross reactivity has to be obtained to allow consistent blood sample labelling and documentation before start of study drug, regardless whether another blood sample for HIT testing according to local practice had been obtained at the time of suspicion of HIT
Note, although use of non-heparin treatment for suspected HIT is allowed before enrollment of the subject into the HITSOVA study, the study drug should be started as soon as possible, but no later than 48 hours. In such situation, all time points specified in this protocol, will be calculated from the time of first dose of study drug.
HIT diagnosis will be confirmed serologically by the HIPA assay and a specific PF4/heparin IgG ELISA test for the HIT IgG by the nominated central laboratory based in Greifswald, Germany Subjects with a positive HIPA assay and a positive HIT IgG antigen test with optical density (OD) \> 0.5 will be classified as confirmed HIT, and treatment with randomized study drug will continue.Subjects with negative HIPA assay and a positive HIT IgG antigen test with an optical density (OD) \>0.5 and subjects with a positive HIPA assay but a negative HIT IgG antigen test OD ≤0.5 will be classified as suspected HIT and treatment with randomized study drug will continue. These subjects will later 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.
During the treatment period if it becomes necessary 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 suspected HIT by the HIPA assay or HIT IgG..
Clinical signs of HIT are
* New thrombosis, on either side (arterial or venous) of the circulation
* Acute systemic reaction when heparin infusion was given:
* Fever
* Chills
* High blood pressure
* Tachycardia
* Shortness of breath
* Chest pain
* Transient global amnesia
* White clot syndrome
* Skin necrosis
* Occlusion of an extracorporeal circuit
Pediatric subjects will not be included in every country in this study. The countries that allow inclusion of pediatric patients are France, USA,and Italy.
It is anticipated that some subjects will be dosed with alternative non-heparin anti-coagulants prior to completing enrollment steps for this study. These subjects can be enrolled in the study as long as the exposure to those treatments is less than 48 hours.
Baseline/screening (Day 0) and enrollment into the study (Day1) can occur on the same day. In this case the assesments for Day 0 and Day 1, should only be performed once.
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 7
Not provided
At the time of enrollmentsubjects are excluded from the study if any of the following criteria apply:
-
Premature infants (corrected age <37 weeks gestational age)
-
Subjects undergoing Extracorporeal Membrane Oxygenation (ECMO) treatment
-
Fibrinolytic therapy <24 hours before enrollment
-
Lumbar puncture or spinal/epidural catheter placement within the past 48 hours
-
Severe hepatic impairment (Child-Pugh Class C) Note: in patients with suspected/confirmed severe liver disease, Child-Pugh C stage of liver disease must be excluded before start of treatment. For calculating Child-Pugh score, laboratory parameters in the patient file on INR, prothrombin time, serum albumin and total bilirubin taken can be taken, if they have been obtained within the last 48 hours before randomization. In all other patients these parameters have to be measured before start of treatment to identify potential exclusion criteria.
-
Active bleeding
-
Subjects with the following conditions to be excluded if alternative antithrombotic treatments are available:
(i) Severe hemorrhagic diathesis, (ii) Traumatic damage to the central nervous system (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
-
An unexplained activated partial thromboplastin time (aPTT) > 2 x the normal range
-
A hemorrhagic cerebrovascular accident within the previous 3 months
-
Severe, uncontrolled hypertension defined as blood pressure >180/110 mmHg
-
Diabetic retinopathy
-
Acute bacterial endocarditis
-
Expectation of a long-term (> 3 weeks) hemodialysis requirement before the end of the acute treatment
-
Hypersensitivity to the active substances or to any of the excipients
-
Hypersensitivity to sulphite
-
Any investigational drug(s) use within 4 weeks preceding screening or anticipated use during the course of the study
-
Pregnant or breastfeeding woman
-
Use of intra-aortic balloon pump, or ventricular assist device
-
Use of any non-heparin anticoagulant treatment for suspected HIT for more than 48 hours before enrollment.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Danaparoid Sodium 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. Argatroban 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.
- Primary Outcome Measures
Name Time Method Composite Efficacy Response Day 44 Efficacy will be assessed by the number of subjects with suspected HIT who respond to treatment. A responder is defined as a subject who has not experienced any of the following from Day 1 to Day 44:
1. New or extended venous and/or arterial thrombosis, including gangrene/skin necrosis
2. All-cause mortality
3. Unplanned amputation, including ischemic gut resection
Efficacy endpoints as defined above will be assessed by clinical exam with special attention to assessments for thromboses, gangrene, and skin necrosis. Clinically suspected thrombosis will be confirmed/ruled out by objective measures, e.g. compression ultrasound.
