COVID-19, COVID-19 Pulmonary Complications
Conditions
Keywords
Corona Virus, COVID-19
Brief summary
The primary objective of this study was to evaluate if the addition of zanubrutinib to supportive care increases the respiratory failure-free survival rate at Day 28 in participants hospitalized for Corona Virus Disease 2019 (COVID-19) and pulmonary distress not receiving mechanical ventilation.
Interventions
DRUGZanubrutinib
320 mg (4 x 80 mg) capsules administered orally once daily
DRUGSupportive Care
Supportive care treatment was selected and administered as deemed appropriate by the study investigator
DRUGPlacebo
Placebo to match zanubrutinib
Sponsors
BeiGene
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
Key Inclusion Criteria: 1. Hospitalization for COVID-19 infection 2. Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV)-2 infection confirmed by polymerase chain reaction (PCR) 3. Participant requires supplemental oxygen for pulmonary distress related to COVID-19 infection, and has been on supplemental oxygen for no more than 96 hours from time of screening Key
Exclusion criteria
1. Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel, symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction 2. On a Bruton's tyrosine kinase (BTK) inhibitor 3. Planned or concurrent use of a host modifiers/immune-based therapies or anti-CD20 monoclonal antibody treatment 4. Participants with prior of current hematologic malignancy or solid tumor malignancy with treatment within 6 months prior to study entry NOTE: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Respiratory Failure-free Survival | Up to Day 28 | Number of participants with respiratory failure-free survival, defined as not having died or gone into respiratory failure on or before Day 28 |
| Time to Breathing Room Air | Up to 7 months | Time to return to breathing room air is defined as the time from randomization date to the earliest time where the participant is stable on room air without supplemental oxygen. Total follow-up time in days is the total time of all participants from the randomization date to the first event date or Day 28 if there is no event. The rate was calculated as total number of events in which a participant returned to breathing room air on or before Day 28 divided by the total follow-up time in days. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Discharged Alive | Up to Day 28 | Number of participants discharged alive on or before Day 28 |
| Number of Participants Discharged Alive From the ICU | Up to Day 28 | Number of participants discharged alive from the intensive care unit (ICU) on or before Day 28 |
| Number of Participants With Improvement in the World Health Organization (WHO) 8-point Ordinal Scale | Up to Day 28 | Number of participants with improvement in WHO 8-point-scale, in which improvement was considered a score that changed from ≥4 at baseline to ≤ 3 at Day 28 as assessed by the investigator. Scoring ranges from 0 = uninfected with no clinical or virologic evidence of disease to 8 = dead. |
| Number of Participants Experiencing Respiratory Failure or Death | Up to Day 28 | Number of participants experiencing respiratory failure or death on or before Day 28 |
| Duration of Hospitalization | Up to Day 28 | Number of days hospitalized on or before Day 28 |
| PaO2:FiO2 Ratio | Baseline, Day 7, Day 14, Day 21 and Day 28 | Partial pressure of oxygen (PaO2):fraction of inspired oxygen (FiO2) ratio |
| Number of Participants With Adverse Events | Up to 7 months | Number of participants with treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), treatment-related adverse events (AEs), and TEAEs grade 3 or higher, including laboratory findings |
| Duration of Mechanical Ventilation | Up to Day 28 | Number of days on mechanical ventilation on or before Day 28 |
| Number of Participants With All-cause Mortality | Up to Day 28 | Number of participants with all-cause mortality on or before Day 28 |
Countries
United States
Participant flow
Recruitment details
A total of 63 participants were randomized to receive zanubrutinib or placebo; four were randomized to the placebo group, but did not receive placebo treatment due to death (1 participant) and investigator decision (3 participants).
