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

• Sponsor: University of North Carolina, Chapel Hill (Other)
• Overall Status: Completed
• CT.gov ID: NCT02527798
• Collaborator: Duke University (Other), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (NIH), The Emmes Company, LLC (Industry)
• Enrollment: 82
• Locations: 21
• Arms: 6
• Actual Duration (Months): 46.6
• Patients Per Site: 3.9
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This study will describe the safety of furosemide in premature infants at risk of bronchopulmonary dysplasia and determine the preliminary effectiveness and pharmacokinetics (PK) of furosemide. Funding Source - FDA OOPD

Condition or Disease	Intervention/Treatment	Phase
Bronchopulmonary Dysplasia	Drug: Furosemide Cohort 1; Drug: Furosemide Cohort 2; Drug: Furosemide Cohort 3; Other: Placebo	Phase 2

Detailed Description

Infants will receive a placebo or furosemide for 28 days. Blood samples will be collected for pharmacokinetic analysis.Premature infants will be randomized to receive placebo or furosemide in a dose escalating approach.

Follow up information will be collected up to 7 days after the last dose and at 36 weeks post menstrual age. The final study assessment will occur at the time of discharge, early termination or transfer.

Study Design

• Study Type: Interventional
• Actual Enrollment: 82 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Other
• Official Title: Safety of Furosemide in Premature Infants at Risk of Bronchopulmonary Dysplasia
• Actual Study Start Date: Nov 27, 2015
• Actual Primary Completion Date: Oct 15, 2019
• Actual Study Completion Date: Oct 15, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 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.	Drug: 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.; Other Names: Lasix
Placebo Comparator: 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).	Other: Placebo; Sugar water will be administered in a equivalent volume as drug intervention.; Other Names: sugar water
Experimental: 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.	Drug: 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.; Other Names: Lasix
Experimental: 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.	Drug: 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.; Other Names: Lasix
Placebo Comparator: 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).	Other: Placebo; Sugar water will be administered in a equivalent volume as drug intervention.; Other Names: sugar water
Placebo Comparator: 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).	Other: Placebo; Sugar water will be administered in a equivalent volume as drug intervention.; Other Names: sugar water

Outcome Measures

Primary Outcome Measures

1. Safety as Determined by Adverse Events [35 days for each participant]

   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.

Secondary Outcome Measures

1. Moderate-Severe BPD or Death Risk Throughout Weekly Treatment [Risk measured weekly through Week 4]

   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.

2. Number of Participants With Moderate-Severe BPD or Death Risk as Clinically Determined [36 weeks postmenstrual age]

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

3. Clearance [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.]

   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.

4. Volume of Distribution [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.]

   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.

5. Half-life [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.]

   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.

6. Area Under the Plasma Concentration Versus Time Curve [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 PK data were collected from the two Furosemide cohorts and includes all 39 active drug recipients.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 7 Days to 28 Days
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Receiving positive airway pressure (nasal continuous airway pressure, nasal intermittent positive pressure ventilation, or nasal cannula flow > 1LPM) or mechanical ventilation (high frequency or conventional)

2. < 29 weeks gestational age at birth

3. 7-28 days postnatal age at time of first study dose

Exclusion Criteria:

1. Exposure to any diuretic ≤ 72 hours prior to first study dose

2. Previous enrollment and dosing in current study, "Safety of Furosemide in Premature Infants at Risk of Bronchopulmonary Dysplasia"

