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

• Sponsor: Tufts Medical Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT04425538
• Collaborator: National Institutes of Health (NIH) (NIH)
• Enrollment: 17
• Location: 1
• Arm: 1
• Actual Duration (Months): 7.7
• Patients Per Site Per Month: 2.2

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
COVID-19	Drug: Infliximab	Phase 2

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 Design

• Study Type: Interventional
• Actual Enrollment: 17 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2 Trial of Infliximab in Coronavirus Disease 2019 (COVID-19).
• Actual Study Start Date: Jun 1, 2020
• Actual Primary Completion Date: Jan 22, 2021
• Actual Study Completion Date: Jan 22, 2021

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Time to Improvement in Oxygenation [28 Days]

   Time to improvement in oxygenation (increase in SpO2/FiO2 of 50 or greater compared to the baseline SpO2/FiO2)

2. Number of p[Atients With Improvement in Oxygenation [28 Days]

   Number of participants who showed improvement in oxygenation (increase in SpO2/FiO2 of 50 or greater compared to the baseline SpO2/FiO2)

Secondary Outcome Measures

1. 28-Day Survival Status [28 Days]

   Number of patients who were confirmed to be alive 28 days from enrollment onto the study.

2. Duration of Supplemental Oxygen Administration by Nasal Cannula [28 Days]

   Duration of supplemental oxygen administration by nasal cannula, simple face mask, or other similar oxygen delivery device

3. Duration of Non-invasive Ventilation or by Non-rebreather Mask or High-flow Nasal Cannula [28 Days]

   Duration of non-invasive ventilation or by non-rebreather mask or high-flow nasal cannula

4. Number of Patients Requiring Mechanical Ventilation [28 Days]

   Number of patients enrolled who required mechanical ventilation

5. Number of Patients Requiring Vasopressor Support [28 Days]

   Number of participants who required vasopressor support

6. Number of Patients Requiring Extracorporeal Membrane Oxygenation [28 Days]

   Number of patients requiring extracorporeal membrane oxygenation

7. Number of Patients With Fever [28 Days]

   Number of patients who exhibited fever during the study period

8. Correlation of Dynamic Changes in IP-10 to Cytokine Profile [3 Days]

   Correlation of dynamic changes in IP-10 to cytokine profile between day 3 and baseline

9. Duration of Hospitalization [28 Days]

   Duration of hospitalization

10. Number of Patients Who Developed Secondary Infections [28 Days]

    Number of patients who developed secondary infections

11. Number of Patients Requiring Supplemental Oxygen Administration by Nasal Cannula [28 Days]

    Incidence of supplemental oxygen administration by nasal cannula, simple face mask, or other similar oxygen delivery device

12. Duration of Mechanical Ventilation [28 Days]

    duration of use of mechanical ventilation (for patients requiring mechanical ventilation)

13. Number of Patients Requiring Non-invasive Ventilation or by Non-rebreather Mask or High-flow Nasal Cannula [28 Days]

    Number of participants who required non-invasive ventilation or by non-rebreather mask or high-flow nasal cannula

14. Assessment of Cytokine and Inflammatory Profile at Baseline [Baseline]

    Assessment of cytokine and inflammatory profile at baseline (TNFα, IL-1b, IL-2, IL-6, ferritin) after therapy

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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:

6. Respiratory frequency ≥30/min

7. Blood oxygen saturation ≤93% on RA

8. Partial pressure of arterial oxygen to fraction of inspired oxygen ratio (PaO2/FiO2) <300

9. 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:

10. Myocardial infarction (within last month)

11. Moderate or severe heart failure (New York Heart Association (NYHA) class III or IV)

12. Acute stroke (within last month)

13. Uncontrolled malignancy

14. 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Tufts Medical Center	Boston	Massachusetts	United States	02111

Sponsors and Collaborators

• Tufts Medical Center
• National Institutes of Health (NIH)

Investigators

• Principal Investigator: Paul Mathew, MD, Tufts Medical Center

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jun 22, 2020

More Information

Publications

None provided.

