Study Assessing Safety & Effectiveness of a Catheter Lock Solution in Dialysis Patients to Prevent Bloodstream Infection

• Sponsor: CorMedix (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02651428
• Collaborator: PPD (Industry), JMI Laboratories (Other), Spectra Clinical Research (Other), Davita Clinical Research (Industry), Frenova Renal Research (Other)
• Enrollment: 806
• Locations: 5
• Arms: 2
• Duration (Months): 34
• Patients Per Site: 161.2
• Patients Per Site Per Month: 4.7

Study Details

Study Description

Brief Summary

The purpose of this study is determine safety and effectiveness of Neutrolin, a catheter lock solution, for prevention of central venous catheter associated bloodstream infection in hemodialysis patients.

Condition or Disease	Intervention/Treatment	Phase
Kidney Failure, Chronic; Catheter-Related Infections	Drug: Neutrolin; Drug: Heparin	Phase 3

Detailed Description

The objective of this study is to demonstrate the efficacy and safety of Neutrolin® as a catheter lock solution (CLS) on prevention of catheter-related bloodstream infection (CRBSI), and the incidence of treatment-emergent adverse events in subjects receiving hemodialysis (HD) for the treatment of End Stage Renal Disease (ESRD) when compared with heparin 4,000 USP Units/4mL (1,000 USP Units/mL).

This is a randomized, double-blind, active control, parallel-arm, multicenter study. Six hundred and thirty two subjects will be randomized in a 1:1 ratio to receive either Neutrolin® or the active control heparin (Heparin sodium USP 1,000 units/mL, Benzyl alcohol 9.45 mg/mL and Sodium chloride 9.0 mg/mL) as a CLS.

Approximately 632 randomized subjects are planned for this trial. In this study, one-half of the subjects (316 subjects) will receive Neutrolin as a study drug and the other half will receive heparin 4,000 USP Units/4mL (1,000 USP Units/mL) with benzyl alcohol preservative as a comparator. Subjects will be assigned in a 1:1 ratio using permuted blocks without additional stratification for both groups.

The primary objective of this study is to demonstrate the effectiveness of Neutrolin® as a CLS in ESRD subjects undergoing HD treatment using a permanent, cuffed, tunneled silicone or polyurethane HD catheter. The study will evaluate whether Neutrolin® is superior to the active control heparin by documenting the time to CRBSI and consequently delaying the time until the occurrence of CRBSI.

Study Design

• Study Type: Interventional
• Actual Enrollment: 806 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Prevention
• Official Title: Phase 3 Prospective, Multicenter, Double-blind, Randomized, Active Control Study to Demonstrate Safety & Effectiveness of Neutrolin in Preventing Catheter-related Bloodstream Infection in Subjects on Hemodialysis for End Stage Renal Disease
• Study Start Date: Dec 1, 2015
• Actual Primary Completion Date: Oct 1, 2018
• Actual Study Completion Date: Oct 1, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Neutrolin arm Neutrolin: Neutrolin will be added to the central venous catheter after dialysis as a lock solution	Drug: Neutrolin; Neutrolin® will be instilled into central venous HD catheters at the discontinuation of all dialysis sessions and will be withdrawn prior to the initiation of the next dialysis session; Other Names: 1.35% taurolidine, 3.5% citrate, heparin 1,000 USP Units/mL
Active Comparator: Heparin arm Heparin: Heparin will be added to the central venous catheter after dialysis as a lock solution	Drug: Heparin; Heparin will be instilled into central venous HD catheters at the discontinuation of all dialysis sessions and will be withdrawn prior to the initiation of the next dialysis session; Other Names: Heparin Sodium

Outcome Measures

Primary Outcome Measures

1. Presence of a CAC-Adjudicated Catheter-Related Bloodstream Infection (CRBSI) in Subjects Receiving Hemodialysis for the Treatment of End Stage Renal Disease (ESRD): Final Analysis [The event time was the number of days from randomization until the occurrence of a CAC-Adjudicated CRBSI or until the subject was censored. The mean participant duration of exposure to study drug was 174 days (range 4-884 days).]

   CRBSI was defined as the same organism grown from at least one positive blood culture from a peripheral site or bloodline sample, or either the arterial or venous catheter hub. The final assessment of CRBSI was determined by a Clinical Adjudication Committee (CAC) who used both clinical documentation and blood culture results in their assessment.

Secondary Outcome Measures

1. Participants With a Study Catheter Removal for Any Reason [The event time was the number of days from randomization until catheter removal for any reason or until the subject was censored. The mean participant duration of exposure to study drug was 174 days (range 4-884 days).]

   Analysis of all catheter removals during the study or until the catheter was removed

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Subject has ESRD and undergoes chronic HD at least two times per week

2. Subject has a HD catheter that has demonstrated the ability to achieve a minimum blood flow of at least 250 mL/min for at least two consecutive dialysis sessions blood flow to enable successful HD

3. The HD catheter is implanted with the tip in a jugular or subclavian vein

4. The subject is not expected to expire within 180 days

5. The subject is likely to require the use of a CVC for at least 90 days

6. The subject (or the legal guardian) understands the nature of the study and provides written informed consent prior to the study enrollment

7. The subject is willing to comply with specified follow-up evaluations and prescribed dialysis therapy and

8. If female and of childbearing potential, the subject must have a negative pregnancy test at the screening visit (i.e., subject is not pregnant); not be lactating; and use an acceptable method of contraception, including abstinence, a barrier method (diaphragm or condom), Depo-Provera, or hormonal contraceptive (oral, implant, ring, patch) for the duration of the study. (NOTE: The subject must have used the chosen method of birth control for at least 1 month/cycle prior to enrollment into the study).

