API-AHAI - Efficacy of Prolonged Anticoagulation for Primary Prevention of Venous Thromboembolic Disease in Autoimmune Hemolytic Anemia: a Prospective, Phase II, Randomized, Multicenter Study

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Centre Hospitalier Universitaire De Dijon

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Immune System Diseases [C20]

Trial duration

3 Feb 2022 → ongoing

Decision date (initial)

2024-07-15

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

External identifiers

EU CT number

2024-513191-17-00

EudraCT number

2021-002358-99

ClinicalTrials.gov

NCT05089227

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy

To evaluate the efficacy of prolonged prophylactic anticoagulation for 12 weeks with heparin therapy (enoxaparin 4000 IU/day subcutaneously) during hospitalization followed by oral anticoagulation with apixaban (2.5 mg morning and evening), on the occurrence of venous thromboembolism (VTE) at 24 weeks in patients with warm-type autoantibody AIHA at diagnosis or relapse.

Secondary objectives 4

1. Describe the time to onset of thromboembolic events
2. Study the tolerability of apixaban in prophylactic doses
3. Describe biological markers of thromboembolic risk in AIHA
4. Exploratory: compare VTE frequency and time to onset between intervention and standard arms

Conditions and MedDRA coding

autoimmune hemolytic anemia

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 5

1. Patient who provided free, written and informed consent
2. Patient aged ≥ 18 years
3. Patient with a diagnosis of primary or secondary autoimmune hemolytic anemia (AIHA) (infections, hematologic diseases, systemic diseases), according to the following criteria: - Hemoglobin <12 g/dL - and decreased haptoglobin (<0,4 g/L) - and positive direct antiglobulin test (direct Coombs test) (IgG +/- C3d)
4. Newly diagnosed or relapsed patient (relapse is defined as a decrease in basal hemoglobin in association with AIHA - thus meeting the above criteria: Hb <12 g/dl and haptoglobin <0.4 g/L and IgG-positive TDA with or without C3d - and for whom the investigator deems it necessary to initiate etiological treatment specific to AIHA)
5. Patient with an estimated life expectancy of more than 6 months

Exclusion criteria 20

1. Patients with immediate symptomatic VTE, confirmed by appropriate complementary examinations (venous Doppler of the lower limbs, thoracic CT angiography or pulmonary scintigraphy).
2. Patients on curative anticoagulation (VTE, atrial fibrillation)
3. Patient on dual antiplatelet treatment
4. Patient with active bleeding
5. Patient with a known condition or lesion at risk of bleeding
6. Patient with ischemic stroke with hemorrhagic transformation within 6 months prior to inclusion
7. Patient on preventive anticoagulation for 14 days or more
8. Patient with a contraindication to apixaban: - Known hypersensitivity to the molecule or to any of the excipients, - thrombocytopenia <100 G/L, - kidney failure (glomerular filtration rate < 30 ml/min/1.73m²), - Active liver disease (liver failure defined as Factor V <50% or INR >1.5, ALT elevation >2 times the upper limit of normal)
9. Patients receiving concomitant treatment with potent CYP3A4 inducers (rifampicin, phenytoin, carbamazepine, phenobarbital, St. John's wort) or potent CYP3A4 inhibitors (azole antifungals, HIV protease inhibitors), if these treatments cannot be discontinued or modified.
10. Patients with a contraindication to enoxaparin: - hypersensitivity to enoxaparin sodium, heparin or its derivatives, including other low-molecular-weight heparins (LMWH), or to any of the excipients, - history of heparin-induced thrombocytopenia
11. Patient with cold agglutinin-related AIHA (C3d-positive ADT alone with identification of cold agglutinins)
12. Patient with severe hemostasis disorders: - hypofibrinogenemia < 2 g/L, - disseminated intravascular coagulation (APTT prolongation >1.2, and PT <50%, and thrombocytopenia <100 G/L, and D-Dimer >500 μg/L) - hemophilia
13. Patient whose clinical condition requires hospitalization in an intensive care unit
14. Patient who has already participated in the study
15. Patient not affiliated to national health insurance
16. Patient under legal protection (curatorship, guardianship)
17. Patient subject to a court order
18. Pregnant, parturient or breastfeeding women
19. Patient with physiological capacity to procreate (having had her first menstrual period and not menopausal and not presenting permanent sterility (hysterectomy, bilateral salpingectomy, bilateral oophorectomy)) and unable to have effective contraception (i.e., provided by an estrogenprogestin oral contraceptive or progestogen, a contraceptive implant, an intrauterine device or a tubal ligation)
20. Patient of legal age who is unable to provide consent

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Occurrence of clinical venous thromboembolic events (deep vein thrombosis (DVT) and pulmonary embolism (PE)) within 24 weeks of randomization defined by the presence of DVT confirmed by venous Doppler and/or PE confirmed by thoracic CT angiography or ventilation/perfusion lung scintigraphy.

Secondary endpoints 8

1. Time to onset of venous thromboembolic events within 24 weeks of AIHA diagnosis or relapse
2. Occurrence of AE and SAE:Occurrence of a major hemorrhagic event, defined by the ISTH as clinically significant acute bleeding associated with one or more of the following: decrease in hemoglobin level of more than 2 g/dL or transfusion of at least 2 packed red blood cells (provided transfusion is not justified by AIHA), hemorrhage at a critical site (cerebral, spinal cord, retroperitoneal, intraocular, muscular with compartment syndrome, pericardial) or resulting in death
3. Occurrence of AE and SAE: Clinically significant non-major bleeding, defined as bleeding which does not meet the criteria for a major bleeding event, but which requires either medical attention or unscheduled medical contact (consultation or telephone), or which necessitates transient or permanent discontinuation of treatment, or which is responsible for discomfort or a reduction in the patient's quality of life.
4. Occurrence of AE and SAE: Minor bleeding defined as any bleeding that does not meet the criteria for major or clinically significant non-major bleeding.
5. Occurrence of AE and SAE: Any major cardiovascular event, whether fatal or not
6. Occurrence of AE and SAE: Other adverse events: splanchnic venous thrombosis
7. Occurrence of death
8. Determination of biological factors that may contribute to or be correlated with thromboembolic risk (D-dimer, sCD163, plasma hemoglobin, NETose, etc.)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Auxiliary 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Centre Hospitalier Universitaire De Dijon

Sponsor organisation

Centre Hospitalier Universitaire De Dijon

Address

1 Boulevard Jeanne D Arc, Bp 77908 Bp 77908

City

Dijon

Postcode

21000

Country

France

Scientific contact point

Organisation

Centre Hospitalier Universitaire De Dijon

Contact name

Chef de projets recherche

Public contact point

Organisation

Centre Hospitalier Universitaire De Dijon

Contact name

Chef de projets recherche

Locations

1 EU/EEA country · 14 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 7 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications