Safety Study of Soluble Ferric Pyrophosphate (SFP) in Dialysate in CKD Patients Receiving Chronic Hemodialysis

• Sponsor: Rockwell Medical Technologies, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01503021
• Collaborator: (none)
• Enrollment: 718
• Locations: 31
• Arms: 2
• Duration (Months): 26
• Patients Per Site: 23.2
• Patients Per Site Per Month: 0.9

Study Details

Study Description

Brief Summary

The purpose of the parent study is to assess the short-term safety and tolerability of soluble ferric pyrophosphate (SFP) in dialysate administered to a large number of representative adult chronic kidney disease patients on hemodialysis (CKD-HD).

The purpose of the extension study is to assess the long-term safety and tolerability of SFP.

Condition or Disease	Intervention/Treatment	Phase
End Stage Renal Disease; Chronic Kidney Disease	Drug: SFP; Other: Placebo	Phase 3

Detailed Description

Parent Study: randomized, double-blinded, crossover, up to 6 weeks, 700 patients. Patients were randomized to receive SFP 2 µmoles (110 µg) iron/L of dialysate in liquid bicarbonate concentrate or placebo (standard liquid bicarbonate concentrate) x 2 weeks, then a 1 week washout, then crossed over to the alternate treatment x 2 weeks.

Extension Study: open-label, single active arm, uncontrolled study, up to 53 weeks, 300 patients. Following completion of the RMTI-SFP-6 parent study, patients could enter the extension study, where they received SFP 2 µmoles (110 µg) iron/L of dialysate in liquid bicarbonate concentrate for up to 52 weeks.

Study Design

• Study Type: Interventional
• Actual Enrollment: 718 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-Blinded, Placebo-Controlled, Crossover, Multicenter Phase III Safety Study of Soluble Ferric Pyrophosphate (SFP) in Dialysate in Chronic Kidney Disease Patients Receiving Chronic Hemodialysis
• Study Start Date: Nov 1, 2011
• Actual Primary Completion Date: Jan 1, 2014
• Actual Study Completion Date: Jan 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Other: SFP/Placebo Soluble ferric pyrophosphate (SFP) 2 µmoles (110 µg) iron/L of dialysate in liquid bicarbonate concentrate x 2 weeks, then 1 week washout, then standard liquid bicarbonate concentrate without SFP x 2 weeks	Drug: SFP; Dialysis with SFP administered via the liquid bicarbonate concentrate at a concentration of 2 µmoles (110 µg) iron/L of dialysate; Other Names: Soluble ferric pyrophosphate ; Other: Placebo; Dialysis with standard liquid bicarbonate concentrate without iron; Other Names: Standard liquid bicarbonate concentrate
Other: Placebo/SFP Standard liquid bicarbonate concentrate without SFP x 2 weeks, then 1 week washout, then soluble ferric pyrophosphate (SFP) 2 µmoles (110 µg) iron/L of dialysate in liquid bicarbonate concentrate x 2 weeks.	Drug: SFP; Dialysis with SFP administered via the liquid bicarbonate concentrate at a concentration of 2 µmoles (110 µg) iron/L of dialysate; Other Names: Soluble ferric pyrophosphate ; Other: Placebo; Dialysis with standard liquid bicarbonate concentrate without iron; Other Names: Standard liquid bicarbonate concentrate

Outcome Measures

Primary Outcome Measures

1. Incidence of Treatment-emergent Adverse Events [Up to 7 weeks for the Parent (Crossover) Study and up to 53 weeks for Extension Study]

   Adverse events for a given intervention (SFP or Placebo) are counted from the date of the first day of dosing of the intervention until 7 days after the last day of dosing of the intervention.

2. Incidence of Treatment-emergent Adverse Events of Intradialytic Hypotension [Up to 7 weeks for the Parent (Crossover) Study and up to 53 weeks for Extension Study]

   Adverse events for a given intervention (SFP or Placebo) are counted from the date of the first day of dosing of the intervention until 7 days after the last day of dosing of the intervention. For each adverse event, investigators assessed whether the event met the protocol criteria for intradialytic hypotension. Intradialytic hypotension events were only to have been reported as adverse events if they exceeded the individual subject's baseline pattern of intradialytic hypotension.

