Trial Outcomes & Findings for Prevention of S. Aureus Pneumonia Study in Mechanically Ventilated Subjects Who Are Heavily Colonized With S. Aureus. (NCT NCT02940626)

Last Updated: 2019-07-31

Results Overview

Percentage of subjects in the MITT population who have or have not developed S. aureus (SA) pneumonia after a single intravenous (IV) dose of ASN100, based on sponsor defined outcome (SDO1). For each arm, the empirical proportion is defined by a ratio, which is the number of SA pneumonia events divided by the total number of subjects in the arm. The inference about the difference of two population rates is based on the empirical counterpart; specifically, the point estimate, 95% confidence interval and p-value for the rate difference. Subjects discontinued from the study due to any cause prior to Day 22 were considered as not developing SA pneumonia for the primary efficacy analysis.

Recruitment status

TERMINATED

Study phase

PHASE2

Target enrollment

155 participants

Primary outcome timeframe

Incidence of S. aureus pneumonia up to but not including Day 22

Results posted on

2019-07-31

Participant Flow

Subjects were randomized at 35 centers in the United States, Austria, Czechia, France, India, Israel, Poland, Portugal, Romania, Serbia, Spain, Rep. of Georgia, and Russian Federation

Eligible subjects underwent daily screening of endotracheal aspirates to determine if they met randomization criteria. Only subjects who were randomized are included in the study analysis and summarized in the Participant Flow. A single subject was randomized/treated in a site-specific pneumonia treatment sub-study.

Participant milestones

Participant milestones
Measure	ASN100 ASN100 administered as 2 separate intravenous (IV) infusions ASN100 3600 mg: monoclonal antibody combination of ASN-1(1800 mg) and ASN-2(1800 mg) \[administered once\]	Placebo Placebo administered as 2 separate intravenous (IV) infusions Placebo: Placebo \[administered once\]
Overall Study STARTED	77	78
Overall Study Randomized Into Primary Prevention Study	77	77
Overall Study Randomized Into Treatment Sub-study	0	1
Overall Study Received Study Treatment	77	77
Overall Study Completed Through Study Day 22	42	49
Overall Study COMPLETED	30	43
Overall Study NOT COMPLETED	47	35

Reasons for withdrawal

Reasons for withdrawal
Measure	ASN100 ASN100 administered as 2 separate intravenous (IV) infusions ASN100 3600 mg: monoclonal antibody combination of ASN-1(1800 mg) and ASN-2(1800 mg) \[administered once\]	Placebo Placebo administered as 2 separate intravenous (IV) infusions Placebo: Placebo \[administered once\]
Overall Study Death	40	32
Overall Study Lost to Follow-up	5	2
Overall Study Withdrawal by Subject	1	0
Overall Study Transfer to Hospice Care	1	0
Overall Study Prohibited Concomitant Medication	0	1

