Trial Outcomes & Findings for Continuous Soluble Ferric Pyrophosphate (SFP) Iron Delivery Via Dialysate in Hemodialysis Patients (NCT NCT01286012)

Last Updated: 2018-10-01

Results Overview

The statistical endpoint is the change from baseline between groups at End of Treatment, where the baseline prescribed ESA dose (expressed as U/week epoetin) per subject is defined as the average weekly dose of ESA prescribed for administration over the two-week period of time immediately prior to randomization. The end-of-treatment prescribed ESA dose (expressed as U/week epoetin) per subject is defined as the average weekly dose of ESA prescribed for administration over the last two weeks of the treatment period.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

108 participants

Primary outcome timeframe

Hemoglobin measured weekly and serum ferritin and Transferrin Saturation (TSAT) determined every other week; ESA dose recorded at each visit for 36 weeks.

Results posted on

2018-10-01

Participant Flow

Participant milestones

Participant milestones
Measure	SFP in Liquid Bicarbonate Soluble Ferric Pyrophosphate in liquid bicarbonate: Subjects will receive hemodialysis containing SFP at 2 µM (11 µg iron/dL of dialysate) at every dialysis session, for a total duration of 36 weeks.	Placebo: Conventional Liquid Bicarbonate Control concentrate lacking SFP does not contain SFP (total iron = 0) Subjects will receive hemodialysis containing conventional liquid bicarbonate lacking iron (placebo) at every dialysis session, for a total duration of 36 weeks.
Overall Study STARTED	54	54
Overall Study COMPLETED	41	40
Overall Study NOT COMPLETED	13	14

Reasons for withdrawal

Reasons for withdrawal
Measure	SFP in Liquid Bicarbonate Soluble Ferric Pyrophosphate in liquid bicarbonate: Subjects will receive hemodialysis containing SFP at 2 µM (11 µg iron/dL of dialysate) at every dialysis session, for a total duration of 36 weeks.	Placebo: Conventional Liquid Bicarbonate Control concentrate lacking SFP does not contain SFP (total iron = 0) Subjects will receive hemodialysis containing conventional liquid bicarbonate lacking iron (placebo) at every dialysis session, for a total duration of 36 weeks.
Overall Study Adverse Event	3	3
Overall Study Death	2	3
Overall Study Protocol Violation	1	1
Overall Study Withdrawal by Subject	4	4
Overall Study Physician Decision	2	0
Overall Study peritoneal dialysis, randomized in error	1	3

Baseline Characteristics

Continuous Soluble Ferric Pyrophosphate (SFP) Iron Delivery Via Dialysate in Hemodialysis Patients

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	SFP in Liquid Bicarbonate n=54 Participants Soluble Ferric Pyrophosphate in liquid bicarbonate: Subjects will be randomized in a 1:1 ratio to receive hemodialysis containing SFP at 2 µM (11 µg iron/dL of dialysate) or conventional solutions lacking iron (placebo) at every dialysis session, for a total duration of 36 weeks.	Placebo: Conventional Liquid Bicarbonate n=49 Participants Control concentrate lacking SFP does not contain SFP (total iron = 0) Subjects will receive hemodialysis containing conventional liquid bicarbonate lacking iron (placebo) at every dialysis session, for a total duration of 36 weeks.	Total n=103 Participants Total of all reporting groups
Age, Continuous	59.4 years STANDARD_DEVIATION 12.40 • n=5 Participants	58.5 years STANDARD_DEVIATION 13.89 • n=7 Participants	59 years STANDARD_DEVIATION 13.07 • n=5 Participants
Sex: Female, Male Female	23 Participants n=5 Participants	17 Participants n=7 Participants	40 Participants n=5 Participants
Sex: Female, Male Male	31 Participants n=5 Participants	32 Participants n=7 Participants	63 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 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
Race (NIH/OMB) Black or African American	22 Participants n=5 Participants	17 Participants n=7 Participants	39 Participants n=5 Participants
Race (NIH/OMB) White	31 Participants n=5 Participants	32 Participants n=7 Participants	63 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	20 Participants n=5 Participants	21 Participants n=7 Participants	41 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	34 Participants n=5 Participants	28 Participants n=7 Participants	62 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants

PRIMARY outcome

Timeframe: Hemoglobin measured weekly and serum ferritin and Transferrin Saturation (TSAT) determined every other week; ESA dose recorded at each visit for 36 weeks.