3. Incidence of Related Suspected Hypersensitivity Reactions [Up to 7 weeks for the Parent (Crossover) Study and up to 53 weeks for Extension Study]

   Adverse events for a given intervention (SFP or Placebo) are counted from the date of the first day of dosing of the intervention until 7 days after the last day of dosing of the intervention. For each adverse event, investigators assessed whether the event met protocol criteria for suspected hypersensitivity reactions.

Secondary Outcome Measures

1. Incidence of Composite Cardiovascular Events [Up to 7 weeks for the Parent (Crossover) Study and up to 53 weeks for Extension Study]

   Adverse events for a given intervention (SFP or Placebo) are counted from the date of the first day of dosing of the intervention until 7 days after the last day of dosing of the intervention. Adverse event terms meeting criteria for composite cardiovascular events were pre-specified in the statistical analysis plan for the study.

2. Incidence of Hemodialysis Vascular Access Thrombotic Events [Up to 7 weeks for the Parent (Crossover) Study and up to 53 weeks for Extension Study]

   Adverse events for a given intervention (SFP or Placebo) are counted from the date of the first day of dosing of the intervention until 7 days after the last day of dosing of the intervention. Adverse event terms meeting criteria for hemodialysis vascular access thrombotic events were pre-specified in the statistical analysis plan for the study.

3. Incidence of Other Thrombotic Events [Up to 7 weeks for the Parent (Crossover) Study and up to 53 weeks for Extension Study]

   Adverse events for a given intervention (SFP or Placebo) are counted from the date of the first day of dosing of the intervention until 7 days after the last day of dosing of the intervention. Adverse event terms meeting criteria for other thrombotic events were pre-specified in the statistical analysis plan for the study.

4. Incidence of Systemic/Serious Infections [Up to 7 weeks for the Parent (Crossover) Study and up to 53 weeks for Extension Study]

   Adverse events for a given intervention (SFP or Placebo) are counted from the date of the first day of dosing of the intervention until 7 days after the last day of dosing of the intervention. Adverse events of systemic/serious infections were defined in the statistical analysis plan for the study to include infections for which the subject was administered at least 3 doses of an IV antibiotic, and infections for which the subject was hospitalized.

5. Incidence of Serious Adverse Events [Up to 7 weeks for the Parent (Crossover) Study and up to 53 weeks for Extension Study]

   Adverse events for a given intervention (SFP or Placebo) are counted from the date of the first day of dosing of the intervention until 7 days after the last day of dosing of the intervention. For each adverse event, investigators assessed whether the event met seriousness criteria.

Other Outcome Measures

1. Serum Iron Change From Pre-dialysis to Post-dialysis at Week 2 [Pre-dialysis and post-dialysis during study week 2 of the Parent (Crossover) Study]

   Serum iron was assessed from samples obtained pre-dialysis and post-dialysis at a single hemodialysis during study week 2. Because of the crossover nature of the study, the week 2 values reflect effects of SFP in the SFP/Placebo arm and effects of Placebo in the Placebo/SFP arm.

2. Serum Iron Change From Pre-dialysis to Post-dialysis at Week 5 [Pre-dialysis and post-dialysis during study week 5 of the Parent (Crossover) Study]

   Serum iron was assessed from samples obtained pre-dialysis and post-dialysis at a single hemodialysis during study week 5. Because of the crossover nature of the study, the week 5 values reflect effects of Placebo in the SFP/Placebo arm and effects of SFP in the Placebo/SFP arm.

3. Unsaturated Iron-binding Capacity Change From Pre-dialysis to Post-dialysis at Week 2 [Pre-dialysis and post-dialysis during study week 2 of the Parent (Crossover) Study]

   Unsaturated iron-binding capacity was assessed from samples obtained pre-dialysis and post-dialysis at a single hemodialysis during study week 2. Because of the crossover nature of the study, the week 2 values reflect effects of SFP in the SFP/Placebo arm and effects of Placebo in the Placebo/SFP arm.