Exclusion Criteria:

1. Subjects who received antibiotics within the last 14 days

2. Visible evidence of compromised skin integrity is present at the catheter exit site or evidence of a catheter exit site infection

3. Subject has received any thrombolytic treatment (i.e., tPA) in their current catheter within 30 days of randomization

4. Fill volume of HD catheter is unknown or cannot be determined

5. Subjects using any type of antimicrobial-coated or heparin-coated catheter

6. Documented chronic bleeding diathesis, active or recurrent bleeding within 1 month prior to randomization

7. Documented history of an atrial thrombus or known hypercoagulable state

8. Subjects with open, non-healing skin ulcers

9. Current requirement for systemic immunosuppression that would increase risk of infection

10. Active malignancy requiring or anticipated to require chemotherapy likely to cause leukopenia and/or immunosuppression

11. Known allergy or absolute contraindication to citrate, taurolidine or heparin or a history of heparin-induced thrombocytopenia

12. Unstable malignancy

13. Cirrhosis with encephalopathy

14. Subject is currently taking another medication with known systemic drug interaction with citrate, taurolidine, or heparin

15. Subject is currently enrolled in another investigational device and/or drug trial or has participated in another investigational device and/or drug trial within 30 days prior to enrollment

16. Subject is anticipated to receive a renal transplant within 90 days (subjects can be on the transplant list, but a subject with a known or anticipated transplant date within the next 90 days should be excluded)

17. Any other medical condition which renders the subject unable to or unlikely to complete the study, or which would interfere with optimal participation in the study or produce significant risk to the subject.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Riverside Nephrology Physicians/Van Buren Dialysis center	Riverside	California	United States	92503
2	North America Research Institute	San Dimas	California	United States	91773
3	North Beach Dialysis Center Inc.	Miami Gardens	Florida	United States	33169
4	Lower Manhattan Dialysis Center	New York	New York	United States	10016
5	Diagnostic Clinic of Houston	Houston	Texas	United States	77004

Sponsors and Collaborators

• CorMedix
• PPD
• JMI Laboratories
• Spectra Clinical Research
• Davita Clinical Research
• Frenova Renal Research

Investigators

• Study Director: Antony Pfaffle, MD, Chief Scientific Officer

Study Documents (Full-Text)

• Study Protocol - Oct 6, 2017
• Statistical Analysis Plan - Jan 29, 2018

More Information

Publications

None provided.

• Responsible Party: CorMedix
• ClinicalTrials.gov Identifier: NCT02651428
• Other Study ID Numbers: LOCK-IT-100
• First Posted: Jan 11, 2016
• Last Update Posted: Aug 31, 2021
• Last Verified: Aug 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by CorMedix: Kidney Failure, Chronic; Catheter-Related Infections; Central Venous Catheter
• Additional relevant MeSH terms: Infections; Communicable Diseases; Sepsis; Catheter-Related Infections; Renal Insufficiency; Kidney Failure, Chronic; Taurolidine; Heparin; Calcium heparin

Study Results

Participant Flow

Arm/Group Title	Neutrolin Arm	Heparin Arm
Arm/Group Description	Neutrolin: Neutrolin will be added to the central venous catheter after dialysis as a lock solution Neutrolin: Neutrolin® will be instilled into central venous HD catheters at the discontinuation of all dialysis sessions and will be withdrawn prior to the initiation of the next dialysis session	Heparin: Heparin will be added to the central venous catheter after dialysis as a lock solution Heparin: Heparin will be instilled into central venous HD catheters at the discontinuation of all dialysis sessions and will be withdrawn prior to the initiation of the next dialysis session
Period Title: Overall Study
STARTED	403	403
COMPLETED	359	359
NOT COMPLETED	44	44

Baseline Characteristics

Arm/Group Title	Neutrolin Arm	Heparin Arm	Total
Arm/Group Description	Neutrolin: Neutrolin will be added to the central venous catheter after dialysis as a lock solution Neutrolin: Neutrolin® will be instilled into central venous HD catheters at the discontinuation of all dialysis sessions and will be withdrawn prior to the initiation of the next dialysis session	Heparin: Heparin will be added to the central venous catheter after dialysis as a lock solution Heparin: Heparin will be instilled into central venous HD catheters at the discontinuation of all dialysis sessions and will be withdrawn prior to the initiation of the next dialysis session	Total of all reporting groups
Overall Participants	403	403	806
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	60.8 (14.22)	60.9 (14.39)	60.9 (14.30)
Sex: Female, Male (Count of Participants)
Female	184 45.7%	154 38.2%	338 41.9%
Male	219 54.3%	249 61.8%	468 58.1%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	3 0.7%	2 0.5%	5 0.6%
Asian	15 3.7%	18 4.5%	33 4.1%
Native Hawaiian or Other Pacific Islander	10 2.5%	4 1%	14 1.7%
Black or African American	126 31.3%	112 27.8%	238 29.5%
White	248 61.5%	262 65%	510 63.3%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	1 0.2%	5 1.2%	6 0.7%
Region of Enrollment (participants) [Number]
United States	403 100%	403 100%	806 100%

Outcome Measures

1. Primary Outcome

Title	Presence of a CAC-Adjudicated Catheter-Related Bloodstream Infection (CRBSI) in Subjects Receiving Hemodialysis for the Treatment of End Stage Renal Disease (ESRD): Final Analysis
Description	CRBSI was defined as the same organism grown from at least one positive blood culture from a peripheral site or bloodline sample, or either the arterial or venous catheter hub. The final assessment of CRBSI was determined by a Clinical Adjudication Committee (CAC) who used both clinical documentation and blood culture results in their assessment.
Time Frame	The event time was the number of days from randomization until the occurrence of a CAC-Adjudicated CRBSI or until the subject was censored. The mean participant duration of exposure to study drug was 174 days (range 4-884 days).

Outcome Measure Data

Analysis Population Description

Full Analysis Population - all subjects randomized and receiving one or more doses of study medication.

Arm/Group Title	Neutrolin Arm	Heparin Arm
Arm/Group Description	Neutrolin: Neutrolin will be added to the central venous catheter after dialysis as a lock solution Neutrolin: Neutrolin® will be instilled into central venous HD catheters at the discontinuation of all dialysis sessions and will be withdrawn prior to the initiation of the next dialysis session	Heparin: Heparin will be added to the central venous catheter after dialysis as a lock solution Heparin: Heparin will be instilled into central venous HD catheters at the discontinuation of all dialysis sessions and will be withdrawn prior to the initiation of the next dialysis session
Measure Participants	397	398
Count of Participants [Participants]	9 2.2%	32 7.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Neutrolin Arm, Heparin Arm
	Comments	The null hypothesis was that there was no difference in the survival functions for CRBSI between the two treatments. Based on 80% power to detect a 55% reduction in the risk of CRBSI relative to the control treatment, a 1:1 randomization, a 2-sided log-rank test, one interim analysis using the method of Pocock, and an overall alpha of 0.05, it was determined that 56 CRBSIs would be needed. These are the results of the final analysis.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0006
	Comments	The threshold significance level at the interim and final statistical analyses for the primary efficacy endpoint was 0.0294.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.29
	Confidence Interval	(2-Sided) 95%; 0.14 to 0.62
	Parameter Dispersion	Type: Value:
	Estimation Comments	The numerator for the hazard ratio was the estimated hazard for the Neutrolin treatment arm, and the denominator was the estimated hazard for the Heparin treatment arm.

