Trial Outcomes & Findings for Extracellular Vesicle Infusion Treatment for COVID-19 Associated ARDS (NCT NCT04493242)

Last Updated: 2024-02-13

Results Overview

To evaluate the 60-day mortality rate for IP 15mL as a treatment for COVID-19 associated moderate to severe ARDS compared to placebo. Reducing the mortality rate for hospitalized patients with COVID-19 associated ARDS is a measure of the treatment effect.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

102 participants

Primary outcome timeframe

60 days

Results posted on

2024-02-13

Participant Flow

A total of 121 subjects were screened and 102 subjects were enrolled in the study at 6 investigative sites in the United States from 24 SEP 2020 to 22 MAY 2021.

Subjects that remained eligible per inclusion/exclusion criteria were randomized and equally distributed in the three study arms.

Participant milestones

Participant milestones
Measure	Experimental Dose 2 Normal saline 85 mL and ExoFlo 15 mL ExoFlo: Intravenous administration of bone marrow mesenchymal stem cell derived extracellular vesicles	Experimental Dose 1 Normal saline 90 mL and ExoFlo 10 mL ExoFlo: Intravenous administration of bone marrow mesenchymal stem cell derived extracellular vesicles	Placebo Normal saline 100 mL Intravenous normal saline: Placebo
Overall Study STARTED	34	34	34
Overall Study Received 1 Dose Only	7	5	7
Overall Study Received 2 Doses	27	29	27
Overall Study Subjects Who Did Not Receive a Full Dose at Any Dose (Dose 1 or 2)	1	0	0
Overall Study COMPLETED	20	16	17
Overall Study NOT COMPLETED	14	18	17

Reasons for withdrawal

Reasons for withdrawal
Measure	Experimental Dose 2 Normal saline 85 mL and ExoFlo 15 mL ExoFlo: Intravenous administration of bone marrow mesenchymal stem cell derived extracellular vesicles	Experimental Dose 1 Normal saline 90 mL and ExoFlo 10 mL ExoFlo: Intravenous administration of bone marrow mesenchymal stem cell derived extracellular vesicles	Placebo Normal saline 100 mL Intravenous normal saline: Placebo
Overall Study Death	10	14	16
Overall Study Lost to Follow-up	1	1	0
Overall Study Withdrawal by Subject	1	0	0
Overall Study Subjects Discharged from Hospital Prior to End of Study	1	1	0
Overall Study Subjects Whose Status as of the End of Study Was Unknown	1	2	1

