Trial Outcomes & Findings for Efficacy of Tocilizumab on Patients With COVID-19 (NCT NCT04356937)

Last Updated: 2021-07-27

Results Overview

Time from administration of the investigational agent (or placebo) to requiring mechanical ventilation and intubation, or death for subjects who die prior to intubation. The percentages of patients who have been intubated or died as of day 14 and day 28 are estimated from the Kaplan-Meier curve.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

243 participants

Primary outcome timeframe

28 days

Results posted on

2021-07-27

Participant Flow

Participant milestones

Participant milestones
Measure	Tocilizumab Standard care plus a single dose of tocilizumab (8 mg/kg administered intravenously, not to exceed 800 mg)	Placebo Standard care plus placebo
Randomization (Safety Population) STARTED	161	82
Randomization (Safety Population) COMPLETED	161	82
Randomization (Safety Population) NOT COMPLETED	0	0
Treatment (mITT Population) STARTED	161	82
Treatment (mITT Population) COMPLETED	161	81
Treatment (mITT Population) NOT COMPLETED	0	1

Reasons for withdrawal

Reasons for withdrawal
Measure	Tocilizumab Standard care plus a single dose of tocilizumab (8 mg/kg administered intravenously, not to exceed 800 mg)	Placebo Standard care plus placebo
Treatment (mITT Population) Intubated before receiving study treatment	0	1

Baseline Characteristics

Efficacy of Tocilizumab on Patients With COVID-19

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Tocilizumab n=161 Participants Review effect of Tocilizumab on multi-organ dysfunction in a phase 3 randomized controlled trial among hospitalized patients with COVID-19 infection. Participants will receive an intravenous (IV) injection of 8 mg/kg (not to exceed 800 mg) tocilizumab. Specifically, as compared to placebo, we will test whether tocilizumab is associated with a reduction in multi-organ dysfunction among hospitalized COVID-19 adult patients with elevated inflammatory measures. Tocilizumab: Patients will receive the standard treatment for COVID-19 per MGH guidance and also be randomized (2:1) to one of the following arms: 1. Tocilizumab 8mg x 1 2. Standard of care/Placebo	Standard of Care Plus Placebo n=82 Participants Participants will receive an placebo intravenous (IV) injection of 8 mg/kg (not to exceed 800 mg).Specifically, as compared to placebo, we will test whether tocilizumab is associated with a reduction in multi-organ dysfunction among hospitalized COVID-19 adult patients with elevated inflammatory measures. Placebos: Patients will receive the standard treatment for COVID-19 per MGH guidance and also be randomized (2:1) to one of the following arms: 1. Tocilizumab 8mg x 1 2. Standard of care/Placebo	Total n=243 Participants Total of all reporting groups
Age, Continuous	61.6 years n=99 Participants	56.5 years n=107 Participants	59.8 years n=206 Participants
Sex: Female, Male Female	65 Participants n=99 Participants	37 Participants n=107 Participants	102 Participants n=206 Participants
Sex: Female, Male Male	96 Participants n=99 Participants	45 Participants n=107 Participants	141 Participants n=206 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	70 Participants n=99 Participants	39 Participants n=107 Participants	109 Participants n=206 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	84 Participants n=99 Participants	35 Participants n=107 Participants	119 Participants n=206 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	7 Participants n=99 Participants	8 Participants n=107 Participants	15 Participants n=206 Participants
Race/Ethnicity, Customized Race or ethnic group · American Indian or Alaska Native	1 Participants n=99 Participants	0 Participants n=107 Participants	1 Participants n=206 Participants
Race/Ethnicity, Customized Race or ethnic group · Asian	7 Participants n=99 Participants	2 Participants n=107 Participants	9 Participants n=206 Participants
Race/Ethnicity, Customized Race or ethnic group · Black	24 Participants n=99 Participants	16 Participants n=107 Participants	40 Participants n=206 Participants
Race/Ethnicity, Customized Race or ethnic group · Native Hawaiian or Pacific Islander	0 Participants n=99 Participants	1 Participants n=107 Participants	1 Participants n=206 Participants
Race/Ethnicity, Customized Race or ethnic group · White	71 Participants n=99 Participants	33 Participants n=107 Participants	104 Participants n=206 Participants
Race/Ethnicity, Customized Race or ethnic group · Other	35 Participants n=99 Participants	15 Participants n=107 Participants	50 Participants n=206 Participants
Race/Ethnicity, Customized Race or ethnic group · Unknown	23 Participants n=99 Participants	15 Participants n=107 Participants	38 Participants n=206 Participants
Region of Enrollment United States	161 Participants n=99 Participants	82 Participants n=107 Participants	243 Participants n=206 Participants
BMI	29.9 kg/m^2 n=99 Participants	30.2 kg/m^2 n=107 Participants	30.1 kg/m^2 n=206 Participants
BMI ≥ 30 kg/m^2	80 Participants n=99 Participants	42 Participants n=107 Participants	122 Participants n=206 Participants
Days from symptom onset to randomization	9.0 days n=99 Participants	10.0 days n=107 Participants	9.0 days n=206 Participants
Hypertension	80 Participants n=99 Participants	38 Participants n=107 Participants	118 Participants n=206 Participants
Heart failure	17 Participants n=99 Participants	7 Participants n=107 Participants	24 Participants n=206 Participants
History of myocardial infarction	15 Participants n=99 Participants	6 Participants n=107 Participants	21 Participants n=206 Participants
Chronic obstructive pulmonary disorder	15 Participants n=99 Participants	7 Participants n=107 Participants	22 Participants n=206 Participants
Asthma	15 Participants n=99 Participants	7 Participants n=107 Participants	22 Participants n=206 Participants
Smoking status Current smoker	7 Participants n=99 Participants	0 Participants n=107 Participants	7 Participants n=206 Participants
Smoking status Former smoker	46 Participants n=99 Participants	26 Participants n=107 Participants	72 Participants n=206 Participants
Smoking status Lifelong nonsmoker	99 Participants n=99 Participants	48 Participants n=107 Participants	147 Participants n=206 Participants
Smoking status Unknown	9 Participants n=99 Participants	8 Participants n=107 Participants	17 Participants n=206 Participants
Diabetes	45 Participants n=99 Participants	30 Participants n=107 Participants	75 Participants n=206 Participants
History of cancer	22 Participants n=99 Participants	8 Participants n=107 Participants	30 Participants n=206 Participants

