ANTIcoagulation in Severe COVID-19 Patients

NCT04808882 | Completed Phase 2 DMC

• 2 other identifiers: APHP2016242020-A03531-38
• Study Type: interventional
• Target: 353
• Locations: 1 country
• Sites: 1

Brief Summary

Coronavirus disease 2019 (COVID-19), a viral respiratory illness caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), may predispose patients to thrombotic disease due to a state of profound inflammation, platelet activation, and endothelial dysfunction leading to respiratory distress and increased mortality. The incidence of macrovascular thrombotic events varies from 10 to 30% in COVID-19 hospitalized patients depending on the type of arterial or vein thrombosis captured and severity of illness . Observational results in patients receiving routine low-dose prophylactic anticoagulation (LD-PA), several institutions have recently released guidance statement to prevent macrovascular thrombotic events with dose escalation anticoagulation. In these recommendations, high-dose prophylactic anticoagulation (HD-PA) and therapeutic anticoagulation (TA) can be employed either empirically or based on the body mass index and increased D-dimer values. No randomized trial has validated this approach, and other recent recommendations challenge this approach. Microvascular thrombotic events are also of major concern in critically ill patients with COVID-19, even in the absence of obvious macrovascular thrombotic events. A large review of autopsy findings in COVID-19-related deaths reported micro thrombi in small pulmonary vessels. More generally, COVID-19-induced endothelitis and coagulopathy across vascular beds of different organs lead to widespread microvascular thrombosis with microangiopathy and occlusion of capillaries. Thus, in severe COVID-19 patients requiring oxygen therapy without initial macrovascular thrombotic event, a HD-PA or a TA could be beneficial by limiting the extension of microvascular thrombosis and the evolution of the lung and multi-organ microcirculatory dysfunction. In a large observational cohort of 2,773 COVID-19 patients, a lower in-hospital mortality in ventilated patients receiving TA as compared to those receiving PA (29.1% vs. 62.7%). Our hypothesis is dual: i) first, that TA and HD-PA strategies mitigate microthrombosis and each limit the progression of COVID-19, including respiratory failure and multi-organ dysfunction, with in fine a decreased mortality and duration of disease, as compared to a low-dose PA; ii) second, that TA outperforms HD-PA in this setting.

Conditions

Severe COVID-19 Pneumonia

Keywords

COVID-19; Anticoagulation

Outcome Measures

Primary Outcomes (2)

• All-cause mortality

  Day-28

• Number of days to clinical improvement

  Clinical improvement will be assessed through a seven-category ordinal scale derived from the WHO scale, using the following categories: 1. not hospitalized with resumption of normal activities; 2. not hospitalized, but unable to resume normal activities; 3. hospitalized, not requiring supplemental oxygen; 4. hospitalized, requiring supplemental oxygen; 5. hospitalized, requiring nasal high-flow oxygen therapy, noninvasive mechanical ventilation, or both; 6. hospitalized, requiring ECMO, invasive mechanical ventilation, or both; and 7. death. As all included patients will at least require oxygen supplementation, live discharge from hospital will represent a minimal 2-points decrease in the 7-points scale, thus a clinical improvement.

  Day-28

Secondary Outcomes (19)

• Net clinical benefit of anticoagulation assessed by the absence of thrombotic event, major bleeding event, Heparin Induced Thrombocytopenia and all-cause death

  Day-28

• All-cause deaths

  Day-28 and Day-90

• Proportion of patients with at least one thrombotic event at Day-28

  Day-28

• Proportion of patients with at least one major bleeding event (MBE) at Day-28

  Day-28

• Proportion of patients with at least one life-threatening bleeding event at Day-28

  Day-28

Study Arms (3)

Low dose prophylactic anticoagulation

EXPERIMENTAL

LD-PA

Drug: Tinzaparin, Low dose prophylactic anticoagulation

High dose prophylactic anticoagulation

EXPERIMENTAL

HD-PA

Drug: Tinzaparin, High dose prophylactic anticoagulation

Therapeutic anticoagulation

EXPERIMENTAL

TA

Drug: Tinzaparin,Therapeutic anticoagulation

Interventions

Tinzaparin, Low dose prophylactic anticoagulation DRUG

Participants randomized to the LD-PA strategie will receive the low weight molecular heparin (LMWH) tinzaparin, considering its contraindications, recommended dose ranges and monitoring if applicable, as follows: LD-PA : 3500 IU/24h. Depending on the type of tinzaparin pre-filled syringe available in the participating center, the dose of 4000 IU/24h will be allowed in place of 3500 IU/24h. If tinzaparin is not punctually available, the use of enoxaparin will be allowed as follows: LD-PA: 4000 IU/24h. After day-14, or hospital discharge, or in case of an indication for TA, or of serious adverse event related to anticoagulation, the investigational anticoagulation strategy will be discontinued and anticoagulation treatment will be left at the discretion of attending physicians. Recommendations for the management of COVID-19 pneumonia will be followed, including the use of dexamethasone. These recommendations will be subject to modifications based on the new literature data.

Also known as: LD-PA

Low dose prophylactic anticoagulation

Tinzaparin, High dose prophylactic anticoagulation DRUG

Participants randomized to the HD-PA strategie will receive the low weight molecular heparin (LMWH) tinzaparin, considering its contraindications, recommended dose ranges and monitoring if applicable, as follows: HD-PA : 7000 IU/24h. If tinzaparin is not punctually available, the use of enoxaparin will be allowed as follows: HD-PA: 4000 IU/12h. After day-14, or hospital discharge, or in case of an indication for TA, or of serious adverse event related to anticoagulation, the investigational anticoagulation strategy will be discontinued and anticoagulation treatment will be left at the discretion of attending physicians. Recommendations for the management of COVID-19 pneumonia will be followed, including the use of dexamethasone. These recommendations will be subject to modifications based on the new literature data.