- Secondary Outcome Measures
Name Time Method Major Bleeding Day 44 Incidence of fatal or non-fatal major bleeding
Consistent increases in platelet count Days 14 Percentage of subjects with increase in platelet count to values ≥ 100,000/ μL
Death due to TE or bleeding Day 44 Death due to TE or bleeding
New or extended thrombosis Day 44 New of extended thrombosis, including gangrene/skin necrosis
Unplanned amputation Day 44 Unplanned amputation, including ischemic gut resection
All-cause mortality Day 44 All-cause mortality
Trial Locations
- Locations (35)
Wojewódzki Szpital Zespolony im. L. Rydygiera
🇵🇱Toruń, Poland
The Ohio State University Wexner Medical Center
🇺🇸Columbus, Ohio, United States
University of Minnesota Medical Center
🇺🇸Minneapolis, Minnesota, United States
Duke University Medical Center
🇺🇸Durham, North Carolina, United States
The University of Texas MD Anderson Cancer Center
🇺🇸Houston, Texas, United States
Jewish General Hospital
🇨🇦Montréal, Canada
CHU St Etienne; Avenue Albert Raimond
🇫🇷Saint-Priest-en-Jarez, Rhone- Alpes, France
Vivantes Klinikum im Friedrichhain Hämophiliezentrum, Gerinnungssprechstunde Landsberger Allee 49
🇩🇪Berlin, Berlin-Brandenburg, Germany
Regional Hospital after N.N Burdenko
🇷🇺Penza, Russian Federation
Oncology Center
🇷🇺Omsk, Russian Federation
Städtisches Klinkum Dresden
🇩🇪Dresden, Saxony, Germany
First City Hospital N.A. E.E. Volosevich
🇷🇺Arkhangelsk, Russian Federation
Centre Hospitalier Universitaire Amiens Picardie
🇫🇷Amiens, Somme, France
University Clinical Centre of the Republic of Srpska, Clinic for cardiology
🇧🇦Banja Luka, Bosnia and Herzegovina
The Institute for Pulmonary Disease of Vojvodina, Pulmonary thromboembolism department
🇷🇸Novi Sad, Sremska Kamenica, Serbia
Clinical Center of the Republic of Srpska, Medical Intesnive Care Unit
🇧🇦Banja Luka, Republika Srpska, Bosnia and Herzegovina
Universitatstklinikum Halle (Saale), Medizinische Klinik III
🇩🇪Halle (Saale), Saxony-Anhalt, Germany
Clinical centre of Serbia, Clinic for Pulmonology
🇷🇸Belgrade, Serbia
Instiute of Cardiovascular Diseases "Dedinje"
🇷🇸Belgrade, Serbia
Moscow City Hospital 67
🇷🇺Moscow, Russian Federation
University Clinical Centre of the Republic of Srpska, Lung Clinic
🇧🇦Banja Luka, Bosnia and Herzegovina
Clinical Center University of Sarajevo, Clinic for Heart, Blood Vessels and Rheumatic Diseases
🇧🇦Sarajevo, Bosnia and Herzegovina
Clinical Center University of Sarajevo, Clinic for Lung Diseases
🇧🇦Sarajevo, Bosnia and Herzegovina
Universitätsklinikum Gießen und Marburg GmbH, Klinik für Herz-, Kinderherz- und Gefäßchirurgie Standort Gießen
🇩🇪Giesen, Lower Saxony, Germany
DIJON University Hospital
🇫🇷Dijon, Burgundy, France
Zentrum für Klinische Transfusionsmedizin
🇩🇪Tübingen, Germany
AOU Careggi, SOD Malattie Aterotrombotiche
🇮🇹Firenze, Florence, Italy
University Hospital Greifswald Dpt. of Hematology
🇩🇪Greifswald, Germany
Centrum Medyczne HCP Sp. z o.o. Szpital im. Św. Jana Pawła II
🇵🇱Poznań, Poland
Instituto Scientifico San Raffaele- Servizio Coagulazione e Centro Trombosi
🇮🇹Milano, Italy
ASST Papa Giovanni XIII, Servizio di Immunoematologia e Medicina Trasfusionale
🇮🇹Bergamo, Lombardy, Italy
Clinical Centre of Serbia, Clinic for Emergency Internal Medicine
🇷🇸Belgrade, Serbia
Clinical Hospital № 122 N. A. L.G. Sokolov
🇷🇺Saint Petersburg, Russian Federation
Azienda Ospedaliero Universitaria S.Orsola-Malpighi - UO Angiologia e Malattie della Coagulazione
🇮🇹Bologna, Emilia-Romagna, Italy
Shands University of Florida
🇺🇸Gainesville, Florida, United States