Trial Outcomes & Findings for Safety of Furosemide in Premature Infants at Risk of Bronchopulmonary Dysplasia (BPD) (NCT NCT02527798)

Last Updated: 2021-12-28

Results Overview

Safety was assessed following the initial study-specific procedure (e.g., screening blood draws, dosing) through 7 days post last study dose by frequency and incidence of adverse events and serious adverse events.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

82 participants

Primary outcome timeframe

35 days for each participant

Results posted on

2021-12-28

Participant Flow

Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.

Participant milestones

Participant milestones
Measure	Furosemide Cohort 1 Within cohort 1, infants will be randomized using a 3:1 scheme to receive furosemide or placebo. Those randomized to receive furosemide will receive (1mg/kg daily intravenously or 2 mg/kg daily enterally for 28 days. Furosemide Cohort 1: furosemide 1 mg/kg q 24 hours IV or 2 mg/kg q 24 hours enterally Cohorts will be enrolled sequentially after a safety review.	Placebo Cohort 1 Infants randomized to the placebo treatment group will receive the equivalent volume of dextrose 5% for IV use or enteral use (if receiving enteral study drug). Placebo: Sugar water will be administered in a equivalent volume as drug intervention.	Furosemide Cohort 2 Cohort 2 Infants will receive furosemide (1mg/kg every 6 hours intravenously or 2 mg/kg every 6 hours daily enterally) for 28 days. Furosemide Cohort 2: furosemide 1 mg/kg q 6 hours IV or 2 mg/kg q 6 hours enterally Cohorts will be enrolled sequentially after a safety review.	Placebo Cohort 2 Infants randomized to the placebo treatment group will receive the equivalent volume of dextrose 5% for IV use or enteral use (if receiving enteral study drug). Placebo: Sugar water will be administered in a equivalent volume as drug intervention.
Overall Study STARTED	32	10	30	10
Overall Study Randomized, Not Dosed	31	9	30	10
Overall Study Pharmacokinetic (PK) Population	20	0	19	0
Overall Study COMPLETED	29	8	25	9
Overall Study NOT COMPLETED	3	2	5	1

Reasons for withdrawal

Reasons for withdrawal
Measure	Furosemide Cohort 1 Within cohort 1, infants will be randomized using a 3:1 scheme to receive furosemide or placebo. Those randomized to receive furosemide will receive (1mg/kg daily intravenously or 2 mg/kg daily enterally for 28 days. Furosemide Cohort 1: furosemide 1 mg/kg q 24 hours IV or 2 mg/kg q 24 hours enterally Cohorts will be enrolled sequentially after a safety review.	Placebo Cohort 1 Infants randomized to the placebo treatment group will receive the equivalent volume of dextrose 5% for IV use or enteral use (if receiving enteral study drug). Placebo: Sugar water will be administered in a equivalent volume as drug intervention.	Furosemide Cohort 2 Cohort 2 Infants will receive furosemide (1mg/kg every 6 hours intravenously or 2 mg/kg every 6 hours daily enterally) for 28 days. Furosemide Cohort 2: furosemide 1 mg/kg q 6 hours IV or 2 mg/kg q 6 hours enterally Cohorts will be enrolled sequentially after a safety review.	Placebo Cohort 2 Infants randomized to the placebo treatment group will receive the equivalent volume of dextrose 5% for IV use or enteral use (if receiving enteral study drug). Placebo: Sugar water will be administered in a equivalent volume as drug intervention.
Overall Study Physician Decision	1	0	1	1
Overall Study Death	0	0	1	0
Overall Study Withdrawal by Subject	0	1	2	0
Overall Study Reason undisclosed	1	0	1	0
Overall Study Did not receive intervention	1	1	0	0