PRIMARY outcome

Timeframe: 28 days

Population: Modified intention-to-treat (mITT) population, which includes 242 patients (161 in the tocilizumab group and 81 in the placebo group) who underwent randomization and received either tocilizumab or placebo before intubation or death

Outcome measures

Outcome measures
Measure	Tocilizumab n=161 Participants Standard care plus a single dose of tocilizumab (8 mg/kg administered intravenously, not to exceed 800 mg)	Placebo n=81 Participants Standard care plus placebo
Mechanical Ventilation or Death 14 days	9.9 percentage of patients with event Interval 6.2 to 15.7	10.0 percentage of patients with event Interval 5.1 to 18.9
Mechanical Ventilation or Death 28 days	10.6 percentage of patients with event Interval 6.7 to 16.6	12.5 percentage of patients with event Interval 6.9 to 22.0

SECONDARY outcome

Timeframe: 28 days

Time from administration of the investigational medication (or placebo) to at least one point worsening on the clinical improvement scale for subjects requiring supplemental oxygen (score \>= 3) at baseline, or at least two point worsening otherwise (score = 2 at baseline). The percentages of patients who have worsened as of day 14 and day 28 are estimated from the Kaplan-Meier curve. Ordinal Scale 1. Discharged 2. Non-ICU hospital ward not requiring supplemental oxygen 3. Non-ICU 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 ECMO or mechanical ventilation and additional organ support 7. Death

Outcome measures

Outcome measures
Measure	Tocilizumab n=161 Participants Standard care plus a single dose of tocilizumab (8 mg/kg administered intravenously, not to exceed 800 mg)	Placebo n=81 Participants Standard care plus placebo
Clinical Worsening on Ordinal Scale Day 14	18.0 percentage of patients with event Interval 12.9 to 24.9	14.9 percentage of patients with event Interval 8.7 to 24.7
Clinical Worsening on Ordinal Scale Day 28	19.3 percentage of patients with event Interval 14.0 to 26.2	17.4 percentage of patients with event Interval 10.7 to 27.7

SECONDARY outcome

Timeframe: 28 days

Population: A subset of 204 patients from the modified intention-to-treat (mITT) population who required at least supplemental oxygen at baseline. 138 patients in the tocilizumab group and 66 patients in the placebo group required at least supplemental oxygen at baseline.