• Responsible Party: Tufts Medical Center
• ClinicalTrials.gov Identifier: NCT04425538
• Other Study ID Numbers: STUDY00000564
• First Posted: Jun 11, 2020
• Last Update Posted: Apr 20, 2022
• Last Verified: Apr 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Tufts Medical Center: COVID-19
• Additional relevant MeSH terms: COVID-19; Infliximab

Study Results

Participant Flow

Arm/Group Title	Infliximab
Arm/Group Description	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. Infliximab: Either infliximab or infliximab-abda will be used at the discretion of the investigator
Period Title: Overall Study
STARTED	17
COMPLETED	17
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Infliximab
Arm/Group Description	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. Infliximab: Either infliximab or infliximab-abda will be used at the discretion of the investigator
Overall Participants	17
Age, Customized (Count of Participants)
18-40 years	1 5.9%
41-60 years	7 41.2%
>60 years	9 52.9%
Sex: Female, Male (Count of Participants)
Female	4 23.5%
Male	13 76.5%
Race/Ethnicity, Customized (Count of Participants)
Caucasian	4 23.5%
Black/African American	2 11.8%
Chinese	3 17.6%
Other Asian	2 11.8%
Hispanic/Latino	4 23.5%
Other	1 5.9%
Unknown	1 5.9%
Region of Enrollment (participants) [Number]
United States	17 100%

Outcome Measures

1. Primary Outcome

Title	Time to Improvement in Oxygenation
Description	Time to improvement in oxygenation (increase in SpO2/FiO2 of 50 or greater compared to the baseline SpO2/FiO2)
Time Frame	28 Days

Outcome Measure Data

Analysis Population Description

15 patients met this endpoint whereby duration data could be obtained

Arm/Group Title	Infliximab
Arm/Group Description	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. Infliximab: Either infliximab or infliximab-abda will be used at the discretion of the investigator
Measure Participants	15
Median (Full Range) [Days]	4

2. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Infliximab
Arm/Group Description	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. Infliximab: Either infliximab or infliximab-abda will be used at the discretion of the investigator
Measure Participants	17
Count of Participants [Participants]	15 88.2%

3. Secondary Outcome

Title	28-Day Survival Status
Description	Number of patients who were confirmed to be alive 28 days from enrollment onto the study.
Time Frame	28 Days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Infliximab
Arm/Group Description	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. Infliximab: Either infliximab or infliximab-abda will be used at the discretion of the investigator
Measure Participants	17
Count of Participants [Participants]	15 88.2%

4. Secondary Outcome

Title	Duration of Supplemental Oxygen Administration by Nasal Cannula
Description	Duration of supplemental oxygen administration by nasal cannula, simple face mask, or other similar oxygen delivery device
Time Frame	28 Days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Infliximab
Arm/Group Description	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. Infliximab: Either infliximab or infliximab-abda will be used at the discretion of the investigator
Measure Participants	17
Median (Full Range) [Days]	3

5. Secondary Outcome

Title	Duration of Non-invasive Ventilation or by Non-rebreather Mask or High-flow Nasal Cannula
Description	Duration of non-invasive ventilation or by non-rebreather mask or high-flow nasal cannula
Time Frame	28 Days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Infliximab
Arm/Group Description	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. Infliximab: Either infliximab or infliximab-abda will be used at the discretion of the investigator
Measure Participants	17
Median (Full Range) [Days]	2.5

6. Secondary Outcome

Title	Number of Patients Requiring Mechanical Ventilation
Description	Number of patients enrolled who required mechanical ventilation
Time Frame	28 Days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Infliximab
Arm/Group Description	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. Infliximab: Either infliximab or infliximab-abda will be used at the discretion of the investigator
Measure Participants	17
Count of Participants [Participants]	7 41.2%

7. Secondary Outcome

Title	Number of Patients Requiring Vasopressor Support
Description	Number of participants who required vasopressor support
Time Frame	28 Days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Infliximab
Arm/Group Description	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. Infliximab: Either infliximab or infliximab-abda will be used at the discretion of the investigator
Measure Participants	17
Count of Participants [Participants]	3 17.6%

8. Secondary Outcome

Title	Number of Patients Requiring Extracorporeal Membrane Oxygenation
Description	Number of patients requiring extracorporeal membrane oxygenation
Time Frame	28 Days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Infliximab
Arm/Group Description	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. Infliximab: Either infliximab or infliximab-abda will be used at the discretion of the investigator
Measure Participants	17
Count of Participants [Participants]	1 5.9%

9. Secondary Outcome

Title	Number of Patients With Fever
Description	Number of patients who exhibited fever during the study period
Time Frame	28 Days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Infliximab
Arm/Group Description	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. Infliximab: Either infliximab or infliximab-abda will be used at the discretion of the investigator
Measure Participants	17
Count of Participants [Participants]	12 70.6%

10. Secondary Outcome

Title	Correlation of Dynamic Changes in IP-10 to Cytokine Profile
Description	Correlation of dynamic changes in IP-10 to cytokine profile between day 3 and baseline
Time Frame	3 Days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Infliximab
Arm/Group Description	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. Infliximab: Either infliximab or infliximab-abda will be used at the discretion of the investigator
Measure Participants	17
CXCL9	0.652
IL-15	0.605
FLT-3L	0.601
IL-12p40	0.585
IL-3	.571
M-CSF	0.564
MDC	0.528
IFN-A2	0.509
IL-5	.501
IL-18	.484