Baseline Characteristics

Prevention of S. Aureus Pneumonia Study in Mechanically Ventilated Subjects Who Are Heavily Colonized With S. Aureus.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	ASN100 n=76 Participants ASN100 administered as 2 separate intravenous (IV) infusions ASN100 3600 mg: monoclonal antibody combination of ASN-1(1800 mg) and ASN-2(1800 mg) \[administered once\]	Placebo n=76 Participants Placebo administered as 2 separate intravenous (IV) infusions Placebo: Placebo \[administered once\]	Total n=152 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=39 Participants	0 Participants n=41 Participants	0 Participants n=35 Participants
Age, Categorical Between 18 and 65 years	40 Participants n=39 Participants	43 Participants n=41 Participants	83 Participants n=35 Participants
Age, Categorical >=65 years	36 Participants n=39 Participants	33 Participants n=41 Participants	69 Participants n=35 Participants
Age, Continuous	63.5 years n=39 Participants	62 years n=41 Participants	62.5 years n=35 Participants
Sex: Female, Male Female	26 Participants n=39 Participants	26 Participants n=41 Participants	52 Participants n=35 Participants
Sex: Female, Male Male	50 Participants n=39 Participants	50 Participants n=41 Participants	100 Participants n=35 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	2 Participants n=39 Participants	3 Participants n=41 Participants	5 Participants n=35 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	70 Participants n=39 Participants	71 Participants n=41 Participants	141 Participants n=35 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	4 Participants n=39 Participants	2 Participants n=41 Participants	6 Participants n=35 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=39 Participants	0 Participants n=41 Participants	0 Participants n=35 Participants
Race (NIH/OMB) Asian	1 Participants n=39 Participants	0 Participants n=41 Participants	1 Participants n=35 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=39 Participants	0 Participants n=41 Participants	0 Participants n=35 Participants
Race (NIH/OMB) Black or African American	0 Participants n=39 Participants	2 Participants n=41 Participants	2 Participants n=35 Participants
Race (NIH/OMB) White	71 Participants n=39 Participants	74 Participants n=41 Participants	145 Participants n=35 Participants
Race (NIH/OMB) More than one race	0 Participants n=39 Participants	0 Participants n=41 Participants	0 Participants n=35 Participants
Race (NIH/OMB) Unknown or Not Reported	4 Participants n=39 Participants	0 Participants n=41 Participants	4 Participants n=35 Participants
Region of Enrollment Romania	1 participants n=39 Participants	2 participants n=41 Participants	3 participants n=35 Participants
Region of Enrollment United States	10 participants n=39 Participants	11 participants n=41 Participants	21 participants n=35 Participants
Region of Enrollment Czechia	1 participants n=39 Participants	0 participants n=41 Participants	1 participants n=35 Participants
Region of Enrollment Portugal	0 participants n=39 Participants	1 participants n=41 Participants	1 participants n=35 Participants
Region of Enrollment India	1 participants n=39 Participants	0 participants n=41 Participants	1 participants n=35 Participants
Region of Enrollment Russia	19 participants n=39 Participants	23 participants n=41 Participants	42 participants n=35 Participants
Region of Enrollment Spain	1 participants n=39 Participants	1 participants n=41 Participants	2 participants n=35 Participants
Region of Enrollment Austria	1 participants n=39 Participants	0 participants n=41 Participants	1 participants n=35 Participants
Region of Enrollment Poland	4 participants n=39 Participants	5 participants n=41 Participants	9 participants n=35 Participants
Region of Enrollment Georgia	34 participants n=39 Participants	29 participants n=41 Participants	63 participants n=35 Participants
Region of Enrollment Israel	1 participants n=39 Participants	3 participants n=41 Participants	4 participants n=35 Participants
Region of Enrollment France	1 participants n=39 Participants	0 participants n=41 Participants	1 participants n=35 Participants
Region of Enrollment Serbia	2 participants n=39 Participants	1 participants n=41 Participants	3 participants n=35 Participants
Body Mass Index Category	26.98 kg/m^2 STANDARD_DEVIATION 5.985 • n=39 Participants	27.17 kg/m^2 STANDARD_DEVIATION 4.335 • n=41 Participants	27.07 kg/m^2 STANDARD_DEVIATION 5.209 • n=35 Participants

PRIMARY outcome

Timeframe: Incidence of S. aureus pneumonia up to but not including Day 22

Population: MITT: There are 2 SDO definitions. SDO1 meets either respiratory OR signs/symptoms requirements while SDO2 must meet BOTH. Individual assessments for each randomized subject were collapsed to assign a SDO1/SDO2 of Yes, No, Indeterminate (insufficient data to assign a SDO of Yes or No), or Censored (subject died prior to the Day 22 assessment).