Time from administration of the investigational agent (or placebo) to absence of the need for supplemental oxygen among those who require at least supplemental oxygen at baseline. The percentages of patients who have discontinued supplemental oxygen as of day 14 and day 28 are estimated from the Kaplan-Meier curve.

Outcome measures

Outcome measures
Measure	Tocilizumab n=138 Participants Standard care plus a single dose of tocilizumab (8 mg/kg administered intravenously, not to exceed 800 mg)	Placebo n=66 Participants Standard care plus placebo
Discontinuation of Supplemental Oxygen Among Patients Receiving it at Baseline Day 14	75.4 percentage of patients with event Interval 67.9 to 82.2	78.8 percentage of patients with event Interval 68.3 to 87.7
Discontinuation of Supplemental Oxygen Among Patients Receiving it at Baseline Day 28	82.6 percentage of patients with event Interval 75.9 to 88.4	84.9 percentage of patients with event Interval 75.2 to 92.2

OTHER_PRE_SPECIFIED outcome

Timeframe: 28 days

Time from initiation of supplemental oxygen to end of supplemental oxygen use during 28-day study follow-up period. We includes all subjects in the analysis by assigning all subjects who did not receive supplemental oxygen a value of 0. Subjects who died prior to discontinuation of supplemental oxygen were given a value of the number of days from when supplemental oxygen began until the end of the follow-up period.

Outcome measures

Outcome measures
Measure	Tocilizumab n=161 Participants Standard care plus a single dose of tocilizumab (8 mg/kg administered intravenously, not to exceed 800 mg)	Placebo n=81 Participants Standard care plus placebo
Duration of Supplemental Oxygen	4.0 days Interval 1.8 to 11.6	3.9 days Interval 1.1 to 9.2

OTHER_PRE_SPECIFIED outcome

Timeframe: 28 days

Population: A subset of 19 patients from the modified intention-to-treat (mITT) population who received mechanical ventilation during the study follow-up period. 11 patients in the tocilizumab group and 8 patients in the placebo group received mechanical ventilation.

Time from initiation of mechanical ventilation to end of mechanical ventilation during 28-day study follow-up period, among patients who received mechanical ventilation. Event times of patients who died without discontinuation of mechanical ventilation were censored at 28 days. Median and inter-quartile range (IQR) were estimated using Kaplan-Meier curves. The upper limit for the IQR was not reached for both arms and entered as 28 in the outcome measure data table.

Outcome measures

Outcome measures
Measure	Tocilizumab n=11 Participants Standard care plus a single dose of tocilizumab (8 mg/kg administered intravenously, not to exceed 800 mg)	Placebo n=8 Participants Standard care plus placebo
Duration of Mechanical Ventilation	15.0 days Interval 12.6 to The upper limit for the IQR was not reached in the tocilizumab group.	27.9 days Interval 16.3 to The upper limit for the IQR was not reached in the placebo group.

OTHER_PRE_SPECIFIED outcome

Timeframe: 28 days

Time from administration of the investigational agent (or placebo) to death. The percentage of patients who have died as of day 14 and day 28 are estimated from the Kaplan-Meier curve.

Outcome measures

Outcome measures
Measure	Tocilizumab n=161 Participants Standard care plus a single dose of tocilizumab (8 mg/kg administered intravenously, not to exceed 800 mg)	Placebo n=81 Participants Standard care plus placebo
Mortality Day 14	4.4 percentage of patients with event Interval 2.1 to 8.9	1.3 percentage of patients with event Interval 0.2 to 8.7
Mortality Day 28	5.6 percentage of patients with event Interval 3.0 to 10.5	3.8 percentage of patients with event Interval 1.2 to 11.3

OTHER_PRE_SPECIFIED outcome

Timeframe: 28 days

Population: A subset of 233 patients from the modified intention-to-treat (mITT) population who were not in the ICU at baseline. 157 patients in the tocilizumab group and 76 patients in the placebo group were not in the ICU at baseline.

