Steroids and Unfractionated Heparin in Critically Ill Patients With Pneumonia From COVID-19 Infection

NCT04528888 | Unknown Phase 3 DMC

• 1 other identifier: Staunch-19-1.1-26-04-20
• Study Type: interventional
• Target: 210
• Locations: 1 country
• Sites: 1

Brief Summary

SARS-CoV-2 infection seems to induce in most critical cases an excessive and aberrant hyper-inflammatory host immune response that is associated with a so-called "cytokine storm", moreover pro-thrombotic derangements of haemostatic system is another common finding in most severe forms of COVID19 infections, which may be explained by the activation of coagulative cascade primed by inflammatory stimuli, in line with what is observed in many other forms of sepsis. Targeting inflammatory responses exploiting steroids' anti-inflammatory activity along with thrombosis prevention may be a promising therapeutic option to improve patients' outcome. Despite the biological plausibility, no good evidence is available on the efficacy and safety of heparin on sepsis patients, and many issues have to be addressed, regarding the proper timing, dosages and administration schedules of anticoagulant drugs. The primary objective is to assess the hypothesis that an adjunctive therapy with steroids and unfractionated heparin (UFH) or with steroids and low molecular weight heparin (LMWH) are more effective in reducing any-cause mortality in critically-ill patients with pneumonia from COVID- 19 infection compared to low molecular weight heparin (LMWH) alone. Mortality will be measured at 28 days. The study is designed as a multicenter, national, interventional, randomized, investigator sponsored, three arms study. Patients, who satisfy all inclusion criteria and no exclusion criteria, will be randomly assigned in a ratio 1:1:1 to one of the three treatment groups: LMWH group, LMWH+steroids or UFH+steroid group. A possible result showing the efficacy of the composite treatment in reducing the mortality rate among critically ill patients with pneumonia from COVID-19 infection will lead to a revision of the current clinical approach to this disease.

Conditions

Covid19; SARS-CoV Infection; Pneumonia, Viral; Coagulopathy

Keywords

Steroids; heparine; critically-ill; ARDS; COVID19; sars-cOv-2

Outcome Measures

Primary Outcomes (1)

• All-cause mortality at day 28

  All-cause mortality at day 28, defined as the comparison of proportions of patients death for any cause at day 28 from randomization.

  Day 28 from randomization

Secondary Outcomes (15)

• All-cause mortality at ICU discharge

  from randomization to ICU discharge, censored at day 30

• All-cause mortality at hospital discharge

  from randomization to ICU discharge, censored at day 90

• Need of rescue administration of high-dose steroids or immune-modulatory drugs

  from randomization to ICU discharge, censored at day 28

• New organ dysfunction during ICU stay

  From randomization to ICU discharge, censored at day 28

• Grade of organ dysfunction during ICU stay

  From randomization to ICU discharge, censored at day 28

Other Outcomes (30)

• Mean arterial pressure

  Daily from inclusion until ICU discharge, censored day 28

• hearth rate

  Daily from inclusion until ICU discharge, censored day 28

• respiratory rate

  Daily from inclusion until ICU discharge, censored day 28

Study Arms (3)

LMWH group

ACTIVE COMPARATOR

The treatments will be initiated as soon as possible after randomization (maximum allowed starting time 12h after randomization). Patients in this group will be administered enoxaparin at standard prophylactic dose (i.e., 4000 UI once day, increased to 6000 UI once day for patients weighting more than 90 kg). The treatment with enoxaparin will be initiated as soon as possible after randomization (maximum allowed starting time 12h after randomization). The treatment will be administered subcutaneously, daily up to ICU discharge. After ICU discharge it may be continued or interrupted in the destination ward up to clinical judgement of the attending physician.

Drug: Enoxaparin

LMWH + steroids group

EXPERIMENTAL

The treatments will be initiated as soon as possible after randomization (maximum allowed starting time 12h after randomization). Patients in this group will receive enoxaparin and methylprednisolone. Enoxaparin will be administered at standard prophylactic dose (i.e., 4000 UI once day, increased to 6000 UI once day for patients weighting more than 90 kg). The treatment will be administered subcutaneously daily up to ICU discharge. After ICU discharge it may be continued or interrupted in the destination ward up to clinical judgement of the attending physician. Methylprednisolone will be administered intravenously with an initial bolus of 0,5 mg/kg followed by administration of 0,5 mg/kg 4 times daily for 7 days, 0,5 mg/kg 3 times daily from day 8 to day 10, 0,5 mg/kg 2 times daily at days 11 and 12 and 0,5 mg/kg once daily at days 13 and 14.

Drug: Enoxaparin; Drug: Methylprednisolone

UFH + steroid group

EXPERIMENTAL

The treatments will be initiated as soon as possible after randomization (maximum 12h). Patients will receive unfractionated heparin and methylprednisolone. Unfractionated heparin will be administered intravenously at therapeutic doses. The infusion will be started at an infusion rate of 18 IU/kg/hour and then modified to attain APTT Ratio in the range 1.5-2.0. aPTT will be periodically checked at intervals no longer than 12 hours. The treatment with unfractionated heparin will be administered up to ICU discharge. After ICU discharge anticoagulant therapy may be interrupted or switched to prophylaxis with LMWH in the destination ward up to clinical judgement of the attending physician. Methylprednisolone will be administered intravenously with an initial bolus of 0,5 mg/kg followed by administration of 0,5 mg/kg 4 times daily for 7 days, 0,5 mg/kg 3 times daily from day 8 to day 10, 0,5 mg/kg 2 times daily at days 11 and 12 and 0,5 mg/kg once daily at days 13 and 14.

