Efficacy Assessment of Methylprednisolone and Heparin in Patients With COVID-19 Pneumonia

Efficacy Assessment of Methylprednisolone and Heparin in Patients With COVID-19 Pneumonia: A Randomized, Controlled, 2x2 Factorial Study

The COVID-19 pandemic has been spreading continuously, and in Brazil, until July 19, 2020, there have been more than 2,000,000 cases with more than 79,000 deaths, with daily increases. The present study proposes to evaluate the efficacy of methylprednisolone and heparin in treatment of patients with COVID-19 pneumonia in a randomized, controlled, 2x2 factorial study.

Study Overview

• Status: Withdrawn
• Conditions: COVID-19
• Intervention / Treatment: Drug: Methylprednisolone; Drug: Heparin

• Study Type: Interventional
• Phase: Phase 3

Contacts and Locations

Study Locations

• Brazil
  • Rio de Janeiro, Brazil
    • D'Or Institute for Research and Education

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:

• Confirmed diagnosis of COVID-19 by RT-PCR or serology with presence of IgM positive antibodies;
• Lung image (X-ray or chest CT) with involvement of at least 25% of the parenchyma;
• O2 saturation in ambient air less than or equal to 93%

• Alteration of inflammatory tests

  • D-Dimer above the reference value and
  • Elevation of C-reactive protein, ferritin or lactic dehydrogenase
• Sign the consent form.

Exclusion Criteria:

• QT interval prolongation
• Imminence of orotracheal intubation (intubation prediction in the first 4 hours after randomization)
• Women who are pregnant or breastfeeding
• Corticosteroid allergy or intolerance
• Chronic corticosteroid users (prednisone equivalent > 10 mg daily)
• Patients diagnosed with cancer with increased bleeding potential
• Patients in hemodialysis
• History of peptic ulcer
• Herpes zoster infection
• History or active treatment of tuberculosis
• Systemic fungal infection
• Use of anticoagulation due to previous pathology
• Glaucoma
• Live virus vaccine up to 90 days before randomization
• Known coagulopathy or thrombocytopenia (<40,000/mm3) or hypofibrinogenemia (< 50 mg/dL)
• Recent bleeding
• Another limiting comorbidity for administering the therapies provided for in this protocol in in researcher's opinion

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Methylprednisolone + Standard treatment; Participants will receive the standard treatment and methylprednisolone.	Drug: Methylprednisolone; Methylprednisolone 0.5 mg/kg every 12 hours intravenously for the first 14 days; followed by 0.5 mg/kg/day from day 15 to day 21; followed by 0.25mg/kg/day from day 22 to day 25; followed by 0.125 mg/kg/day, from day 26 to day 28 of treatment.
Experimental: Full-dose heparin + Standard treatment; Participants will receive the standard treatment and full-dose heparin,	Drug: Heparin; Enoxaparin 1 mg/kg subcutaneously every 12 hours (if creatinine clearance greater than 40ml/min) or Unfractionated heparin dosed to target activated partial thromboplastin time (aPTT) between 1.5 - 2.0 times the normal value (if creatinine clearance less or equal to 40ml/min). The treatment period with full-dose heparin will be 7 days. After 7 days of full-dose heparin, patients will continue using prophylactic dose of heparin, according to the standard treatment routine.
Experimental: Methylprednisolone + Full-dose heparin + Standard treatment; Participants will receive the standard treatment, methylprednisolone and full-dose heparin	Drug: Methylprednisolone; Methylprednisolone 0.5 mg/kg every 12 hours intravenously for the first 14 days; followed by 0.5 mg/kg/day from day 15 to day 21; followed by 0.25mg/kg/day from day 22 to day 25; followed by 0.125 mg/kg/day, from day 26 to day 28 of treatment.; Drug: Heparin; Enoxaparin 1 mg/kg subcutaneously every 12 hours (if creatinine clearance greater than 40ml/min) or Unfractionated heparin dosed to target activated partial thromboplastin time (aPTT) between 1.5 - 2.0 times the normal value (if creatinine clearance less or equal to 40ml/min). The treatment period with full-dose heparin will be 7 days. After 7 days of full-dose heparin, patients will continue using prophylactic dose of heparin, according to the standard treatment routine.
No Intervention: Standard treatment; Participants will receive the standard treatment

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Rate of invasive mechanical ventilation	28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Severity assessment by ordinal severity scale	Severity assessment will be performed using the ordinal severity scale during hospitalization.	3 days, 7 days, 14 days, 28 days after randomization
Severity assessment by SOFA score	Severity assessment will be performed using the SOFA score during hospitalization.	3 days, 7 days, 14 days, 28 days after randomization
Length of hospital stay		28 days
Length of stay in intensive care		28 days
Death rate		14 days, 28 days, 60 days, 90 days after randomization

Collaborators and Investigators

• Sponsor: D'Or Institute for Research and Education
• Investigators: Principal Investigator: Eduardo M Rego, MD, PhD, D'Or Institute for Research and Education

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.

Study record dates

Study Major Dates

• Study Start (Actual): July 20, 2020
• Primary Completion (Anticipated): December 31, 2022
• Study Completion (Anticipated): December 31, 2022

Study Registration Dates

• First Submitted: July 20, 2020
• First Submitted That Met QC Criteria: July 23, 2020
• First Posted (Actual): July 24, 2020

Study Record Updates

• Last Update Posted (Actual): August 11, 2021
• Last Update Submitted That Met QC Criteria: August 4, 2021
• Last Verified: August 1, 2021

More Information

Terms related to this study

• Keywords: SARS-CoV-2; Anticoagulation; Methylprednisolone; Heparin; Respiratory failure; Coagulopathy
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Lung Diseases; COVID-19; Pneumonia; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Fibrinolytic Agents; Fibrin Modulating Agents; Antineoplastic Agents; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Neuroprotective Agents; Protective Agents; Anticoagulants; Prednisolone; Methylprednisolone Acetate; Methylprednisolone; Methylprednisolone Hemisuccinate; Prednisolone acetate; Prednisolone hemisuccinate; Prednisolone phosphate; Heparin
• Other Study ID Numbers: 31180820600005249

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

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