A Phase 2 Trial of Infliximab in Coronavirus Disease 2019 (COVID-19).

The investigators hypothesize that early institution of TNFα inhibitor therapy in patients with severe COVID-19 infections will prevent further clinical deterioration and reduce the need for advanced cardiorespiratory support and early mortality. To address this hypothesis, a prospective, single center, phase 2 trial is proposed to assess the efficacy of infliximab or infliximab-abda in hospitalized adult patients with severe or critical COVID-19. Observations from this study will inform the conduct of prospective randomized controlled studies to follow.

Study Overview

• Status: Completed
• Conditions: COVID-19
• Intervention / Treatment: Drug: Infliximab

Detailed Description

The investigators hypothesize that early institution of TNFα inhibitor therapy in patients with severe COVID-19 infections will prevent further clinical deterioration and reduce the need for advanced cardiorespiratory support and early mortality. To address this hypothesis, a prospective, single center, phase 2 trial is proposed to assess the efficacy of infliximab or infliximab-abda in hospitalized adult patients with severe or critical COVID-19. Observations from this study will inform the conduct of prospective randomized controlled studies to follow.

Infliximab and Infliximab-abda are TNFα inhibitors currently FDA-approved for the treatment of autoimmune disorders, including Crohn's disease and rheumatoid arthritis. The risks and adverse reactions are described in the approved prescribing information for infliximab (or infliximab-abda). Infliximab will be used when available. Should infliximab be unavailable in the pharmacy, infliximab-abda, a biosimilar, will be used.

Treatment with infliximab or infliximab-abda 5mg/kg IV should ideally be administered within 6 hours of enrollment, and no more than 24 hours following enrollment. Pre-medication with Tylenol 650 mg once 30 minutes prior to infusion would be recommended. Other pre-medications may be given at the discretion of the treating physician. These include diphenhydramine 50mg by mouth, as well as prednisone 20mg by mouth, both given 30 minutes prior to infusion. Pulse and blood pressure should be monitored every 30 minutes during the infusion, and patients should be monitored for at least 30 minutes following the infusion.

Retreatment with infliximab is permitted at treating physician discretion 7-21 days following primary therapy and based on initial response; the usual treatment schedule is every 2 weeks, this interval is not strictly enforced given the uncertainty of outcomes with primary therapy.

• Study Type: Interventional
• Enrollment (Actual): 17
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02111
      • Tufts Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age 18 years or older
2. Able to provide informed consent
3. Hospitalized adult patients with pneumonia evidenced by chest X-ray or CT scan
4. Laboratory (RT-PCR) confirmed infection with 2019-nCoV or strongly suspected to be infected with SARS-COV2 with confirmation studies pending

5. And at least one of the following:

   1. Respiratory frequency ≥30/min
   2. Blood oxygen saturation ≤93% on RA
   3. Partial pressure of arterial oxygen to fraction of inspired oxygen ratio (PaO2/FiO2) <300
   4. Worsening of lung involvement, defined as an increase in number and/or extension of pulmonary areas of consolidation, need for increased FiO2 to maintain stable O2 saturation, or worsening O2 saturation of >3% with stable FiO2

Exclusion Criteria:

1. Treatment with any TNFα inhibitor in the past 30 days
2. Known hypersensitivity to any TNFα inhibitor, murine proteins, or any component of the formulation
3. Presence of any of the following abnormal laboratory values at screening: absolute neutrophil count (ANC) less than 1000 mm3, hemoglobin <8.0g/L, platelets <50,000 per mm3, or AST or ALT greater than 5 x ULN
4. Known active or latent Hepatitis B
5. Known or suspected active tuberculosis (TB) or a history of incompletely treated or latent TB.
6. Pregnancy
7. Intubated for >48hours
8. Patients with uncontrolled systemic bacterial or fungal infections (Patients with a history of positive bacterial or fungal cultures but on enrollment are on appropriate therapy with negative repeat cultures may be enrolled)

9. Serious co-morbidity, including:

   1. Myocardial infarction (within last month)
   2. Moderate or severe heart failure (New York Heart Association (NYHA) class III or IV)
   3. Acute stroke (within last month)
   4. Uncontrolled malignancy
   5. Stage 4 severe chronic kidney disease or requiring dialysis (i.e. estimated glomerular filtration rate (eGFR) < 30 ml /min/1.73 m^2) at baseline