Baseline Characteristics

Safety of Furosemide in Premature Infants at Risk of Bronchopulmonary Dysplasia (BPD)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Furosemide Cohort 1 n=31 Participants Within cohort 1, infants will be randomized using a 3:1 scheme to receive furosemide or placebo. Those randomized to receive furosemide will receive (1mg/kg daily intravenously or 2 mg/kg daily enterally for 28 days. Furosemide Cohort 1: furosemide 1 mg/kg q 24 hours IV or 2 mg/kg q 24 hours enterally Cohorts will be enrolled sequentially after a safety review.	Placebo Cohort 1 n=9 Participants Infants randomized to the placebo treatment group will receive the equivalent volume of dextrose 5% for IV use or enteral use (if receiving enteral study drug). Placebo: Sugar water will be administered in a equivalent volume as drug intervention.	Furosemide Cohort 2 n=30 Participants Cohort 2 Infants will receive furosemide (1mg/kg every 6 hours intravenously or 2 mg/kg every 6 hours daily enterally) for 28 days. Furosemide Cohort 2: furosemide 1 mg/kg q 6 hours IV or 2 mg/kg q 6 hours enterally Cohorts will be enrolled sequentially after a safety review.	Placebo Cohort 2 n=10 Participants Infants randomized to the placebo treatment group will receive the equivalent volume of dextrose 5% for IV use or enteral use (if receiving enteral study drug). Placebo: Sugar water will be administered in a equivalent volume as drug intervention.	Furosemide Cohort 3 Cohort 3 Infants will receive furosemide (2mg/kg every 6 hours intravenously or 4 mg/kg every 6 hours daily enterally) for 28 days. Furosemide Cohort 3: furosemide 2 mg/kg q 6 hours IV or 4 mg/kg q 6 hours enterally Cohorts will be enrolled sequentially after a safety review.	Placebo Cohort 3 Infants randomized to the placebo treatment group will receive the equivalent volume of dextrose 5% for IV use or enteral use (if receiving enteral study drug). Placebo: Sugar water will be administered in a equivalent volume as drug intervention.	Total n=80 Participants Total of all reporting groups
Age, Customized Gestational Age	26.4 weeks STANDARD_DEVIATION 1.4 • n=5 Participants	26.3 weeks STANDARD_DEVIATION 1.9 • n=7 Participants	25.6 weeks STANDARD_DEVIATION 1.4 • n=5 Participants	25.5 weeks STANDARD_DEVIATION 1.8 • n=4 Participants	—	—	26.0 weeks STANDARD_DEVIATION 1.5 • n=8 Participants
Age, Customized Post Natal Age	17 Days STANDARD_DEVIATION 7 • n=5 Participants	18 Days STANDARD_DEVIATION 7 • n=7 Participants	22 Days STANDARD_DEVIATION 6 • n=5 Participants	24 Days STANDARD_DEVIATION 4 • n=4 Participants	—	—	20 Days STANDARD_DEVIATION 7 • n=8 Participants
Sex: Female, Male Female	17 Participants n=5 Participants	5 Participants n=7 Participants	16 Participants n=5 Participants	3 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=8 Participants	41 Participants n=8 Participants
Sex: Female, Male Male	14 Participants n=5 Participants	4 Participants n=7 Participants	14 Participants n=5 Participants	7 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=8 Participants	39 Participants n=8 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	3 Participants n=5 Participants	0 Participants n=7 Participants	7 Participants n=5 Participants	2 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=8 Participants	12 Participants n=8 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	28 Participants n=5 Participants	8 Participants n=7 Participants	22 Participants n=5 Participants	8 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=8 Participants	66 Participants n=8 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=8 Participants	2 Participants n=8 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=8 Participants	1 Participants n=8 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=8 Participants	0 Participants n=8 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=8 Participants	0 Participants n=8 Participants
Race (NIH/OMB) Black or African American	10 Participants n=5 Participants	7 Participants n=7 Participants	9 Participants n=5 Participants	3 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=8 Participants	29 Participants n=8 Participants
Race (NIH/OMB) White	18 Participants n=5 Participants	2 Participants n=7 Participants	16 Participants n=5 Participants	6 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=8 Participants	42 Participants n=8 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=8 Participants	1 Participants n=8 Participants
Race (NIH/OMB) Unknown or Not Reported	3 Participants n=5 Participants	0 Participants n=7 Participants	4 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=8 Participants	7 Participants n=8 Participants
Region of Enrollment United States	31 Participants n=5 Participants	9 Participants n=7 Participants	30 Participants n=5 Participants	10 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=8 Participants	80 Participants n=8 Participants

PRIMARY outcome

Timeframe: 35 days for each participant

Population: Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3. Data are reported for the safety population.

Outcome measures

Outcome measures
Measure	Furosemide Cohort 1 n=31 Participants Within cohort 1, infants were randomized using a 3:1 scheme to receive furosemide or placebo. Those randomized to receive furosemide will receive 1mg/kg daily intravenously or 2 mg/kg daily enterally for 28 days. Furosemide Cohort 1: furosemide 1 mg/kg q 24 hours IV or 2 mg/kg q 24 hours enterally Cohorts will be enrolled sequentially after a safety review.	Placebo Cohort 1 n=9 Participants Infants randomized to the placebo treatment group will receive the equivalent volume of dextrose 5% for IV use or enteral use (if receiving enteral study drug). Placebo: Sugar water will be administered in a equivalent volume as drug intervention.	Furosemide Cohort 2 n=30 Participants Cohort 2 Infants will receive furosemide (1mg/kg every 6 hours intravenously or 2 mg/kg every 6 hours daily enterally) for 28 days. Furosemide Cohort 2: furosemide 1 mg/kg q 6 hours IV or 2 mg/kg q 6 hours enterally Cohorts will be enrolled sequentially after a safety review.	Placebo Cohort 2 n=10 Participants Infants randomized to the placebo treatment group will receive the equivalent volume of dextrose 5% for IV use or enteral use (if receiving enteral study drug). Placebo: Sugar water will be administered in a equivalent volume as drug intervention.	Furosemide Cohort 3 Cohort 3 Infants will receive furosemide (2mg/kg every 6 hours intravenously or 4 mg/kg every 6 hours daily enterally) for 28 days. Furosemide Cohort 3: furosemide 2 mg/kg q 6 hours IV or 4 mg/kg q 6 hours enterally Cohorts will be enrolled sequentially after a safety review.	Placebo Cohort 3 Infants randomized to the placebo treatment group will receive the equivalent volume of dextrose 5% for IV use or enteral use (if receiving enteral study drug). Placebo: Sugar water will be administered in a equivalent volume as drug intervention.	Total n=80 Participants Sum of all groups
Safety as Determined by Adverse Events	123 Events	29 Events	100 Events	49 Events	—	—	293 Events

SECONDARY outcome

Timeframe: Risk measured weekly through Week 4

Population: Data are reported for the safety population. Overall 82 participants were randomized, but 2 were not dosed. 80 participants were analyzed for BPD status. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.