4. Unsaturated Iron-binding Capacity Change From Pre-dialysis to Post-dialysis at Week 5 [Pre-dialysis and post-dialysis during study week 5 of the Parent (Crossover) Study]

   Unsaturated iron-binding capacity was assessed from samples obtained pre-dialysis and post-dialysis at a single hemodialysis during study week 5. Because of the crossover nature of the study, the week 5 values reflect effects of Placebo in the SFP/Placebo arm and effects of SFP in the Placebo/SFP arm.

5. Transferrin Saturation Change From Pre-dialysis to Post-dialysis at Week 2 [Pre-dialysis and post-dialysis during study week 2 of the Parent (Crossover) Study]

   Transferrin saturation (based on TIBC derived from transferrin levels) was assessed from samples obtained pre-dialysis and post-dialysis at a single hemodialysis during study week 2. Because of the crossover nature of the study, the week 2 values reflect effects of SFP in the SFP/Placebo arm and effects of Placebo in the Placebo/SFP arm.

6. Transferrin Saturation Change From Pre-dialysis to Post-dialysis at Week 5 [Pre-dialysis and post-dialysis during study week 5 of the Parent (Crossover) Study]

   Transferrin saturation (based on TIBC derived from transferrin levels) was assessed from samples obtained pre-dialysis and post-dialysis at a single hemodialysis during study week 5. Because of the crossover nature of the study, the week 5 values reflect effects of Placebo in the SFP/Placebo arm and effects of SFP in the Placebo/SFP arm.

7. Ferritin [Baseline, up to 53 weeks for Extension Study]

   The baseline and end of treatment predialysis ferritin levels were evaluated for the 52-week extension study to determine whether soluble ferric pyrophosphate increases iron stores.

8. Serum Iron [Baseline, up to 53 weeks for Extension Study]

   The baseline and end of treatment predialysis serum iron levels were evaluated for the 52-week extension study to determine the effect of soluble ferric pyrophosphate on serum iron.

9. Transferrin Saturation [Baseline, up to 53 weeks for Extension Study]

   The baseline and end of treatment predialysis transferrin saturation were evaluated for the 52-week extension study to confirm clearance of iron derived from soluble ferric pyrophosphate.

10. Incidence of Patients Meeting Hy's Law Criteria [Up to 7 weeks for the Parent (Crossover) Study and up to 53 weeks for Extension Study]

    The peak alanine aminotransferase and the peak total bilirubin levels were evaluated per patient. Laboratory values for a given intervention (SFP or Placebo) are counted from the date of the first day of dosing of the intervention until 7 days after the last day of dosing of the intervention. Patients with alanine aminotransferase more than three times the upper limit of normal and also total bilirubin more than two times the upper limit of normal are counted.

Eligibility Criteria

Criteria

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

Parent Study, Double Blinded, Crossover:

Key Inclusion Criteria:

1. Adult ≥ 18 years of age.

2. Has chronic kidney disease (CKD) receiving maintenance hemodialysis (HD) (CKD-HD subjects) and regularly undergoing 2 or more dialysis sessions per week.

3. Stable pre-dialysis Hgb ≥ 9.0 to ≤ 12.5 g/dL.

4. Stable pre-dialysis TSAT ≥ 15% to ≤ 45%.

5. Stable pre-dialysis ferritin ≥ 100 to ≤ 1200 µg/L (1200 ng/mL).

Key Exclusion Criteria:

1. Any previous exposure to SFP.

2. Therapy with intravenous, intramuscular or oral iron at any time between the first/screening visit and the randomization visit, or anticipated requirement for iron supplementation during the study period.

3. Non-tunneled vascular catheter for dialysis.

4. Scheduled for kidney transplant within the next 8 weeks.

5. Active infection requiring systemic antimicrobial or antifungal therapy within 2 weeks prior to screening, or during screening period prior to randomization.

6. Hospitalization within 1 month prior to screening (except for vascular access surgery).

Extension Study, Open Label, Single Active Arm:

Key Inclusion Criteria:

1. Participated in Parent Study RMTI-SFP-6 and completed the follow-up/early term visit.

2. Hemoglobin ≤12.0 g/dL at screening.

3. TSAT ≤45% at screening. (Excursion of TSAT by ≤10% outside this range permitted only if all other inclusion/exclusion criteria are met).