3. Hemodynamically significant patent ductus arteriosus, as determined by the investigator

4. Major congenital anomaly (e.g. congenital diaphragmatic hernia, congenital pulmonary adenomatoid malformation)

5. Meconium aspiration syndrome

6. Known allergy to any diuretic

7. Serum creatinine >1.7 mg/dL < 24 hours prior to first study dose

8. BUN >50 mg/dL < 24 hours prior to first study dose

9. Na <125 mmol/L < 24 hours prior to first study dose

10. K ≤2.5 mmol/L < 24 hours prior to first study dose

11. Ca ≤ 6 mg/dL < 24 hours prior to first study dose

12. Indirect bilirubin >10 mg/dL < 24 hours prior to first study dose

13. Any condition which would make the participant, in the opinion of the investigator, unsuitable for the study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Arkansas Children's Hospital/University of Arkansas for Medical Sciences	Little Rock	Arkansas	United States	72202
2	Loma Linda University Medical Center	Loma Linda	California	United States	92354
3	University of Florida Jacskonville Shands Medical Center	Jacksonville	Florida	United States	32209
4	Wolfson Children's Hospital	Jacksonville	Florida	United States	32209
5	John's Hopkins Al Children's Hospital	Saint Petersburg	Florida	United States	33701
6	South Miami Hospital	South Miami	Florida	United States	33143
7	University of Illinois at Chicago	Chicago	Illinois	United States	60612
8	Wesley Medical Center	Wichita	Kansas	United States	67214
9	University of Kentucky Medical Center	Lexington	Kentucky	United States	40536
10	Floating Hospital for Children at Tufts Medical Center	Boston	Massachusetts	United States	02111
11	UMass Memorial Medical Center	Worcester	Massachusetts	United States	01605
12	University of Michigan Medical Center	Ann Arbor	Michigan	United States	48109-4225
13	Children's Mercy Hospital and Clinics	Kansas City	Missouri	United States	64108
14	University Medical Center of Southern Nevada	Las Vegas	Nevada	United States	89102
15	The University of North Carolina at Chapel Hill/North Carolina Children's Hospital	Chapel Hill	North Carolina	United States	27599-7596
16	New Hanover Regional Medical Center	Wilmington	North Carolina	United States	28403
17	MetroHealth Medical Center	Cleveland	Ohio	United States	44109
18	Nationwide Children's Hospital/The Ohio State University	Columbus	Ohio	United States	43205
19	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma	United States	73104
20	Virginia Commonwealth University	Richmond	Virginia	United States	23298
21	West Virginia University	Morgantown	West Virginia	United States	26506

Sponsors and Collaborators

• University of North Carolina, Chapel Hill
• Duke University
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• The Emmes Company, LLC

Investigators

• Principal Investigator: Matthew Laughon, MD, MPH, University of North Carolina, Chapel Hill
• Study Chair: Jason E Lang, MD, MPH, Duke University

Study Documents (Full-Text)

• Study Protocol - Sep 27, 2019
• Statistical Analysis Plan - Nov 11, 2016

More Information

Publications

None provided.

• Responsible Party: University of North Carolina, Chapel Hill
• ClinicalTrials.gov Identifier: NCT02527798
• Other Study ID Numbers: 15-1978; HHSN27500033; HHSN27500035; 5R01FD005101-02
• First Posted: Aug 19, 2015
• Last Update Posted: Dec 28, 2021
• Last Verified: Sep 1, 2021

• Additional relevant MeSH terms: Bronchopulmonary Dysplasia; Furosemide

Study Results

Participant Flow

Pre-assignment Detail	Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.

Arm/Group Title	Furosemide Cohort 1	Placebo Cohort 1	Furosemide Cohort 2	Placebo Cohort 2	Furosemide Cohort 3	Placebo Cohort 3
Arm/Group Description	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.	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.	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.	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.	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.	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.
Period Title: Overall Study
STARTED	32	10	30	10	0	0
Randomized, Not Dosed	31	9	30	10	0	0
Pharmacokinetic (PK) Population	20	0	19	0	0	0
COMPLETED	29	8	25	9	0	0
NOT COMPLETED	3	2	5	1	0	0