2. Secondary Outcome

Title	Participants With a Study Catheter Removal for Any Reason
Description	Analysis of all catheter removals during the study or until the catheter was removed
Time Frame	The event time was the number of days from randomization until catheter removal for any reason or until the subject was censored. The mean participant duration of exposure to study drug was 174 days (range 4-884 days).

Outcome Measure Data

Analysis Population Description

Full Analysis Population - all subjects randomized and receiving one or more doses of study medication.

Arm/Group Title	Neutrolin Arm	Heparin Arm
Arm/Group Description	Neutrolin: Neutrolin will be added to the central venous catheter after dialysis as a lock solution Neutrolin: Neutrolin® will be instilled into central venous HD catheters at the discontinuation of all dialysis sessions and will be withdrawn prior to the initiation of the next dialysis session	Heparin: Heparin will be added to the central venous catheter after dialysis as a lock solution Heparin: Heparin will be instilled into central venous HD catheters at the discontinuation of all dialysis sessions and will be withdrawn prior to the initiation of the next dialysis session
Measure Participants	397	398
Count of Participants [Participants]	236 58.6%	225 55.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Neutrolin Arm, Heparin Arm
	Comments	The null hypothesis was that there was no difference in the time until catheter removal for any reason between the two treatments.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4161
	Comments	The threshold for statistical significance was p < 0.05.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.08
	Confidence Interval	(2-Sided) 95%; 0.90 to 1.29
	Parameter Dispersion	Type: Value:
	Estimation Comments	The numerator for the hazard ratio was the estimated hazard for the Neutrolin treatment arm, and the denominator was the estimated hazard for the Heparin treatment arm.