Moderate-severe BPD or death risk was defined by the NICHD Neonatal Research Network (NRN) BPD outcome estimator which provides an estimate of the risk of BPD (none, mild, moderate, severe) or death by postnatal day and is presented as a percentage. For this protocol, the categories were dichotomized to none-mild vs. moderate-severe-death. The risk of BPD or death was defined by the NICHD NRN BPD estimator on days 7, 14, 21 and 28 of study drug using the closest day available from the BPD estimator. The BPD estimator includes infants up to 28 postnatal days; for infants in this protocol older than that, 28-day estimates are used.

Outcome measures

Outcome measures
Measure	Furosemide Cohort 1 n=31 Participants Within cohort 1, infants were randomized using a 3:1 scheme to receive furosemide or placebo. Those randomized to receive furosemide will receive 1mg/kg daily intravenously or 2 mg/kg daily enterally for 28 days. Furosemide Cohort 1: furosemide 1 mg/kg q 24 hours IV or 2 mg/kg q 24 hours enterally Cohorts will be enrolled sequentially after a safety review.	Placebo Cohort 1 n=9 Participants Infants randomized to the placebo treatment group will receive the equivalent volume of dextrose 5% for IV use or enteral use (if receiving enteral study drug). Placebo: Sugar water will be administered in a equivalent volume as drug intervention.	Furosemide Cohort 2 n=30 Participants Cohort 2 Infants will receive furosemide (1mg/kg every 6 hours intravenously or 2 mg/kg every 6 hours daily enterally) for 28 days. Furosemide Cohort 2: furosemide 1 mg/kg q 6 hours IV or 2 mg/kg q 6 hours enterally Cohorts will be enrolled sequentially after a safety review.	Placebo Cohort 2 n=10 Participants Infants randomized to the placebo treatment group will receive the equivalent volume of dextrose 5% for IV use or enteral use (if receiving enteral study drug). Placebo: Sugar water will be administered in a equivalent volume as drug intervention.	Furosemide Cohort 3 Cohort 3 Infants will receive furosemide (2mg/kg every 6 hours intravenously or 4 mg/kg every 6 hours daily enterally) for 28 days. Furosemide Cohort 3: furosemide 2 mg/kg q 6 hours IV or 4 mg/kg q 6 hours enterally Cohorts will be enrolled sequentially after a safety review.	Placebo Cohort 3 Infants randomized to the placebo treatment group will receive the equivalent volume of dextrose 5% for IV use or enteral use (if receiving enteral study drug). Placebo: Sugar water will be administered in a equivalent volume as drug intervention.	Total n=80 Participants Sum of all groups
Moderate-Severe BPD or Death Risk Throughout Weekly Treatment Week 0	57.9 percent probability of BPD or death risk Standard Deviation 20.5	52.8 percent probability of BPD or death risk Standard Deviation 23.0	66.7 percent probability of BPD or death risk Standard Deviation 16.8	70.9 percent probability of BPD or death risk Standard Deviation 22.2	—	—	62.3 percent probability of BPD or death risk Standard Deviation 20.2
Moderate-Severe BPD or Death Risk Throughout Weekly Treatment Week 1	55.4 percent probability of BPD or death risk Standard Deviation 21.2	55.5 percent probability of BPD or death risk Standard Deviation 20.6	65.9 percent probability of BPD or death risk Standard Deviation 17.5	71.6 percent probability of BPD or death risk Standard Deviation 20.4	—	—	61.4 percent probability of BPD or death risk Standard Deviation 20.3
Moderate-Severe BPD or Death Risk Throughout Weekly Treatment Week 2	52.1 percent probability of BPD or death risk Standard Deviation 23.3	56.2 percent probability of BPD or death risk Standard Deviation 21.8	61 percent probability of BPD or death risk Standard Deviation 18.3	65.0 percent probability of BPD or death risk Standard Deviation 18.4	—	—	57.6 percent probability of BPD or death risk Standard Deviation 20.9
Moderate-Severe BPD or Death Risk Throughout Weekly Treatment Week 3	52.1 percent probability of BPD or death risk Standard Deviation 28	40.4 percent probability of BPD or death risk Standard Deviation 25.2	61.3 percent probability of BPD or death risk Standard Deviation 18.2	57.9 percent probability of BPD or death risk Standard Deviation 30.7	—	—	54.9 percent probability of BPD or death risk Standard Deviation 25.4
Moderate-Severe BPD or Death Risk Throughout Weekly Treatment Week 4	44.0 percent probability of BPD or death risk Standard Deviation 23.6	40.9 percent probability of BPD or death risk Standard Deviation 27.9	53.0 percent probability of BPD or death risk Standard Deviation 20.6	54.4 percent probability of BPD or death risk Standard Deviation 34.1	—	—	48.2 percent probability of BPD or death risk Standard Deviation 25.0

SECONDARY outcome

Timeframe: 36 weeks postmenstrual age

Population: Data are reported for the safety population. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.

Moderate-severe BPD or death risk was defined using the NICHD Neonatal Research Network BPD outcome estimator.