Baseline Characteristics

Arm/Group Title	Furosemide Cohort 1	Placebo Cohort 1	Furosemide Cohort 2	Placebo Cohort 2	Furosemide Cohort 3	Placebo Cohort 3	Total
Arm/Group Description	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.	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.	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.	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.	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.	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 of all reporting groups
Overall Participants	31	9	30	10	0	0	80
Age, Customized (weeks) [Mean (Standard Deviation) ]
Gestational Age	26.4 (1.4)	26.3 (1.9)	25.6 (1.4)	25.5 (1.8)	26.0 (1.5)
Age, Customized (Days) [Mean (Standard Deviation) ]
Post Natal Age	17 (7)	18 (7)	22 (6)	24 (4)	20 (7)
Sex: Female, Male (Count of Participants)
Female	17 54.8%	5 55.6%	16 53.3%	3 30%	0 NaN	0 NaN	41 51.3%
Male	14 45.2%	4 44.4%	14 46.7%	7 70%	0 NaN	0 NaN	39 48.8%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	3 9.7%	0 0%	7 23.3%	2 20%	0 NaN	0 NaN	12 15%
Not Hispanic or Latino	28 90.3%	8 88.9%	22 73.3%	8 80%	0 NaN	0 NaN	66 82.5%
Unknown or Not Reported	0 0%	1 11.1%	1 3.3%	0 0%	0 NaN	0 NaN	2 2.5%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	1 10%	0 NaN	0 NaN	1 1.3%
Asian	0 0%	0 0%	0 0%	0 0%	0 NaN	0 NaN	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 NaN	0 NaN	0 0%
Black or African American	10 32.3%	7 77.8%	9 30%	3 30%	0 NaN	0 NaN	29 36.3%
White	18 58.1%	2 22.2%	16 53.3%	6 60%	0 NaN	0 NaN	42 52.5%
More than one race	0 0%	0 0%	1 3.3%	0 0%	0 NaN	0 NaN	1 1.3%
Unknown or Not Reported	3 9.7%	0 0%	4 13.3%	0 0%	0 NaN	0 NaN	7 8.8%
Region of Enrollment (Count of Participants)
United States	31 100%	9 100%	30 100%	10 100%	0 NaN	0 NaN	80 100%

Outcome Measures

1. Primary Outcome

Title	Safety as Determined by Adverse Events
Description	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.
Time Frame	35 days for each participant

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Furosemide Cohort 1	Placebo Cohort 1	Furosemide Cohort 2	Placebo Cohort 2	Furosemide Cohort 3	Placebo Cohort 3	Total
Arm/Group Description	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.	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.	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.	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.	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.	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.	Sum of all groups
Measure Participants	31	9	30	10	0	0	80
Number [Events]	123	29	100	49	293

2. Secondary Outcome

Title	Moderate-Severe BPD or Death Risk Throughout Weekly Treatment
Description	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.
Time Frame	Risk measured weekly through Week 4

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Furosemide Cohort 1	Placebo Cohort 1	Furosemide Cohort 2	Placebo Cohort 2	Furosemide Cohort 3	Placebo Cohort 3	Weekly Total
Arm/Group Description	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.	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.	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.	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.	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.	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.	Weekly total (Cohort 1 Furosemide/Placebo and Cohort 2 Furosemide/Placebo
Measure Participants	31	9	30	10	0	0	80
Week 0	57.9 (20.5)	52.8 (23.0)	66.7 (16.8)	70.9 (22.2)	62.3 (20.2)
Week 1	55.4 (21.2)	55.5 (20.6)	65.9 (17.5)	71.6 (20.4)	61.4 (20.3)
Week 2	52.1 (23.3)	56.2 (21.8)	61 (18.3)	65.0 (18.4)	57.6 (20.9)
Week 3	52.1 (28)	40.4 (25.2)	61.3 (18.2)	57.9 (30.7)	54.9 (25.4)
Week 4	44.0 (23.6)	40.9 (27.9)	53.0 (20.6)	54.4 (34.1)	48.2 (25.0)

3. Secondary Outcome

Title	Number of Participants With Moderate-Severe BPD or Death Risk as Clinically Determined
Description	Moderate-severe BPD or death risk was defined using the NICHD Neonatal Research Network BPD outcome estimator.
Time Frame	36 weeks postmenstrual age

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Furosemide Cohort 1	Furosemide Cohort 2	Placebo Cohort 1	Placebo Cohort 2	Furosemide Cohort 3	Placebo Cohort 3
Arm/Group Description	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.	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.	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.	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.	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.	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.
Measure Participants	31	30	9	10	0	0
Count of Participants [Participants]	17 54.8%	22 244.4%	6 20%	6 60%

4. Secondary Outcome

Title	Clearance
Description	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.
Time Frame	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.