Outcome measures

Outcome measures
Measure	ASN100 n=76 Participants ASN100 administered as 2 separate intravenous (IV) infusions ASN100: monoclonal antibody combination of ASN-1 and ASN-2	Placebo n=76 Participants Placebo administered as 2 separate intravenous (IV) infusions Placebo: Placebo
Efficacy of a Single Intravenous (IV) Dose of ASN100 Developed S. aureus Pneumonia	5 Participants	7 Participants
Efficacy of a Single Intravenous (IV) Dose of ASN100 Did Not Develop S. aureus Pneumonia	42 Participants	48 Participants
Efficacy of a Single Intravenous (IV) Dose of ASN100 Censored	20 Participants	17 Participants
Efficacy of a Single Intravenous (IV) Dose of ASN100 Indeterminate	9 Participants	4 Participants

SECONDARY outcome

Timeframe: 21 days

Population: Modified Intent to Treat (MITT): Includes All subjects in ITT Population (randomized) who received study drug and were heavily colonized with S. aureus determined by quantitative or semi-quant. culture of an ETA specimen. Exclusion from the MITT was determined programmatically. Subjects on MV \< 2 days post treatment were excluded from analysis.

Duration of mechanical ventilation during the first 21 days post-randomization for subjects in the Modified Intent-to-Treat (MITT) Population

Outcome measures

Outcome measures
Measure	ASN100 n=73 Participants ASN100 administered as 2 separate intravenous (IV) infusions ASN100: monoclonal antibody combination of ASN-1 and ASN-2	Placebo n=71 Participants Placebo administered as 2 separate intravenous (IV) infusions Placebo: Placebo
Duration of Mechanical Ventilation	11.6 Days Standard Deviation 7.47	10.1 Days Standard Deviation 6.93

SECONDARY outcome

Timeframe: 21 days

Population: Modified Intent to Treat (MITT): Includes all subjects in ITT Population (randomized) who received study drug and were heavily colonized with S. aureus determined by quantitative/semi-quant. culture of an ETA specimen. Exclusion from the MITT determined programmatically. Subjects not listed as being in ICU post treatment were excluded from analysis

Total length of ICU stay during the first 21 days post-randomization for subjects in the MITT Population

Outcome measures

Outcome measures
Measure	ASN100 n=74 Participants ASN100 administered as 2 separate intravenous (IV) infusions ASN100: monoclonal antibody combination of ASN-1 and ASN-2	Placebo n=75 Participants Placebo administered as 2 separate intravenous (IV) infusions Placebo: Placebo
Length of ICU Stay	13.7 Days Standard Deviation 6.69	13.6 Days Standard Deviation 7.21

SECONDARY outcome

Timeframe: 28 days

Population: Modified Intent to treat (MITT): includes all subjects in the ITT Population (randomized subjects) who receive study drug and who are heavily colonized with S. aureus as determined by quantitative or semi-quantitative culture of an ETA specimen. Exclusion from the MITT Population was determined programmatically for each ITT subject.

28-day all-cause mortality in the MITT Population

Outcome measures

Outcome measures
Measure	ASN100 n=76 Participants ASN100 administered as 2 separate intravenous (IV) infusions ASN100: monoclonal antibody combination of ASN-1 and ASN-2	Placebo n=76 Participants Placebo administered as 2 separate intravenous (IV) infusions Placebo: Placebo
28-day All-cause Mortality	30 Participants	25 Participants

SECONDARY outcome

Timeframe: through day 90

Population: Pharmacokinetic (PK) Population: All subjects in the MITT population with at least 1 serum PK sample collected post-dose. Of the 76 subjects who received ASN100, 74 were included in the PK analysis as a result of 2 not having sufficient data. Additional reductions in the number of participants analyzed is due to missing or out of window samples.

The levels of ASN-1 and ASN-2 measured at completion of study medication infusion, and at 6 hr, 24 hr, Day 4, Day 7, Day 14, Day 22, and Day 90 (final study visit) in subjects who are hospitalized or are able to return to the clinic for blood sampling.

Outcome measures

Outcome measures
Measure	ASN100 n=71 Participants ASN100 administered as 2 separate intravenous (IV) infusions ASN100: monoclonal antibody combination of ASN-1 and ASN-2	Placebo n=73 Participants Placebo administered as 2 separate intravenous (IV) infusions Placebo: Placebo
ASN-1 and ASN-2 Maximum Serum Concentration (Cmax)	414.43 μg/mL Standard Deviation 125.55	460.88 μg/mL Standard Deviation 149.76

SECONDARY outcome

Timeframe: through day 90

The levels of ASN-1 and ASN-2 measured at completion of study medication infusion, and at 6 hr, 24 hr, Day 4, Day 7, Day 14, Day 22, and Day 90 after completion