Outcome measures

Outcome measures
Measure	Furosemide Cohort 1 n=31 Participants Within cohort 1, infants were randomized using a 3:1 scheme to receive furosemide or placebo. Those randomized to receive furosemide will receive 1mg/kg daily intravenously or 2 mg/kg daily enterally for 28 days. Furosemide Cohort 1: furosemide 1 mg/kg q 24 hours IV or 2 mg/kg q 24 hours enterally Cohorts will be enrolled sequentially after a safety review.	Placebo Cohort 1 n=30 Participants Infants randomized to the placebo treatment group will receive the equivalent volume of dextrose 5% for IV use or enteral use (if receiving enteral study drug). Placebo: Sugar water will be administered in a equivalent volume as drug intervention.	Furosemide Cohort 2 n=9 Participants Cohort 2 Infants will receive furosemide (1mg/kg every 6 hours intravenously or 2 mg/kg every 6 hours daily enterally) for 28 days. Furosemide Cohort 2: furosemide 1 mg/kg q 6 hours IV or 2 mg/kg q 6 hours enterally Cohorts will be enrolled sequentially after a safety review.	Placebo Cohort 2 n=10 Participants Infants randomized to the placebo treatment group will receive the equivalent volume of dextrose 5% for IV use or enteral use (if receiving enteral study drug). Placebo: Sugar water will be administered in a equivalent volume as drug intervention.	Furosemide Cohort 3 Cohort 3 Infants will receive furosemide (2mg/kg every 6 hours intravenously or 4 mg/kg every 6 hours daily enterally) for 28 days. Furosemide Cohort 3: furosemide 2 mg/kg q 6 hours IV or 4 mg/kg q 6 hours enterally Cohorts will be enrolled sequentially after a safety review.	Placebo Cohort 3 Infants randomized to the placebo treatment group will receive the equivalent volume of dextrose 5% for IV use or enteral use (if receiving enteral study drug). Placebo: Sugar water will be administered in a equivalent volume as drug intervention.	Total Sum of all groups
Number of Participants With Moderate-Severe BPD or Death Risk as Clinically Determined	17 Participants	22 Participants	6 Participants	6 Participants	—	—	—

SECONDARY outcome

Timeframe: After study drug administration completion within 30 minutes, 2-4 hours, 6-8 hours, 12-16 hours, and 20-22 hours; within 30 minutes prior to the next dose; and within 48-72 hours of the final study drug administration.

Population: Data was collected from the Furosemide cohort 1 and 2, and combined. In total 39 active drug recipients participated in the population PK.

Data was collected from Furosemide/Active Cohort 1 and Cohort 2 and combined Cohorts. In total 39 active drug recipients participated. PK samples were collected after 7 days on study drug at recommended time points through 28 days on study drug plus one elimination (post drug discontinuation) time point.

Outcome measures

Outcome measures
Measure	Furosemide Cohort 1 n=20 Participants Within cohort 1, infants were randomized using a 3:1 scheme to receive furosemide or placebo. Those randomized to receive furosemide will receive 1mg/kg daily intravenously or 2 mg/kg daily enterally for 28 days. Furosemide Cohort 1: furosemide 1 mg/kg q 24 hours IV or 2 mg/kg q 24 hours enterally Cohorts will be enrolled sequentially after a safety review.	Placebo Cohort 1 n=19 Participants Infants randomized to the placebo treatment group will receive the equivalent volume of dextrose 5% for IV use or enteral use (if receiving enteral study drug). Placebo: Sugar water will be administered in a equivalent volume as drug intervention.	Furosemide Cohort 2 n=39 Participants Cohort 2 Infants will receive furosemide (1mg/kg every 6 hours intravenously or 2 mg/kg every 6 hours daily enterally) for 28 days. Furosemide Cohort 2: furosemide 1 mg/kg q 6 hours IV or 2 mg/kg q 6 hours enterally Cohorts will be enrolled sequentially after a safety review.	Placebo Cohort 2 Infants randomized to the placebo treatment group will receive the equivalent volume of dextrose 5% for IV use or enteral use (if receiving enteral study drug). Placebo: Sugar water will be administered in a equivalent volume as drug intervention.	Furosemide Cohort 3 Cohort 3 Infants will receive furosemide (2mg/kg every 6 hours intravenously or 4 mg/kg every 6 hours daily enterally) for 28 days. Furosemide Cohort 3: furosemide 2 mg/kg q 6 hours IV or 4 mg/kg q 6 hours enterally Cohorts will be enrolled sequentially after a safety review.	Placebo Cohort 3 Infants randomized to the placebo treatment group will receive the equivalent volume of dextrose 5% for IV use or enteral use (if receiving enteral study drug). Placebo: Sugar water will be administered in a equivalent volume as drug intervention.	Total Sum of all groups
Clearance	16.3 (mL/h/kg) Interval 3.7 to 36.0	21.8 (mL/h/kg) Interval 7.7 to 43.6	18 (mL/h/kg) Interval 3.7 to 43.6	—	—	—	—

SECONDARY outcome

Population: Data was collected from the Furosemide Cohort 1 and Cohort 2 and combined. In total, 39 active drug recipients participated in the population PK.