Population: MITT population: Randomized subjects who received at least one dose of study drug and also received ESA during the treatment period.

Outcome measures

Outcome measures
Measure	SFP in Liquid Bicarbonate n=52 Participants Soluble Ferric Pyrophosphate in liquid bicarbonate: Subjects will be randomized in a 1:1 ratio to receive hemodialysis containing SFP at 2 µM (11 µg iron/dL of dialysate) or conventional solutions lacking iron (placebo) at every dialysis session, for a total duration of 36 weeks.	Placebo: Conventional Liquid Bicarbonate n=51 Participants Control concentrate lacking SFP does not contain SFP (total iron = 0) Subjects will receive hemodialysis containing conventional liquid bicarbonate lacking iron (placebo) at every dialysis session, for a total duration of 36 weeks.
The Percent Change From Baseline in ESA Dose Required to Maintain Hemoglobin in the Target Range, Adjusted for Hgb.	4.9 Percent change Standard Error 12.07	39.8 Percent change Standard Error 12.18

SECONDARY outcome

Timeframe: ESA dose is monitored and recorded at each dialysis session for 36 weeks.

The change from baseline in prescribed ESA dose at end-of-treatment was categorized as being greater than or equal to 25%, 10 to less than 25%, -10 to 10%, greater than -25 to -10% and less than or equal to -25%. The number of subjects in each treatment group that fit each category was compared.

Outcome measures

Outcome measures
Measure	SFP in Liquid Bicarbonate n=52 Participants Soluble Ferric Pyrophosphate in liquid bicarbonate: Subjects will be randomized in a 1:1 ratio to receive hemodialysis containing SFP at 2 µM (11 µg iron/dL of dialysate) or conventional solutions lacking iron (placebo) at every dialysis session, for a total duration of 36 weeks.	Placebo: Conventional Liquid Bicarbonate n=51 Participants Control concentrate lacking SFP does not contain SFP (total iron = 0) Subjects will receive hemodialysis containing conventional liquid bicarbonate lacking iron (placebo) at every dialysis session, for a total duration of 36 weeks.
The Distribution of Changes From Baseline in the Prescribed ESA Dose Between the Two Treatment Arms ESA dose change > or = to 25%	16 Participants	20 Participants
The Distribution of Changes From Baseline in the Prescribed ESA Dose Between the Two Treatment Arms ESA dose change > -25% to -10%	3 Participants	3 Participants
The Distribution of Changes From Baseline in the Prescribed ESA Dose Between the Two Treatment Arms ESA dose change >10 to 25%	5 Participants	4 Participants
The Distribution of Changes From Baseline in the Prescribed ESA Dose Between the Two Treatment Arms ESA dose change > -10% to 10%	12 Participants	9 Participants
The Distribution of Changes From Baseline in the Prescribed ESA Dose Between the Two Treatment Arms ESA dose change < or = to -25%	16 Participants	15 Participants

SECONDARY outcome

Timeframe: 36 weeks

The number of patients in each treatment group who had maintained their hemoglobin between 95 and 115 grams/liter at the end of treatment was quantified.

Outcome measures

Outcome measures
Measure	SFP in Liquid Bicarbonate n=52 Participants Soluble Ferric Pyrophosphate in liquid bicarbonate: Subjects will be randomized in a 1:1 ratio to receive hemodialysis containing SFP at 2 µM (11 µg iron/dL of dialysate) or conventional solutions lacking iron (placebo) at every dialysis session, for a total duration of 36 weeks.	Placebo: Conventional Liquid Bicarbonate n=51 Participants Control concentrate lacking SFP does not contain SFP (total iron = 0) Subjects will receive hemodialysis containing conventional liquid bicarbonate lacking iron (placebo) at every dialysis session, for a total duration of 36 weeks.
Stability of Hemoglobin Over Time (Maintenance of Hemoglobin Between 9.5-11.5 g/dL.	30 Participants	30 Participants

SECONDARY outcome

Timeframe: 36 weeks

The absolute amount of IV iron administered to subjects in each treatment group was divided by the number of weeks on study and the number of subjects per treatment group such that the mean dose of IV iron (mg) per week per subject (for the entire treatment group) was calculated.