The percentage of subjects requiring ICU admission between baseline and 28 days is calculated by dividing the number of subjects requiring ICU admission over their hospitalization by the number of evaluable subjects (i.e., the number of subjects not in the ICU at the time of investigational treatment administration).

Outcome measures

Outcome measures
Measure	Tocilizumab n=157 Participants Standard care plus a single dose of tocilizumab (8 mg/kg administered intravenously, not to exceed 800 mg)	Placebo n=76 Participants Standard care plus placebo
ICU Admission or Death Among Those Not in the ICU at the Time of Administration of Investigational Agent (or Placebo)	15.9 percentage of patients with event	15.8 percentage of patients with event

OTHER_PRE_SPECIFIED outcome

Timeframe: 28 days

Time from administration of the investigational medication (or placebo) to initial hospital discharge. Event times for patient who die are censored at day 29 to indicate that they never left the hospital during the follow-up period. The percentages of patients who were discharged as of day 14 and day 28 are estimated from the Kaplan-Meier curve.

Outcome measures

Outcome measures
Measure	Tocilizumab n=161 Participants Standard care plus a single dose of tocilizumab (8 mg/kg administered intravenously, not to exceed 800 mg)	Placebo n=81 Participants Standard care plus placebo
Hospital Discharge Day 14	86.3 percentage of patients with event Interval 80.6 to 91.1	81.5 percentage of patients with event Interval 72.4 to 89.0
Hospital Discharge Day 28	91.3 percentage of patients with event Interval 86.3 to 95.0	88.9 percentage of patients with event Interval 81.0 to 94.5

OTHER_PRE_SPECIFIED outcome

Timeframe: 28 days

Time to first improvement from administration of the investigational agent (or placebo) of at least 2 points (or the maximum amount) on the ordinal scale. Event times for patients who died prior to reaching this endpoint are censored at 29 days. Ordinal Scale 1. Discharged 2. Non-ICU hospital ward not requiring supplemental oxygen 3. Non-ICU 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 ECMO or mechanical ventilation and additional organ support 7. Death

Outcome measures

Outcome measures
Measure	Tocilizumab n=161 Participants Standard care plus a single dose of tocilizumab (8 mg/kg administered intravenously, not to exceed 800 mg)	Placebo n=81 Participants Standard care plus placebo
Clinical Improvement on Ordinal Scale Day 14	86.3 percentage of patients with event Interval 80.6 to 91.1	81.5 percentage of patients with event Interval 72.4 to 89.0
Clinical Improvement on Ordinal Scale Day 28	91.3 percentage of patients with event Interval 86.3 to 95.1	88.9 percentage of patients with event Interval 81.0 to 94.5