Outcome measures

Outcome measures
Measure	Furosemide Cohort 1 n=20 Participants Within cohort 1, infants were randomized using a 3:1 scheme to receive furosemide or placebo. Those randomized to receive furosemide will receive 1mg/kg daily intravenously or 2 mg/kg daily enterally for 28 days. Furosemide Cohort 1: furosemide 1 mg/kg q 24 hours IV or 2 mg/kg q 24 hours enterally Cohorts will be enrolled sequentially after a safety review.	Placebo Cohort 1 n=19 Participants Infants randomized to the placebo treatment group will receive the equivalent volume of dextrose 5% for IV use or enteral use (if receiving enteral study drug). Placebo: Sugar water will be administered in a equivalent volume as drug intervention.	Furosemide Cohort 2 n=39 Participants Cohort 2 Infants will receive furosemide (1mg/kg every 6 hours intravenously or 2 mg/kg every 6 hours daily enterally) for 28 days. Furosemide Cohort 2: furosemide 1 mg/kg q 6 hours IV or 2 mg/kg q 6 hours enterally Cohorts will be enrolled sequentially after a safety review.	Placebo Cohort 2 Infants randomized to the placebo treatment group will receive the equivalent volume of dextrose 5% for IV use or enteral use (if receiving enteral study drug). Placebo: Sugar water will be administered in a equivalent volume as drug intervention.	Furosemide Cohort 3 Cohort 3 Infants will receive furosemide (2mg/kg every 6 hours intravenously or 4 mg/kg every 6 hours daily enterally) for 28 days. Furosemide Cohort 3: furosemide 2 mg/kg q 6 hours IV or 4 mg/kg q 6 hours enterally Cohorts will be enrolled sequentially after a safety review.	Placebo Cohort 3 Infants randomized to the placebo treatment group will receive the equivalent volume of dextrose 5% for IV use or enteral use (if receiving enteral study drug). Placebo: Sugar water will be administered in a equivalent volume as drug intervention.	Total Sum of all groups
Volume of Distribution	236.7 mL Interval 148.9 to 366.5	242.8 mL Interval 148.9 to 380.2	242.8 mL Interval 149.2 to 380.2	—	—	—	—

SECONDARY outcome

Population: Data were collected from the two Furosemide cohorts and the combined analysis includes all 39 active drug recipients who participated in the population PK .

Outcome measures

Outcome measures
Measure	Furosemide Cohort 1 n=20 Participants Within cohort 1, infants were randomized using a 3:1 scheme to receive furosemide or placebo. Those randomized to receive furosemide will receive 1mg/kg daily intravenously or 2 mg/kg daily enterally for 28 days. Furosemide Cohort 1: furosemide 1 mg/kg q 24 hours IV or 2 mg/kg q 24 hours enterally Cohorts will be enrolled sequentially after a safety review.	Placebo Cohort 1 n=19 Participants Infants randomized to the placebo treatment group will receive the equivalent volume of dextrose 5% for IV use or enteral use (if receiving enteral study drug). Placebo: Sugar water will be administered in a equivalent volume as drug intervention.	Furosemide Cohort 2 n=39 Participants Cohort 2 Infants will receive furosemide (1mg/kg every 6 hours intravenously or 2 mg/kg every 6 hours daily enterally) for 28 days. Furosemide Cohort 2: furosemide 1 mg/kg q 6 hours IV or 2 mg/kg q 6 hours enterally Cohorts will be enrolled sequentially after a safety review.	Placebo Cohort 2 Infants randomized to the placebo treatment group will receive the equivalent volume of dextrose 5% for IV use or enteral use (if receiving enteral study drug). Placebo: Sugar water will be administered in a equivalent volume as drug intervention.	Furosemide Cohort 3 Cohort 3 Infants will receive furosemide (2mg/kg every 6 hours intravenously or 4 mg/kg every 6 hours daily enterally) for 28 days. Furosemide Cohort 3: furosemide 2 mg/kg q 6 hours IV or 4 mg/kg q 6 hours enterally Cohorts will be enrolled sequentially after a safety review.	Placebo Cohort 3 Infants randomized to the placebo treatment group will receive the equivalent volume of dextrose 5% for IV use or enteral use (if receiving enteral study drug). Placebo: Sugar water will be administered in a equivalent volume as drug intervention.	Total Sum of all groups
Half-life	9.8 hours Interval 4.4 to 43.5	7.3 hours Interval 3.6 to 20.6	8.8 hours Interval 3.6 to 43.5	—	—	—	—

SECONDARY outcome

Population: Data was collected from Furosemide/Active Cohort 1 and Cohort 2 and combined Cohorts. In total 39 active drug recipients participated. PK samples were collected after 7 days on study drug at recommended time points through 28 days on study drug plus one elimination (post drug discontinuation) time point.

Population PK data were collected from the two Furosemide cohorts and includes all 39 active drug recipients.

Outcome measures

Outcome measures
Measure	Furosemide Cohort 1 n=20 Participants Within cohort 1, infants were randomized using a 3:1 scheme to receive furosemide or placebo. Those randomized to receive furosemide will receive 1mg/kg daily intravenously or 2 mg/kg daily enterally for 28 days. Furosemide Cohort 1: furosemide 1 mg/kg q 24 hours IV or 2 mg/kg q 24 hours enterally Cohorts will be enrolled sequentially after a safety review.	Placebo Cohort 1 n=19 Participants Infants randomized to the placebo treatment group will receive the equivalent volume of dextrose 5% for IV use or enteral use (if receiving enteral study drug). Placebo: Sugar water will be administered in a equivalent volume as drug intervention.	Furosemide Cohort 2 n=39 Participants Cohort 2 Infants will receive furosemide (1mg/kg every 6 hours intravenously or 2 mg/kg every 6 hours daily enterally) for 28 days. Furosemide Cohort 2: furosemide 1 mg/kg q 6 hours IV or 2 mg/kg q 6 hours enterally Cohorts will be enrolled sequentially after a safety review.	Placebo Cohort 2 Infants randomized to the placebo treatment group will receive the equivalent volume of dextrose 5% for IV use or enteral use (if receiving enteral study drug). Placebo: Sugar water will be administered in a equivalent volume as drug intervention.	Furosemide Cohort 3 Cohort 3 Infants will receive furosemide (2mg/kg every 6 hours intravenously or 4 mg/kg every 6 hours daily enterally) for 28 days. Furosemide Cohort 3: furosemide 2 mg/kg q 6 hours IV or 4 mg/kg q 6 hours enterally Cohorts will be enrolled sequentially after a safety review.	Placebo Cohort 3 Infants randomized to the placebo treatment group will receive the equivalent volume of dextrose 5% for IV use or enteral use (if receiving enteral study drug). Placebo: Sugar water will be administered in a equivalent volume as drug intervention.	Total Sum of all groups
Area Under the Plasma Concentration Versus Time Curve	2165 mg*h/L Interval 1011.0 to 6059.0	6016 mg*h/L Interval 2801.0 to 12330.0	4639 mg*h/L Interval 1011.0 to 12330.0	—	—	—	—