Participants by arm
| Arm | Count |
|---|---|
| Zanubrutinib + Supportive Care Zanubrutinib 320 mg orally once daily for 28 days. Supportive care treatment selected and administered as deemed appropriate by the study investigator. | 30 |
| Placebo + Supportive Care Placebo orally once daily for 28 days. Supportive care treatment selected and administered as deemed appropriate by the study investigator. | 33 |
| Total | 63 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 3 | 4 |
| Overall Study | Lost to Follow-up | 11 | 8 |
| Overall Study | Physician Decision | 0 | 3 |
| Overall Study | Withdrawal by Subject | 3 | 1 |
Baseline characteristics
| Characteristic | Placebo + Supportive Care | Total | Zanubrutinib + Supportive Care |
|---|---|---|---|
| Age, Continuous | 56.0 Years STANDARD_DEVIATION 13.3 | 56.0 Years STANDARD_DEVIATION 12.83 | 56.0 Years STANDARD_DEVIATION 12.51 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 6 Participants | 19 Participants | 13 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 26 Participants | 42 Participants | 16 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 2 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 2 Participants | 4 Participants | 2 Participants |
| Race/Ethnicity, Customized Black or African American | 5 Participants | 8 Participants | 3 Participants |
| Race/Ethnicity, Customized Not Reported | 0 Participants | 2 Participants | 2 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 2 Participants | 1 Participants |
| Race/Ethnicity, Customized Unknown | 0 Participants | 3 Participants | 3 Participants |
| Race/Ethnicity, Customized White | 25 Participants | 44 Participants | 19 Participants |
| Sex: Female, Male Female | 16 Participants | 32 Participants | 16 Participants |
| Sex: Female, Male Male | 17 Participants | 31 Participants | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 3 / 30 | 4 / 33 |
| other Total, other adverse events | 19 / 30 | 20 / 29 |
| serious Total, serious adverse events | 4 / 30 | 7 / 29 |
Outcome results
Primary
Number of Participants With Respiratory Failure-free Survival
Number of participants with respiratory failure-free survival, defined as not having died or gone into respiratory failure on or before Day 28
Time frame: Up to Day 28
Population: The Intent-to-Treat (ITT) Analysis Set includes all randomized participants
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Zanubrutinib + Supportive Care | Number of Participants With Respiratory Failure-free Survival | 27 Participants |
| Placebo + Supportive Care | Number of Participants With Respiratory Failure-free Survival | 28 Participants |
p-value: 0.409995% CI: [0.349, 7.391]Unstratified 1-sided Fisher's exact test
Primary
Time to Breathing Room Air
Time to return to breathing room air is defined as the time from randomization date to the earliest time where the participant is stable on room air without supplemental oxygen. Total follow-up time in days is the total time of all participants from the randomization date to the first event date or Day 28 if there is no event. The rate was calculated as total number of events in which a participant returned to breathing room air on or before Day 28 divided by the total follow-up time in days.
Time frame: Up to 7 months
Population: The Intent-to-Treat (ITT) Analysis Set includes all randomized participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Zanubrutinib + Supportive Care | Time to Breathing Room Air | 0.060 Events / total follow-up in days |
| Placebo + Supportive Care | Time to Breathing Room Air | 0.061 Events / total follow-up in days |
p-value: 0.761995% CI: [0.511, 1.648]Log Rank
Secondary
Duration of Hospitalization
Number of days hospitalized on or before Day 28
Time frame: Up to Day 28
Population: The Intent-to-Treat (ITT) Analysis Set includes all randomized participants, excluding participants who died before event completion
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Zanubrutinib + Supportive Care | Duration of Hospitalization | 6.5 Days |
| Placebo + Supportive Care | Duration of Hospitalization | 5.0 Days |
Secondary
Duration of Mechanical Ventilation
Number of days on mechanical ventilation on or before Day 28
Time frame: Up to Day 28
Population: The Intent-to-Treat (ITT) Analysis Set includes all randomized participants, excluding participants who died before event completion; Here, overall number of participants analyzed represents participants who progressed from supplemental oxygen to mechanical ventilation and are evaluable for this outcome measure
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Zanubrutinib + Supportive Care | Duration of Mechanical Ventilation | 4.0 Days |
| Placebo + Supportive Care | Duration of Mechanical Ventilation | 13.5 Days |
Secondary
Number of Participants Discharged Alive
Number of participants discharged alive on or before Day 28
Time frame: Up to Day 28
Population: The Intent-to-Treat (ITT) Analysis Set includes all randomized participants