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Infliximab; All patients enrolled into this trial will be assigned to the Infliximab arm. Patients will be treated with infliximab on Day 1, and may be re-treated per protocol and at the discretion of the investigator.	Drug: Infliximab; Either infliximab or infliximab-abda will be used at the discretion of the investigator; Other Names: infliximab-abda

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Improvement in Oxygenation	Time to improvement in oxygenation (increase in SpO2/FiO2 of 50 or greater compared to the baseline SpO2/FiO2)	28 Days
Number of p[Atients With Improvement in Oxygenation	Number of participants who showed improvement in oxygenation (increase in SpO2/FiO2 of 50 or greater compared to the baseline SpO2/FiO2)	28 Days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
28-Day Survival Status	Number of patients who were confirmed to be alive 28 days from enrollment onto the study.	28 Days
Duration of Supplemental Oxygen Administration by Nasal Cannula	Duration of supplemental oxygen administration by nasal cannula, simple face mask, or other similar oxygen delivery device	28 Days
Duration of Non-invasive Ventilation or by Non-rebreather Mask or High-flow Nasal Cannula	Duration of non-invasive ventilation or by non-rebreather mask or high-flow nasal cannula	28 Days
Number of Patients Requiring Mechanical Ventilation	Number of patients enrolled who required mechanical ventilation	28 Days
Number of Patients Requiring Vasopressor Support	Number of participants who required vasopressor support	28 Days
Number of Patients Requiring Extracorporeal Membrane Oxygenation	Number of patients requiring extracorporeal membrane oxygenation	28 Days
Number of Patients With Fever	Number of patients who exhibited fever during the study period	28 Days
Correlation of Dynamic Changes in IP-10 to Cytokine Profile	Correlation of dynamic changes in IP-10 to cytokine profile between day 3 and baseline	3 Days
Duration of Hospitalization	Duration of hospitalization	28 Days
Number of Patients Who Developed Secondary Infections	Number of patients who developed secondary infections	28 Days
Number of Patients Requiring Supplemental Oxygen Administration by Nasal Cannula	Incidence of supplemental oxygen administration by nasal cannula, simple face mask, or other similar oxygen delivery device	28 Days
Duration of Mechanical Ventilation	duration of use of mechanical ventilation (for patients requiring mechanical ventilation)	28 Days
Number of Patients Requiring Non-invasive Ventilation or by Non-rebreather Mask or High-flow Nasal Cannula	Number of participants who required non-invasive ventilation or by non-rebreather mask or high-flow nasal cannula	28 Days
Assessment of Cytokine and Inflammatory Profile at Baseline	Assessment of cytokine and inflammatory profile at baseline (TNFα, IL-1b, IL-2, IL-6, ferritin) after therapy	Baseline

Collaborators and Investigators

• Sponsor: Tufts Medical Center
• Collaborators: National Institutes of Health (NIH)
• Investigators: Principal Investigator: Paul Mathew, MD, Tufts Medical Center

Publications and helpful links

General Publications

• Hachem H, Godara A, Schroeder C, Fein D, Mann H, Lawlor C, Marshall J, Klein A, Poutsiaka D, Breeze JL, Joshi R, Mathew P. Rapid and sustained decline in CXCL-10 (IP-10) annotates clinical outcomes following TNF-alpha antagonist therapy in hospitalized patients with severe and critical COVID-19 respiratory failure. medRxiv. 2021 Jun 2:2021.05.29.21258010. doi: 10.1101/2021.05.29.21258010. Preprint.
• Hachem H, Godara A, Schroeder C, Fein D, Mann H, Lawlor C, Marshall J, Klein A, Poutsiaka D, Breeze JL, Joshi R, Mathew P. Rapid and sustained decline in CXCL-10 (IP-10) annotates clinical outcomes following TNFalpha-antagonist therapy in hospitalized patients with severe and critical COVID-19 respiratory failure. J Clin Transl Sci. 2021 Jun 25;5(1):e146. doi: 10.1017/cts.2021.805. eCollection 2021.

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2020
• Primary Completion (Actual): January 22, 2021
• Study Completion (Actual): January 22, 2021

Study Registration Dates

• First Submitted: June 8, 2020
• First Submitted That Met QC Criteria: June 8, 2020
• First Posted (Actual): June 11, 2020

Study Record Updates

• Last Update Posted (Actual): April 20, 2022
• Last Update Submitted That Met QC Criteria: April 15, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Keywords: COVID-19
• 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; Antirheumatic Agents; Gastrointestinal Agents; Dermatologic Agents; Infliximab
• Other Study ID Numbers: STUDY00000564

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