Drug: Methylprednisolone; Drug: unfractionated heparin

Interventions

Enoxaparin DRUG

Enoxaparin will be administered subcutaneously at standard prophylactic dose (i.e., 4000 UI once day, increased to 6000 UI once day for patients weighting more than 90 kg). The treatment will be administered daily up to ICU discharge. After ICU discharge it may be continued or interrupted in the destination ward up to clinical judgement of the attending physician.

Also known as: Inhixa

LMWH + steroids group; LMWH group

Methylprednisolone DRUG

Methylprednisolone will be administered intravenously with an initial bolus of 0,5 mg/kg followed by administration of 0,5 mg/kg 4 times daily for 7 days, 0,5 mg/kg 3 times daily from day 8 to day 10, 0,5 mg/kg 2 times daily at days 11 and 12 and 0,5 mg/kg once daily at days 13 and 14.

Also known as: solu-medrol

LMWH + steroids group; UFH + steroid group

unfractionated heparin DRUG

Patients in this group will receive unfractionated heparin and methylprednisolone. Unfractionated heparin will be administered intravenously at therapeutic doses. The infusion will be started at an infusion rate of 18 IU/kg/hour and then modified to attain APTT Ratio in the range 1.5-2.0. aPTT will be periodically checked at intervals no longer than 12 hours. The treatment with unfractionated heparin will be administered up to ICU discharge. After ICU discharge anticoagulant therapy may be interrupted or switched to prophylaxis with LMWH in the destination ward up to clinical judgement of the attending physician.

Also known as: Veracer

UFH + steroid group

Eligibility Criteria

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

You may qualify if:

• Positive SARS-CoV-2 diagnostic (on pharyngeal swab of deep airways material)
• Positive pressure ventilation (either non-invasive or invasive) from \> 24 hours
• Invasive mechanical ventilation from \< 96 hours
• P/F ratio \< 150
• D-dimer level \> 6 x upper limit of local reference range
• PCR \> 6 fold upper limit of local reference range

You may not qualify if:

• Age \< 18 years
• On-going treatment with anticoagulant drugs
• Platelet count \<100.000/mmc
• History of heparin-induced thrombocytopenia
• Allergy to sodium enoxaparine or other LMWH, unfractionated heparin or metylprednisolone;
• Active bleeding or on-going clinical condition deemed at high risk of bleeding contraindicating anticoagulant treatment
• Recent (in the last 1 month prior to randomization) brain, spinal or ophthalmic surgery
• Chronic assumption or oral corticosteroids
• Clinical decision to withhold life-sustaining treatment or "too sick to benefit";
• Presence of other severe diseases impairing life expectancy (e.g. patients are not expected to survive 28 days given their pre-existing medical condition);
• Lack or withdrawal of informed consent.

Sponsors & Collaborators

• Massimo Girardis: lead

Study Sites (1)

ICU- University Hospital Modena

Modena, 41124, Italy

RECRUITING

Related Publications (1)

• 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.

  PMID: 35244208 DERIVED

MeSH Terms

Conditions

COVID-19; Severe Acute Respiratory Syndrome; Pneumonia, Viral; Hemostatic Disorders; Critical Illness

Interventions

Enoxaparin; Methylprednisolone; Methylprednisolone Hemisuccinate; Heparin

Condition Hierarchy (Ancestors)

Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases; Vascular Diseases; Cardiovascular Diseases; Hemorrhagic Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Heparin, Low-Molecular-Weight; Glycosaminoglycans; Polysaccharides; Carbohydrates; Prednisolone; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds

Study Officials

• Massimo Girardis, PI

  University of Modena and Reggio Emilia

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Massimo Girardis, PD

CONTACT

0594225878; massimo.girardis@unimore.it

Stefano Busani

CONTACT

0594224897; stefanobusani7@gmail.com

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Masking Details: The study in conceived as open-label: the patients and all the health-care personnel will be aware of the assigned group.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor

Model Details: The study is designed as a multicenter, national, interventional, randomized, investigator sponsored, three arms study. Patients, who satisfy all inclusion criteria and no exclusion criteria, will be randomly assigned to one of the three treatment groups in a ratio 1:1:1. A block randomisation will be used with variable block sizes (block size 4-6-8), stratified by centre. Central randomisation will be performed using a secure, web-based, randomisation system. The allocation sequence will be generated by the study statistician using computer generated random numbers.

Study Record Dates

• First Submitted: August 21, 2020
• First Posted: August 27, 2020
• Study Start: November 25, 2020
• Primary Completion: June 30, 2021
• Study Completion: July 30, 2021
• Last Updated: May 6, 2021

Record last verified: 2021-05

Data Sharing

• IPD Sharing: Will not share

Locations

IT (1)