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Furosemide Cohort 1	Furosemide Cohort 2	Furosemide (Cohort 1 and Cohort 2)
Arm/Group Description	PK Population: Furosemide/Active drug arms from Cohort 1	PK Population: Furosemide/Active drug arms from Cohort 2	PK Population: Furosemide/Active drug arms from Cohort 1 and Cohort 2
Measure Participants	20	19	39
Median (Full Range) [(mL/h/kg)]	16.3	21.8	18

5. Secondary Outcome

Title	Volume of Distribution
Description	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.
Time Frame	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.

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Furosemide Cohort 1	Furosemide Cohort 2	Furosemide All (Cohort 1 and Cohort 2)
Arm/Group Description	PK Population: Furosemide/Active drug arms from Cohort 1	PK Population: Furosemide/Active drug arms from Cohort 2	PK Population: Furosemide/Active drug arms from Cohort 1 and Cohort 2
Measure Participants	20	19	39
Median (Full Range) [mL]	236.7	242.8	242.8

6. Secondary Outcome

Title	Half-life
Description	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.
Time Frame	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.

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Furosemide Cohort 1	Furosemide Cohort 2	Furosemide Cohort 1 and Cohort 2
Arm/Group Description	PK Population: Furosemide/Active drug from Cohort 1	PK Population: Furosemide/Active drug from Cohort 2	PK Population: Combined Furosemide/Active drug from Cohort 1 and Cohort 2
Measure Participants	20	19	39
Median (Full Range) [hours]	9.8	7.3	8.8

7. Secondary Outcome

Title	Area Under the Plasma Concentration Versus Time Curve
Description	Population PK data were collected from the two Furosemide cohorts and includes all 39 active drug recipients.
Time Frame	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.

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Furosemide Cohort 1	Furosemide Cohort 2	Furosemide (Cohort 1 and Cohort 2)
Arm/Group Description	PK Population: Furosemide/Active drug from Cohort 1	PK Population: Furosemide/Active drug from Cohort 2	PK Population: Furosemide/Active drug from Cohort 1 and Cohort 2
Measure Participants	20	19	39
Median (Full Range) [mg*h/L]	2165	6016	4639

