COVID-19
Conditions
Keywords
COVID-19
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.
Interventions
DRUGInfliximab
Either infliximab or infliximab-abda will be used at the discretion of the investigator
Sponsors
National Institutes of Health (NIH)
Tufts Medical Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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: 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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) |
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| Number of Patients Requiring Mechanical Ventilation | 28 Days | Number of patients enrolled who required mechanical ventilation |
| Number of Patients Requiring Vasopressor Support | 28 Days | Number of participants who required vasopressor support |
| Number of Patients Requiring Extracorporeal Membrane Oxygenation | 28 Days | Number of patients requiring extracorporeal membrane oxygenation |
| Number of Patients With Fever | 28 Days | Number of patients who exhibited fever during the study period |
| 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 |
| 28-Day Survival Status | 28 Days | Number of patients who were confirmed to be alive 28 days from enrollment onto the study. |
| Number of Patients Who Developed Secondary Infections | 28 Days | Number of patients who developed secondary infections |
| 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 |
| Duration of Mechanical Ventilation | 28 Days | duration of use of mechanical ventilation (for patients requiring mechanical ventilation) |
| 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 |
| 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 |
| Duration of Hospitalization | 28 Days | Duration of hospitalization |
| 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 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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.
Infliximab: Either infliximab or infliximab-abda will be used at the discretion of the investigator | 17 |
| Total | 17 |
Baseline characteristics
| Characteristic | Infliximab |
|---|---|
| Age, Customized 18-40 years | 1 Participants |
| Age, Customized 41-60 years | 7 Participants |
| Age, Customized >60 years | 9 Participants |
| Race/Ethnicity, Customized Black/African American | 2 Participants |
| Race/Ethnicity, Customized Caucasian | 4 Participants |
| Race/Ethnicity, Customized Chinese | 3 Participants |
| Race/Ethnicity, Customized Hispanic/Latino | 4 Participants |
| Race/Ethnicity, Customized Other | 1 Participants |
| Race/Ethnicity, Customized Other Asian | 2 Participants |
| Race/Ethnicity, Customized Unknown | 1 Participants |
| Region of Enrollment United States | 17 participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 2 / 17 |
| other Total, other adverse events | 16 / 17 |
| serious Total, serious adverse events | 2 / 17 |
Outcome results
Primary
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)
Time frame: 28 Days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Infliximab | Number of p[Atients With Improvement in Oxygenation | 15 Participants |
Primary
Time to Improvement in Oxygenation
Time to improvement in oxygenation (increase in SpO2/FiO2 of 50 or greater compared to the baseline SpO2/FiO2)
Time frame: 28 Days
Population: 15 patients met this endpoint whereby duration data could be obtained
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Infliximab | Time to Improvement in Oxygenation | 4 Days |
Secondary
28-Day Survival Status
Number of patients who were confirmed to be alive 28 days from enrollment onto the study.
Time frame: 28 Days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Infliximab | 28-Day Survival Status | 15 Participants |
Secondary
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
Time frame: Baseline
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Infliximab | Assessment of Cytokine and Inflammatory Profile at Baseline | TNFα | 109.2 ng/mL | Standard Deviation 53.4 |
| Infliximab | Assessment of Cytokine and Inflammatory Profile at Baseline | IL-1β | 42.3 ng/mL | Standard Deviation 97.8 |
| Infliximab | Assessment of Cytokine and Inflammatory Profile at Baseline | IL-2 | 1.46 ng/mL | Standard Deviation 2.21 |
| Infliximab | Assessment of Cytokine and Inflammatory Profile at Baseline | IL-6 | 69.2 ng/mL | Standard Deviation 130.85 |
| Infliximab | Assessment of Cytokine and Inflammatory Profile at Baseline | Ferritin | 1972.12 ng/mL | Standard Deviation 1517.56 |
Secondary
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
Time frame: 3 Days
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Infliximab | Correlation of Dynamic Changes in IP-10 to Cytokine Profile | IL-12p40 | 0.585 Correlation coefficient |
| Infliximab | Correlation of Dynamic Changes in IP-10 to Cytokine Profile | CXCL9 | 0.652 Correlation coefficient |
| Infliximab | Correlation of Dynamic Changes in IP-10 to Cytokine Profile | IL-15 | 0.605 Correlation coefficient |
| Infliximab | Correlation of Dynamic Changes in IP-10 to Cytokine Profile | FLT-3L | 0.601 Correlation coefficient |
| Infliximab | Correlation of Dynamic Changes in IP-10 to Cytokine Profile | IL-3 | .571 Correlation coefficient |
| Infliximab | Correlation of Dynamic Changes in IP-10 to Cytokine Profile | M-CSF | 0.564 Correlation coefficient |
| Infliximab | Correlation of Dynamic Changes in IP-10 to Cytokine Profile | MDC | 0.528 Correlation coefficient |
| Infliximab | Correlation of Dynamic Changes in IP-10 to Cytokine Profile | IFN-A2 | 0.509 Correlation coefficient |
| Infliximab | Correlation of Dynamic Changes in IP-10 to Cytokine Profile | IL-5 | .501 Correlation coefficient |
| Infliximab | Correlation of Dynamic Changes in IP-10 to Cytokine Profile | IL-18 | .484 Correlation coefficient |
Secondary
Duration of Hospitalization
Duration of hospitalization
Time frame: 28 Days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Infliximab | Duration of Hospitalization | 8 days |
Secondary
Duration of Mechanical Ventilation
duration of use of mechanical ventilation (for patients requiring mechanical ventilation)
Time frame: 28 Days
Population: 7 of 17 enrolled patients required mechanical ventilation
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Infliximab | Duration of Mechanical Ventilation | 10 days |
Secondary
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
Time frame: 28 Days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Infliximab | Duration of Non-invasive Ventilation or by Non-rebreather Mask or High-flow Nasal Cannula | 2.5 Days |
Secondary
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
Time frame: 28 Days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Infliximab | Duration of Supplemental Oxygen Administration by Nasal Cannula | 3 Days |
Secondary
Number of Patients Requiring Extracorporeal Membrane Oxygenation
Number of patients requiring extracorporeal membrane oxygenation
Time frame: 28 Days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Infliximab | Number of Patients Requiring Extracorporeal Membrane Oxygenation | 1 Participants |
Secondary
Number of Patients Requiring Mechanical Ventilation
Number of patients enrolled who required mechanical ventilation
Time frame: 28 Days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Infliximab | Number of Patients Requiring Mechanical Ventilation | 7 Participants |
Secondary
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
Time frame: 28 Days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Infliximab | Number of Patients Requiring Non-invasive Ventilation or by Non-rebreather Mask or High-flow Nasal Cannula | 8 Participants |
Secondary
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
Time frame: 28 Days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Infliximab | Number of Patients Requiring Supplemental Oxygen Administration by Nasal Cannula | 14 Participants |
Secondary
Number of Patients Requiring Vasopressor Support
Number of participants who required vasopressor support
Time frame: 28 Days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Infliximab | Number of Patients Requiring Vasopressor Support | 3 Participants |
Secondary
Number of Patients Who Developed Secondary Infections
Number of patients who developed secondary infections
Time frame: 28 Days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Infliximab | Number of Patients Who Developed Secondary Infections | 7 Participants |
Secondary
Number of Patients With Fever
Number of patients who exhibited fever during the study period
Time frame: 28 Days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Infliximab | Number of Patients With Fever | 12 Participants |