Adverse Events

Furosemide Cohort 1

Serious events: 5 serious events

Other events: 28 other events

Deaths: 0 deaths

Placebo Cohort 1

Serious events: 1 serious events

Other events: 9 other events

Deaths: 0 deaths

Furosemide Cohort 2

Serious events: 6 serious events

Other events: 28 other events

Deaths: 1 deaths

Placebo Cohort 2

Serious events: 0 serious events

Other events: 9 other events

Deaths: 0 deaths

Furosemide Cohort 3

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Placebo Cohort 3

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Furosemide Cohort 1 n=31 participants at risk Within cohort 1, infants will be randomized using a 3:1 scheme to receive furosemide or placebo. Those randomized to receive furosemide will receive (1mg/kg daily intravenously or 2 mg/kg daily enterally for 28 days. Furosemide Cohort 1: furosemide 1 mg/kg q 24 hours IV or 2 mg/kg q 24 hours enterally Cohorts will be enrolled sequentially after a safety review.	Placebo Cohort 1 n=9 participants at risk Infants randomized to the placebo treatment group will receive the equivalent volume of dextrose 5% for IV use or enteral use (if receiving enteral study drug). Placebo: Sugar water will be administered in a equivalent volume as drug intervention.	Furosemide Cohort 2 n=30 participants at risk Cohort 2 Infants will receive furosemide (1mg/kg every 6 hours intravenously or 2 mg/kg every 6 hours daily enterally) for 28 days. Furosemide Cohort 2: furosemide 1 mg/kg q 6 hours IV or 2 mg/kg q 6 hours enterally Cohorts will be enrolled sequentially after a safety review.	Placebo Cohort 2 n=10 participants at risk Infants randomized to the placebo treatment group will receive the equivalent volume of dextrose 5% for IV use or enteral use (if receiving enteral study drug). Placebo: Sugar water will be administered in a equivalent volume as drug intervention.	Furosemide Cohort 3 Cohort 3 Infants will receive furosemide (2mg/kg every 6 hours intravenously or 4 mg/kg every 6 hours daily enterally) for 28 days. Furosemide Cohort 3: furosemide 2 mg/kg q 6 hours IV or 4 mg/kg q 6 hours enterally Cohorts will be enrolled sequentially after a safety review.	Placebo Cohort 3 Infants randomized to the placebo treatment group will receive the equivalent volume of dextrose 5% for IV use or enteral use (if receiving enteral study drug). Placebo: Sugar water will be administered in a equivalent volume as drug intervention.
Congenital, familial and genetic disorders Patent ductus arteriosus	3.2% 1/31 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/9 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/30 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/10 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.
Vascular disorders Shock	3.2% 1/31 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/9 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/30 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/10 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.
Nervous system disorders Hydrocephalus	0.00% 0/31 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	11.1% 1/9 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/30 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/10 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.
Gastrointestinal disorders Volvulus	0.00% 0/31 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	11.1% 1/9 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/30 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/10 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.
Infections and infestations Meningitis herpes	0.00% 0/31 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	11.1% 1/9 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/30 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/10 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.
Nervous system disorders Intraventricular haemorrhage	0.00% 0/31 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	11.1% 1/9 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/30 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/10 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.
Gastrointestinal disorders Necrotising colitis	0.00% 0/31 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	11.1% 1/9 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/30 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/10 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.
Nervous system disorders Seizure	3.2% 1/31 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/9 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/30 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/10 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.
Infections and infestations Sepsis	0.00% 0/31 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/9 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	3.3% 1/30 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/10 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.
Reproductive system and breast disorders Respiratory failure	0.00% 0/31 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/9 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	3.3% 1/30 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/10 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.
Respiratory, thoracic and mediastinal disorders Acute Respiratory Failure	0.00% 0/31 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/9 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	3.3% 1/30 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/10 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.
Renal and urinary disorders Renal Failure	0.00% 0/31 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/9 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	3.3% 1/30 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/10 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.
Infections and infestations Respiratory track infection viral	0.00% 0/31 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/9 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	3.3% 1/30 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/10 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.