Adverse Events

Time Frame	Following provision of Informed consent through final assessment, a total of approximately 35 days.
Adverse Event Reporting Description	Based on Cohort 2 safety data analysis, enrollment was stopped prior to Cohort 3.
Arm/Group Title	Furosemide Cohort 1		Placebo Cohort 1		Furosemide Cohort 2		Placebo Cohort 2		Furosemide Cohort 3		Placebo Cohort 3
Arm/Group Description	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.		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.		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.		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.		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.		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.
All Cause Mortality
	Furosemide Cohort 1		Placebo Cohort 1		Furosemide Cohort 2		Placebo Cohort 2		Furosemide Cohort 3		Placebo Cohort 3
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/31 (0%)		0/9 (0%)		1/30 (3.3%)		0/10 (0%)		0/0 (NaN)		0/0 (NaN)
Serious Adverse Events
	Furosemide Cohort 1		Placebo Cohort 1		Furosemide Cohort 2		Placebo Cohort 2		Furosemide Cohort 3		Placebo Cohort 3
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/31 (16.1%)		1/9 (11.1%)		6/30 (20%)		0/10 (0%)		0/0 (NaN)		0/0 (NaN)
Congenital, familial and genetic disorders
Patent ductus arteriosus	1/31 (3.2%)	1	0/9 (0%)	0	0/30 (0%)	0	0/10 (0%)	0	0/0 (NaN)	0	0/0 (NaN)	0
Gastrointestinal disorders
Volvulus	0/31 (0%)	0	1/9 (11.1%)	1	0/30 (0%)	0	0/10 (0%)	0	0/0 (NaN)	0	0/0 (NaN)	0
Necrotising colitis	1/31 (3.2%)	1	0/9 (0%)	0	0/30 (0%)	0	0/10 (0%)	0	0/0 (NaN)	0	0/0 (NaN)	0
Necrotising colitis	0/31 (0%)	0	1/9 (11.1%)	1	0/30 (0%)	0	0/10 (0%)	0	0/0 (NaN)	0	0/0 (NaN)	0
Infections and infestations
Meningitis herpes	0/31 (0%)	0	1/9 (11.1%)	1	0/30 (0%)	0	0/10 (0%)	0	0/0 (NaN)	0	0/0 (NaN)	0
Sepsis	0/31 (0%)	0	0/9 (0%)	0	1/30 (3.3%)	1	0/10 (0%)	0	0/0 (NaN)	0	0/0 (NaN)	0
Respiratory track infection viral	0/31 (0%)	0	0/9 (0%)	0	1/30 (3.3%)	1	0/10 (0%)	0	0/0 (NaN)	0	0/0 (NaN)	0
Sepsis	0/31 (0%)	0	0/9 (0%)	0	1/30 (3.3%)	1	1/10 (10%)	1	1/0 (Infinity)	1	1/0 (Infinity)	1
Nervous system disorders
Hydrocephalus	0/31 (0%)	0	1/9 (11.1%)	1	0/30 (0%)	0	0/10 (0%)	0	0/0 (NaN)	0	0/0 (NaN)	0
Intraventricular haemorrhage	0/31 (0%)	0	1/9 (11.1%)	1	0/30 (0%)	0	0/10 (0%)	0	0/0 (NaN)	0	0/0 (NaN)	0
Seizure	1/31 (3.2%)	1	0/9 (0%)	0	0/30 (0%)	0	0/10 (0%)	0	0/0 (NaN)	0	0/0 (NaN)	0
Renal and urinary disorders
Renal Failure	0/31 (0%)	0	0/9 (0%)	0	1/30 (3.3%)	1	0/10 (0%)	0	0/0 (NaN)	0	0/0 (NaN)	0
