Severe COVID-19 Pneumonia
Conditions
Keywords
COVID-19 related severe pneumonia
Brief summary
Phase II & Phase III: This is a pragmatic, adaptive, randomized, multicenter phase II/III study evaluating IFX-1 for the treatment of COVID-19 related severe pneumonia. The study consists of two parts: Phase II, an open-label, randomized, 2-arm phase evaluating best supportive care (BSC) + IFX-1 (Arm A) and BSC alone (Arm B); and Phase III, a double-blind, placebo-controlled, randomized phase comparing standard of care (SOC) + IFX-1 (Arm A) versus SOC + placebo-to-match (Arm B)
Detailed description
The phase II and Phase III portions enrolled patients subsequently. 1st patient was enrolled in the phase III portion on 1st October 2020.
Interventions
DRUGIFX-1 + BSC
Phase II study part: IFX-1 + BSC
DRUGBSC
Phase II study part: BSC
DRUGIFX-1 + SOC
Phase III study part: IFX-1 + SOC
DRUGPlacebo + SOC
Phase III study part: Placebo + SOC
Sponsors
InflaRx GmbH
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Masking description
Phase II: Open label study (30 patients), Phase III: Double- blind (360 patients)
Intervention model description
Two phases with 2 parallel arms each
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Phase II Inclusion Criteria: * At least 18 years of age or older * Clinically evident or otherwise confirmed severe pneumonia * SARS-CoV-2 infection confirmation (tested positive in last 14 days before randomization with locally available test system)
Exclusion criteria
* Known history of progressed COPD as evidenced by use of daily maintenance treatment with long-acting bronchodilators or inhaled/oral corticosteroids for \> 2 months * Patient moribund or expected to die in next 24h according to the judgment of the investigator * Known severe congestive heart failure (New York Heart Association \[NYHA\] Class III- IV) * Received organ or bone marrow transplantation in past 3 months * Known cardio-pulmonary mechanical resuscitation in past 14 days Phase III: Inclusion Criteria: * At least 18 years of age or older * Patient on invasive mechanical ventilation (but not more than 48h post intubation at time point of first IMP administration) * Patients with a PaO2 / FiO2 ratio of \< 200 and \> 60 at randomization (one representative measurement within 6h before randomization) * SARS-CoV-2 infection confirmation (tested positive in last 14 days before randomization with locally available test system)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase II: Relative Change From Baseline in Oxygenation Index in Supine Position at Day 5 (FAS) | Baseline and Day 5 | Relative change (%) from baseline in Oxygenation Index (OI; partial pressure of oxygen in the arterial blood (PaO2) / fractional inspired oxygen (FiO2)) in supine position for ≥2 hours at day 5 (FAS) |
| Phase III: 28-day All-cause Mortality (FAS) | Day 28 | Number and percentage of deaths (all-cause) until Day 28 (FAS) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase II: Late Response Until Day 28 After Enrollment | Baseline until Day 28 | Number of patients (%) reaching a late response until day 28 (FAS) |
| Phase II: Relative Change From Baseline in Oxygenation Index in Supine Position (FAS) | Baseline, Day 3, Day 7, Day 9, Day 11, Day 15 | Relative change (%) from baseline in Oxygenation Index (OI) in supine position for ≥2 hours at days 3, 7, 9, 11, and 15 (FAS) |
| Phase III: 60-day All-cause Mortality (FAS) | Day 60 | Number and percentage of deaths (all-cause) until Day 60 (FAS) |
| Phase II: All-cause 28-day Mortality (FAS) | Day 28 | Number and percentage of deaths (all-cause) until Day 28 (FAS) |
| Phase III: Percentage of Patients Developing Acute Kidney Failure Until Day 28 (FAS) | Day 28 | Percentage of patients developing acute kidney failure (estimated glomerular filtration rate \[eGFR\] \< 15 mL/min/1.73m², assessed by the Chronic Kidney Disease Epidemiology Collaboration \[CKD-EPI\] equation requiring race information) until Day 28 (FAS) |
| Phase III: Percentage of Patients Free of Any Renal Replacement Therapy Within 28 Days Upon Randomization (FAS) | Day 28 | Percentage of patients free of any renal replacement therapy (RRT) within 28 days upon randomization (FAS), number of patients free of any RRT = number of patients - number of patients with RRT initiated after randomization until Day 28 |