Other adverse events

Other adverse events
Measure	Furosemide Cohort 1 n=31 participants at risk Within cohort 1, infants will be randomized using a 3:1 scheme to receive furosemide or placebo. Those randomized to receive furosemide will receive (1mg/kg daily intravenously or 2 mg/kg daily enterally for 28 days. Furosemide Cohort 1: furosemide 1 mg/kg q 24 hours IV or 2 mg/kg q 24 hours enterally Cohorts will be enrolled sequentially after a safety review.	Placebo Cohort 1 n=9 participants at risk Infants randomized to the placebo treatment group will receive the equivalent volume of dextrose 5% for IV use or enteral use (if receiving enteral study drug). Placebo: Sugar water will be administered in a equivalent volume as drug intervention.	Furosemide Cohort 2 n=30 participants at risk Cohort 2 Infants will receive furosemide (1mg/kg every 6 hours intravenously or 2 mg/kg every 6 hours daily enterally) for 28 days. Furosemide Cohort 2: furosemide 1 mg/kg q 6 hours IV or 2 mg/kg q 6 hours enterally Cohorts will be enrolled sequentially after a safety review.	Placebo Cohort 2 n=10 participants at risk Infants randomized to the placebo treatment group will receive the equivalent volume of dextrose 5% for IV use or enteral use (if receiving enteral study drug). Placebo: Sugar water will be administered in a equivalent volume as drug intervention.	Furosemide Cohort 3 Cohort 3 Infants will receive furosemide (2mg/kg every 6 hours intravenously or 4 mg/kg every 6 hours daily enterally) for 28 days. Furosemide Cohort 3: furosemide 2 mg/kg q 6 hours IV or 4 mg/kg q 6 hours enterally Cohorts will be enrolled sequentially after a safety review.	Placebo Cohort 3 Infants randomized to the placebo treatment group will receive the equivalent volume of dextrose 5% for IV use or enteral use (if receiving enteral study drug). Placebo: Sugar water will be administered in a equivalent volume as drug intervention.
Skin and subcutaneous tissue disorders Petechiae	0.00% 0/31 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/9 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/30 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	10.0% 1/10 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.
Respiratory, thoracic and mediastinal disorders Chronic Respiratory Disease	16.1% 5/31 • Number of events 5 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/9 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/30 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/10 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.
Blood and lymphatic system disorders Anaemia	12.9% 4/31 • Number of events 5 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/9 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	3.3% 1/30 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	10.0% 1/10 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.
Blood and lymphatic system disorders Anaemia neonatal	12.9% 4/31 • Number of events 4 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	22.2% 2/9 • Number of events 2 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/30 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/10 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.
Blood and lymphatic system disorders Bandaemia	0.00% 0/31 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/9 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/30 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	10.0% 1/10 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.
Blood and lymphatic system disorders Thrombocytopenia	9.7% 3/31 • Number of events 3 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/9 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/30 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	10.0% 1/10 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.
Cardiac disorders Cardiopulmonary failure	0.00% 0/31 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/9 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/30 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	10.0% 1/10 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.
Cardiac disorders Supraventricular extrasystoles	0.00% 0/31 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/9 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/30 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	10.0% 1/10 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.
Cardiac disorders Tachycardia	3.2% 1/31 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/9 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	10.0% 3/30 • Number of events 4 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/10 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.
Congenital, familial and genetic disorders Patent ductus arteriosus	9.7% 3/31 • Number of events 3 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/9 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	13.3% 4/30 • Number of events 5 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	10.0% 1/10 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.
Endocrine disorders Inappropriate antidiuretic hormone secretion	0.00% 0/31 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/9 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/30 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	10.0% 1/10 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.
Eye disorders Eyelid oedema	0.00% 0/31 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/9 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/30 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	10.0% 1/10 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.
Eye disorders Retinopathy of prematurity	9.7% 3/31 • Number of events 3 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	11.1% 1/9 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	3.3% 1/30 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	10.0% 1/10 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.
Gastrointestinal disorders abdominal distension	9.7% 3/31 • Number of events 4 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	11.1% 1/9 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/30 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	10.0% 1/10 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.
Gastrointestinal disorders Ileus	0.00% 0/31 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/9 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/30 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	10.0% 1/10 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.
Gastrointestinal disorders Inguinal hernia	3.2% 1/31 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	11.1% 1/9 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/30 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	10.0% 1/10 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.
Gastrointestinal disorders Necrotising colitis	6.5% 2/31 • Number of events 2 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	11.1% 1/9 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/30 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	10.0% 1/10 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.
Gastrointestinal disorders Vomiting	0.00% 0/31 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/9 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/30 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	20.0% 2/10 • Number of events 2 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.
Infections and infestations Pneumonia escherichia	0.00% 0/31 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	11.1% 1/9 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/30 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/10 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.
Infections and infestations Sepsis	3.2% 1/31 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	11.1% 1/9 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	6.7% 2/30 • Number of events 2 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/10 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.
Infections and infestations Tracheitis	0.00% 0/31 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/9 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/30 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	10.0% 1/10 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.
Infections and infestations Urinary tract infection	0.00% 0/31 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	11.1% 1/9 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	3.3% 1/30 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/10 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.
Infections and infestations Urinary tract infection bacterial	0.00% 0/31 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	11.1% 1/9 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	3.3% 1/30 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/10 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.
Injury, poisoning and procedural complications Skin abrasion	0.00% 0/31 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/9 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/30 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	10.0% 1/10 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.
Investigations Blood alkaline phosphatase increased	0.00% 0/31 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	11.1% 1/9 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/30 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/10 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.
Investigations Blood bicarbonate increased	0.00% 0/31 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/9 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	13.3% 4/30 • Number of events 5 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	10.0% 1/10 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.
Investigations Blood creatinine increased	6.5% 2/31 • Number of events 2 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/9 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	16.7% 5/30 • Number of events 5 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/10 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.
General disorders Oedema peripheral	0.00% 0/31 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/9 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/30 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	10.0% 1/10 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.