Reproductive system and breast disorders
Respiratory failure	0/31 (0%)	0	0/9 (0%)	0	1/30 (3.3%)	1	0/10 (0%)	0	0/0 (NaN)	0	0/0 (NaN)	0
Respiratory, thoracic and mediastinal disorders
Acute Respiratory Failure	0/31 (0%)	0	0/9 (0%)	0	1/30 (3.3%)	1	0/10 (0%)	0	0/0 (NaN)	0	0/0 (NaN)	0
Vascular disorders
Shock	1/31 (3.2%)	1	0/9 (0%)	0	0/30 (0%)	0	0/10 (0%)	0	0/0 (NaN)	0	0/0 (NaN)	0
Other (Not Including Serious) Adverse Events
	Furosemide Cohort 1		Placebo Cohort 1		Furosemide Cohort 2		Placebo Cohort 2		Furosemide Cohort 3		Placebo Cohort 3
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	28/31 (90.3%)		9/9 (100%)		28/30 (93.3%)		9/10 (90%)		0/0 (NaN)		0/0 (NaN)
Blood and lymphatic system disorders
Anaemia	4/31 (12.9%)	5	0/9 (0%)	0	1/30 (3.3%)	1	1/10 (10%)	1	1/0 (Infinity)	1	1/0 (Infinity)	1
Anaemia neonatal	4/31 (12.9%)	4	2/9 (22.2%)	2	0/30 (0%)	0	0/10 (0%)	0	0/0 (NaN)	0	0/0 (NaN)	0
Bandaemia	0/31 (0%)	0	0/9 (0%)	0	0/30 (0%)	0	1/10 (10%)	1	1/0 (Infinity)	1	1/0 (Infinity)	1
Thrombocytopenia	3/31 (9.7%)	3	0/9 (0%)	0	0/30 (0%)	0	1/10 (10%)	1	1/0 (Infinity)	1	1/0 (Infinity)	1
Cardiac disorders
Cardiopulmonary failure	0/31 (0%)	0	0/9 (0%)	0	0/30 (0%)	0	1/10 (10%)	1	1/0 (Infinity)	1	1/0 (Infinity)	1
Supraventricular extrasystoles	0/31 (0%)	0	0/9 (0%)	0	0/30 (0%)	0	1/10 (10%)	1	1/0 (Infinity)	1	1/0 (Infinity)	1
Tachycardia	1/31 (3.2%)	1	0/9 (0%)	0	3/30 (10%)	4	0/10 (0%)	0	0/0 (NaN)	0	0/0 (NaN)	0
Congenital, familial and genetic disorders
Patent ductus arteriosus	3/31 (9.7%)	3	0/9 (0%)	0	4/30 (13.3%)	5	1/10 (10%)	1	1/0 (Infinity)	1	1/0 (Infinity)	1
Endocrine disorders
Inappropriate antidiuretic hormone secretion	0/31 (0%)	0	0/9 (0%)	0	0/30 (0%)	0	1/10 (10%)	1	1/0 (Infinity)	1	1/0 (Infinity)	1
Eye disorders
Eyelid oedema	0/31 (0%)	0	0/9 (0%)	0	0/30 (0%)	0	1/10 (10%)	1	1/0 (Infinity)	1	1/0 (Infinity)	1
Retinopathy of prematurity	3/31 (9.7%)	3	1/9 (11.1%)	1	1/30 (3.3%)	1	1/10 (10%)	1	1/0 (Infinity)	1	1/0 (Infinity)	1
Gastrointestinal disorders
abdominal distension	3/31 (9.7%)	4	1/9 (11.1%)	1	0/30 (0%)	0	1/10 (10%)	1	1/0 (Infinity)	1	1/0 (Infinity)	1
Ileus	0/31 (0%)	0	0/9 (0%)	0	0/30 (0%)	0	1/10 (10%)	1	1/0 (Infinity)	1	1/0 (Infinity)	1
Inguinal hernia	1/31 (3.2%)	1	1/9 (11.1%)	1	0/30 (0%)	0	1/10 (10%)	1	1/0 (Infinity)	1	1/0 (Infinity)	1
Necrotising colitis	2/31 (6.5%)	2	1/9 (11.1%)	1	0/30 (0%)	0	1/10 (10%)	1	1/0 (Infinity)	1	1/0 (Infinity)	1
Vomiting	0/31 (0%)	0	0/9 (0%)	0	0/30 (0%)	0	2/10 (20%)	2	2/0 (Infinity)	2	2/0 (Infinity)	2
General disorders
