COVID-19 Pneumonia
Conditions
Brief summary
This study (EMPACTA) will a) evaluate the efficacy and safety of tocilizumab (TCZ) compared with a placebo in combination with standard of care (SOC) in hospitalized participants with COVID-19 pneumonia, and b) include an optional long-term extension for eligible participants to explore the long-term sequelae of resolved COVID-19 pneumonia.
Interventions
DRUGPlacebo
Participants will receive one dose of IV placebo matched to TCZ. Up to one additional dose may be given.
DRUGTocilizumab
Participants will receive one IV infusion of TCZ 8 mg/kg, with a maximum dose of 800 mg. Up to one additional dose may be given.
Sponsors
Genentech, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Hospitalized * COVID-19 pneumonia confirmed by a positive polymerase chain reaction (PCR) of any specimen and radiographic imaging * SpO2 \< 94% while on ambient air Inclusion Criteria Specific to Long-Term Extension * Participated in Study ML42528 (EMPACTA) (includes participants who completed or discontinued early from the main study)
Exclusion criteria
* Known severe allergic reactions to TCZ or other monoclonal antibodies * Require continuous positive airway pressure (CPAP), bilevel positive airway pressure (BIPAP), or invasive mechanical ventilation * Suspected active bacterial, fungal, viral, or other infection (besides COVID-19) * In the opinion of the investigator, progression to death is imminent and inevitable within the next 24 hours, irrespective of the provision of treatments * Immunocompromised (besides well-controlled HIV) or on immunosuppressive therapy (except for steroids for COVID), advanced cancer * Have received oral anti-rejection or immunomodulatory drugs (including TCZ) within the past 3 months * Participating in another interleukin (IL)-6 antagonist clinical trial or other drug clinical trials (participation in COVID-19 anti-viral trials may be permitted if approved by Medical Monitor) * Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \> 10 x upper limit of normal (ULN) detected within 24 hours at screening (according to local laboratory reference ranges) * Absolute neutrophil count (ANC) \< 1000/uL at screening (according to local laboratory reference ranges) * Platelet count \< 50,000/uL at screening (according to local laboratory reference ranges) * Pregnant or breastfeeding, or positive pregnancy test in a pre-dose examination * Treatment with an investigational drug within 5 half lives or 30 days (whichever is longer) of randomization (investigational COVID-19 antivirals may be permitted if approved by Medical Monitor) * Any serious medical condition or abnormality of clinical laboratory tests that, in the investigator's judgment, precludes the patient's safe participation in and completion of the study * Any history of Diverticulitis or GI perforation * Use of systemic corticosteroids unless on a stable chronic dose
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cumulative Proportion of Participants Who Died or Required Mechanical Ventilation by Day 28 | Up to Day 28 | Cumulative proportion is measured as a percentage of participants meeting the endpoint. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Improvement of at Least 2 Categories Relative to Baseline on a 7-Category Ordinal Scale of Clinical Status | Up to Day 28 | Clinical status was assessed using a 7-category ordinal scale: 1. \- Discharged (or ready for discharge as evidenced by normal body temperature and respiratory rate, and stable oxygen saturation on ambient air or \</=2 liters supplemental oxygen) 2. \- Non- intensive care unit (ICU) hospital ward (or ready for hospital ward) not requiring supplemental oxygen 3. \- Non-ICU hospital ward (or ready for hospital ward) requiring supplemental oxygen 4. \- ICU or non-ICU hospital ward, requiring non-invasive ventilation or high-flow oxygen 5. \- ICU, requiring intubation and mechanical ventilation 6. \- ICU, requiring extracorporeal membrane oxygenation (ECMO) or mechanical ventilation and additional organ support 7. \- Death |
| Time to Clinical Failure, Defined as the Time to Death, Mechanical Ventilation, ICU Admission, or Withdrawal (Whichever Occurred First) | Up to Day 28 | — |
| Time to Hospital Discharge or Ready for Discharge (as Evidenced by Normal Body Temperature and Respiratory Rate, and Stable Oxygen Saturation on Ambient Air or >/= 2 Liters (L) Supplemental Oxygen) | Up to Day 28 | — |