Hepatobiliary disorders Cholestasis	0.00% 0/31 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/9 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/30 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	20.0% 2/10 • Number of events 2 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.
Hepatobiliary disorders Hyperbilirubinaemia	0.00% 0/31 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/9 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	3.3% 1/30 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	10.0% 1/10 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.
Investigations Bilirubin conjugate increased	6.5% 2/31 • Number of events 2 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	11.1% 1/9 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/30 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/10 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.
Investigations Blood sodium decreased	6.5% 2/31 • Number of events 5 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/9 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/30 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/10 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.
Investigations Blood urea increased	0.00% 0/31 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	88.9% 8/9 • Number of events 8 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/30 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/10 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.
Investigations Cardiac murmur	9.7% 3/31 • Number of events 3 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/9 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/30 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	10.0% 1/10 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.
Investigations Chest X-ray abnormal	0.00% 0/31 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/9 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/30 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	10.0% 1/10 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.
Investigations Gamma-glutamyltransferase increased	0.00% 0/31 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	11.1% 1/9 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/30 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/10 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.
Investigations Platelet count decreased	3.2% 1/31 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	11.1% 1/9 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/30 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/10 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.
Investigations Sputum culture positive	0.00% 0/31 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/9 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/30 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	10.0% 1/10 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.
Metabolism and nutrition disorders Electrolyte imbalance	9.7% 3/31 • Number of events 3 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	22.2% 2/9 • Number of events 2 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	6.7% 2/30 • Number of events 2 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	10.0% 1/10 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.
Metabolism and nutrition disorders Hypercalcaemia	0.00% 0/31 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/9 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	3.3% 1/30 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	10.0% 1/10 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.
Metabolism and nutrition disorders Hyperphosphataemia	12.9% 4/31 • Number of events 4 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	11.1% 1/9 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/30 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/10 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.
Metabolism and nutrition disorders Hypocalcaemia	3.2% 1/31 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	11.1% 1/9 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/30 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/10 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.
Metabolism and nutrition disorders Hypokalaemia	6.5% 2/31 • Number of events 2 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/9 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	13.3% 4/30 • Number of events 5 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	10.0% 1/10 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.
Metabolism and nutrition disorders Hyponatraemia	32.3% 10/31 • Number of events 10 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	11.1% 1/9 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	23.3% 7/30 • Number of events 8 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/10 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.
Metabolism and nutrition disorders Hypophosphataemia	3.2% 1/31 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/9 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/30 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	20.0% 2/10 • Number of events 2 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.
Metabolism and nutrition disorders Metabolic acidosis	3.2% 1/31 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	22.2% 2/9 • Number of events 2 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	6.7% 2/30 • Number of events 2 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/10 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.
Musculoskeletal and connective tissue disorders Growth retardation	3.2% 1/31 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	11.1% 1/9 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/30 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/10 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.
Musculoskeletal and connective tissue disorders Osteopenia	3.2% 1/31 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	11.1% 1/9 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	3.3% 1/30 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/10 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Haemangioma of bone	0.00% 0/31 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/9 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/30 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	10.0% 1/10 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.
Nervous system disorders Hydrocephalus	0.00% 0/31 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	11.1% 1/9 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/30 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/10 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.
Nervous system disorders Hypertonia	0.00% 0/31 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/9 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/30 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	10.0% 1/10 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.
Nervous system disorders Periventricular leukomalacia	0.00% 0/31 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/9 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/30 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	10.0% 1/10 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.
Nervous system disorders Seizure	9.7% 3/31 • Number of events 3 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	11.1% 1/9 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/30 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	10.0% 1/10 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.
Renal and urinary disorders Oliguria	3.2% 1/31 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/9 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	3.3% 1/30 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	10.0% 1/10 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.
Reproductive system and breast disorders Testicular swelling	0.00% 0/31 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	11.1% 1/9 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/30 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/10 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.
Respiratory, thoracic and mediastinal disorders Atelectasis	3.2% 1/31 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/9 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	3.3% 1/30 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	10.0% 1/10 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.
Respiratory, thoracic and mediastinal disorders Bronchopulmonary dysplasia	0.00% 0/31 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	11.1% 1/9 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	3.3% 1/30 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	10.0% 1/10 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.
Respiratory, thoracic and mediastinal disorders Hypercapnia	0.00% 0/31 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/9 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/30 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	10.0% 1/10 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.
Respiratory, thoracic and mediastinal disorders Hypoxia	0.00% 0/31 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/9 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	3.3% 1/30 • Number of events 2 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	10.0% 1/10 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.
Respiratory, thoracic and mediastinal disorders Respiratory acidosis	0.00% 0/31 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	11.1% 1/9 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	3.3% 1/30 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	10.0% 1/10 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.
Respiratory, thoracic and mediastinal disorders Respiratory failure	6.5% 2/31 • Number of events 3 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	11.1% 1/9 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	6.7% 2/30 • Number of events 2 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/10 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.
Vascular disorders Embolism	3.2% 1/31 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/9 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	0.00% 0/30 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	10.0% 1/10 • Number of events 1 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.	— 0/0 • Following provision of Informed consent through final assessment, a total of approximately 35 days. Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.

Additional Information

Leigh Gosnell

Duke University

Phone: 919-668-1280

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place