Adverse Events

Tocilizumab

Serious events: 19 serious events

Other events: 20 other events

Deaths: 9 deaths

Placebo

Serious events: 8 serious events

Other events: 26 other events

Deaths: 4 deaths

Serious adverse events

Other adverse events

Additional Information

DRAI Director of Clinical Trials

Massachusetts General Hospital

Phone: 617-726-7938

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Serious adverse events
Measure	Tocilizumab n=161 participants at risk Standard care plus a single dose of tocilizumab (8 mg/kg administered intravenously, not to exceed 800 mg)	Placebo n=81 participants at risk；n=82 participants at risk Standard care plus placebo
Hepatobiliary disorders Elevated liver function test: Alanine aminotransferase	0.62% 1/161 • Number of events 1 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).	1.2% 1/82 • Number of events 1 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).
Hepatobiliary disorders Elevated liver function test: Aspartate transaminase	0.62% 1/161 • Number of events 1 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).	1.2% 1/82 • Number of events 1 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).
Cardiac disorders Arterial ischemia	0.62% 1/161 • Number of events 1 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).	0.00% 0/82 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).
Vascular disorders Deep venous thrombosis	1.2% 2/161 • Number of events 2 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).	2.4% 2/82 • Number of events 2 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).
Infections and infestations Infection	2.5% 4/161 • Number of events 4 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).	7.3% 6/82 • Number of events 6 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).
Blood and lymphatic system disorders Neutrophil count decreased	1.2% 2/161 • Number of events 2 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).	0.00% 0/82 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).
Cardiac disorders Myocardial infarction	0.00% 0/161 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).	1.2% 1/82 • Number of events 1 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).
Vascular disorders Pulmonary embolism	0.62% 1/161 • Number of events 1 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).	2.4% 2/82 • Number of events 2 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).
Nervous system disorders Seizure	0.00% 0/161 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).	1.2% 1/82 • Number of events 1 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).
Nervous system disorders Stroke	1.2% 2/161 • Number of events 2 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).	0.00% 0/82 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).
Gastrointestinal disorders Continued anorexia	0.62% 1/161 • Number of events 1 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).	0.00% 0/82 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).
Respiratory, thoracic and mediastinal disorders Hypoxia	1.2% 2/161 • Number of events 2 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).	2.4% 2/82 • Number of events 3 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).
Vascular disorders Hypotension	1.9% 3/161 • Number of events 3 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).	2.4% 2/82 • Number of events 2 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).
Blood and lymphatic system disorders Febrile Neutropenia	0.62% 1/161 • Number of events 1 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).	0.00% 0/82 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).
Blood and lymphatic system disorders Elevated Partial Thromboplastin Time	0.62% 1/161 • Number of events 1 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).	1.2% 1/82 • Number of events 1 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).
Cardiac disorders Cardiogenic Shock	0.62% 1/161 • Number of events 1 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).	0.00% 0/82 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).
Renal and urinary disorders Low output from nephrostomy tube	0.62% 1/161 • Number of events 1 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).	0.00% 0/82 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).
Renal and urinary disorders Patient re-hospitalized because dialysis could not be arranged any other way	0.62% 1/161 • Number of events 1 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).	0.00% 0/82 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).
Musculoskeletal and connective tissue disorders Hip fracture requiring hospitalization	0.62% 1/161 • Number of events 1 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).	0.00% 0/82 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).
Respiratory, thoracic and mediastinal disorders Pulmonary Fibrosis	0.62% 1/161 • Number of events 1 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).	0.00% 0/82 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).
Respiratory, thoracic and mediastinal disorders Tracheostomy	0.00% 0/161 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).	1.2% 1/82 • Number of events 1 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).
Respiratory, thoracic and mediastinal disorders Tachypnea	0.00% 0/161 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).	1.2% 1/82 • Number of events 1 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).
Nervous system disorders Parasthesia	0.00% 0/161 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).	1.2% 1/82 • Number of events 1 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).
Respiratory, thoracic and mediastinal disorders Dysphagia	0.00% 0/161 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).	1.2% 1/82 • Number of events 1 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).
Respiratory, thoracic and mediastinal disorders respiratory failure and intubation	0.00% 0/161 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).	1.2% 1/82 • Number of events 1 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).
Cardiac disorders Bradycardia	0.00% 0/161 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).	1.2% 1/82 • Number of events 1 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).
Respiratory, thoracic and mediastinal disorders Respiratory Acidosis	0.00% 0/161 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).	1.2% 1/82 • Number of events 1 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).
Skin and subcutaneous tissue disorders Hypothermia	0.00% 0/161 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).	1.2% 1/82 • Number of events 1 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).
Blood and lymphatic system disorders Anemia	0.00% 0/161 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).	1.2% 1/82 • Number of events 1 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).
Cardiac disorders Hypertension	0.00% 0/161 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).	1.2% 1/82 • Number of events 1 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).
Cardiac disorders Hospitalization for Syncope	0.00% 0/161 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).	1.2% 1/82 • Number of events 1 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).
Skin and subcutaneous tissue disorders Grade 3: Rash/allergic reaction	0.00% 0/161 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).	1.2% 1/82 • Number of events 1 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).
Renal and urinary disorders Renal injury	0.00% 0/161 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).	1.2% 1/82 • Number of events 1 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).
Blood and lymphatic system disorders Bleeding	0.00% 0/161 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).	1.2% 1/82 • Number of events 1 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).