Adverse Events

Time Frame	Through a participant's study completion. The mean participant duration of exposure to study drug was 174 days (range 4-884 days).
Adverse Event Reporting Description	Adverse events were collected for all participants who received study drug, the Full Analysis Population (n=398 Neutrolin, n=399 Heparin). Subjects who did not receive study medication are not included in the adverse event reporting.
Arm/Group Title	Neutrolin Arm		Heparin Arm
Arm/Group Description	Neutrolin: Neutrolin will be added to the central venous catheter after dialysis as a lock solution Neutrolin: Neutrolin® will be instilled into central venous HD catheters at the discontinuation of all dialysis sessions and will be withdrawn prior to the initiation of the next dialysis session		Heparin: Heparin will be added to the central venous catheter after dialysis as a lock solution Heparin: Heparin will be instilled into central venous HD catheters at the discontinuation of all dialysis sessions and will be withdrawn prior to the initiation of the next dialysis session
All Cause Mortality
	Neutrolin Arm		Heparin Arm
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	18/398 (4.5%)		21/399 (5.3%)
Serious Adverse Events
	Neutrolin Arm		Heparin Arm
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	159/398 (39.9%)		167/399 (41.9%)
Blood and lymphatic system disorders
Anemia	3/398 (0.8%)	3	4/399 (1%)	4
Hemorrhagic anemia	1/398 (0.3%)	1	0/399 (0%)	0
Heparin-induced thrombocytopenia	0/398 (0%)	0	1/399 (0.3%)	1
Lymphadenitis	0/398 (0%)	0	1/399 (0.3%)	1
Nephrogenic anemia	3/398 (0.8%)	3	4/399 (1%)	4
Normocytic anemia	0/398 (0%)	0	1/399 (0.3%)	1
Pancytopenia	1/398 (0.3%)	1	1/399 (0.3%)	1
Thrombocytopenia	2/398 (0.5%)	2	0/399 (0%)	0
Cardiac disorders
Acute coronary syndrome	1/398 (0.3%)	1	2/399 (0.5%)	2
Acute myocardial infarction	5/398 (1.3%)	5	13/399 (3.3%)	13
Angina pectoris	5/398 (1.3%)	5	5/399 (1.3%)	5
Angina unstable	0/398 (0%)	0	3/399 (0.8%)	3
Atrial fibrillation	2/398 (0.5%)	2	6/399 (1.5%)	6
Atrial tachycardia	0/398 (0%)	0	2/399 (0.5%)	2
Bradycardia	1/398 (0.3%)	1	0/399 (0%)	0
Cardiac arrest	2/398 (0.5%)	2	5/399 (1.3%)	5
Cardiac failure	0/398 (0%)	0	1/399 (0.3%)	1
Cardiac failure acute	0/398 (0%)	0	2/399 (0.5%)	2
Cardiac failure congestive	12/398 (3%)	12	7/399 (1.8%)	7
Cardiac tamponade	0/398 (0%)	0	1/399 (0.3%)	1
Cardiac valve disease	0/398 (0%)	0	1/399 (0.3%)	1
Cardio-respiratory arrest	2/398 (0.5%)	2	1/399 (0.3%)	1
Cardiomyopathy	0/398 (0%)	0	1/399 (0.3%)	1
Coronary artery disease	2/398 (0.5%)	2	3/399 (0.8%)	3
Coronary artery occlusion	2/398 (0.5%)	2	0/399 (0%)	0
Ischemic cardiomyopathy	1/398 (0.3%)	1	0/399 (0%)	0
Left ventricular failure	1/398 (0.3%)	1	3/399 (0.8%)	3
Mitral valve incompetence	0/398 (0%)	0	1/399 (0.3%)	1
Myocardial infarction	1/398 (0.3%)	1	3/399 (0.8%)	3
Nodal arrhythmia	1/398 (0.3%)	1	0/399 (0%)	0
Pericardial effusion	1/398 (0.3%)	1	2/399 (0.5%)	2
Pulseless electrical activity	1/398 (0.3%)	1	0/399 (0%)	0
Supraventricular tachycardia	0/398 (0%)	0	1/399 (0.3%)	1
Tachycardia	1/398 (0.3%)	1	2/399 (0.5%)	2
Congenital, familial and genetic disorders
Protein C deficiency	1/398 (0.3%)	1	0/399 (0%)	0
Endocrine disorders
Hyperthyroidism secondary	0/398 (0%)	0	1/399 (0.3%)	1
Myxoedema	0/398 (0%)	0	1/399 (0.3%)	1
Eye disorders
Blindness cortical	1/398 (0.3%)	1	0/399 (0%)	0
Visual impairment	0/398 (0%)	0	1/399 (0.3%)	1
Gastrointestinal disorders
Abdominal pain	2/398 (0.5%)	2	4/399 (1%)	4
Abdominal pain upper	0/398 (0%)	0	1/399 (0.3%)	1
Ascites	2/398 (0.5%)	2	1/399 (0.3%)	1
Colitis ischemic	1/398 (0.3%)	1	0/399 (0%)	0
Constipation	1/398 (0.3%)	1	0/399 (0%)	0
Diabetic gastroparesis	1/398 (0.3%)	1	1/399 (0.3%)	1
Diarrhea	2/398 (0.5%)	2	0/399 (0%)	0
Dumping syndrome	0/398 (0%)	0	1/399 (0.3%)	1
Duodenal ulcer	1/398 (0.3%)	1	0/399 (0%)	0
Dysphagia	1/398 (0.3%)	1	0/399 (0%)	0
Gastric ulcer	1/398 (0.3%)	1	0/399 (0%)	0
Gastric ulcer hemorrhage	1/398 (0.3%)	1	1/399 (0.3%)	1
Gastritis	0/398 (0%)	0	1/399 (0.3%)	1
Gastrointestinal hemorrhage	4/398 (1%)	4	6/399 (1.5%)	6
Hematemesis	3/398 (0.8%)	3	1/399 (0.3%)	1
Hemorrhoidal hemorrhage	0/398 (0%)	0	1/399 (0.3%)	1
Incarcerated inguinal hernia	1/398 (0.3%)	1	0/399 (0%)	0
Intestinal infarction	1/398 (0.3%)	1	0/399 (0%)	0