4. Serum ferritin ≤1000 µg/L at screening. (Excursion of ferritin by ≤10% outside this range permitted only if all other inclusion/exclusion criteria are met).

Key Exclusion Criteria:

1. Had a serious adverse event attributable (i.e., probably, possibly, or definitely related) to study drug or had an adverse event attributable to study drug that necessitated premature withdrawal from the double-blind, placebo-controlled crossover phase of the parent study RMTI-SFP-6.

2. Non-tunneled vascular catheter for dialysis.

3. Scheduled for kidney transplant within 12 weeks after entry into extension phase.

4. Active infection requiring systemic antimicrobial or antifungal therapy within 2 weeks prior to dosing.

5. Pregnancy or intention to become pregnant during the study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Mobile	Alabama	United States	36688
2		Northridge	California	United States	91324
3		Arvada	Colorado	United States	80002
4		Westminster	Colorado	United States	80031
5		Lauderhill	Florida	United States	33319
6		Marietta	Georgia	United States	30060
7		Chicago	Illinois	United States	60616
8		Peoria	Illinois	United States	61603
9		Columbus	Indiana	United States	47201
10		Wichita	Kansas	United States	67214
11		Baton Rouge	Louisiana	United States	70808
12		Shreveport	Louisiana	United States	71101
13		Camp Springs	Maryland	United States	20748
14		Gulfport	Mississippi	United States	39501
15		McComb	Mississippi	United States	39648
16		Tupelo	Mississippi	United States	38801
17		St. Peters	Missouri	United States	63376
18		Lincoln	Nebraska	United States	68510
19		Reno	Nevada	United States	89511
20		Rocky Mount	North Carolina	United States	27804
21		Dayton	Ohio	United States	45428
22		Columbia	South Carolina	United States	29209
23	Research Across America	Houston	Texas	United States	75234
24		Houston	Texas	United States	77051
25		Irving	Texas	United States	75061
26		Mission	Texas	United States	78572
27		Temple	Texas	United States	76508
28		Tyler	Texas	United States	75701
29		Courtice	Ontario	Canada	L1E 3C3
30		Montreal	Quebec	Canada	H3A 1A1
31		Regina	Saskatchewan	Canada	54P 0W5

Sponsors and Collaborators

• Rockwell Medical Technologies, Inc.

Investigators

• Study Director: Ray Pratt, MD, Rockwell Medical, Inc

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Rockwell Medical Technologies, Inc.
• ClinicalTrials.gov Identifier: NCT01503021
• Other Study ID Numbers: RMTI-SFP-6
• First Posted: Jan 2, 2012
• Last Update Posted: Oct 25, 2016
• Last Verified: Sep 1, 2016

• Keywords provided by Rockwell Medical Technologies, Inc.: Soluble ferric pyrophosphate; Chronic kidney disease; Chronic hemodialysis; Ferric pyrophosphate citrate
• Additional relevant MeSH terms: Kidney Diseases; Renal Insufficiency, Chronic; Kidney Failure, Chronic

Study Results

Participant Flow

Arm/Group Title	SFP/Placebo	Placebo/SFP
Arm/Group Description	Soluble ferric pyrophosphate (SFP) 2 µmoles (110 µg) iron/L of dialysate in liquid bicarbonate concentrate x 2 weeks, then 1 week washout, then standard liquid bicarbonate concentrate without SFP x 2 weeks	Standard liquid bicarbonate concentrate without SFP x 2 weeks, then 1 week washout, then soluble ferric pyrophosphate (SFP) 2 µmoles (110 µg) iron/L of dialysate in liquid bicarbonate concentrate x 2 weeks.
Period Title: Overall Study
STARTED	360	358
Dosed	351	352
Completed Treatment	333	333
COMPLETED	333	332
NOT COMPLETED	27	26