Outcome measures

Outcome measures
Measure	ASN100 n=71 Participants ASN100 administered as 2 separate intravenous (IV) infusions ASN100: monoclonal antibody combination of ASN-1 and ASN-2	Placebo n=73 Participants Placebo administered as 2 separate intravenous (IV) infusions Placebo: Placebo
ASN-1 and ASN-2 Time to Maximum Concentration (Tmax) in Serum	6.34 Hours (from end of infusion) Standard Deviation 10.25	4.52 Hours (from end of infusion) Standard Deviation 5.77

SECONDARY outcome

Timeframe: through day 90

The levels of ASN-1 and ASN-2 measured at completion of study medication infusion, and at 6 hr, 24 hr, Day 4, Day 7, Day 14, Day 22, and Day 90 after completion

Outcome measures

Outcome measures
Measure	ASN100 n=71 Participants ASN100 administered as 2 separate intravenous (IV) infusions ASN100: monoclonal antibody combination of ASN-1 and ASN-2	Placebo n=73 Participants Placebo administered as 2 separate intravenous (IV) infusions Placebo: Placebo
ASN-1 and ASN-2 Area Under the Concentration-time Curve in Serum	44192.3 μg*h/mL Standard Deviation 25080.9	49366.7 μg*h/mL Standard Deviation 29337.9

SECONDARY outcome

Timeframe: through day 90

The levels of ASN-1 and ASN-2 measured at completion of study medication infusion, and at 6 hr, 24 hr, Day 4, Day 7, Day 14, Day 22, and Day 90 after completion

Outcome measures

Outcome measures
Measure	ASN100 n=54 Participants ASN100 administered as 2 separate intravenous (IV) infusions ASN100: monoclonal antibody combination of ASN-1 and ASN-2	Placebo n=58 Participants Placebo administered as 2 separate intravenous (IV) infusions Placebo: Placebo
ASN-1 and ASN-2 Terminal Elimination Half-life (t1/2) in Serum	178.9 Hours Standard Deviation 101.13	185.1 Hours Standard Deviation 136.09

Adverse Events

ASN100

Serious events: 49 serious events

Other events: 74 other events

Deaths: 41 deaths

Placebo

Serious events: 38 serious events

Other events: 69 other events

Deaths: 32 deaths

Serious adverse events

Other adverse events

Additional Information

Vice President, Clinical Operations

X4 Pharmaceuticals (merged with Arsanis)

