Anticoagulation in Patients Suffering From COVID-19 Disease The ANTI-CO Trial

Anticoagulation in Patients Suffering From COVID-19 Disease-The Anti-Co Trial

Patients with COVID-19 associated ARDS and mechanical ventilation have a high mortality. Part of the disease is an activation of the coagulation system which seems to contribute to clotformation in the pulmonary bloodstream. Recently we implemented an algorithm applying higher doses of heparins (LMWH). However, this approach could not inhibit clotformation enough. Bivalirudin could prevent clotformation better and support dissolving existing clots.

Therefore, we want to compare 50 patients with the standard treatment with 50 patients under bivalirudin treatment which we normally apply in patients with a HIT-syndrome.

Our primary outcome measure is oxygenation reflected as P/F ratio.

Study Overview

• Status: Unknown
• Conditions: Anticoagulation in COVID-19 ARDS
• Intervention / Treatment: Drug: Standard treatment; Drug: Bivalirudin Injection

Detailed Description

The pandemic of COVID-19, a newly upcoming viral disease caused by SARS-CoV-2, puts the whole worlds health system under pressure.

Patients suffering from this disease mainly develop respiratory symptoms, which can lead to severe acute respiratory distress syndrome (ARDS) necessitating ICU admission in 10-20% of the cases admitted to hospital. In addition to these symptoms, patients show lymphopenia, cardiac symptoms and altered coagulation profiles. Although those patients are treated in the ICU the mortality there is more than 20% due to multiorgan failure.

One of the recent insights in this disease is its effect on the coagulation system. Meanwhile we know that the coagulation system gets activated. Furthermore, it seems that clot formation takes place in the pulmonary micro-vasculature which could contribute to the widely observed gas-exchange impairment. Therefore, many centers apply empiric anticoagulation for their COVID-patients. At the moment, we at HMC, also apply an empirical anticoagulation protocol as our standard approach. However, this is a symptomatic treatment without good proof.

Bivalirudin is a well-known agent which is used in HMC for cases in which anticoagulation is needed, but a contraindication for heparin exists (i.e. HIT syndrome). This drug has an interesting pharmacologic profile. It acts independent of antithrombin (AT), the physiological compound which enhances heparin effects under normal circumstances. This lack of dependence on AT, makes Bivalirudin an attractive choice in light of the contradictory reports on the levels of AT during COVID infection. If AT levels are decreased during the infection, heparin (as well as LMWH) cannot work efficiently, which would render our treatment less effective. Luckily, bivalirudin acts without the support of AT, so we could bypass this problem. In addition, bivalirudin has some fibrinolytic activities. It inhibits clot-bound thrombin which as a result destabilizes the clot rendering it more susceptible to thrombolysis. This property partially supports the dissolving of clots and could support re-opening the pulmonary microcirculation.

Objectives:

To prove the positive effect of anticoagulation with bivalirudin intravenously on gas-exchange in patients with COVID-19 and respiratory failure on invasive mechanical ventilation.

• Study Type: Interventional
• Enrollment (Anticipated): 100
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Marcus Lance, MD, PhD; Phone Number: 33530292 00974; Email: mlance@hamad.qa
• Study Contact Backup: Name: Stefan Roehrig, MD, MBA; Phone Number: 66030924 00974; Email: srohrig@hamad.qa

Study Locations

• Qatar
  • Doha, Qatar
    • Recruiting
    • Hamad Medical Corporation
    • Contact: Nadir Kharma, MD; Phone Number: 55118621 00974; Email: nkharma@hamad.qa

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 99 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Adult patient (≥ 18 years of age)
• Positive COVID-test
• Under mechanical ventilation
• D-Dimers>1.2 mg/L

Exclusion Criteria:

• Pregnancy
• Allergy to the drug (bivalirudin)
• Inherited coagulation abnormalities
• No informed consent

Study Plan

How is the study designed?

Design Details

• Primary Purpose: SUPPORTIVE_CARE
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Standard treatment; In this arm the patients will be treated according to our standard anticoagulation protocol. The patients will not be treated with Bivalirudin (the investigational drug).	Drug: Standard treatment; This group will receive standard anticoagulation with LMWH/UFH
EXPERIMENTAL: Bivalirudin arm; The patients will be anticoagulated according to the institutional HIT-protocol which uses Bivalirudin as anticoagulant.	Drug: Bivalirudin Injection; The patients will receive iv Bivalirudin according to the institutional HIT protocol.; Other Names: anticoagulation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
P/F ratio	the P/F ratio is a surrogate parameter for oxygenation in ARDS.	three days of intervention

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Kidney function	The kidney function frequently is deteriorated in COVID-19 patients	three days of intervention

Collaborators and Investigators

• Sponsor: Hamad Medical Corporation
• Investigators: Principal Investigator: Marcus Lance, MD, PhD, HMC

Publications and helpful links

General Publications

• Flumignan RL, Civile VT, Tinoco JDS, Pascoal PI, Areias LL, Matar CF, Tendal B, Trevisani VF, Atallah AN, Nakano LC. Anticoagulants for people hospitalised with COVID-19. Cochrane Database Syst Rev. 2022 Mar 4;3(3):CD013739. doi: 10.1002/14651858.CD013739.pub2.
• Kharma N, Roehrig S, Shible AA, Elshafei MS, Osman D, Elsaid IM, Mustafa SF, Aldabi A, Smain OAM, Lance MD. Anticoagulation in critically ill patients on mechanical ventilation suffering from COVID-19 disease, The ANTI-CO trial: A structured summary of a study protocol for a randomised controlled trial. Trials. 2020 Sep 7;21(1):769. doi: 10.1186/s13063-020-04689-1.

Study record dates

Study Major Dates

• Study Start (ANTICIPATED): June 28, 2020
• Primary Completion (ANTICIPATED): September 28, 2020
• Study Completion (ANTICIPATED): March 28, 2021

Study Registration Dates

• First Submitted: June 23, 2020
• First Submitted That Met QC Criteria: June 23, 2020
• First Posted (ACTUAL): June 24, 2020

Study Record Updates

• Last Update Posted (ACTUAL): June 24, 2020
• Last Update Submitted That Met QC Criteria: June 23, 2020
• Last Verified: June 1, 2020

More Information

Terms related to this study

• Keywords: Anticoagulation; COVID-19; ARDS
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protease Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Bivalirudin
• Other Study ID Numbers: MRC-05-082

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: this will depend on IRB advice

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No