Baseline Characteristics

Arm/Group Title	SFP/Placebo	Placebo/SFP	Total
Arm/Group Description	Soluble ferric pyrophosphate (SFP) 2 µM (110 µg) iron/L of dialysate in liquid bicarbonate concentrate x 2 weeks, then 1 week washout, then standard liquid bicarbonate concentrate without SFP x 2 weeks	Standard liquid bicarbonate concentrate without SFP x 2 weeks, then 1 week washout, then soluble ferric pyrophosphate (SFP) 2 µM (110 µg) iron/L of dialysate in liquid bicarbonate concentrate x 2 weeks.	Total of all reporting groups
Overall Participants	351	352	703
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	59.9 (13.18)	59.5 (13.30)	59.7 (13.23)
Sex: Female, Male (Count of Participants)
Female	137 39%	141 40.1%	278 39.5%
Male	214 61%	211 59.9%	425 60.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	90 25.6%	106 30.1%	196 27.9%
Not Hispanic or Latino	261 74.4%	246 69.9%	507 72.1%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	5 1.4%	0 0%	5 0.7%
Asian	6 1.7%	8 2.3%	14 2%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	154 43.9%	145 41.2%	299 42.5%
White	185 52.7%	194 55.1%	379 53.9%
More than one race	1 0.3%	5 1.4%	6 0.9%
Unknown or Not Reported	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Incidence of Treatment-emergent Adverse Events
Description	Adverse events for a given intervention (SFP or Placebo) are counted from the date of the first day of dosing of the intervention until 7 days after the last day of dosing of the intervention.
Time Frame	Up to 7 weeks for the Parent (Crossover) Study and up to 53 weeks for Extension Study

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of study drug (SFP or placebo, as applicable).

Arm/Group Title	Soluble Ferric Pyrophosphate	Placebo	Open-label Soluble Ferric Pyrophosphate
Arm/Group Description	Parent Study: Blinded soluble ferric pyrophosphate administered via the liquid bicarbonate concentrate to yield a final dialysate concentration of 2 micromolar (110 micrograms) iron/liter.	Parent Study: Blinded standard liquid bicarbonate concentrate	Extension Study: Open-label soluble ferric pyrophosphate administered via the liquid bicarbonate concentrate to yield a final dialysate concentration of 2 micromolar (110 micrograms) iron/liter.
Measure Participants	693	687	309
Number [percentage of participants]	31.6 9%	35.1 10%	95.1 13.5%

2. Primary Outcome

Title	Incidence of Treatment-emergent Adverse Events of Intradialytic Hypotension
Description	Adverse events for a given intervention (SFP or Placebo) are counted from the date of the first day of dosing of the intervention until 7 days after the last day of dosing of the intervention. For each adverse event, investigators assessed whether the event met the protocol criteria for intradialytic hypotension. Intradialytic hypotension events were only to have been reported as adverse events if they exceeded the individual subject's baseline pattern of intradialytic hypotension.
Time Frame	Up to 7 weeks for the Parent (Crossover) Study and up to 53 weeks for Extension Study

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of study drug (SFP or placebo, as applicable).

Arm/Group Title	Soluble Ferric Pyrophosphate	Placebo	Open-label Soluble Ferric Pyrophosphate
Arm/Group Description	Parent Study: Blinded soluble ferric pyrophosphate administered via the liquid bicarbonate concentrate to yield a final dialysate concentration of 2 micromolar (110 micrograms) iron/liter.	Parent Study: Blinded standard liquid bicarbonate concentrate	Extension Study: Open-label soluble ferric pyrophosphate administered via the liquid bicarbonate concentrate to yield a final dialysate concentration of 2 micromolar (110 micrograms) iron/liter.
Measure Participants	693	687	309
Number [percentage of participants]	4.3 1.2%	4.9 1.4%	12.6 1.8%

3. Primary Outcome

Title	Incidence of Related Suspected Hypersensitivity Reactions
Description	Adverse events for a given intervention (SFP or Placebo) are counted from the date of the first day of dosing of the intervention until 7 days after the last day of dosing of the intervention. For each adverse event, investigators assessed whether the event met protocol criteria for suspected hypersensitivity reactions.
Time Frame	Up to 7 weeks for the Parent (Crossover) Study and up to 53 weeks for Extension Study

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of study drug (SFP or placebo, as applicable).