Phone: (857) 529-8300

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Serious adverse events
Measure	ASN100 n=77 participants at risk ASN100 administered as 2 separate intravenous (IV) infusions ASN100: monoclonal antibody combination of ASN-1 and ASN-2	Placebo n=77 participants at risk Placebo administered as 2 separate intravenous (IV) infusions Placebo: Placebo
Blood and lymphatic system disorders Thrombocytopenia	1.3% 1/77 • Number of events 1 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.	0.00% 0/77 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.
Cardiac disorders Cardiac Arrest	6.5% 5/77 • Number of events 5 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.	1.3% 1/77 • Number of events 1 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.
Cardiac disorders Cardiac Failture Acute	2.6% 2/77 • Number of events 2 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.	2.6% 2/77 • Number of events 2 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.
Cardiac disorders Ventricular Fibrillation	1.3% 1/77 • Number of events 1 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.	2.6% 2/77 • Number of events 2 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.
Cardiac disorders Cardiovascular Insufficiency	2.6% 2/77 • Number of events 2 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.	0.00% 0/77 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.
Cardiac disorders Ventricular Asytole	2.6% 2/77 • Number of events 2 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.	0.00% 0/77 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.
Cardiac disorders Bradycardia	0.00% 0/77 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.	1.3% 1/77 • Number of events 1 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.
Cardiac disorders Cardiac Disorder	1.3% 1/77 • Number of events 1 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.	0.00% 0/77 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.
Cardiac disorders Cardiac Failure Congestive	0.00% 0/77 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.	1.3% 1/77 • Number of events 2 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.
Cardiac disorders Cardiopulmonary Failure	0.00% 0/77 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.	1.3% 1/77 • Number of events 1 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.
Cardiac disorders Coronary Artery Disease	0.00% 0/77 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.	1.3% 1/77 • Number of events 1 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.
Cardiac disorders Left ventricular Failure	1.3% 1/77 • Number of events 1 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.	0.00% 0/77 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.
Cardiac disorders Myocardial Infarction	0.00% 0/77 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.	1.3% 1/77 • Number of events 1 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.
Cardiac disorders Pericardial Haemorrhage	0.00% 0/77 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.	1.3% 1/77 • Number of events 1 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.
Cardiac disorders Ventricular Rupture	0.00% 0/77 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.	1.3% 1/77 • Number of events 1 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.
Gastrointestinal disorders Haematemesis	0.00% 0/77 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.	1.3% 1/77 • Number of events 1 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.
Gastrointestinal disorders Ileus	1.3% 1/77 • Number of events 1 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.	0.00% 0/77 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.
Gastrointestinal disorders Intestinal Obstruction	1.3% 1/77 • Number of events 1 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.	0.00% 0/77 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.
General disorders Multiple Organ Dysfunction Syndrome	1.3% 1/77 • Number of events 1 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.	3.9% 3/77 • Number of events 3 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.
General disorders Death	0.00% 0/77 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.	1.3% 1/77 • Number of events 1 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.
Hepatobiliary disorders Hepatic Cirrhosis	1.3% 1/77 • Number of events 1 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.	0.00% 0/77 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.
Immune system disorders Drug Hypersensitivity	0.00% 0/77 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.	1.3% 1/77 • Number of events 1 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.
Infections and infestations Septic Shock	3.9% 3/77 • Number of events 3 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.	3.9% 3/77 • Number of events 3 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.
Infections and infestations Pneumonia	3.9% 3/77 • Number of events 3 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.	1.3% 1/77 • Number of events 1 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.
Infections and infestations Sepsis	2.6% 2/77 • Number of events 2 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.	0.00% 0/77 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.
Infections and infestations Meningitis	1.3% 1/77 • Number of events 1 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.	0.00% 0/77 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.
Infections and infestations Meningitis Bacterial	1.3% 1/77 • Number of events 1 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.	0.00% 0/77 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.
Infections and infestations Splenic Abscess	1.3% 1/77 • Number of events 1 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.	0.00% 0/77 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.
Injury, poisoning and procedural complications Brain Herniation	5.2% 4/77 • Number of events 4 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.	2.6% 2/77 • Number of events 2 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.
Injury, poisoning and procedural complications Craniocerebral Injury	2.6% 2/77 • Number of events 2 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.	0.00% 0/77 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.
Injury, poisoning and procedural complications Spinal Shock	0.00% 0/77 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.	1.3% 1/77 • Number of events 1 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.
Metabolism and nutrition disorders Hyperkalemia	1.3% 1/77 • Number of events 1 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.	0.00% 0/77 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.
Metabolism and nutrition disorders Metabolic Acidosis	0.00% 0/77 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.	1.3% 1/77 • Number of events 1 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Neoplasm Progression	0.00% 0/77 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.	1.3% 1/77 • Number of events 1 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.
Nervous system disorders Cerebral Congestion	7.8% 6/77 • Number of events 6 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.	3.9% 3/77 • Number of events 3 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.
Nervous system disorders Brain Oedema	3.9% 3/77 • Number of events 3 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.	5.2% 4/77 • Number of events 4 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.
Nervous system disorders Coma	3.9% 3/77 • Number of events 3 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.	3.9% 3/77 • Number of events 3 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.
Nervous system disorders Ischemia Stroke	3.9% 3/77 • Number of events 3 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.	2.6% 2/77 • Number of events 2 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.
Nervous system disorders Haemorrhagic Transformation Stroke	2.6% 2/77 • Number of events 2 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.	0.00% 0/77 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.
Nervous system disorders Nervous System Disorder	0.00% 0/77 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.	2.6% 2/77 • Number of events 2 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.