Baseline Characteristics

Unknown BMI for one subject in Experimental Dose 2 arm.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Experimental Dose 2 n=34 Participants Normal saline 85 mL and ExoFlo 15 mL ExoFlo: Intravenous administration of bone marrow mesenchymal stem cell derived extracellular vesicles	Experimental Dose 1 n=34 Participants Normal saline 90 mL and ExoFlo 10 mL ExoFlo: Intravenous administration of bone marrow mesenchymal stem cell derived extracellular vesicles	Placebo n=34 Participants Normal saline 100 mL Intravenous normal saline: Placebo	Total n=102 Participants Total of all reporting groups
Age, Continuous	56.8 Years STANDARD_DEVIATION 14.97 • n=34 Participants	62.1 Years STANDARD_DEVIATION 13.47 • n=34 Participants	58.5 Years STANDARD_DEVIATION 11.76 • n=34 Participants	59.1 Years STANDARD_DEVIATION 13.52 • n=102 Participants
Age, Customized Age ≥ 65	8 Participants n=34 Participants	14 Participants n=34 Participants	10 Participants n=34 Participants	32 Participants n=102 Participants
Age, Customized Age < 65	26 Participants n=34 Participants	20 Participants n=34 Participants	24 Participants n=34 Participants	70 Participants n=102 Participants
Sex: Female, Male Female	12 Participants n=34 Participants	13 Participants n=34 Participants	10 Participants n=34 Participants	35 Participants n=102 Participants
Sex: Female, Male Male	22 Participants n=34 Participants	21 Participants n=34 Participants	24 Participants n=34 Participants	67 Participants n=102 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=34 Participants	0 Participants n=34 Participants	0 Participants n=34 Participants	0 Participants n=102 Participants
Race (NIH/OMB) Asian	4 Participants n=34 Participants	1 Participants n=34 Participants	1 Participants n=34 Participants	6 Participants n=102 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=34 Participants	0 Participants n=34 Participants	0 Participants n=34 Participants	0 Participants n=102 Participants
Race (NIH/OMB) Black or African American	5 Participants n=34 Participants	1 Participants n=34 Participants	4 Participants n=34 Participants	10 Participants n=102 Participants
Race (NIH/OMB) White	21 Participants n=34 Participants	31 Participants n=34 Participants	26 Participants n=34 Participants	78 Participants n=102 Participants
Race (NIH/OMB) More than one race	0 Participants n=34 Participants	0 Participants n=34 Participants	0 Participants n=34 Participants	0 Participants n=102 Participants
Race (NIH/OMB) Unknown or Not Reported	4 Participants n=34 Participants	1 Participants n=34 Participants	3 Participants n=34 Participants	8 Participants n=102 Participants
BMI	34.98 kg/m^2 STANDARD_DEVIATION 9.459 • n=33 Participants • Unknown BMI for one subject in Experimental Dose 2 arm.	35.63 kg/m^2 STANDARD_DEVIATION 10.939 • n=34 Participants • Unknown BMI for one subject in Experimental Dose 2 arm.	34.24 kg/m^2 STANDARD_DEVIATION 8.526 • n=34 Participants • Unknown BMI for one subject in Experimental Dose 2 arm.	34.95 kg/m^2 STANDARD_DEVIATION 9.615 • n=101 Participants • Unknown BMI for one subject in Experimental Dose 2 arm.
Respiratory Rate	23.8 breaths/min STANDARD_DEVIATION 5.38 • n=34 Participants	24.4 breaths/min STANDARD_DEVIATION 5.41 • n=34 Participants	25.2 breaths/min STANDARD_DEVIATION 7.90 • n=34 Participants	24.5 breaths/min STANDARD_DEVIATION 6.31 • n=102 Participants
Intubated Prior to Enrolling into the Study	2 Participants n=34 Participants	1 Participants n=34 Participants	4 Participants n=34 Participants	7 Participants n=102 Participants
Time from the First COVID-19 Diagnosis to the First IP Dose Date	10.0 days STANDARD_DEVIATION 6.55 • n=34 Participants	9.1 days STANDARD_DEVIATION 4.36 • n=34 Participants	9.5 days STANDARD_DEVIATION 4.12 • n=34 Participants	9.5 days STANDARD_DEVIATION 5.09 • n=102 Participants
Total SOFA Score	3.2 scores on a scale STANDARD_DEVIATION 1.78 • n=34 Participants • Unknown SOFA score for one subject in the placebo arm.	2.9 scores on a scale STANDARD_DEVIATION 1.20 • n=34 Participants • Unknown SOFA score for one subject in the placebo arm.	3.2 scores on a scale STANDARD_DEVIATION 1.88 • n=33 Participants • Unknown SOFA score for one subject in the placebo arm.	3.1 scores on a scale STANDARD_DEVIATION 1.64 • n=101 Participants • Unknown SOFA score for one subject in the placebo arm.
P/F Ratio	115.202 mmHg STANDARD_DEVIATION 61.5299 • n=17 Participants • Unknown P/F Ratio data from 17 subjects in experimental dose 2, 15 subjects in experimental dose 1, and 16 subjects in placebo arms.	113.824 mmHg STANDARD_DEVIATION 48.5386 • n=19 Participants • Unknown P/F Ratio data from 17 subjects in experimental dose 2, 15 subjects in experimental dose 1, and 16 subjects in placebo arms.	102.952 mmHg STANDARD_DEVIATION 43.0002 • n=18 Participants • Unknown P/F Ratio data from 17 subjects in experimental dose 2, 15 subjects in experimental dose 1, and 16 subjects in placebo arms.	110.634 mmHg STANDARD_DEVIATION 50.6610 • n=54 Participants • Unknown P/F Ratio data from 17 subjects in experimental dose 2, 15 subjects in experimental dose 1, and 16 subjects in placebo arms.
P/F Ratio P/F Ratio < 100 mmHg	10 Participants n=34 Participants	9 Participants n=34 Participants	10 Participants n=34 Participants	29 Participants n=102 Participants
P/F Ratio P/F Ratio ≥ 100 mmHg	7 Participants n=34 Participants	10 Participants n=34 Participants	8 Participants n=34 Participants	25 Participants n=102 Participants
P/F Ratio Unknown P/F Ratio	17 Participants n=34 Participants	15 Participants n=34 Participants	16 Participants n=34 Participants	48 Participants n=102 Participants
Prior Therapy Remdesivir	17 Participants n=30 Participants • Measured for those subjects that started prior therapy prior to the first dose of IP.	21 Participants n=27 Participants • Measured for those subjects that started prior therapy prior to the first dose of IP.	23 Participants n=30 Participants • Measured for those subjects that started prior therapy prior to the first dose of IP.	61 Participants n=87 Participants • Measured for those subjects that started prior therapy prior to the first dose of IP.
Prior Therapy Convalescent Plasma	7 Participants n=30 Participants • Measured for those subjects that started prior therapy prior to the first dose of IP.	9 Participants n=27 Participants • Measured for those subjects that started prior therapy prior to the first dose of IP.	9 Participants n=30 Participants • Measured for those subjects that started prior therapy prior to the first dose of IP.	25 Participants n=87 Participants • Measured for those subjects that started prior therapy prior to the first dose of IP.
Prior Therapy Dexamethasone	26 Participants n=30 Participants • Measured for those subjects that started prior therapy prior to the first dose of IP.	25 Participants n=27 Participants • Measured for those subjects that started prior therapy prior to the first dose of IP.	27 Participants n=30 Participants • Measured for those subjects that started prior therapy prior to the first dose of IP.	78 Participants n=87 Participants • Measured for those subjects that started prior therapy prior to the first dose of IP.