| Phase III: Percentage of Patients With an Improvement in the 8-point Ordinal Scale (FAS) | Day 15, Day 28 | Percentage of patients with an improvement in the 8-point ordinal scale (Day 15, Day 28), the scale ranges from 0 = 'No clinical or virological evidence of infection' to 8 = 'Death' with higher scores meaning greater limitation and ventilation/organ support |
| Phase II: Early Response at Day 7 After Enrollment | Day 7 | Number of patients (%) achieving an early response at day 7 after enrollment (FAS) |
Countries
Belgium, Brazil, France, Germany, Mexico, Netherlands, Peru, Russia, South Africa
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Phase II: IFX-1 + BSC Phase II study part: IFX-1: 800mg intravenously administered, BSC: Best supportive care | 15 |
| Phase II: BSC Phase II study part: BSC: Best supportive care | 15 |
| Phase III: IFX-1 + SOC Phase III study part: IFX-1: 800mg intravenously administered, SOC: Standard of care | 177 |
| Phase III: Placebo + SOC Phase III study part: Placebo: placebo infusion intravenously administered, SOC: Standard of care | 191 |
| Total | 398 |
Baseline characteristics
| Characteristic | Total | Phase II: IFX-1 + BSC | Phase II: BSC | Phase III: IFX-1 + SOC | Phase III: Placebo + SOC |
|---|---|---|---|---|---|
| Age, Continuous | 56.6 years STANDARD_DEVIATION 13.6 | 57.5 years STANDARD_DEVIATION 8.6 | 62.8 years STANDARD_DEVIATION 8.1 | 56.7 years STANDARD_DEVIATION 13.2 | 55.9 years STANDARD_DEVIATION 14.5 |
| Intubation status No | 12 Participants | 7 Participants | 5 Participants | 0 Participants | 0 Participants |
| Intubation status Yes | 386 Participants | 8 Participants | 10 Participants | 177 Participants | 191 Participants |
| Oxygenation index | 131.9 index STANDARD_DEVIATION 42.5 | 137.9 index STANDARD_DEVIATION 51.1 | 144.2 index STANDARD_DEVIATION 41.5 | 131.9 index STANDARD_DEVIATION 39.2 | 130.6 index STANDARD_DEVIATION 44.8 |
| Race/Ethnicity, Customized Ethnicity Hispanic or Latino | 128 Participants | 0 Participants | 0 Participants | 60 Participants | 68 Participants |
| Race/Ethnicity, Customized Ethnicity Missing | 12 Participants | 0 Participants | 0 Participants | 8 Participants | 4 Participants |
| Race/Ethnicity, Customized Ethnicity Not Hispanic or Latino | 173 Participants | 15 Participants | 15 Participants | 70 Participants | 73 Participants |
| Race/Ethnicity, Customized Ethnicity Not Reported | 63 Participants | 0 Participants | 0 Participants | 28 Participants | 35 Participants |
| Race/Ethnicity, Customized Ethnicity Unknown | 22 Participants | 0 Participants | 0 Participants | 11 Participants | 11 Participants |
| Race/Ethnicity, Customized Race American Indian or Alaskan Native | 46 Participants | 0 Participants | 0 Participants | 22 Participants | 24 Participants |
| Race/Ethnicity, Customized Race Asian | 16 Participants | 5 Participants | 2 Participants | 4 Participants | 5 Participants |
| Race/Ethnicity, Customized Race Black or African American | 17 Participants | 2 Participants | 2 Participants | 5 Participants | 8 Participants |
| Race/Ethnicity, Customized Race Multiple | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Native Hawaiian or other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Not reported | 30 Participants | 0 Participants | 0 Participants | 14 Participants | 16 Participants |
| Race/Ethnicity, Customized Race Other | 35 Participants | 0 Participants | 0 Participants | 16 Participants | 19 Participants |
| Race/Ethnicity, Customized Race White | 253 Participants | 8 Participants | 11 Participants | 115 Participants | 119 Participants |
| Sex: Female, Male Female | 124 Participants | 4 Participants | 4 Participants | 52 Participants | 64 Participants |
| Sex: Female, Male Male | 274 Participants | 11 Participants | 11 Participants | 125 Participants | 127 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 15 | 4 / 15 | 62 / 175 | 86 / 189 | 1 / 5 |
| other Total, other adverse events | 14 / 15 | 14 / 15 | 147 / 175 | 154 / 189 | 0 / 5 |
| serious Total, serious adverse events | 9 / 15 | 7 / 15 | 103 / 175 | 122 / 189 | 2 / 5 |