Also known as: HD-PA

High dose prophylactic anticoagulation

Tinzaparin,Therapeutic anticoagulation DRUG

Participants randomized to the TA strategie will receive the low weight molecular heparin (LMWH) tinzaparin, considering its contraindications, recommended dose ranges and monitoring if applicable, as follows: TA : 175 IU/kg/24h. If tinzaparin is not punctually available, the use of enoxaparin will be allowed as follows: TA: 100 IU/kg/12h. After day-14, or hospital discharge, or in case of an indication for TA, or of serious adverse event related to anticoagulation, the investigational anticoagulation strategy will be discontinued and anticoagulation treatment will be left at the discretion of attending physicians. Recommendations for the management of COVID-19 pneumonia will be followed, including the use of dexamethasone. These recommendations will be subject to modifications based on the new literature data.

Also known as: TA

Therapeutic anticoagulation

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age ≥ 18 years ;
• Severe COVID-19 pneumonia, defined by:
• A newly-appeared pulmonary parenchymal infiltrate; AND
• a positive RT-PCR (either upper or lower respiratory tract) for COVID-19 (SARS-CoV-2); AND
• WHO progression scale ≥ 5 (on The Who ordinal scale)
• Written informed consent (patient, next of skin or emergency situation).

You may not qualify if:

• Pregnancy and breast feeding woman;
• Postpartum (6 weeks);
• Extreme weights (\<40 kg or \>100 kg);
• Need for therapeutic anticoagulation (except for COVID-related pulmonary thrombosis);
• Bleeding event related to hemostasis disorders, acute clinically significant bleed, current gastrointestinal ulcer or any organic lesion with high risk for bleeding
• Platelet count \< 50 G/L;
• Within 15 days of recent surgery, within 24 hours of spinal or epidural anesthesia;
• Any prior intracranial hemorrhage, enlarged acute ischemic stroke, known intracranial malformation or neoplasm, acute infectious endocarditis;
• Severe renal failure (creatinine clearance \<30 mL/min);
• Iodine allergy;
• Hypersensitivity to heparin or its derivatives including low-molecular-weight heparin;
• History of type II heparin-induced thrombocytopenia;
• Chronic oxygen supplementation;
• Moribund patient or death expected from underlying disease during the current admission;
• Patient deprived of liberty and persons subject to institutional psychiatric care;

Sponsors & Collaborators

• Assistance Publique - Hôpitaux de Paris: lead

Study Sites (1)

Henri Mondor Hospital

Créteil, 94000, France

Location

Related Publications (2)

• Labbe V, Contou D, Heming N, Megarbane B, Razazi K, Boissier F, Ait-Oufella H, Turpin M, Carreira S, Robert A, Monchi M, Souweine B, Preau S, Doyen D, Vivier E, Zucman N, Dres M, Fejjal M, Noel-Savina E, Bachir M, Jaffal K, Timsit JF, Picos SA, Mariotte E, Martis N, Juguet W, Melica G, Rondeau P, Audureau E, Mekontso Dessap A; ANTICOVID Investigators. Effects of Standard-Dose Prophylactic, High-Dose Prophylactic, and Therapeutic Anticoagulation in Patients With Hypoxemic COVID-19 Pneumonia: The ANTICOVID Randomized Clinical Trial. JAMA Intern Med. 2023 Jun 1;183(6):520-531. doi: 10.1001/jamainternmed.2023.0456.

  PMID: 36946232 DERIVED

• Labbe V, Contou D, Heming N, Megarbane B, Ait-Oufella H, Boissier F, Carreira S, Robert A, Vivier E, Fejjal M, Doyen D, Monchi M, Preau S, Noel-Savina E, Souweine B, Zucman N, Picos SA, Dres M, Juguet W, Mariotte E, Timsit JF, Turpin M, Razazi K, Gendreau S, Baloul S, Voiriot G, Fartoukh M, Audureau E, Mekontso Dessap A. Comparison of standard prophylactic, intermediate prophylactic and therapeutic anticoagulation in patients with severe COVID-19: protocol for the ANTICOVID multicentre, parallel-group, open-label, randomised controlled trial. BMJ Open. 2022 Apr 26;12(4):e059383. doi: 10.1136/bmjopen-2021-059383.

  PMID: 35473740 DERIVED

MeSH Terms

Conditions

COVID-19

Interventions

Tinzaparin

Condition Hierarchy (Ancestors)

Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Heparin, Low-Molecular-Weight; Heparin; Glycosaminoglycans; Polysaccharides; Carbohydrates

Study Officials

• Vincent LABBE, MD

  Assistance Publique Hopitaux de Paris (AP-HP)

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: The research is a multicenter, parallel group, open-label, randomized controlled superiority trial, aiming at comparing three usual strategies of anticoagulation. The primary hierarchical criterion assessed at Day-28, includes all-cause mortality followed by the time to clinical improvement. The three strategies are LD-PA, HD-PA, and TA, with a 1:1:1 ratio

Study Record Dates

• First Submitted: March 8, 2021
• First Posted: March 22, 2021
• Study Start: April 14, 2021
• Primary Completion: January 10, 2022
• Study Completion: March 13, 2022
• Last Updated: September 8, 2022

Record last verified: 2020-12

Data Sharing

• IPD Sharing: Will not share

Locations

FR (1)