Oedema peripheral	0/31 (0%)	0	0/9 (0%)	0	0/30 (0%)	0	1/10 (10%)	1	1/0 (Infinity)	1	1/0 (Infinity)	1
Hepatobiliary disorders
Cholestasis	0/31 (0%)	0	0/9 (0%)	0	0/30 (0%)	0	2/10 (20%)	2	2/0 (Infinity)	2	2/0 (Infinity)	2
Hyperbilirubinaemia	0/31 (0%)	0	0/9 (0%)	0	1/30 (3.3%)	1	1/10 (10%)	1	1/0 (Infinity)	1	1/0 (Infinity)	1
Infections and infestations
Pneumonia escherichia	0/31 (0%)	0	1/9 (11.1%)	1	0/30 (0%)	0	0/10 (0%)	0	0/0 (NaN)	0	0/0 (NaN)	0
Sepsis	1/31 (3.2%)	1	1/9 (11.1%)	1	2/30 (6.7%)	2	0/10 (0%)	0	0/0 (NaN)	0	0/0 (NaN)	0
Tracheitis	0/31 (0%)	0	0/9 (0%)	0	0/30 (0%)	0	1/10 (10%)	1	1/0 (Infinity)	1	1/0 (Infinity)	1
Urinary tract infection	0/31 (0%)	0	1/9 (11.1%)	1	1/30 (3.3%)	1	0/10 (0%)	0	0/0 (NaN)	0	0/0 (NaN)	0
Urinary tract infection bacterial	0/31 (0%)	0	1/9 (11.1%)	1	1/30 (3.3%)	1	0/10 (0%)	0	0/0 (NaN)	0	0/0 (NaN)	0
Injury, poisoning and procedural complications
Skin abrasion	0/31 (0%)	0	0/9 (0%)	0	0/30 (0%)	0	1/10 (10%)	1	1/0 (Infinity)	1	1/0 (Infinity)	1
Investigations
Blood alkaline phosphatase increased	0/31 (0%)	0	1/9 (11.1%)	1	0/30 (0%)	0	0/10 (0%)	0	0/0 (NaN)	0	0/0 (NaN)	0
Blood bicarbonate increased	0/31 (0%)	0	0/9 (0%)	0	4/30 (13.3%)	5	1/10 (10%)	1	1/0 (Infinity)	1	1/0 (Infinity)	1
Blood creatinine increased	2/31 (6.5%)	2	0/9 (0%)	0	5/30 (16.7%)	5	0/10 (0%)	0	0/0 (NaN)	0	0/0 (NaN)	0
Bilirubin conjugate increased	2/31 (6.5%)	2	1/9 (11.1%)	1	0/30 (0%)	0	0/10 (0%)	0	0/0 (NaN)	0	0/0 (NaN)	0
Blood sodium decreased	2/31 (6.5%)	5	0/9 (0%)	0	0/30 (0%)	0	0/10 (0%)	0	0/0 (NaN)	0	0/0 (NaN)	0
Blood urea increased	0/31 (0%)	0	8/9 (88.9%)	8	0/30 (0%)	0	0/10 (0%)	0	0/0 (NaN)	0	0/0 (NaN)	0
Cardiac murmur	3/31 (9.7%)	3	0/9 (0%)	0	0/30 (0%)	0	1/10 (10%)	1	1/0 (Infinity)	1	1/0 (Infinity)	1
Chest X-ray abnormal	0/31 (0%)	0	0/9 (0%)	0	0/30 (0%)	0	1/10 (10%)	1	1/0 (Infinity)	1	1/0 (Infinity)	1
Gamma-glutamyltransferase increased	0/31 (0%)	0	1/9 (11.1%)	1	0/30 (0%)	0	0/10 (0%)	0	0/0 (NaN)	0	0/0 (NaN)	0
Platelet count decreased	1/31 (3.2%)	1	1/9 (11.1%)	1	0/30 (0%)	0	0/10 (0%)	0	0/0 (NaN)	0	0/0 (NaN)	0
Sputum culture positive	0/31 (0%)	0	0/9 (0%)	0	0/30 (0%)	0	1/10 (10%)	1	1/0 (Infinity)	1	1/0 (Infinity)	1
Metabolism and nutrition disorders
Electrolyte imbalance	3/31 (9.7%)	3	2/9 (22.2%)	2	2/30 (6.7%)	2	1/10 (10%)	1	1/0 (Infinity)	1	1/0 (Infinity)	1
Hypercalcaemia	0/31 (0%)	0	0/9 (0%)	0	1/30 (3.3%)	1	1/10 (10%)	1	1/0 (Infinity)	1	1/0 (Infinity)	1
Hyperphosphataemia	4/31 (12.9%)	4	1/9 (11.1%)	1	0/30 (0%)	0	0/10 (0%)	0	0/0 (NaN)	0	0/0 (NaN)	0
Hypocalcaemia	1/31 (3.2%)	1	1/9 (11.1%)	1	0/30 (0%)	0	0/10 (0%)	0	0/0 (NaN)	0	0/0 (NaN)	0