Outcome results
Primary
Phase III: 28-day All-cause Mortality (FAS)
Number and percentage of deaths (all-cause) until Day 28 (FAS)
Time frame: Day 28
Population: Full Analysis Set (FAS) including all randomized patients according to intention-to-treat principle except for patients who were randomized in error AND did not receive IMP.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase II: IFX-1 + BSC | Phase III: 28-day All-cause Mortality (FAS) | Dead | 54 Participants |
| Phase II: IFX-1 + BSC | Phase III: 28-day All-cause Mortality (FAS) | Alive | 115 Participants |
| Phase II: IFX-1 + BSC | Phase III: 28-day All-cause Mortality (FAS) | Missing | 8 Participants |
| Phase II: BSC | Phase III: 28-day All-cause Mortality (FAS) | Dead | 77 Participants |
| Phase II: BSC | Phase III: 28-day All-cause Mortality (FAS) | Alive | 105 Participants |
| Phase II: BSC | Phase III: 28-day All-cause Mortality (FAS) | Missing | 9 Participants |
Comparison: Cox proportional hazards regression model with outcome 28-day all-cause mortality (censored time to event variable with event = Death) including stratification by site; 61 patients from sites with no events (no death) or from single patient sites with death factually make no contribution to the analysis outcome.p-value: 0.094195% CI: [0.502, 1.056]Regression, Cox
Comparison: Cox proportional hazards regression model with outcome 28-day all-cause mortality (censored time to event variable with event = Death) without stratification by site; Post-hoc analysisp-value: 0.026695% CI: [0.476, 0.955]Regression, Cox
Comparison: Cox proportional hazards regression model with outcome 28-day all-cause mortality (censored time to event variable with event = Death) including random effect for site (frailty model); Post-hoc analysisp-value: 0.018195% CI: [0.453, 0.929]Regression, Cox
Comparison: Cox proportional hazards regression model with outcome 28-day all-cause mortality (censored time to event variable with event = Death) including stratification by country; Post-hoc analysisp-value: 0.006795% CI: [0.43, 0.873]Regression, Cox
Comparison: Sensitivity analysis; 369 patients were included in this analysis including the patient that was randomized in error and not treated. Missing values were imputed by multiple imputation.p-value: 0.029395% CI: [-20.8, -1.2]Regression, Logistic
Comparison: Post-hoc analysisp-value: 0.0407Log Rank
Primary
Phase II: Relative Change From Baseline in Oxygenation Index in Supine Position at Day 5 (FAS)
Relative change (%) from baseline in Oxygenation Index (OI; partial pressure of oxygen in the arterial blood (PaO2) / fractional inspired oxygen (FiO2)) in supine position for ≥2 hours at day 5 (FAS)
Time frame: Baseline and Day 5
Population: Full Analysis Set (FAS) including all randomized patients according to intention-to-treat principle.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Phase II: IFX-1 + BSC | Phase II: Relative Change From Baseline in Oxygenation Index in Supine Position at Day 5 (FAS) | 15.5 percentage of change |
| Phase II: BSC | Phase II: Relative Change From Baseline in Oxygenation Index in Supine Position at Day 5 (FAS) | 31.9 percentage of change |
p-value: 0.367795% CI: [-53.2, 20.3]Linear repeated measures model
Secondary
Phase II: All-cause 28-day Mortality (FAS)
Number and percentage of deaths (all-cause) until Day 28 (FAS)
Time frame: Day 28
Population: Full Analysis Set (FAS) including all randomized patients according to intention-to-treat principle.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase II: IFX-1 + BSC | Phase II: All-cause 28-day Mortality (FAS) | 2 Participants |
| Phase II: BSC | Phase II: All-cause 28-day Mortality (FAS) | 4 Participants |
Comparison: Cox proportional hazards regression model with outcome 28-day all-cause mortality (censored time to event variable with event = Death)p-value: 0.649495% CI: [0.103, 4.135]Regression, Cox
Secondary
Phase II: Early Response at Day 7 After Enrollment
Number of patients (%) achieving an early response at day 7 after enrollment (FAS)
Time frame: Day 7
Population: The analysis of early response as planned in the protocol was not performed because the necessary data were not collected.