PRIMARY outcome

Timeframe: 60 days

Population: The Intention to Treat Analysis set consisted of all participants who received study drug. The number of subjects who died within 60 days is captured in the Outcome Measure Data Table.

Outcome measures

Outcome measures
Measure	Experimental Dose 2 n=34 Participants Normal saline 85 mL and ExoFlo 15 mL ExoFlo: Intravenous administration of bone marrow mesenchymal stem cell derived extracellular vesicles	Experimental Dose 1 n=34 Participants Normal saline 90 mL and ExoFlo 10 mL ExoFlo: Intravenous administration of bone marrow mesenchymal stem cell derived extracellular vesicles	Placebo n=34 Participants Normal saline 100 mL Intravenous normal saline: Placebo
Evaluation of 60-day Mortality Rate	10 Participants	14 Participants	16 Participants

SECONDARY outcome

Timeframe: Days 15, 30, 60

Population: The Intention to Treat Analysis set consisted of all participants who received study drug.

Reducing the mortality rate for hospitalized patients with COVID-19 associated ARDS is a measure of the treatment effect.

Outcome measures

Outcome measures
Measure	Experimental Dose 2 n=34 Participants Normal saline 85 mL and ExoFlo 15 mL ExoFlo: Intravenous administration of bone marrow mesenchymal stem cell derived extracellular vesicles	Experimental Dose 1 n=34 Participants Normal saline 90 mL and ExoFlo 10 mL ExoFlo: Intravenous administration of bone marrow mesenchymal stem cell derived extracellular vesicles	Placebo n=34 Participants Normal saline 100 mL Intravenous normal saline: Placebo
Overall Survival Rates Overall Survival Rate at 15 Days (Kaplan-Meier Method)	78.8 Survival Percentage	77.8 Survival Percentage	75.8 Survival Percentage
Overall Survival Rates Overall Survival Rate at 30 Days (Kaplan-Meier Method)	72.7 Survival Percentage	67.7 Survival Percentage	63.7 Survival Percentage
Overall Survival Rates Overall Survival Rate at 60 Days (Kaplan-Meier Method)	69.6 Survival Percentage	53.4 Survival Percentage	51.6 Survival Percentage

SECONDARY outcome

Timeframe: Days 7, 30, 60

Population: The Intention to Treat Analysis Set consisted of all participants who received study drug.