11. Secondary Outcome

Title	Duration of Hospitalization
Description	Duration of hospitalization
Time Frame	28 Days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Infliximab
Arm/Group Description	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. Infliximab: Either infliximab or infliximab-abda will be used at the discretion of the investigator
Measure Participants	17
Median (Full Range) [days]	8

12. Secondary Outcome

Title	Number of Patients Who Developed Secondary Infections
Description	Number of patients who developed secondary infections
Time Frame	28 Days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Infliximab
Arm/Group Description	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. Infliximab: Either infliximab or infliximab-abda will be used at the discretion of the investigator
Measure Participants	17
Count of Participants [Participants]	7 41.2%

13. Secondary Outcome

Title	Number of Patients Requiring Supplemental Oxygen Administration by Nasal Cannula
Description	Incidence of supplemental oxygen administration by nasal cannula, simple face mask, or other similar oxygen delivery device
Time Frame	28 Days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Infliximab
Arm/Group Description	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. Infliximab: Either infliximab or infliximab-abda will be used at the discretion of the investigator
Measure Participants	17
Count of Participants [Participants]	14 82.4%

14. Secondary Outcome

Title	Duration of Mechanical Ventilation
Description	duration of use of mechanical ventilation (for patients requiring mechanical ventilation)
Time Frame	28 Days

Outcome Measure Data

Analysis Population Description

7 of 17 enrolled patients required mechanical ventilation

Arm/Group Title	Infliximab
Arm/Group Description	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. Infliximab: Either infliximab or infliximab-abda will be used at the discretion of the investigator
Measure Participants	7
Median (Full Range) [days]	10

15. Secondary Outcome

Title	Number of Patients Requiring Non-invasive Ventilation or by Non-rebreather Mask or High-flow Nasal Cannula
Description	Number of participants who required non-invasive ventilation or by non-rebreather mask or high-flow nasal cannula
Time Frame	28 Days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Infliximab
Arm/Group Description	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. Infliximab: Either infliximab or infliximab-abda will be used at the discretion of the investigator
Measure Participants	17
Count of Participants [Participants]	8 47.1%

16. Secondary Outcome

Title	Assessment of Cytokine and Inflammatory Profile at Baseline
Description	Assessment of cytokine and inflammatory profile at baseline (TNFα, IL-1b, IL-2, IL-6, ferritin) after therapy
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Infliximab
Arm/Group Description	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. Infliximab: Either infliximab or infliximab-abda will be used at the discretion of the investigator
Measure Participants	17
TNFα	109.2 (53.4)
IL-1β	42.3 (97.8)
IL-2	1.46 (2.21)
IL-6	69.2 (130.85)
Ferritin	1972.12 (1517.56)

Adverse Events

Time Frame	Adverse events and serious adverse events were collected for each patient beginning at the time of first infliximab dose through 28 days following the last dose of infliximab. Study-wide, adverse event collection was conducted for approximately 8 months.
Adverse Event Reporting Description	Serious adverse events and all-cause mortality were collected according to clinicaltrials.gov definitions. For other adverse events, only adverse events of special interest were collected for the purposes of this trial. Adverse events of special interest include infusion reactions from infliximab treatment, anaphylaxis, and any other event deemed by the investigator to be directly related to infliximab treatment.
Arm/Group Title	Infliximab
Arm/Group Description	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. Infliximab: Either infliximab or infliximab-abda will be used at the discretion of the investigator
All Cause Mortality
	Infliximab
	Affected / at Risk (%)	# Events
Total	2/17 (11.8%)
Serious Adverse Events
	Infliximab
	Affected / at Risk (%)	# Events
Total	2/17 (11.8%)
Cardiac disorders
Cardiac Arrest	1/17 (5.9%)	1
Infections and infestations
Covid-Associated Pulmonary Aspergillosis	1/17 (5.9%)	1
Other (Not Including Serious) Adverse Events
	Infliximab
	Affected / at Risk (%)	# Events
Total	16/17 (94.1%)
Cardiac disorders
Atrial Fibrillation	1/17 (5.9%)
Intermittent Sinus Bradycardia	1/17 (5.9%)
General disorders
Acute Infusion Reaction	2/17 (11.8%)
Infections and infestations
Lung Infection	8/17 (47.1%)
Herpes Simplex Reactivation	2/17 (11.8%)
Investigations
AST Elevation	9/17 (52.9%)
ALT Elevation	8/17 (47.1%)
Hyperglycemia	1/17 (5.9%)
Renal and urinary disorders
Acute Kidney Injury	3/17 (17.6%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.