Intestinal ischemia	0/398 (0%)	0	1/399 (0.3%)	1
Intestinal obstruction	1/398 (0.3%)	1	0/399 (0%)	0
Large intestine perforation	0/398 (0%)	0	1/399 (0.3%)	1
Lower gastrointestinal hemorrhage	2/398 (0.5%)	2	1/399 (0.3%)	1
Mallory-Weiss syndrome	1/398 (0.3%)	1	0/399 (0%)	0
Nausea	1/398 (0.3%)	1	0/399 (0%)	0
Esophageal ulcer hemorrhage	0/398 (0%)	0	1/399 (0.3%)	1
Esophageal varices hemorrhage	0/398 (0%)	0	1/399 (0.3%)	1
Esophagitis	0/398 (0%)	0	1/399 (0.3%)	1
Esophagitis ulcerative	0/398 (0%)	0	1/399 (0.3%)	1
Pancreatitis	3/398 (0.8%)	3	0/399 (0%)	0
Pancreatitis acute	3/398 (0.8%)	3	0/399 (0%)	0
Peptic ulcer	0/398 (0%)	0	1/399 (0.3%)	1
Small intestinal obstruction	1/398 (0.3%)	1	0/399 (0%)	0
Upper gastrointestinal hemorrhage	2/398 (0.5%)	2	0/399 (0%)	0
Vomiting	5/398 (1.3%)	5	1/399 (0.3%)	1
General disorders
Asthenia	3/398 (0.8%)	3	2/399 (0.5%)	2
Chest pain	1/398 (0.3%)	1	2/399 (0.5%)	2
Complication associated with device	1/398 (0.3%)	1	0/399 (0%)	0
Death	5/398 (1.3%)	5	2/399 (0.5%)	2
Drug withdrawal syndrome	1/398 (0.3%)	1	0/399 (0%)	0
Impaired healing	0/398 (0%)	0	1/399 (0.3%)	1
Multiple organ dysfunction syndrome	0/398 (0%)	0	1/399 (0.3%)	1
Non-cardiac chest pain	5/398 (1.3%)	5	1/399 (0.3%)	1
Edema peripheral	0/398 (0%)	0	1/399 (0.3%)	1
Pain	1/398 (0.3%)	1	1/399 (0.3%)	1
Pyrexia	0/398 (0%)	0	3/399 (0.8%)	3
Hepatobiliary disorders
Biliary diskynesia	1/398 (0.3%)	1	0/399 (0%)	0
Cholangitis	1/398 (0.3%)	1	0/399 (0%)	0
Cholecystitis	2/398 (0.5%)	2	0/399 (0%)	0
Cholecystitis acute	1/398 (0.3%)	1	1/399 (0.3%)	1
Cholecystitis chronic	1/398 (0.3%)	1	0/399 (0%)	0
Cholelithiasis	3/398 (0.8%)	3	0/399 (0%)	0
Hemobilia	1/398 (0.3%)	1	0/399 (0%)	0
Hepatic cirrhosis	1/398 (0.3%)	1	0/399 (0%)	0
Hepatic failure	1/398 (0.3%)	1	0/399 (0%)	0
Hepatic cholestatic	0/398 (0%)	0	1/399 (0.3%)	1
Jaundice	1/398 (0.3%)	1	0/399 (0%)	0
Jaundice cholestatic	0/398 (0%)	0	1/399 (0.3%)	1
Immune system disorders
Hypogammaglobulinemia	0/398 (0%)	0	1/399 (0.3%)	1
Infections and infestations
Abdominal abscess	0/398 (0%)	0	1/399 (0.3%)	1
Abscess neck	1/398 (0.3%)	1	0/399 (0%)	0
Appendicitis perforated	2/398 (0.5%)	2	0/399 (0%)	0
Arteriovenous fistula site infection	1/398 (0.3%)	1	1/399 (0.3%)	1
Arteriovenous graft site infection	1/398 (0.3%)	1	0/399 (0%)	0
Bacteremia	5/398 (1.3%)	5	7/399 (1.8%)	7
Bacterial sepsis	1/398 (0.3%)	1	0/399 (0%)	0
Bronchitis	2/398 (0.5%)	2	2/399 (0.5%)	2
Bronchitis bacterial	1/398 (0.3%)	1	0/399 (0%)	0
Carbuncle	1/398 (0.3%)	1	0/399 (0%)	0
Catheter site cellulitis	1/398 (0.3%)	1	0/399 (0%)	0
Cellulitis	7/398 (1.8%)	7	2/399 (0.5%)	2
Clostridium difficile colitis	1/398 (0.3%)	1	3/399 (0.8%)	3
Clostridium difficile infection	4/398 (1%)	4	0/399 (0%)	0
Device related infection	6/398 (1.5%)	6	8/399 (2%)	8
Device related sepsis	2/398 (0.5%)	2	4/399 (1%)	4
Diabetic foot infection	0/398 (0%)	0	1/399 (0.3%)	1
Endocarditis	0/398 (0%)	0	2/399 (0.5%)	2
Endocarditis staphylococcal	1/398 (0.3%)	1	1/399 (0.3%)	1
Endophthalmitis	0/398 (0%)	0	1/399 (0.3%)	1
Enterococcal bacteremia	0/398 (0%)	0	1/399 (0.3%)	1
Enterococcal infection	0/398 (0%)	0	1/399 (0.3%)	1
Escherichia urinary tract infection	0/398 (0%)	0	1/399 (0.3%)	1
Gangrene	3/398 (0.8%)	3	5/399 (1.3%)	5
Gastritis viral	0/398 (0%)	0	1/399 (0.3%)	1
Gastroenteritis	2/398 (0.5%)	2	0/399 (0%)	0
Gastroenteritis viral	0/398 (0%)	0	1/399 (0.3%)	1
Histoplasmosis	1/398 (0.3%)	1	0/399 (0%)	0
Infected skin ulcer	0/398 (0%)	0	1/399 (0.3%)	1
Infectious pleural effusion	0/398 (0%)	0	1/399 (0.3%)	1
Influenza	2/398 (0.5%)	2	3/399 (0.8%)	3
Intervertebral discitis	0/398 (0%)	0	1/399 (0.3%)	1
Klebsiella bacteremia	1/398 (0.3%)	1	0/399 (0%)	0
Localized infection	2/398 (0.5%)	2	1/399 (0.3%)	1
Necrotizing soft tissue infection	0/398 (0%)	0	1/399 (0.3%)	1
Oral candidiasis	0/398 (0%)	0	1/399 (0.3%)	1
Orchitis	1/398 (0.3%)	1	0/399 (0%)	0
Oropharyngeal candidiasis	1/398 (0.3%)	1	0/399 (0%)	0
Osteomyelitis	4/398 (1%)	4	4/399 (1%)	4
Osteomyelitis acute	0/398 (0%)	0	1/399 (0.3%)	1
Pancreatic abscess	1/398 (0.3%)	1	0/399 (0%)	0
Pneumococcal sepsis	1/398 (0.3%)	1	0/399 (0%)	0
Pneumonia	12/398 (3%)	12	21/399 (5.3%)	21
Pneumonia haemophilus	1/398 (0.3%)	1	0/399 (0%)	0
Pneumonia staphylococcal	0/398 (0%)	0	1/399 (0.3%)	1
Postoperative wound infection	1/398 (0.3%)	1	0/399 (0%)	0