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Zanubrutinib + Supportive Care | Number of Participants Discharged Alive | 26 Participants |
| Placebo + Supportive Care | Number of Participants Discharged Alive | 28 Participants |
Secondary
Number of Participants Discharged Alive From the ICU
Number of participants discharged alive from the intensive care unit (ICU) on or before Day 28
Time frame: Up to Day 28
Population: The Intent-to-Treat (ITT) Analysis Set includes all randomized participants; Here, overall number of participants analyzed represents participants who were admitted to the ICU and are evaluable for this outcome measure
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Zanubrutinib + Supportive Care | Number of Participants Discharged Alive From the ICU | 3 Participants |
| Placebo + Supportive Care | Number of Participants Discharged Alive From the ICU | 2 Participants |
Secondary
Number of Participants Experiencing Respiratory Failure or Death
Number of participants experiencing respiratory failure or death on or before Day 28
Time frame: Up to Day 28
Population: The Intent-to-Treat (ITT) Analysis Set includes all randomized participants
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Zanubrutinib + Supportive Care | Number of Participants Experiencing Respiratory Failure or Death | 3 Participants |
| Placebo + Supportive Care | Number of Participants Experiencing Respiratory Failure or Death | 5 Participants |
Secondary
Number of Participants With Adverse Events
Number of participants with treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), treatment-related adverse events (AEs), and TEAEs grade 3 or higher, including laboratory findings
Time frame: Up to 7 months
Population: The Safety Analysis Set includes all participants who received any dose of study drug
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Zanubrutinib + Supportive Care | Number of Participants With Adverse Events | Serious adverse event | 4 Participants |
| Zanubrutinib + Supportive Care | Number of Participants With Adverse Events | At least one TEAE | 19 Participants |
| Zanubrutinib + Supportive Care | Number of Participants With Adverse Events | Treatment-related TEAE | 2 Participants |
| Zanubrutinib + Supportive Care | Number of Participants With Adverse Events | Grade 3 or higher | 6 Participants |
| Placebo + Supportive Care | Number of Participants With Adverse Events | Treatment-related TEAE | 1 Participants |
| Placebo + Supportive Care | Number of Participants With Adverse Events | At least one TEAE | 20 Participants |
| Placebo + Supportive Care | Number of Participants With Adverse Events | Serious adverse event | 7 Participants |
| Placebo + Supportive Care | Number of Participants With Adverse Events | Grade 3 or higher | 6 Participants |
Secondary
Number of Participants With All-cause Mortality
Number of participants with all-cause mortality on or before Day 28
Time frame: Up to Day 28
Population: The Intent-to-Treat (ITT) Analysis Set includes all randomized participants
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Zanubrutinib + Supportive Care | Number of Participants With All-cause Mortality | 2 Participants |
| Placebo + Supportive Care | Number of Participants With All-cause Mortality | 4 Participants |
Secondary
Number of Participants With Improvement in the World Health Organization (WHO) 8-point Ordinal Scale
Number of participants with improvement in WHO 8-point-scale, in which improvement was considered a score that changed from ≥4 at baseline to ≤ 3 at Day 28 as assessed by the investigator. Scoring ranges from 0 = uninfected with no clinical or virologic evidence of disease to 8 = dead.
Time frame: Up to Day 28
Population: The Intent-to-Treat (ITT) Analysis Set includes all randomized participants
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Zanubrutinib + Supportive Care | Number of Participants With Improvement in the World Health Organization (WHO) 8-point Ordinal Scale | 22 Participants |
| Placebo + Supportive Care | Number of Participants With Improvement in the World Health Organization (WHO) 8-point Ordinal Scale | 25 Participants |
Secondary
PaO2:FiO2 Ratio
Partial pressure of oxygen (PaO2):fraction of inspired oxygen (FiO2) ratio
Time frame: Baseline, Day 7, Day 14, Day 21 and Day 28
Population: The Intent-to-Treat Analysis Set included all randomized participants; Here, overall number of participants analyzed represents participants who progressed from supplemental oxygen to mechanical ventilation and are evaluable for this outcome measure and number analyzed represents participants with evaluable data at each time point
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Zanubrutinib + Supportive Care | PaO2:FiO2 Ratio | Day 7 | 82.00 mmHg |
| Zanubrutinib + Supportive Care | PaO2:FiO2 Ratio | Day 14 | 32.00 mmHg |
| Placebo + Supportive Care | PaO2:FiO2 Ratio | Baseline | 53.0 mmHg |
| Placebo + Supportive Care | PaO2:FiO2 Ratio | Day 7 | 54.00 mmHg |
| Placebo + Supportive Care | PaO2:FiO2 Ratio | Day 14 | 90.60 mmHg |
| Placebo + Supportive Care | PaO2:FiO2 Ratio | Day 21 | 52.10 mmHg |