Other adverse events
Measure	Tocilizumab n=161 participants at risk Standard care plus a single dose of tocilizumab (8 mg/kg administered intravenously, not to exceed 800 mg)	Placebo n=81 participants at risk；n=82 participants at risk Standard care plus placebo
Renal and urinary disorders Acute kidney injury	0.62% 1/161 • Number of events 1 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).	0.00% 0/81 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).
Blood and lymphatic system disorders Anemia	0.62% 1/161 • Number of events 1 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).	2.5% 2/81 • Number of events 2 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).
Cardiac disorders Bradycardia	0.62% 1/161 • Number of events 1 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).	0.00% 0/81 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).
Eye disorders Conjunctivitis	0.62% 1/161 • Number of events 1 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).	0.00% 0/81 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).
Immune system disorders Decreased poly(ADP-ribosyl)ation	0.62% 1/161 • Number of events 1 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).	0.00% 0/81 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).
Blood and lymphatic system disorders decreased white blood cell count	1.9% 3/161 • Number of events 3 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).	1.2% 1/81 • Number of events 1 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).
Gastrointestinal disorders Diarrhea	1.2% 2/161 • Number of events 2 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).	1.2% 1/81 • Number of events 1 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).
Ear and labyrinth disorders Ear ache	0.62% 1/161 • Number of events 1 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).	0.00% 0/81 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).
Cardiac disorders Hypertension	1.2% 2/161 • Number of events 2 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).	2.5% 2/81 • Number of events 2 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).
Blood and lymphatic system disorders Hypotension	1.2% 2/161 • Number of events 2 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).	3.7% 3/81 • Number of events 3 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).
Renal and urinary disorders Increased alkaline phosphatase	0.62% 1/161 • Number of events 1 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).	1.2% 1/81 • Number of events 1 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).
Cardiac disorders Paroxysmal Atrial fibrillation	0.62% 1/161 • Number of events 1 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).	1.2% 1/81 • Number of events 1 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).
Skin and subcutaneous tissue disorders Pruritic Rash	0.62% 1/161 • Number of events 1 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).	0.00% 0/81 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).
Nervous system disorders Worsening confusion	0.62% 1/161 • Number of events 1 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).	1.2% 1/81 • Number of events 1 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).
Injury, poisoning and procedural complications worsening lower extremity wound	0.62% 1/161 • Number of events 1 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).	0.00% 0/81 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).
Gastrointestinal disorders Constipation	0.00% 0/161 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).	1.2% 1/81 • Number of events 1 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).
Blood and lymphatic system disorders decreased hemoglobin	0.00% 0/161 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).	1.2% 1/81 • Number of events 1 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).
Renal and urinary disorders acute kidney injury with AGMA and hyperkalemia	0.00% 0/161 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).	1.2% 1/81 • Number of events 1 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).
Vascular disorders Acute superficial thrombophlebitis	0.00% 0/161 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).	1.2% 1/81 • Number of events 1 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).
Nervous system disorders Dizziness	0.00% 0/161 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).	1.2% 1/81 • Number of events 1 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).
Injury, poisoning and procedural complications FALL WITH ABRASION	0.00% 0/161 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).	2.5% 2/81 • Number of events 2 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).
Nervous system disorders Headache	0.00% 0/161 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).	1.2% 1/81 • Number of events 1 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).
Blood and lymphatic system disorders hypomagnesemia	0.00% 0/161 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).	1.2% 1/81 • Number of events 1 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).
Blood and lymphatic system disorders Mild edema	0.00% 0/161 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).	2.5% 2/81 • Number of events 2 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).
Respiratory, thoracic and mediastinal disorders Mucus plugging	0.00% 0/161 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).	1.2% 1/81 • Number of events 1 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).
Respiratory, thoracic and mediastinal disorders Oropharyngeal Dysphagia	0.00% 0/161 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).	1.2% 1/81 • Number of events 1 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).
Gastrointestinal disorders Vomitting	0.00% 0/161 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).	1.2% 1/81 • Number of events 1 • 0-28 days. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE * death * It is life threatening * It requires or prolongs inpatient hospitalization. * It results in persistent or significant disability/incapacity * It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. * It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above).