Psoas abscess	1/398 (0.3%)	1	0/399 (0%)	0
Pyelonephritis	1/398 (0.3%)	1	0/399 (0%)	0
Pyelonephritis acute	1/398 (0.3%)	1	0/399 (0%)	0
Respiratory tract infection viral	0/398 (0%)	0	1/399 (0.3%)	1
Sepsis	9/398 (2.3%)	9	14/399 (3.5%)	14
Septic shock	5/398 (1.3%)	5	1/399 (0.3%)	1
Serratia bacteremia	0/398 (0%)	0	1/399 (0.3%)	1
Sinusitis	0/398 (0%)	0	1/399 (0.3%)	1
Staphylococcal infection	0/398 (0%)	0	1/399 (0.3%)	1
Staphylococcal sepsis	1/398 (0.3%)	1	4/399 (1%)	4
Stenotrophomanas infection	0/398 (0%)	0	1/399 (0.3%)	1
Streptococcal bacteremia	0/398 (0%)	0	1/399 (0.3%)	1
Streptococcal sepsis	0/398 (0%)	0	1/399 (0.3%)	1
Subcutaneous abscess	1/398 (0.3%)	1	1/399 (0.3%)	1
Tracheobronchitis	0/398 (0%)	0	1/399 (0.3%)	1
Tuberculosis	0/398 (0%)	0	1/399 (0.3%)	1
Upper respiratory tract infection	1/398 (0.3%)	1	1/399 (0.3%)	1
Urinary tract infection	2/398 (0.5%)	2	2/399 (0.5%)	2
Urinary tract infection bacterial	0/398 (0%)	0	1/399 (0.3%)	1
Urosepsis	2/398 (0.5%)	2	1/399 (0.3%)	1
Viral infection	1/398 (0.3%)	1	0/399 (0%)	0
Viral sepsis	0/398 (0%)	0	1/399 (0.3%)	1
Injury, poisoning and procedural complications
Abdominal wound dehiscence	1/398 (0.3%)	1	0/399 (0%)	0
Anemia postoperative	0/398 (0%)	0	1/399 (0.3%)	1
Ankle fracture	0/398 (0%)	0	1/399 (0.3%)	1
Arteriovenous fistula occlusion	1/398 (0.3%)	1	0/399 (0%)	0
Arteriovenous fistula site complication	1/398 (0.3%)	1	3/399 (0.8%)	3
Arteriovenous fistula site hematoma	1/398 (0.3%)	1	0/399 (0%)	0
Arteriovenous graft thrombosis	2/398 (0.5%)	2	0/399 (0%)	0
Eschar	1/398 (0.3%)	1	0/399 (0%)	0
Fall	1/398 (0.3%)	1	1/399 (0.3%)	1
Femur fracture	1/398 (0.3%)	1	0/399 (0%)	0
Foot fracture	1/398 (0.3%)	1	0/399 (0%)	0
Fractured coccyx	0/398 (0%)	0	1/399 (0.3%)	1
Fractured sacrum	0/398 (0%)	0	1/399 (0.3%)	1
Gastrostomy failure	0/398 (0%)	0	1/399 (0.3%)	1
Head injury	1/398 (0.3%)	1	1/399 (0.3%)	1
Hip fracture	0/398 (0%)	0	1/399 (0.3%)	1
Incision site hemorrhage	0/398 (0%)	0	1/399 (0.3%)	1
Limb surgery	0/398 (0%)	0	1/399 (0.3%)	1
Pneumothorax traumatic	1/398 (0.3%)	1	0/399 (0%)	0
Post procedural complication	1/398 (0.3%)	1	0/399 (0%)	0
Procedural hypotension	1/398 (0.3%)	1	0/399 (0%)	0
Procedural pain	1/398 (0.3%)	1	0/399 (0%)	0
Pubis fracture	1/398 (0.3%)	1	0/399 (0%)	0
Pulmonary contusion	0/398 (0%)	0	1/399 (0.3%)	1
Spinal compression fracture	0/398 (0%)	0	1/399 (0.3%)	1
Subdural hematoma	0/398 (0%)	0	2/399 (0.5%)	2
Toxicity to various agents	0/398 (0%)	0	1/399 (0.3%)	1
Transplant dysfunction	0/398 (0%)	0	1/399 (0.3%)	1
Vascular access complication	0/398 (0%)	0	1/399 (0.3%)	1
Vascular graft complication	1/398 (0.3%)	1	1/399 (0.3%)	1
Investigations
Blood creatinine phosphokinase MB increased	0/398 (0%)	0	1/399 (0.3%)	1
Blood culture positive	1/398 (0.3%)	1	0/399 (0%)	0
Blood potassium increased	1/398 (0.3%)	1	0/399 (0%)	0
Ejection fraction increased	0/398 (0%)	0	1/399 (0.3%)	1
Hemoglobin decreased	1/398 (0.3%)	1	0/399 (0%)	0
International normalized ration increased	2/398 (0.5%)	2	0/399 (0%)	0
Metabolism and nutrition disorders
Diabetes mellitus inadequate control	0/398 (0%)	0	1/399 (0.3%)	1
Diabetic ketoacidosis	1/398 (0.3%)	1	3/399 (0.8%)	3
Failure to thrive	2/398 (0.5%)	2	0/399 (0%)	0
Fluid overload	14/398 (3.5%)	14	12/399 (3%)	12
Gout	1/398 (0.3%)	1	0/399 (0%)	0
Hyperglycemia	0/398 (0%)	0	1/399 (0.3%)	1
Hyperkalemia	10/398 (2.5%)	10	8/399 (2%)	8
Hyperosmolar state	0/398 (0%)	0	1/399 (0.3%)	1
Hypoglycaemia	6/398 (1.5%)	6	6/399 (1.5%)	6
Hypovolemia	1/398 (0.3%)	1	0/399 (0%)	0
Lactic acidosis	2/398 (0.5%)	2	0/399 (0%)	0
Metabolic acidosis	1/398 (0.3%)	1	1/399 (0.3%)	1
Metabolic disorder	0/398 (0%)	0	1/399 (0.3%)	1
Musculoskeletal and connective tissue disorders
Arthritis	1/398 (0.3%)	1	0/399 (0%)	0
Back pain	1/398 (0.3%)	1	1/399 (0.3%)	1
Costochondritis	1/398 (0.3%)	1	0/399 (0%)	0
Intervertebral disc degeneration	0/398 (0%)	0	1/399 (0.3%)	1
Intervertebral disc protrusion	1/398 (0.3%)	1	0/399 (0%)	0
Joint effusion	0/398 (0%)	0	1/399 (0.3%)	1
Lumbar spinal stenosis	0/398 (0%)	0	1/399 (0.3%)	1
Muscular weakness	1/398 (0.3%)	1	1/399 (0.3%)	1
Musculoskeletal chest pain	2/398 (0.5%)	2	0/399 (0%)	0
Myopathy	1/398 (0.3%)	1	0/399 (0%)	0
Back pain	0/398 (0%)	0	1/399 (0.3%)	1
Pain in extremity	0/398 (0%)	0	1/399 (0.3%)	1
Rotator cuff syndrome	1/398 (0.3%)	1	1/399 (0.3%)	1