| Clinical Status on 7-Category Ordinal Scale at Day 28 | Day 28 | Clinical status was assessed using a 7-category ordinal scale: 1. \- Discharged (or ready for discharge as evidenced by normal body temperature and respiratory rate, and stable oxygen saturation on ambient air or \</=2 liters supplemental oxygen) 2. \- Non- intensive care unit (ICU) hospital ward (or ready for hospital ward) not requiring supplemental oxygen 3. \- Non-ICU hospital ward (or ready for hospital ward) requiring supplemental oxygen 4. \- ICU or non-ICU hospital ward, requiring non-invasive ventilation or high-flow oxygen 5. \- ICU, requiring intubation and mechanical ventilation 6. \- ICU, requiring extracorporeal membrane oxygenation (ECMO) or mechanical ventilation and additional organ support 7. \- Death |
| Percentage of Participants With Adverse Events | Up to Day 60 | — |
| Mortality Rate by Day 28 | Up to Day 28 | — |
Countries
Brazil, Kenya, Mexico, Peru, South Africa, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Tocilizumab Participants received one IV infusion of TCZ in addition to SOC with up to one additional infusion. | 249 |
| Placebo Participants received one intravenous (IV) infusion of placebo, in addition to SOC, with up to one additional infusion. | 128 |
| Total | 377 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 24 | 11 |
| Overall Study | Transferred to a different facility for care | 0 | 2 |
Baseline characteristics
| Characteristic | Placebo | Total | Tocilizumab |
|---|---|---|---|
| Age, Continuous | 55.6 Years STANDARD_DEVIATION 14.9 | 55.9 Years STANDARD_DEVIATION 14.4 | 56.0 Years STANDARD_DEVIATION 14.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 68 Participants | 211 Participants | 143 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 60 Participants | 166 Participants | 106 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 25 Participants | 77 Participants | 52 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 6 Participants | 5 Participants |
| Race (NIH/OMB) Black or African American | 22 Participants | 57 Participants | 35 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 6 Participants | 4 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 12 Participants | 31 Participants | 19 Participants |
| Race (NIH/OMB) White | 65 Participants | 199 Participants | 134 Participants |
| Sex: Female, Male Female | 55 Participants | 154 Participants | 99 Participants |
| Sex: Female, Male Male | 73 Participants | 223 Participants | 150 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 29 / 250 | 15 / 127 |
| other Total, other adverse events | 28 / 250 | 8 / 127 |
| serious Total, serious adverse events | 38 / 250 | 25 / 127 |
Outcome results
Primary
Cumulative Proportion of Participants Who Died or Required Mechanical Ventilation by Day 28
Cumulative proportion is measured as a percentage of participants meeting the endpoint.
Time frame: Up to Day 28
Population: mITT population = all randomized participants who received study treatment, grouped according to the treatment assigned at randomization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tocilizumab | Cumulative Proportion of Participants Who Died or Required Mechanical Ventilation by Day 28 | 12.04 Percentage of Participants |
| Placebo | Cumulative Proportion of Participants Who Died or Required Mechanical Ventilation by Day 28 | 19.26 Percentage of Participants |
Secondary
Clinical Status on 7-Category Ordinal Scale at Day 28
Clinical status was assessed using a 7-category ordinal scale: 1. \- Discharged (or ready for discharge as evidenced by normal body temperature and respiratory rate, and stable oxygen saturation on ambient air or \</=2 liters supplemental oxygen) 2. \- Non- intensive care unit (ICU) hospital ward (or ready for hospital ward) not requiring supplemental oxygen 3. \- Non-ICU hospital ward (or ready for hospital ward) requiring supplemental oxygen 4. \- ICU or non-ICU hospital ward, requiring non-invasive ventilation or high-flow oxygen 5. \- ICU, requiring intubation and mechanical ventilation 6. \- ICU, requiring extracorporeal membrane oxygenation (ECMO) or mechanical ventilation and additional organ support 7. \- Death
Time frame: Day 28
Population: mITT population = all randomized participants who received study treatment, grouped according to the treatment assigned at randomization.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tocilizumab | Clinical Status on 7-Category Ordinal Scale at Day 28 | 3 | 2.0 Percentage of participants |
| Tocilizumab | Clinical Status on 7-Category Ordinal Scale at Day 28 | 5 | 0.8 Percentage of participants |
| Tocilizumab | Clinical Status on 7-Category Ordinal Scale at Day 28 | 2 | 0.4 Percentage of participants |
| Tocilizumab | Clinical Status on 7-Category Ordinal Scale at Day 28 | 6 | 0 Percentage of participants |
| Tocilizumab | Clinical Status on 7-Category Ordinal Scale at Day 28 | 4 | 0.4 Percentage of participants |
