Clinical trial NCT04400799: Enoxaparin for Primary Thromboprophylaxis in Ambulatory Patients With COVID-19
Official title: Enoxaparin for Primary Thromboprophylaxis in Ambulatory Patients With Coronavirus: The Multicenter Randomized Controlled Ovid Trial
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: COVID-19
Pulmonary Embolism, Deep Vein Thrombosis
Lead sponsor: University of Zurich
Sponsor class: OTHER
Collaborators: name: Insel Gruppe AG, University Hospital Bern
name: University Hospital, Geneva
name: Centre Hospitalier Universitaire Vaudois
name: University Hospital, Basel, Switzerland
name: Oncology Institute of Southern Switzerland
name: Clinica Luganese Moncucco
name: University Hospital Freiburg
name: Mainz University
First posted: 2020-05-26
Enrollment: 475
Sex: ALL
Minimum age (years): 50
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The OVID study will show whether prophylactic-dose enoxaparin improves survival and reduces unplanned hospitalizations in ambulatory patients aged 50 or older diagnosed with COVID-19, a novel viral disease characterized by severe systemic, pulmonary, and vessel inflammation and coagulation activation.

Detailed description: The following points represent, in summary, the rationale for studying the use of thromboprophylaxis in ambulatory patients with COVID-19:

1. The risk of thromboembolic events in patients with COVID-19 during anticoagulant prophylaxis exceeds that observed in medical patients, usually \<3%, even in the presence of seasonal viral infections
2. The cumulative risk of VTE in hospitalized COVID-19 patients is at least 20%, but possibly higher, as described in several publications
3. The absolute VTE risk in COVID-19 patients requiring intensive care is 69% if screening strategies are implemented
4. Half of the VTE events, mostly PE, were diagnosed at hospital admission, suggesting that these events developed during the quarantine period.

Our hypothesis is that early thromboprophylaxis may prevent or limit coagulopathy, and reduce thromboembolic complications leading to hospitalization or death, in the presence of a mild COVID disease among outpatients.

The study will be conducted as a multicentre randomized open-label controlled trial. In the study, a total of 1,000 adult patients aged 50 or older with COVID-19 and candidates to ambulatory treatment will be randomized to receive enoxaparin 40 mg sc qD or no treatment for a total of 14 days. The primary outcome will be assessed within 30 days of enrolment.

We implemented two logistical solutions to integrate the process of SARS-CoV2 testing, pre-screening, screening (hot-line and flyers), in-hospital recruitment, enrolment and randomization/allocation. A nationwide OVID Hot-Line telephone number will be made available in 3 languages (German, French, Italian) for interested patients or test centers to contact the Hot-Line. Standard hygiene precautions will be met at the study centers to avoid spreading of SARS-CoV2 among other patients or health care workers. Principles of patient and investigator safety will be applied. Standard procedures concerning privacy, discussion with patients on details of the study, collection of informed consent, and instruction on how to administer the study medication will be maintained in conformity with GCP recommendations. This will also include outcome measurements to be conducted by telephone with standardized questionnaire.

Enoxaparin (Clexane®) will be given at the recommended dose of 4,000 IU antiXa activity (40 mg/0.4 ml) once daily by SC injection for 14 days.

A single interim analysis is planned at time when the outcomes of 50% of the patients (n=460 plus drop-outs) have been observed (anticipated in February 2022).

Eligibility criteria: Inclusion Criteria:

1. Patients aged 50 years or older with a positive test for SARS-CoV2 in the past 5 days and eligible for ambulatory treatment.
2. Presence of respiratory symptoms (i.e. cough, sore throat, or shortness of breath) or body temperature \>37.5° C.
3. Ability of the patient to travel to the study center by private transportation, performed either by accompanying person from same household or by the patient him/herself
4. Ability to comply with standard hygiene requirements at the time of in-hospital visit, including a face mask and hand disinfectant.
5. Ability to walk from car to study center or reach it using a wheel chair transport with the help of an accompanying person from the same household also complying with standard hygiene requirements.
6. Ability to self-administer prefilled enoxaparin injections after instructions received at the study center or availability of a person living with the patient to administer enoxaparin.