Spinal column stenosis	0/398 (0%)	0	1/399 (0.3%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Chronic lymphocytic leukemia	1/398 (0.3%)	1	4/399 (1%)	4
Lung neoplasm malignant	0/398 (0%)	0	1/399 (0.3%)	1
Neoplasm malignant	0/398 (0%)	0	1/399 (0.3%)	1
Small cell lung cancer	0/398 (0%)	0	1/399 (0.3%)	1
Urine leiomyoma	1/398 (0.3%)	1	0/399 (0%)	0
Nervous system disorders
Altered state of consciousness	1/398 (0.3%)	1	0/399 (0%)	0
Autonomic nervous system imbalance	0/398 (0%)	0	1/399 (0.3%)	1
Carotid artery occlusion	1/398 (0.3%)	1	0/399 (0%)	0
Carpal tunnel syndrome	0/398 (0%)	0	1/399 (0.3%)	1
Cerebellar hemorrhage	0/398 (0%)	0	1/399 (0.3%)	1
Cerebellar stroke	1/398 (0.3%)	1	0/399 (0%)	0
Cerebral hemorrhage	1/398 (0.3%)	1	0/399 (0%)	0
Cerebral infarction	1/398 (0.3%)	1	0/399 (0%)	0
Cerebral ischemia	0/398 (0%)	0	1/399 (0.3%)	1
Cerebrovascular accident	4/398 (1%)	4	5/399 (1.3%)	5
Dementia	1/398 (0.3%)	1	0/399 (0%)	0
Dizziness	1/398 (0.3%)	1	0/399 (0%)	0
Dizziness postural	1/398 (0.3%)	1	0/399 (0%)	0
Encephalopathy	0/398 (0%)	0	3/399 (0.8%)	3
Guillain-Barre syndrome	0/398 (0%)	0	1/399 (0.3%)	1
Hemorrhage intracranial	0/398 (0%)	0	1/399 (0.3%)	1
Hemorrhagic stroke	0/398 (0%)	0	1/399 (0.3%)	1
Headache	1/398 (0.3%)	1	0/399 (0%)	0
Hepatic encephalopathy	1/398 (0.3%)	1	0/399 (0%)	0
Hyperglycemic seizure	0/398 (0%)	0	1/399 (0.3%)	1
Hypertensive encephalopathy	0/398 (0%)	0	2/399 (0.5%)	2
Hypoxic-ischemic encephalopathy	0/398 (0%)	0	1/399 (0.3%)	1
Loss of consciousness	1/398 (0.3%)	1	1/399 (0.3%)	1
Metabolic encephalopathy	2/398 (0.5%)	2	2/399 (0.5%)	2
Neuralgia	0/398 (0%)	0	1/399 (0.3%)	1
Paraesthesia	0/398 (0%)	0	1/399 (0.3%)	1
Posterior reversible encephalopathy syndrome	0/398 (0%)	0	1/399 (0.3%)	1
Seizure	2/398 (0.5%)	2	1/399 (0.3%)	1
Somnolence	1/398 (0.3%)	1	0/399 (0%)	0
Syncope	4/398 (1%)	4	1/399 (0.3%)	1
Toxic encephalopathy	0/398 (0%)	0	1/399 (0.3%)	1
Transient ischemic attack	2/398 (0.5%)	2	0/399 (0%)	0
Pregnancy, puerperium and perinatal conditions
Abortion spontaneous	1/398 (0.3%)	1	0/399 (0%)	0
Product Issues
Device breakage	0/398 (0%)	0	1/399 (0.3%)	1
Device dislocation	3/398 (0.8%)	3	1/399 (0.3%)	1
Device malfunction	6/398 (1.5%)	6	1/399 (0.3%)	1
Thrombosis in device	0/398 (0%)	0	1/399 (0.3%)	1
Psychiatric disorders
Delirium	1/398 (0.3%)	1	0/399 (0%)	0
Mental status changes	2/398 (0.5%)	2	5/399 (1.3%)	5
Suicidal ideation	0/398 (0%)	0	1/399 (0.3%)	1
Renal and urinary disorders
Azotemia	0/398 (0%)	0	1/399 (0.3%)	1
End stage renal disease	2/398 (0.5%)	2	1/399 (0.3%)	1
Nephrolithiasis	1/398 (0.3%)	1	1/399 (0.3%)	1
Renal failure	0/398 (0%)	0	1/399 (0.3%)	1
Renal hematoma	1/398 (0.3%)	1	0/399 (0%)	0
Reproductive system and breast disorders
Penile swelling	0/398 (0%)	0	1/399 (0.3%)	1
Respiratory, thoracic and mediastinal disorders
Acute pulmonary oedema	2/398 (0.5%)	2	1/399 (0.3%)	1
Acute respiratory distress syndrome	0/398 (0%)	0	1/399 (0.3%)	1
Acute respiratory failure	4/398 (1%)	4	1/399 (0.3%)	1
Asthma	2/398 (0.5%)	2	1/399 (0.3%)	1
Bronchiectasis	0/398 (0%)	0	1/399 (0.3%)	1
Chronic obstructive pulmonary disease	6/398 (1.5%)	6	2/399 (0.5%)	2
Cough	1/398 (0.3%)	1	0/399 (0%)	0
Dyspnea	2/398 (0.5%)	2	5/399 (1.3%)	5
Dyspnea exertional	1/398 (0.3%)	1	0/399 (0%)	0
Epistaxis	1/398 (0.3%)	1	0/399 (0%)	0
Hemoptysis	1/398 (0.3%)	1	0/399 (0%)	0
Hypoxia	0/398 (0%)	0	1/399 (0.3%)	1
Pleural effusion	3/398 (0.8%)	3	1/399 (0.3%)	1
Pneumonia aspiration	1/398 (0.3%)	1	0/399 (0%)	0
Pneumonitis	1/398 (0.3%)	1	0/399 (0%)	0
Pneumothorax	2/398 (0.5%)	2	0/399 (0%)	0
Pulmonary embolism	1/398 (0.3%)	1	0/399 (0%)	0
Pulmonary hypertension	0/398 (0%)	0	1/399 (0.3%)	1
Pulmonary edema	5/398 (1.3%)	5	4/399 (1%)	4
Respiratory failure	7/398 (1.8%)	7	9/399 (2.3%)	9
Skin and subcutaneous tissue disorders
Decubitus ulcer	0/398 (0%)	0	1/399 (0.3%)	1
Diabetic foot	2/398 (0.5%)	2	0/399 (0%)	0
Skin ulcer	2/398 (0.5%)	2	0/399 (0%)	0
Swelling face	0/398 (0%)	0	1/399 (0.3%)	1
Vascular disorders
Accelerated hypertension	2/398 (0.5%)	2	1/399 (0.3%)	1
Angiopathy	0/398 (0%)	0	1/399 (0.3%)	1
Aortic dissection	0/398 (0%)	0	1/399 (0.3%)	1
Aortic stenosis	1/398 (0.3%)	1	2/399 (0.5%)	2
Arterial hemorrhage	0/398 (0%)	0	1/399 (0.3%)	1
Arteriosclerosis	0/398 (0%)	0	1/399 (0.3%)	1