Discharge is an unbiased measure of overall clinical improvement.

Outcome measures

Outcome measures
Measure	Experimental Dose 2 n=34 Participants Normal saline 85 mL and ExoFlo 15 mL ExoFlo: Intravenous administration of bone marrow mesenchymal stem cell derived extracellular vesicles	Experimental Dose 1 n=34 Participants Normal saline 90 mL and ExoFlo 10 mL ExoFlo: Intravenous administration of bone marrow mesenchymal stem cell derived extracellular vesicles	Placebo n=34 Participants Normal saline 100 mL Intravenous normal saline: Placebo
Proportion of Discharged Patients Subjects Who Discharged Within 7 Days	11 Participants	9 Participants	11 Participants
Proportion of Discharged Patients Subjects Who Discharged Within 30 Days	19 Participants	17 Participants	17 Participants
Proportion of Discharged Patients Subjects Who Discharged Within 60 Days	20 Participants	18 Participants	17 Participants

SECONDARY outcome

Timeframe: Number of days from the date of randomization until documented discharge from hospital, up to 60 days.

Population: Intention-to-Treat (ITT) Analysis set consists of all randomized patients. Patients were analyzed according to the randomized treatment arm.

Discharge is an unbiased measure of overall clinical improvement.

Outcome measures

Outcome measures
Measure	Experimental Dose 2 n=34 Participants Normal saline 85 mL and ExoFlo 15 mL ExoFlo: Intravenous administration of bone marrow mesenchymal stem cell derived extracellular vesicles	Experimental Dose 1 n=34 Participants Normal saline 90 mL and ExoFlo 10 mL ExoFlo: Intravenous administration of bone marrow mesenchymal stem cell derived extracellular vesicles	Placebo n=34 Participants Normal saline 100 mL Intravenous normal saline: Placebo
Time to Discharge	22 days Interval 6.0 to N/A: The upper 95% confidence interval cannot be estimated due to an insufficient number of discharged participants to estimate a standard error.	29 days Interval 9.0 to N/A: The upper 95% confidence interval cannot be estimated due to an insufficient number of discharged participants to estimate a standard error.	NA days Interval 7.0 to Median was not reached due to an insufficient number of discharged patients. N/A: The upper 95% confidence interval cannot be estimated due to an insufficient number of discharged participants to estimate a standard error.

SECONDARY outcome

Timeframe: 61 days

Population: The Safety Analysis Set consisted of all participants who received study drug.

Safety comparison performed between IP 15 mL and placebo arms

Outcome measures

Outcome measures
Measure	Experimental Dose 2 n=34 Participants Normal saline 85 mL and ExoFlo 15 mL ExoFlo: Intravenous administration of bone marrow mesenchymal stem cell derived extracellular vesicles	Experimental Dose 1 n=34 Participants Normal saline 90 mL and ExoFlo 10 mL ExoFlo: Intravenous administration of bone marrow mesenchymal stem cell derived extracellular vesicles	Placebo n=34 Participants Normal saline 100 mL Intravenous normal saline: Placebo
Incidence of Treatment Emergent Serious Adverse Events Any TEAEs- Any Grade	24 Participants	26 Participants	23 Participants
Incidence of Treatment Emergent Serious Adverse Events Any TEAEs- Grade 3 or 4	5 Participants	9 Participants	5 Participants
Incidence of Treatment Emergent Serious Adverse Events Serious TEAEs- Any Grade	10 Participants	18 Participants	16 Participants
Incidence of Treatment Emergent Serious Adverse Events Serious TEAEs- Grade 3 or 4	3 Participants	7 Participants	3 Participants
Incidence of Treatment Emergent Serious Adverse Events Study Treatment-Related TEAEs	0 Participants	0 Participants	1 Participants
Incidence of Treatment Emergent Serious Adverse Events Study Treatment-Related Serious TEAEs	0 Participants	0 Participants	0 Participants
Incidence of Treatment Emergent Serious Adverse Events TEAEs That Led to Dose Interruption	1 Participants	0 Participants	0 Participants
Incidence of Treatment Emergent Serious Adverse Events TEAEs That Led to Missing Dose or Discontinued the Treatment Early	0 Participants	0 Participants	1 Participants
Incidence of Treatment Emergent Serious Adverse Events TEAEs That Led to Death	10 Participants	13 Participants	16 Participants