Secondary
Phase III: 60-day All-cause Mortality (FAS)
Number and percentage of deaths (all-cause) until Day 60 (FAS)
Time frame: Day 60
Population: Full Analysis Set (FAS) including all randomized patients according to intention-to-treat principle except for patients who were randomized in error AND did not receive IMP.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase II: IFX-1 + BSC | Phase III: 60-day All-cause Mortality (FAS) | Dead | 62 Participants |
| Phase II: IFX-1 + BSC | Phase III: 60-day All-cause Mortality (FAS) | Alive | 102 Participants |
| Phase II: IFX-1 + BSC | Phase III: 60-day All-cause Mortality (FAS) | Missing | 13 Participants |
| Phase II: BSC | Phase III: 60-day All-cause Mortality (FAS) | Dead | 87 Participants |
| Phase II: BSC | Phase III: 60-day All-cause Mortality (FAS) | Alive | 93 Participants |
| Phase II: BSC | Phase III: 60-day All-cause Mortality (FAS) | Missing | 11 Participants |
Comparison: Cox proportional hazards regression model with outcome 60-day all-cause mortality (censored time to event variable with event = Death); Covariate: Treatment (IFX-1 + SOC)p-value: 0.081595% CI: [0.519, 1.039]Regression, Cox
Secondary
Phase III: Percentage of Patients Developing Acute Kidney Failure Until Day 28 (FAS)
Percentage of patients developing acute kidney failure (estimated glomerular filtration rate \[eGFR\] \< 15 mL/min/1.73m², assessed by the Chronic Kidney Disease Epidemiology Collaboration \[CKD-EPI\] equation requiring race information) until Day 28 (FAS)
Time frame: Day 28
Population: Full Analysis Set (FAS) including all randomized patients according to intention-to-treat principle except for patients who were randomized in error AND did not receive IMP.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase II: IFX-1 + BSC | Phase III: Percentage of Patients Developing Acute Kidney Failure Until Day 28 (FAS) | Acute kidney failure | 8 Participants |
| Phase II: IFX-1 + BSC | Phase III: Percentage of Patients Developing Acute Kidney Failure Until Day 28 (FAS) | No acute kidney failure | 158 Participants |
| Phase II: IFX-1 + BSC | Phase III: Percentage of Patients Developing Acute Kidney Failure Until Day 28 (FAS) | Not evaluable | 11 Participants |
| Phase II: BSC | Phase III: Percentage of Patients Developing Acute Kidney Failure Until Day 28 (FAS) | Acute kidney failure | 12 Participants |
| Phase II: BSC | Phase III: Percentage of Patients Developing Acute Kidney Failure Until Day 28 (FAS) | No acute kidney failure | 168 Participants |
| Phase II: BSC | Phase III: Percentage of Patients Developing Acute Kidney Failure Until Day 28 (FAS) | Not evaluable | 11 Participants |
p-value: 0.410595% CI: [-6.949, 2.787]Regression, Logistic
Secondary
Phase III: Percentage of Patients Free of Any Renal Replacement Therapy Within 28 Days Upon Randomization (FAS)
Percentage of patients free of any renal replacement therapy (RRT) within 28 days upon randomization (FAS), number of patients free of any RRT = number of patients - number of patients with RRT initiated after randomization until Day 28
Time frame: Day 28
Population: Full Analysis Set (FAS) including all randomized patients according to intention-to-treat principle except for patients who were randomized in error AND did not receive IMP.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase II: IFX-1 + BSC | Phase III: Percentage of Patients Free of Any Renal Replacement Therapy Within 28 Days Upon Randomization (FAS) | 160 Participants |
| Phase II: BSC | Phase III: Percentage of Patients Free of Any Renal Replacement Therapy Within 28 Days Upon Randomization (FAS) | 161 Participants |
p-value: 0.042295% CI: [0.297, 0.978]Regression, Cox
Secondary
Phase III: Percentage of Patients With an Improvement in the 8-point Ordinal Scale (FAS)