Dry gangrene	1/398 (0.3%)	1	0/399 (0%)	0
Haematoma	1/398 (0.3%)	1	2/399 (0.5%)	2
Hypertension	4/398 (1%)	4	10/399 (2.5%)	10
Hypertensive crisis	2/398 (0.5%)	2	6/399 (1.5%)	6
Hypertensive emergency	0/398 (0%)	0	2/399 (0.5%)	2
Hypotension	6/398 (1.5%)	6	3/399 (0.8%)	3
Iliac artery occlusion	1/398 (0.3%)	1	0/399 (0%)	0
Jugular vein thrombosis	1/398 (0.3%)	1	2/399 (0.5%)	2
Orthostatic hypotension	0/398 (0%)	0	1/399 (0.3%)	1
Peripheral artery occlusive disease	2/398 (0.5%)	2	1/399 (0.3%)	1
Peripheral artery occlusion	1/398 (0.3%)	1	1/399 (0.3%)	1
Peripheral ischemia	0/398 (0%)	0	1/399 (0.3%)	1
Peripheral vascular disorder	0/398 (0%)	0	1/399 (0.3%)	1
Steal syndrome	4/398 (1%)	4	1/399 (0.3%)	1
Superior vena cava occlusion	0/398 (0%)	0	1/399 (0.3%)	1
Thrombosis	1/398 (0.3%)	1	0/399 (0%)	0
Vasculitis	0/398 (0%)	0	1/399 (0.3%)	1
Vasoconstriction	0/398 (0%)	0	1/399 (0.3%)	1
Venous stenosis	0/398 (0%)	0	1/399 (0.3%)	1
Other (Not Including Serious) Adverse Events
	Neutrolin Arm		Heparin Arm
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	314/398 (78.9%)		315/399 (78.9%)
Blood and lymphatic system disorders
Anemia	8/398 (2%)	8	16/399 (4%)	16
Nephrogenic anemia	10/398 (2.5%)	10	8/399 (2%)	8
Cardiac disorders
Acute myocardial infarction	6/398 (1.5%)	6	14/399 (3.5%)	14
Angina pectoris	10/398 (2.5%)	10	8/399 (2%)	8
Atrial fibrillation	7/398 (1.8%)	7	13/399 (3.3%)	13
Bradycardia	12/398 (3%)	12	11/399 (2.8%)	11
Cardiac failure congestive	16/398 (4%)	16	10/399 (2.5%)	10
Tachycardia	11/398 (2.8%)	11	22/399 (5.5%)	22
Gastrointestinal disorders
Abdominal pain	20/398 (5%)	20	27/399 (6.8%)	27
Constipation	18/398 (4.5%)	18	17/399 (4.3%)	17
Diarrhea	38/398 (9.5%)	38	30/399 (7.5%)	30
Gastrointestinal hemorrhage	6/398 (1.5%)	6	8/399 (2%)	8
Nausea	26/398 (6.5%)	26	43/399 (10.8%)	43
Vomiting	24/398 (6%)	24	31/399 (7.8%)	31
General disorders
Asthenia	15/398 (3.8%)	15	12/399 (3%)	12
Catheter site erythema	7/398 (1.8%)	7	8/399 (2%)	8
Non-cardiac chest pain	10/398 (2.5%)	10	4/399 (1%)	4
Edema peripheral	9/398 (2.3%)	9	19/399 (4.8%)	19
Pain	7/398 (1.8%)	7	10/399 (2.5%)	10
Peripheral swelling	9/398 (2.3%)	9	9/399 (2.3%)	9
Pyrexia	15/398 (3.8%)	15	24/399 (6%)	24
Infections and infestations
Bacteremia	6/398 (1.5%)	6	9/399 (2.3%)	9
Bronchitis	9/398 (2.3%)	9	5/399 (1.3%)	5
Cellulitis	13/398 (3.3%)	13	14/399 (3.5%)	14
Device-related infection	10/398 (2.5%)	10	17/399 (4.3%)	17
Nasopharyngitis	8/398 (2%)	8	3/399 (0.8%)	3
Osteomyelitis	8/398 (2%)	8	5/399 (1.3%)	5
Pneumonia	18/398 (4.5%)	18	28/399 (7%)	28
Sepsis	11/398 (2.8%)	11	21/399 (5.3%)	21
Upper respiratory tract infection	8/398 (2%)	8	15/399 (3.8%)	15
Urinary tract infection	12/398 (3%)	12	15/399 (3.8%)	15
Injury, poisoning and procedural complications
Arteriovenous fistula site complication	13/398 (3.3%)	13	20/399 (5%)	20
Fall	17/398 (4.3%)	17	17/399 (4.3%)	17
Procedural hypotension	18/398 (4.5%)	18	18/399 (4.5%)	18
Metabolism and nutrition disorders
Fluid overload	26/398 (6.5%)	26	21/399 (5.3%)	21
Hyperkalemia	27/398 (6.8%)	27	26/399 (6.5%)	26
Hypoglycemia	14/398 (3.5%)	14	10/399 (2.5%)	10
Musculoskeletal and connective tissue disorders
Back pain	15/398 (3.8%)	15	17/399 (4.3%)	17
Muscle spasm	23/398 (5.8%)	23	36/399 (9%)	36
Pain in extremity	15/398 (3.8%)	15	22/399 (5.5%)	22
Nervous system disorders
Dizziness	22/398 (5.5%)	22	16/399 (4%)	16
Headache	22/398 (5.5%)	22	22/399 (5.5%)	22
Syncope	10/398 (2.5%)	10	4/399 (1%)	4
Product Issues
Device dislocation	9/398 (2.3%)	9	5/399 (1.3%)	5
Device malfunction	68/398 (17.1%)	68	47/399 (11.8%)	47
Device occlusion	9/398 (2.3%)	9	9/399 (2.3%)	9
Thrombosis in device	8/398 (2%)	8	16/399 (4%)	16
Psychiatric disorders
Insomnnia	9/398 (2.3%)	9	7/399 (1.8%)	7
Mental status changes	9/398 (2.3%)	9	12/399 (3%)	12
Respiratory, thoracic and mediastinal disorders
Cough	21/398 (5.3%)	21	30/399 (7.5%)	30
Dyspnea	19/398 (4.8%)	19	30/399 (7.5%)	30
Pleural effusion	9/398 (2.3%)	9	10/399 (2.5%)	10
Pulmonary edema	6/398 (1.5%)	6	8/399 (2%)	8
Respiratory failure	9/398 (2.3%)	9	13/399 (3.3%)	13
Skin and subcutaneous tissue disorders
Skin ulcer	10/398 (2.5%)	10	4/399 (1%)	4
Vascular disorders
Hypertension	27/398 (6.8%)	27	39/399 (9.8%)	39
Hypotension	35/398 (8.8%)	35	27/399 (6.8%)	27

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.