Outcome measures

Outcome measures
Measure	SFP in Liquid Bicarbonate n=52 Participants Soluble Ferric Pyrophosphate in liquid bicarbonate: Subjects will be randomized in a 1:1 ratio to receive hemodialysis containing SFP at 2 µM (11 µg iron/dL of dialysate) or conventional solutions lacking iron (placebo) at every dialysis session, for a total duration of 36 weeks.	Placebo: Conventional Liquid Bicarbonate n=51 Participants Control concentrate lacking SFP does not contain SFP (total iron = 0) Subjects will receive hemodialysis containing conventional liquid bicarbonate lacking iron (placebo) at every dialysis session, for a total duration of 36 weeks.
The Amount of Supplemental Intravenous (IV) Iron Needed During Study Participation.	23.5 mg per week per subject Standard Deviation 54.22	45.6 mg per week per subject Standard Deviation 62.78

SECONDARY outcome

Timeframe: 36 weeks

Iron delivery to the erythron was estimated by Hgb generation in response to erythropoietin (ERI, calculated as ESA dose/Hgb). In addition, ERI was also divided by body weight in kilograms to obtain a modified ERI (ERI/kg).

Outcome measures

Outcome measures
Measure	SFP in Liquid Bicarbonate n=52 Participants Soluble Ferric Pyrophosphate in liquid bicarbonate: Subjects will be randomized in a 1:1 ratio to receive hemodialysis containing SFP at 2 µM (11 µg iron/dL of dialysate) or conventional solutions lacking iron (placebo) at every dialysis session, for a total duration of 36 weeks.	Placebo: Conventional Liquid Bicarbonate n=51 Participants Control concentrate lacking SFP does not contain SFP (total iron = 0) Subjects will receive hemodialysis containing conventional liquid bicarbonate lacking iron (placebo) at every dialysis session, for a total duration of 36 weeks.
Comparison of Iron Delivery to the Erythron From Baseline to End of Treatment Between the Treatment Groups. baseline	10.43 Units/kilogram/week/gram/liter Standard Deviation 6.457	10.38 Units/kilogram/week/gram/liter Standard Deviation 6.471
Comparison of Iron Delivery to the Erythron From Baseline to End of Treatment Between the Treatment Groups. end of treatment	11.71 Units/kilogram/week/gram/liter Standard Deviation 9.808	14.67 Units/kilogram/week/gram/liter Standard Deviation 13.804

Adverse Events

SFP in Liquid Bicarbonate

Serious events: 18 serious events

Other events: 50 other events

Deaths: 0 deaths

Placebo: Conventional Liquid Bicarbonate

Serious events: 20 serious events

Other events: 46 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Raymond Pratt, MD CMO

Rockwell Medical

Phone: 248 960 9009

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee No study results may be submitted for publication without Sponsor's prior written consent. Within 60 days from submission to Sponsor's review, Sponsor may withhold the consent. 1st publication of results is made in conjunction with the presentation of a joint, multicenter publication of results with certain PIs from all sites contributing data.
Publication restrictions are in place

