Efficacy and Safety of Apixaban in COVID-19 Coagulopathy Patients With Respiratory Severity Under Critical Care (ECRU)

Efficacy and Safety of Apixaban in COVID-19 Coagulopathy Patients With Respiratory Severity Under Critical

The purpose of the study is to describe the safety and efficacy outcomes of a cohort of ICU patients with severe COVID-19 respiratory disease treated with therapeutic dose Apixaban for COVID-19 at a tertiary public health care setting.

Study Overview

• Status: Not yet recruiting
• Conditions: COVID-19
• Intervention / Treatment: Drug: Apixaban; Drug: Rivaroxaban

Detailed Description

There is an increased risk of Venous and Arterial thromboembolism in COVID-19 infection. The main reason being that the novel coronavirus SARS-CoV-2 induces hyperinflammation and subsequently immunothrombolism which is wide spread in the body. The angiotensin converting enzyme 2 (ACE2) receptor, which is utilized by the virus to infect the host, is present throughout the human body organs and endothelial cells. Thrombotic microangiopathies are the consequence of this direct endothelial invasion of the virus and widespread endothelial inflammation. Consequently, pervasive dysfunction of the endothelium and apoptosis is seen primarily due to the host immune response and release of pro inflammatory cytokines.

A hypercoagulable state is therefore seen due to the shift in the vascular equilibrium towards a vasoconstrictive and inflammatory response, promoting a microvascular derangement and dysfunctions.

Although this pathological response is not unique to the COVID-19 disease, the systemic coagulopathies observed due to this novel virus are noted to be slightly distinct. These include the increased risk of mortality with the increased level of D-Dimers in nearly 50% of the patients . While mild prolongation of Prothrombin time and thrombocytopenia are not noted to be important predictors of the severity of the disease or its adverse outcomes .

In COVID-19 patients, the International Society on Thrombosis and Hemostasis (ISTH). criteria for Disseminated Intravascular Coagulation (DIC) is seldom met, despite the indication by the typical triad of thrombin time prolonged, decreased platelet counts and increased D-dimer levels .

Although the Disseminated Intravascular Coagulation is low grade, the fibrinolytic system is activated and endogenous tissue plasminogen is released because of the pathogenic inflammation-causing endothelial cell injury and thrombotic angiopathies of the microvascular system. This also contributes to the increased mortalities due to high D-Dimer levels.

WHAT IS KNOWN?

As high as 69% of COVID-19 patients under Critical Care have been reported to experience the incidence of complication related to thromboembolism .

Although the use of unfractionated heparin (UFH) or low molecular weight heparin (LMWH) as anticoagulation prophylaxis has been observed with beneficial results in decreasing COVID-19 mortalities, however, there are reports of high incidences of thromboembolic complications despite the prophylaxis too.

Although prophylactic therapeutic anti coagulation has been reported with reduced incidences of venous thromboembolism (VTE) , a study has shown almost similar incidence of bleeding in the anticoagulation prophylaxis group as compared to the group which did not receive any anticoagulation (3 versus 1.9%, p = 0.20).

RATIONALE:

Since the link between COVID-19 related coagulopathies and mortalities has been established, it is of paramount importance to establish the optimal strategy. When compared to classical anticoagulants including Unfractioned Heparin, the comparatively newer salt of Apixaban belonging to the Direct Oral Anti Coagulants (DOACs) class, has been reported to have decreased rate of unwanted bleeding incidences, lower requirement of regular lab monitoring, fewer drug-drug interactions, increased pharmacokinetic (PK) and pharmacodynamic (PD) predictability and better efficacy .

Due to these advantages particularly the more predictable dose-response curve of Apixaban, its use has markedly increased in many generalized settings in hospitals since its approval. Apart from this, it is also being started in the Critical Units of COVID-19 and continued thereafter.

RELEVANCE, IMPORTANCE AND APPLICABILITY:

The investigators had particular interest in Apixaban in the COVID-19 setting because of the easy twice daily dosing regime, decreased need of regular lab monitoring, decreased room congestion, decreased medical staff exposure and consequently decreased need of Personal Protective Equipment among others. Nevertheless, the anti-inflammatory effects of Apixaban by decreasing plasma induced superoxide productions, are comparable to Unfractioned Heparin and Low Molecular Weight Heparin.

RESEARCH GAP IDENTIFIED:

Despite these numerous purported benefits, to the best of the investigators' knowledge, there are no published reports describing the clinical outcomes of apixaban use in critically ill ICU patients with severe COVID-19 , in Pakistan.

PURPOSE OF STUDY:

As such, the purpose of this study is to describe the safety and efficacy outcomes of a cohort of ICU patients with severe COVID-19 respiratory disease treated with therapeutic dose apixaban for COVID-19 at a tertiary public health care setting.

• Study Type: Interventional
• Enrollment (Anticipated): 40
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Prof. Dr. Muhammad Umar, MBBS; Phone Number: 0092519281011; Email: info@rmur.edu.pk, syedasabaaslam@gmail.com
• Study Contact Backup: Name: Prof. Dr. Fazl ur Rehman Rehman, MBBS; Phone Number: 00923005226950; Email: lonsa25@student.london.ac.uk

Study Locations

• Pakistan
  • Punjab
    • Rawalpindi, Punjab, Pakistan
      • Rawalpindi Medical University
      • Contact: Imran Arshad, MBBS; Phone Number: 00923455060296; Email: lonsa25@student.london.ac.uk

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Adult (≥18 years of age)
• All admitted patients with severe or critical COVID-19
• Confirmed diagnosis of COVID-19 through RT-PCR (attach report) and/or HRCT Chest
• Patients at high risk of coagulopathy demonstrating signs of micro-thrombi induced organ dysfunction or strongly suspected macro thromboembolism

Exclusion Criteria:

• High risk of bleeding as judged by treating physicians
• Contra-indication to therapeutic anti coagulation
• Platelets < 50,000 (attach report)
• INR >1.5
• Evidence of current or recent bleeding

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Interventional Arm; Ecru (Apixaban )Tablets	Drug: Apixaban; Direct Acting Oral Anti coagulant; Other Names: ECRU Tablets
ACTIVE_COMPARATOR: Comparator/control; Rivascot (Rivaroxaban)	Drug: Rivaroxaban; Direct Acting Oral Anti coagulant; Other Names: Rivascot tablets

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Bleeding	The participants with bleeding episodes	10 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clotting	The participants with clotting incidences	10 days

Collaborators and Investigators

• Sponsor: Scotmann Pharmaceuticals
• Collaborators: Rawalpindi Medical College
• Investigators: Principal Investigator: Prof. Dr. Muhammad Umar, MBBS, Rawalpindi Medical College

Study record dates

Study Major Dates

• Study Start (ANTICIPATED): March 1, 2022
• Primary Completion (ANTICIPATED): May 30, 2022
• Study Completion (ANTICIPATED): August 30, 2022

Study Registration Dates

• First Submitted: October 21, 2021
• First Submitted That Met QC Criteria: October 21, 2021
• First Posted (ACTUAL): October 22, 2021

Study Record Updates

• Last Update Posted (ACTUAL): March 10, 2022
• Last Update Submitted That Met QC Criteria: February 22, 2022
• Last Verified: February 1, 2022

More Information

Terms related to this study

• Keywords: Anticoagulation; Apixaban
• 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; Factor Xa Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Rivaroxaban; Apixaban
• Other Study ID Numbers: RMUSCOTMANNECRUTRIAL; U1111-1272-7249 (REGISTRY: ICTRP, WHO)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Proformas

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No