Other adverse events
Measure	ASN100 n=77 participants at risk ASN100 administered as 2 separate intravenous (IV) infusions ASN100: monoclonal antibody combination of ASN-1 and ASN-2	Placebo n=77 participants at risk Placebo administered as 2 separate intravenous (IV) infusions Placebo: Placebo
Blood and lymphatic system disorders Anaemia	19.5% 15/77 • Number of events 17 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.	14.3% 11/77 • Number of events 11 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.
Blood and lymphatic system disorders Thrombocytopenia	6.5% 5/77 • Number of events 5 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.	2.6% 2/77 • Number of events 2 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.
Cardiac disorders Atrial Fibrillation	7.8% 6/77 • Number of events 6 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.	5.2% 4/77 • Number of events 4 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.
Cardiac disorders Tachycardia	6.5% 5/77 • Number of events 5 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.	6.5% 5/77 • Number of events 6 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.
Congenital, familial and genetic disorders Tracheo-oesophageal Fistula	1.3% 1/77 • Number of events 1 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.	5.2% 4/77 • Number of events 4 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.
Gastrointestinal disorders Constipation	3.9% 3/77 • Number of events 3 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.	5.2% 4/77 • Number of events 4 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.
Gastrointestinal disorders Diarrhoea	10.4% 8/77 • Number of events 8 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.	6.5% 5/77 • Number of events 7 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.
General disorders Pyrexia	22.1% 17/77 • Number of events 25 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.	10.4% 8/77 • Number of events 12 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.
Infections and infestations Bronchitis	10.4% 8/77 • Number of events 8 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.	6.5% 5/77 • Number of events 5 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.
Infections and infestations Bronchitis Bacterial	20.8% 16/77 • Number of events 16 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.	9.1% 7/77 • Number of events 7 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.
Infections and infestations Sinusitis	5.2% 4/77 • Number of events 4 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.	2.6% 2/77 • Number of events 2 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.
Infections and infestations Tracheobronchitis	6.5% 5/77 • Number of events 7 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.	9.1% 7/77 • Number of events 8 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.
Infections and infestations Urinary Tract Infection	20.8% 16/77 • Number of events 16 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.	18.2% 14/77 • Number of events 14 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.
Metabolism and nutrition disorders Hyperglycemia	6.5% 5/77 • Number of events 5 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.	5.2% 4/77 • Number of events 4 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.
Metabolism and nutrition disorders Hyperkalemia	9.1% 7/77 • Number of events 9 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.	7.8% 6/77 • Number of events 7 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.
Metabolism and nutrition disorders Hypernatremia	6.5% 5/77 • Number of events 5 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.	3.9% 3/77 • Number of events 4 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.
Metabolism and nutrition disorders Hypoalbuminaemia	10.4% 8/77 • Number of events 8 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.	2.6% 2/77 • Number of events 2 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.
Metabolism and nutrition disorders Hypocalcemia	5.2% 4/77 • Number of events 4 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.	1.3% 1/77 • Number of events 1 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.
Metabolism and nutrition disorders Hypokalemia	11.7% 9/77 • Number of events 10 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.	7.8% 6/77 • Number of events 13 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.
Metabolism and nutrition disorders Metabolic Acidosis	10.4% 8/77 • Number of events 9 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.	3.9% 3/77 • Number of events 4 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.
Renal and urinary disorders Acute Kidney injury	10.4% 8/77 • Number of events 8 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.	6.5% 5/77 • Number of events 5 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.
Renal and urinary disorders Renal Failure	2.6% 2/77 • Number of events 2 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.	5.2% 4/77 • Number of events 4 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.
Respiratory, thoracic and mediastinal disorders Hydrothorax	7.8% 6/77 • Number of events 9 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.	3.9% 3/77 • Number of events 3 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.
Skin and subcutaneous tissue disorders Decubitus Ulcer	3.9% 3/77 • Number of events 4 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.	10.4% 8/77 • Number of events 9 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.
Vascular disorders Hypotension	23.4% 18/77 • Number of events 18 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.	22.1% 17/77 • Number of events 19 • 3 months Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.