Exclusion Criteria:

1. Any acute or chronic condition posing an indication for anticoagulant treatment, e.g. atrial fibrillation, prior VTE, acute confirmed symptomatic VTE, acute coronary syndrome.
2. Anticoagulant thromboprophylaxis deemed necessary in view of the patient's history, comorbidity or predisposing strong risk factors for thrombosis:

   1. Any of the following events occurring in the prior 30 days: fracture of lower limb, hospitalization for heart failure, hip/knee replacement, major trauma, spinal cord injury, stroke,
   2. previous VTE,
   3. histologically confirmed malignancy, which was diagnosed or treated (surgery, chemotherapy, radiotherapy) in the past 6 months, or recurrent, or metastatic, or inoperable.
3. Any clinically relevant bleeding (defined as bleeding requiring hospitalization, transfusion, surgical intervention, invasive procedures, occurring in a critical anatomical site, or causing disability) within 30 days prior to randomization or sign of acute bleeding.
4. Intracerebral bleeding at any time in the past or signs/symptoms consistent with acute intracranial hemorrhage.
5. Hemoglobin \<8 g/dL and platelet count \<50 x 109 cells/L confirmed by recent laboratory test (\<90 days).
6. Subjects with any known coagulopathy or bleeding diathesis, including known significant liver disease associated with coagulopathy.
7. Severe renal insufficiency (baseline creatinine clearance \<30 mL/min calculated using the Cockcroft-Gault formula) confirmed by recent laboratory test (\<90 days).
8. Contraindications to enoxaparin therapy, including prior heparin-induced thrombocytopenia and known hypersensitivity.
9. Current use of dual antiplatelet therapy.
10. Participation in other interventional studies over the past 30 days.
11. Non-compliance or inability to adhere to treatment or lack of a family environment or support system for home treatment.

Primary outcomes:
measure: hospitalizations
timeFrame: 30 days
measure: all-cause death
timeFrame: 30 days
Secondary outcomes:
measure: Number of cardiovascular events
timeFrame: within 14 days, 30 days, and 90 days of randomization
measure: any hospitalizations
timeFrame: within 14 days, 30 days, and 90 days of randomization
measure: all-cause death
timeFrame: within 14 days, 30 days, and 90 days of randomization
measure: Net clinical benefit
timeFrame: within 14 days, 30 days, and 90 days of enrolment.
measure: Disseminated intravascular coagulation
timeFrame: within 14 days, 30 days, and 90 days of enrolment
Other outcomes:
Locations:
city: Freiburg
country: Germany
facility: Universitätsklinikum Freiburg
city: Mainz
country: Germany
facility: Johannes Gutenberg-Universität Mainz
city: Basel
country: Switzerland
facility: University Hospital Basel
city: Bellinzona
country: Switzerland
facility: Clinic of Hematology, Oncology Institute of Southern Switzerland
city: Bern
country: Switzerland
facility: University Hospital Bern
city: Geneva
country: Switzerland
facility: Hôpitaux Universitaires Genève
city: Lugano
country: Switzerland
facility: Clinica Luganese Moncucco
city: Zürich
country: Switzerland
facility: University Hospital Zurich
Study officials:
affiliation: University of Zurich
name: Nils Kucher, Prof.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Barco S, Voci D, Held U, Sebastian T, Bingisser R, Colucci G, Duerschmied D, Frenk A, Gerber B, Gotschi A, Konstantinides SV, Mach F, Robert-Ebadi H, Rosemann T, Simon NR, Spechbach H, Spirk D, Stortecky S, Vaisnora L, Righini M, Kucher N; OVID investigators. Enoxaparin for primary thromboprophylaxis in symptomatic outpatients with COVID-19 (OVID): a randomised, open-label, parallel-group, multicentre, phase 3 trial. Lancet Haematol. 2022 Aug;9(8):e585-e593. doi: 10.1016/S2352-3026(22)00175-2. Epub 2022 Jun 30.
citation: Barco S, Bingisser R, Colucci G, Frenk A, Gerber B, Held U, Mach F, Mazzolai L, Righini M, Rosemann T, Sebastian T, Spescha R, Stortecky S, Windecker S, Kucher N. Enoxaparin for primary thromboprophylaxis in ambulatory patients with coronavirus disease-2019 (the OVID study): a structured summary of a study protocol for a randomized controlled trial. Trials. 2020 Sep 9;21(1):770. doi: 10.1186/s13063-020-04678-4.