SECONDARY outcome

Timeframe: Within 60 days of follow-up

Population: The Intention to Treat Analysis set consisted of all participants who received study drug.

Number of days for which patients are not on mechanical ventilation.

Outcome measures

Outcome measures
Measure	Experimental Dose 2 n=34 Participants Normal saline 85 mL and ExoFlo 15 mL ExoFlo: Intravenous administration of bone marrow mesenchymal stem cell derived extracellular vesicles	Experimental Dose 1 n=34 Participants Normal saline 90 mL and ExoFlo 10 mL ExoFlo: Intravenous administration of bone marrow mesenchymal stem cell derived extracellular vesicles	Placebo n=34 Participants Normal saline 100 mL Intravenous normal saline: Placebo
Ventilation Free Days	41.3 days Standard Deviation 25.78	32.0 days Standard Deviation 26.23	33.9 days Standard Deviation 28.06

Adverse Events

Experimental Dose 2

Serious events: 11 serious events

Other events: 25 other events

Deaths: 10 deaths

Experimental Dose 1

Serious events: 18 serious events

Other events: 25 other events

Deaths: 14 deaths

Placebo

Serious events: 16 serious events

Other events: 22 other events

Deaths: 16 deaths

Serious adverse events

Other adverse events

Additional Information

Dr. Amy Lightner

Direct Biologics, LLC

Phone: 512-354-7124

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Non-disclosure agreements with PIs in place. PIs cannot disclose data for approximately 10 years.
Publication restrictions are in place