Restriction type: OTHER

Measure	SFP in Liquid Bicarbonate n=54 participants at risk Soluble Ferric Pyrophosphate in liquid bicarbonate: Subjects will receive hemodialysis containing SFP at 2 µM (11 µg iron/dL of dialysate) at every dialysis session, for a total duration of 36 weeks.	Placebo: Conventional Liquid Bicarbonate n=49 participants at risk Control concentrate lacking SFP does not contain SFP (total iron = 0) Subjects will receive hemodialysis containing conventional liquid bicarbonate lacking iron (placebo) at every dialysis session, for a total duration of 36 weeks.
Cardiac disorders CARDIAC FAILURE CONGESTIVE	5.6% 3/54 • Number of events 3 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.	4.1% 2/49 • Number of events 2 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.
Cardiac disorders ANGINA PECTORIS	1.9% 1/54 • Number of events 1 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.	4.1% 2/49 • Number of events 2 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.
Cardiac disorders CARDIO-RESPIRATORY ARREST	1.9% 1/54 • Number of events 1 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.	2.0% 1/49 • Number of events 1 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.
Cardiac disorders CARDIAC ARREST	1.9% 1/54 • Number of events 1 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.	0.00% 0/49 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.
Cardiac disorders CARDIAC FAILURE	1.9% 1/54 • Number of events 1 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.	0.00% 0/49 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.
Cardiac disorders CARDIOMYOPATHY	1.9% 1/54 • Number of events 1 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.	0.00% 0/49 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.
Cardiac disorders ACUTE MYOCARDIAL INFARCTION	0.00% 0/54 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.	2.0% 1/49 • Number of events 1 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.
Cardiac disorders ATRIOVENTRICULAR BLOCK SECOND DEGREE	0.00% 0/54 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.	2.0% 1/49 • Number of events 1 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.
Cardiac disorders BRADYCARDIA	0.00% 0/54 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.	2.0% 1/49 • Number of events 1 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.
Gastrointestinal disorders GASTROINTESTINAL HAEMORRHAGE	1.9% 1/54 • Number of events 1 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.	2.0% 1/49 • Number of events 1 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.
Gastrointestinal disorders ABDOMINAL PAIN	1.9% 1/54 • Number of events 1 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.	0.00% 0/49 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.
Gastrointestinal disorders GASTRITIS	0.00% 0/54 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.	2.0% 1/49 • Number of events 1 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.
Gastrointestinal disorders PANCREATITIS	0.00% 0/54 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.	2.0% 1/49 • Number of events 1 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.
General disorders NON-CARDIAC CHEST PAIN	0.00% 0/54 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.	4.1% 2/49 • Number of events 3 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.
General disorders SUDDEN CARDIAC DEATH	0.00% 0/54 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.	2.0% 1/49 • Number of events 1 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.
Infections and infestations PNEUMONIA	3.7% 2/54 • Number of events 2 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.	4.1% 2/49 • Number of events 2 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.
Infections and infestations OSTEOMYELITIS	1.9% 1/54 • Number of events 1 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.	4.1% 2/49 • Number of events 2 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.
Infections and infestations DIABETIC FOOT INFECTION	1.9% 1/54 • Number of events 1 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.	0.00% 0/49 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.
Infections and infestations ENDOCARDITIS	1.9% 1/54 • Number of events 1 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.	0.00% 0/49 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.
Infections and infestations GANGRENE	1.9% 1/54 • Number of events 1 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.	0.00% 0/49 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.
Infections and infestations SUBCUTANEOUS ABSCESS	1.9% 1/54 • Number of events 1 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.	0.00% 0/49 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.
Infections and infestations UPPER RESPIRATORY TRACT INFECTION	1.9% 1/54 • Number of events 1 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.	0.00% 0/49 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.
Infections and infestations DIVERTICULITIS	0.00% 0/54 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.	2.0% 1/49 • Number of events 1 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.
Infections and infestations PYELONEPHRITIS ACUTE	0.00% 0/54 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.	2.0% 1/49 • Number of events 1 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.
Infections and infestations SEPTIC SHOCK	0.00% 0/54 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.	2.0% 1/49 • Number of events 1 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.
Infections and infestations URINARY TRACT INFECTION	0.00% 0/54 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.	2.0% 1/49 • Number of events 1 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.
Injury, poisoning and procedural complications LOWER LIMB FRACTURE	1.9% 1/54 • Number of events 2 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.	0.00% 0/49 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.