Hypokalaemia	2/31 (6.5%)	2	0/9 (0%)	0	4/30 (13.3%)	5	1/10 (10%)	1	1/0 (Infinity)	1	1/0 (Infinity)	1
Hyponatraemia	10/31 (32.3%)	10	1/9 (11.1%)	1	7/30 (23.3%)	8	0/10 (0%)	0	0/0 (NaN)	0	0/0 (NaN)	0
Hypophosphataemia	1/31 (3.2%)	1	0/9 (0%)	0	0/30 (0%)	0	2/10 (20%)	2	2/0 (Infinity)	2	2/0 (Infinity)	2
Metabolic acidosis	1/31 (3.2%)	1	2/9 (22.2%)	2	2/30 (6.7%)	2	0/10 (0%)	0	0/0 (NaN)	0	0/0 (NaN)	0
Musculoskeletal and connective tissue disorders
Growth retardation	1/31 (3.2%)	1	1/9 (11.1%)	1	0/30 (0%)	0	0/10 (0%)	0	0/0 (NaN)	0	0/0 (NaN)	0
Osteopenia	1/31 (3.2%)	1	1/9 (11.1%)	1	1/30 (3.3%)	1	0/10 (0%)	0	0/0 (NaN)	0	0/0 (NaN)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Haemangioma of bone	0/31 (0%)	0	0/9 (0%)	0	0/30 (0%)	0	1/10 (10%)	1	1/0 (Infinity)	1	1/0 (Infinity)	1
Nervous system disorders
Hydrocephalus	0/31 (0%)	0	1/9 (11.1%)	1	0/30 (0%)	0	0/10 (0%)	0	0/0 (NaN)	0	0/0 (NaN)	0
Hypertonia	0/31 (0%)	0	0/9 (0%)	0	0/30 (0%)	0	1/10 (10%)	1	1/0 (Infinity)	1	1/0 (Infinity)	1
Periventricular leukomalacia	0/31 (0%)	0	0/9 (0%)	0	0/30 (0%)	0	1/10 (10%)	1	1/0 (Infinity)	1	1/0 (Infinity)	1
Seizure	3/31 (9.7%)	3	1/9 (11.1%)	1	0/30 (0%)	0	1/10 (10%)	1	1/0 (Infinity)	1	1/0 (Infinity)	1
Renal and urinary disorders
Oliguria	1/31 (3.2%)	1	0/9 (0%)	0	1/30 (3.3%)	1	1/10 (10%)	1	1/0 (Infinity)	1	1/0 (Infinity)	1
Reproductive system and breast disorders
Testicular swelling	0/31 (0%)	0	1/9 (11.1%)	1	0/30 (0%)	0	0/10 (0%)	0	0/0 (NaN)	0	0/0 (NaN)	0
Respiratory, thoracic and mediastinal disorders
Chronic Respiratory Disease	5/31 (16.1%)	5	0/9 (0%)	0	0/30 (0%)	0	0/10 (0%)	0	0/0 (NaN)	0	0/0 (NaN)	0
Atelectasis	1/31 (3.2%)	1	0/9 (0%)	0	1/30 (3.3%)	1	1/10 (10%)	1	1/0 (Infinity)	1	1/0 (Infinity)	1
Bronchopulmonary dysplasia	0/31 (0%)	0	1/9 (11.1%)	1	1/30 (3.3%)	1	1/10 (10%)	1	1/0 (Infinity)	1	1/0 (Infinity)	1
Hypercapnia	0/31 (0%)	0	0/9 (0%)	0	0/30 (0%)	0	1/10 (10%)	1	1/0 (Infinity)	1	1/0 (Infinity)	1
Hypoxia	0/31 (0%)	0	0/9 (0%)	0	1/30 (3.3%)	2	1/10 (10%)	1	1/0 (Infinity)	1	1/0 (Infinity)	1
Respiratory acidosis	0/31 (0%)	0	1/9 (11.1%)	1	1/30 (3.3%)	1	1/10 (10%)	1	1/0 (Infinity)	1	1/0 (Infinity)	1
Respiratory failure	2/31 (6.5%)	3	1/9 (11.1%)	1	2/30 (6.7%)	2	0/10 (0%)	0	0/0 (NaN)	0	0/0 (NaN)	0
Skin and subcutaneous tissue disorders
Petechiae	0/31 (0%)	0	0/9 (0%)	0	0/30 (0%)	0	1/10 (10%)	1	0/0 (NaN)	1	0/0 (NaN)	1
Vascular disorders
Embolism	1/31 (3.2%)	1	0/9 (0%)	0	0/30 (0%)	0	1/10 (10%)	1	0/0 (NaN)	0	0/0 (NaN)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.