Restriction type: OTHER

Serious adverse events
Measure	Experimental Dose 2 n=34 participants at risk Normal saline 85 mL and ExoFlo 15 mL ExoFlo: Intravenous administration of bone marrow mesenchymal stem cell derived extracellular vesicles	Experimental Dose 1 n=34 participants at risk Normal saline 90 mL and ExoFlo 10 mL ExoFlo: Intravenous administration of bone marrow mesenchymal stem cell derived extracellular vesicles	Placebo n=34 participants at risk Normal saline 100 mL Intravenous normal saline: Placebo
Cardiac disorders Acute Myocardial Infarction	2.9% 1/34 • Number of events 1 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	2.9% 1/34 • Number of events 1 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Arteriospasm Coronary	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	2.9% 1/34 • Number of events 1 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Bradycardia	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	2.9% 1/34 • Number of events 1 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Cardiac Arrest	5.9% 2/34 • Number of events 2 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	11.8% 4/34 • Number of events 4 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	11.8% 4/34 • Number of events 4 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Ventricular Fibrillation	2.9% 1/34 • Number of events 1 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Gastrointestinal disorders Pancreatitis	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	2.9% 1/34 • Number of events 1 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
General disorders Hypothermia	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	5.9% 2/34 • Number of events 2 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
General disorders Multiple Organ Dysfunction Syndrome	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	5.9% 2/34 • Number of events 2 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	2.9% 1/34 • Number of events 1 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Infections and infestations COVID-19	2.9% 1/34 • Number of events 1 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Infections and infestations Pneumonia Pseudomonal	2.9% 1/34 • Number of events 1 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Infections and infestations Sepsis	2.9% 1/34 • Number of events 1 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	5.9% 2/34 • Number of events 2 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Infections and infestations Septic Shock	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	2.9% 1/34 • Number of events 1 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Infections and infestations Urosepsis	2.9% 1/34 • Number of events 1 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Investigations Alanine Aminotransferase Increased	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	2.9% 1/34 • Number of events 1 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Investigations Aspartate Aminotransferase Increased	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	2.9% 1/34 • Number of events 1 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Musculoskeletal and connective tissue disorders Musculoskeletal Chest Pain	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	2.9% 1/34 • Number of events 1 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Nervous system disorders Brain Injury	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	2.9% 1/34 • Number of events 1 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Nervous system disorders Brain Oedema	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	2.9% 1/34 • Number of events 1 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Nervous system disorders Cerebrovascular Accident	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	2.9% 1/34 • Number of events 1 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Nervous system disorders Encephalopathy	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	2.9% 1/34 • Number of events 1 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Nervous system disorders Subarachnoid Hemorrhage	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	5.9% 2/34 • Number of events 2 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Renal and urinary disorders Acute Kidney Injury	2.9% 1/34 • Number of events 1 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	2.9% 1/34 • Number of events 1 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	2.9% 1/34 • Number of events 1 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Renal and urinary disorders Renal Failure	2.9% 1/34 • Number of events 1 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Renal and urinary disorders Renal Ischemia	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	2.9% 1/34 • Number of events 1 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Renal and urinary disorders Renal Tubular Necrosis	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	2.9% 1/34 • Number of events 1 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Respiratory, thoracic and mediastinal disorders Acute Respiratory Failure	11.8% 4/34 • Number of events 4 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	35.3% 12/34 • Number of events 12 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	26.5% 9/34 • Number of events 9 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Respiratory, thoracic and mediastinal disorders Hypoxia	5.9% 2/34 • Number of events 2 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Respiratory, thoracic and mediastinal disorders Pneumothorax	5.9% 2/34 • Number of events 2 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	2.9% 1/34 • Number of events 1 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	5.9% 2/34 • Number of events 2 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Respiratory, thoracic and mediastinal disorders Respiratory Failure	8.8% 3/34 • Number of events 3 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	14.7% 5/34 • Number of events 5 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	17.6% 6/34 • Number of events 6 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Vascular disorders Hypotension	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	2.9% 1/34 • Number of events 1 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	2.9% 1/34 • Number of events 1 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Vascular disorders Peripheral Arterial Occlusive Disease	2.9% 1/34 • Number of events 1 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Vascular disorders Peripheral Ischemia	2.9% 1/34 • Number of events 1 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.