Injury, poisoning and procedural complications ARTERIOVENOUS FISTULA SITE COMPLICATION	1.9% 1/54 • Number of events 1 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.	0.00% 0/49 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.
Injury, poisoning and procedural complications ARTERIOVENOUS FISTULA THROMBOSIS	1.9% 1/54 • Number of events 1 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.	0.00% 0/49 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.
Injury, poisoning and procedural complications EXTRADURAL HAEMATOMA	1.9% 1/54 • Number of events 1 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.	0.00% 0/49 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.
Injury, poisoning and procedural complications GASTROINTESTINAL ANASTOMOTIC LEAK	1.9% 1/54 • Number of events 1 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.	0.00% 0/49 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.
Injury, poisoning and procedural complications RADIUS FRACTURE	1.9% 1/54 • Number of events 1 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.	0.00% 0/49 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.
Injury, poisoning and procedural complications STERNAL FRACTURE	1.9% 1/54 • Number of events 1 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.	0.00% 0/49 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.
Injury, poisoning and procedural complications VASCULAR GRAFT THROMBOSIS	1.9% 1/54 • Number of events 1 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.	0.00% 0/49 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.
Injury, poisoning and procedural complications SPINAL COMPRESSION FRACTURE	0.00% 0/54 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.	2.0% 1/49 • Number of events 1 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.
Metabolism and nutrition disorders FLUID OVERLOAD	7.4% 4/54 • Number of events 4 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.	6.1% 3/49 • Number of events 3 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.
Metabolism and nutrition disorders HYPERKALAEMIA	1.9% 1/54 • Number of events 1 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.	0.00% 0/49 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.
Musculoskeletal and connective tissue disorders EXOSTOSIS	1.9% 1/54 • Number of events 2 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.	0.00% 0/49 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) COLON CANCER	1.9% 1/54 • Number of events 1 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.	0.00% 0/49 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) MYELODYSPLASTIC SYNDROME	1.9% 1/54 • Number of events 1 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.	0.00% 0/49 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.
Nervous system disorders HYPOXIC-ISCHAEMIC ENCEPHALOPATHY	1.9% 1/54 • Number of events 1 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.	2.0% 1/49 • Number of events 1 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.
Nervous system disorders VASCULAR DEMENTIA	1.9% 1/54 • Number of events 1 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.	0.00% 0/49 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.
Nervous system disorders TRANSIENT ISCHAEMIC ATTACK	0.00% 0/54 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.	4.1% 2/49 • Number of events 2 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.
Nervous system disorders BRAIN STEM HAEMORRHAGE	0.00% 0/54 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.	2.0% 1/49 • Number of events 1 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.
Nervous system disorders METABOLIC ENCEPHALOPATHY	0.00% 0/54 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.	2.0% 1/49 • Number of events 1 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.
Psychiatric disorders HALLUCINATION	0.00% 0/54 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.	2.0% 1/49 • Number of events 1 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.
Renal and urinary disorders AZOTAEMIA	0.00% 0/54 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.	2.0% 1/49 • Number of events 1 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.
Respiratory, thoracic and mediastinal disorders ACUTE RESPIRATORY FAILURE	1.9% 1/54 • Number of events 1 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.	4.1% 2/49 • Number of events 2 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.
Respiratory, thoracic and mediastinal disorders PLEURAL EFFUSION	1.9% 1/54 • Number of events 1 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.	0.00% 0/49 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.
Respiratory, thoracic and mediastinal disorders HYPOXIA	0.00% 0/54 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.	2.0% 1/49 • Number of events 1 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.
Respiratory, thoracic and mediastinal disorders PULMONARY OEDEMA	0.00% 0/54 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.	2.0% 1/49 • Number of events 1 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.
Respiratory, thoracic and mediastinal disorders RESPIRATORY ACIDOSIS	0.00% 0/54 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.	2.0% 1/49 • Number of events 1 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.
Skin and subcutaneous tissue disorders DIABETIC NEUROPATHIC ULCER	1.9% 1/54 • Number of events 1 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.	0.00% 0/49 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.
Vascular disorders HYPERTENSIVE CRISIS	3.7% 2/54 • Number of events 2 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.	0.00% 0/49 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.
Vascular disorders MALIGNANT HYPERTENSION	0.00% 0/54 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.	2.0% 1/49 • Number of events 1 Safety Population: Subjects who received any amount of study drug, including those who receive the wrong treatment.