| Tocilizumab | Clinical Status on 7-Category Ordinal Scale at Day 28 | 7 | 10.4 Percentage of participants |
| Tocilizumab | Clinical Status on 7-Category Ordinal Scale at Day 28 | 1 | 85.9 Percentage of participants |
| Placebo | Clinical Status on 7-Category Ordinal Scale at Day 28 | 7 | 8.6 Percentage of participants |
| Placebo | Clinical Status on 7-Category Ordinal Scale at Day 28 | 1 | 82.8 Percentage of participants |
| Placebo | Clinical Status on 7-Category Ordinal Scale at Day 28 | 2 | 1.6 Percentage of participants |
| Placebo | Clinical Status on 7-Category Ordinal Scale at Day 28 | 3 | 0.8 Percentage of participants |
| Placebo | Clinical Status on 7-Category Ordinal Scale at Day 28 | 4 | 0.8 Percentage of participants |
| Placebo | Clinical Status on 7-Category Ordinal Scale at Day 28 | 5 | 3.9 Percentage of participants |
| Placebo | Clinical Status on 7-Category Ordinal Scale at Day 28 | 6 | 1.6 Percentage of participants |
Secondary
Mortality Rate by Day 28
Time frame: Up to Day 28
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tocilizumab | Mortality Rate by Day 28 | 10.4 Percentage of Participants |
| Placebo | Mortality Rate by Day 28 | 8.6 Percentage of Participants |
Secondary
Percentage of Participants With Adverse Events
Time frame: Up to Day 60
Population: Safety evaluable population = all participants who received any amount of study drug, grouped according to the treatment first received rather than by the treatment assigned at randomization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tocilizumab | Percentage of Participants With Adverse Events | 50.8 Percentage of participants |
| Placebo | Percentage of Participants With Adverse Events | 52.8 Percentage of participants |
Secondary
Time to Clinical Failure, Defined as the Time to Death, Mechanical Ventilation, ICU Admission, or Withdrawal (Whichever Occurred First)
Time frame: Up to Day 28
Population: mITT population = all randomized participants who received study treatment, grouped according to the treatment assigned at randomization.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tocilizumab | Time to Clinical Failure, Defined as the Time to Death, Mechanical Ventilation, ICU Admission, or Withdrawal (Whichever Occurred First) | NA Days |
| Placebo | Time to Clinical Failure, Defined as the Time to Death, Mechanical Ventilation, ICU Admission, or Withdrawal (Whichever Occurred First) | NA Days |
Secondary
Time to Hospital Discharge or Ready for Discharge (as Evidenced by Normal Body Temperature and Respiratory Rate, and Stable Oxygen Saturation on Ambient Air or >/= 2 Liters (L) Supplemental Oxygen)
Time frame: Up to Day 28
Population: mITT population = all randomized participants who received study treatment, grouped according to the treatment assigned at randomization. Participants not receiving study treatment were excluded from analyses.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tocilizumab | Time to Hospital Discharge or Ready for Discharge (as Evidenced by Normal Body Temperature and Respiratory Rate, and Stable Oxygen Saturation on Ambient Air or >/= 2 Liters (L) Supplemental Oxygen) | 6.0 Days |
| Placebo | Time to Hospital Discharge or Ready for Discharge (as Evidenced by Normal Body Temperature and Respiratory Rate, and Stable Oxygen Saturation on Ambient Air or >/= 2 Liters (L) Supplemental Oxygen) | 7.5 Days |
Secondary
Time to Improvement of at Least 2 Categories Relative to Baseline on a 7-Category Ordinal Scale of Clinical Status
Clinical status was assessed using a 7-category ordinal scale: 1. \- Discharged (or ready for discharge as evidenced by normal body temperature and respiratory rate, and stable oxygen saturation on ambient air or \</=2 liters supplemental oxygen) 2. \- Non- intensive care unit (ICU) hospital ward (or ready for hospital ward) not requiring supplemental oxygen 3. \- Non-ICU hospital ward (or ready for hospital ward) requiring supplemental oxygen 4. \- ICU or non-ICU hospital ward, requiring non-invasive ventilation or high-flow oxygen 5. \- ICU, requiring intubation and mechanical ventilation 6. \- ICU, requiring extracorporeal membrane oxygenation (ECMO) or mechanical ventilation and additional organ support 7. \- Death
Time frame: Up to Day 28
Population: mITT population = all randomized participants who received study treatment, grouped according to the treatment assigned at randomization.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tocilizumab | Time to Improvement of at Least 2 Categories Relative to Baseline on a 7-Category Ordinal Scale of Clinical Status | 6.0 Days |
| Placebo | Time to Improvement of at Least 2 Categories Relative to Baseline on a 7-Category Ordinal Scale of Clinical Status | 7.0 Days |