Clinical trial NCT04425538: A Phase 2 Trial of Infliximab in Coronavirus Disease 2019 (COVID-19).
Official title: A Phase 2 Trial of Infliximab in Coronavirus Disease 2019 (COVID-19).
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: COVID-19
Keywords: COVID-19
Lead sponsor: Tufts Medical Center
Sponsor class: OTHER
Collaborators: name: National Institutes of Health (NIH)
First posted: 2020-06-11
Enrollment: 17
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Time to Improvement in Oxygenation
timeFrame: 28 Days
measure: Number of p[Atients With Improvement in Oxygenation
timeFrame: 28 Days
Secondary outcomes:
measure: 28-Day Survival Status
timeFrame: 28 Days
measure: Duration of Supplemental Oxygen Administration by Nasal Cannula
timeFrame: 28 Days
measure: Duration of Non-invasive Ventilation or by Non-rebreather Mask or High-flow Nasal Cannula
timeFrame: 28 Days
measure: Number of Patients Requiring Mechanical Ventilation
timeFrame: 28 Days
measure: Number of Patients Requiring Vasopressor Support
timeFrame: 28 Days
measure: Number of Patients Requiring Extracorporeal Membrane Oxygenation
timeFrame: 28 Days
measure: Number of Patients With Fever
timeFrame: 28 Days
measure: Correlation of Dynamic Changes in IP-10 to Cytokine Profile
timeFrame: 3 Days
measure: Duration of Hospitalization
timeFrame: 28 Days
measure: Number of Patients Who Developed Secondary Infections
timeFrame: 28 Days
measure: Number of Patients Requiring Supplemental Oxygen Administration by Nasal Cannula
timeFrame: 28 Days
measure: Duration of Mechanical Ventilation
timeFrame: 28 Days
measure: Number of Patients Requiring Non-invasive Ventilation or by Non-rebreather Mask or High-flow Nasal Cannula
timeFrame: 28 Days
measure: Assessment of Cytokine and Inflammatory Profile at Baseline
timeFrame: Baseline
Other outcomes:
Locations:
city: Boston
country: United States
facility: Tufts Medical Center
state: Massachusetts
Study officials:
affiliation: Tufts Medical Center
name: Paul Mathew, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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 [Preprint]. 2021 Jun 2:2021.05.29.21258010. doi: 10.1101/2021.05.29.21258010.
citation: 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.