Percentage of patients with an improvement in the 8-point ordinal scale (Day 15, Day 28), the scale ranges from 0 = 'No clinical or virological evidence of infection' to 8 = 'Death' with higher scores meaning greater limitation and ventilation/organ support
Time frame: Day 15, Day 28
Population: Full Analysis Set (FAS) including all randomized patients according to intention-to-treat principle except for patients who were randomized in error AND did not receive IMP.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase II: IFX-1 + BSC | Phase III: Percentage of Patients With an Improvement in the 8-point Ordinal Scale (FAS) | Improved | 82 Participants |
| Phase II: IFX-1 + BSC | Phase III: Percentage of Patients With an Improvement in the 8-point Ordinal Scale (FAS) | Not improved | 86 Participants |
| Phase II: IFX-1 + BSC | Phase III: Percentage of Patients With an Improvement in the 8-point Ordinal Scale (FAS) | Not evaluable | 9 Participants |
| Phase II: BSC | Phase III: Percentage of Patients With an Improvement in the 8-point Ordinal Scale (FAS) | Improved | 77 Participants |
| Phase II: BSC | Phase III: Percentage of Patients With an Improvement in the 8-point Ordinal Scale (FAS) | Not improved | 104 Participants |
| Phase II: BSC | Phase III: Percentage of Patients With an Improvement in the 8-point Ordinal Scale (FAS) | Not evaluable | 10 Participants |
Comparison: At Day 15p-value: 0.155395% CI: [-2.762, 17.465]Regression, Logistic
Comparison: At Day 28p-value: 0.118195% CI: [-1.968, 18.125]Regression, Logistic
Secondary
Phase II: Late Response Until Day 28 After Enrollment
Number of patients (%) reaching a late response until day 28 (FAS)
Time frame: Baseline until Day 28
Population: The analysis of late response as planned in the protocol was not performed because the necessary data were not collected.
Secondary
Phase II: Relative Change From Baseline in Oxygenation Index in Supine Position (FAS)
Relative change (%) from baseline in Oxygenation Index (OI) in supine position for ≥2 hours at days 3, 7, 9, 11, and 15 (FAS)
Time frame: Baseline, Day 3, Day 7, Day 9, Day 11, Day 15
Population: Full Analysis Set (FAS) including all randomized patients according to intention-to-treat principle.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Phase II: IFX-1 + BSC | Phase II: Relative Change From Baseline in Oxygenation Index in Supine Position (FAS) | Day 7 | 13.1 percentage of change |
| Phase II: IFX-1 + BSC | Phase II: Relative Change From Baseline in Oxygenation Index in Supine Position (FAS) | Day 11 | 45.5 percentage of change |
| Phase II: IFX-1 + BSC | Phase II: Relative Change From Baseline in Oxygenation Index in Supine Position (FAS) | Day 9 | 20.7 percentage of change |
| Phase II: IFX-1 + BSC | Phase II: Relative Change From Baseline in Oxygenation Index in Supine Position (FAS) | Day 15 | 78.5 percentage of change |
| Phase II: IFX-1 + BSC | Phase II: Relative Change From Baseline in Oxygenation Index in Supine Position (FAS) | Day 3 | 7.1 percentage of change |
| Phase II: BSC | Phase II: Relative Change From Baseline in Oxygenation Index in Supine Position (FAS) | Day 15 | 82.6 percentage of change |
| Phase II: BSC | Phase II: Relative Change From Baseline in Oxygenation Index in Supine Position (FAS) | Day 3 | 17.6 percentage of change |
| Phase II: BSC | Phase II: Relative Change From Baseline in Oxygenation Index in Supine Position (FAS) | Day 7 | 36.0 percentage of change |
| Phase II: BSC | Phase II: Relative Change From Baseline in Oxygenation Index in Supine Position (FAS) | Day 9 | 27.8 percentage of change |
| Phase II: BSC | Phase II: Relative Change From Baseline in Oxygenation Index in Supine Position (FAS) | Day 11 | 43.5 percentage of change |