Other adverse events
Measure	Experimental Dose 2 n=34 participants at risk Normal saline 85 mL and ExoFlo 15 mL ExoFlo: Intravenous administration of bone marrow mesenchymal stem cell derived extracellular vesicles	Experimental Dose 1 n=34 participants at risk Normal saline 90 mL and ExoFlo 10 mL ExoFlo: Intravenous administration of bone marrow mesenchymal stem cell derived extracellular vesicles	Placebo n=34 participants at risk Normal saline 100 mL Intravenous normal saline: Placebo
Blood and lymphatic system disorders Lymphopenia	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	2.9% 1/34 • Number of events 1 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Blood and lymphatic system disorders Anaemia	8.8% 3/34 • Number of events 3 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	8.8% 3/34 • Number of events 3 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	5.9% 2/34 • Number of events 2 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Blood and lymphatic system disorders Anaemia Macrocytic	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	2.9% 1/34 • Number of events 1 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Blood and lymphatic system disorders Blood Loss Anaemia	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	2.9% 1/34 • Number of events 1 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Blood and lymphatic system disorders Hypoalbuminaemia	5.9% 2/34 • Number of events 2 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	5.9% 2/34 • Number of events 2 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Blood and lymphatic system disorders Hyponatraemia	5.9% 2/34 • Number of events 2 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Blood and lymphatic system disorders Hypotension	14.7% 5/34 • Number of events 5 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	23.5% 8/34 • Number of events 8 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	23.5% 8/34 • Number of events 8 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Blood and lymphatic system disorders Leukocytosis	8.8% 3/34 • Number of events 3 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	8.8% 3/34 • Number of events 3 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Blood and lymphatic system disorders Macrocytosis	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	2.9% 1/34 • Number of events 1 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Blood and lymphatic system disorders Thrombocytopenia	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	5.9% 2/34 • Number of events 2 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Blood and lymphatic system disorders Thrombocytosis	8.8% 3/34 • Number of events 3 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Angina Pectoris	2.9% 1/34 • Number of events 1 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Atrial Fibrillation	5.9% 2/34 • Number of events 2 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	5.9% 2/34 • Number of events 2 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	8.8% 3/34 • Number of events 3 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Atrial Flutter	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	2.9% 1/34 • Number of events 1 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Bradycardia	2.9% 1/34 • Number of events 1 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	2.9% 1/34 • Number of events 1 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Chest Pain	2.9% 1/34 • Number of events 1 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	2.9% 1/34 • Number of events 1 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Myocardial Ischaemia	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	2.9% 1/34 • Number of events 1 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Sinus Arrest	2.9% 1/34 • Number of events 1 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Sinus Bradycardia	2.9% 1/34 • Number of events 1 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Sinus Tachycardia	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	2.9% 1/34 • Number of events 1 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Tachycardia	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	2.9% 1/34 • Number of events 1 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	5.9% 2/34 • Number of events 2 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Ventricular Tachycardia	2.9% 1/34 • Number of events 1 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Endocrine disorders Blood Glucose Increased	5.9% 2/34 • Number of events 2 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	2.9% 1/34 • Number of events 1 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	2.9% 1/34 • Number of events 1 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Endocrine disorders Diabetes Mellitus	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	2.9% 1/34 • Number of events 1 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Endocrine disorders Hyperglycaemia	2.9% 1/34 • Number of events 1 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	8.8% 3/34 • Number of events 3 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	8.8% 3/34 • Number of events 3 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Endocrine disorders Type 2 Diabetes Mellitus	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	5.9% 2/34 • Number of events 2 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Eye disorders Ophthalmic Herpes Zoster	2.9% 1/34 • Number of events 1 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Gastrointestinal disorders Abdominal Pain	2.9% 1/34 • Number of events 1 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	2.9% 1/34 • Number of events 1 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Gastrointestinal disorders Colonic Abscess	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	2.9% 1/34 • Number of events 1 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Gastrointestinal disorders Constipation	5.9% 2/34 • Number of events 2 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	8.8% 3/34 • Number of events 3 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	14.7% 5/34 • Number of events 5 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Gastrointestinal disorders Diarrhoea	8.8% 3/34 • Number of events 3 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	2.9% 1/34 • Number of events 1 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Gastrointestinal disorders Diverticulitis	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	2.9% 1/34 • Number of events 1 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Gastrointestinal disorders Dyspepsia	2.9% 1/34 • Number of events 1 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	2.9% 1/34 • Number of events 1 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Gastrointestinal disorders Ileus	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	5.9% 2/34 • Number of events 2 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Gastrointestinal disorders Intestinal Perforation	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	2.9% 1/34 • Number of events 1 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Gastrointestinal disorders Nausea	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	2.9% 1/34 • Number of events 1 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Gastrointestinal disorders Oropharyngeal Pain	2.9% 1/34 • Number of events 1 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	2.9% 1/34 • Number of events 1 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Gastrointestinal disorders Pharyngeal Haemorrhage	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	2.9% 1/34 • Number of events 1 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Gastrointestinal disorders Retroperitoneal Haemorrhage	2.9% 1/34 • Number of events 1 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
General disorders Dehydration	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	2.9% 1/34 • Number of events 1 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/34 • Adverse event data was collected within 60 days from the last dose. At each visit, the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.