Arm/Group Title	Soluble Ferric Pyrophosphate	Placebo	Open-label Soluble Ferric Pyrophosphate
Arm/Group Description	Parent Study: Blinded soluble ferric pyrophosphate administered via the liquid bicarbonate concentrate to yield a final dialysate concentration of 2 micromolar (110 micrograms) iron/liter.	Parent Study: Blinded standard liquid bicarbonate concentrate	Extension Study: Open-label soluble ferric pyrophosphate administered via the liquid bicarbonate concentrate to yield a final dialysate concentration of 2 micromolar (110 micrograms) iron/liter.
Measure Participants	693	687	309
Number [percentage of participants]	0 0%	0 0%	0 0%

4. Secondary Outcome

Title	Incidence of Composite Cardiovascular Events
Description	Adverse events for a given intervention (SFP or Placebo) are counted from the date of the first day of dosing of the intervention until 7 days after the last day of dosing of the intervention. Adverse event terms meeting criteria for composite cardiovascular events were pre-specified in the statistical analysis plan for the study.
Time Frame	Up to 7 weeks for the Parent (Crossover) Study and up to 53 weeks for Extension Study

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of study drug (SFP or placebo, as applicable).

Arm/Group Title	Soluble Ferric Pyrophosphate	Placebo	Open-label Soluble Ferric Pyrophosphate
Arm/Group Description	Parent Study: Blinded soluble ferric pyrophosphate administered via the liquid bicarbonate concentrate to yield a final dialysate concentration of 2 micromolar (110 micrograms) iron/liter.	Parent Study: Blinded standard liquid bicarbonate concentrate	Extension Study: Open-label soluble ferric pyrophosphate administered via the liquid bicarbonate concentrate to yield a final dialysate concentration of 2 micromolar (110 micrograms) iron/liter.
Measure Participants	693	687	309
Number [percentage of participants]	1.0 0.3%	0.7 0.2%	13.6 1.9%

5. Secondary Outcome

Title	Incidence of Hemodialysis Vascular Access Thrombotic Events
Description	Adverse events for a given intervention (SFP or Placebo) are counted from the date of the first day of dosing of the intervention until 7 days after the last day of dosing of the intervention. Adverse event terms meeting criteria for hemodialysis vascular access thrombotic events were pre-specified in the statistical analysis plan for the study.
Time Frame	Up to 7 weeks for the Parent (Crossover) Study and up to 53 weeks for Extension Study

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of study drug (SFP or placebo, as applicable).

Arm/Group Title	Soluble Ferric Pyrophosphate	Placebo	Open-label Soluble Ferric Pyrophosphate
Arm/Group Description	Parent Study: Blinded soluble ferric pyrophosphate administered via the liquid bicarbonate concentrate to yield a final dialysate concentration of 2 micromolar (110 micrograms) iron/liter.	Parent Study: Blinded standard liquid bicarbonate concentrate	Extension Study: Open-label soluble ferric pyrophosphate administered via the liquid bicarbonate concentrate to yield a final dialysate concentration of 2 micromolar (110 micrograms) iron/liter.
Measure Participants	693	687	309
Number [percentage of participants]	0.6 0.2%	0.6 0.2%	17.8 2.5%

6. Secondary Outcome

Title	Incidence of Other Thrombotic Events
Description	Adverse events for a given intervention (SFP or Placebo) are counted from the date of the first day of dosing of the intervention until 7 days after the last day of dosing of the intervention. Adverse event terms meeting criteria for other thrombotic events were pre-specified in the statistical analysis plan for the study.
Time Frame	Up to 7 weeks for the Parent (Crossover) Study and up to 53 weeks for Extension Study

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of study drug (SFP or placebo, as applicable).

Arm/Group Title	Soluble Ferric Pyrophosphate	Placebo	Open-label Soluble Ferric Pyrophosphate
Arm/Group Description	Parent Study: Blinded soluble ferric pyrophosphate administered via the liquid bicarbonate concentrate to yield a final dialysate concentration of 2 micromolar (110 micrograms) iron/liter.	Parent Study: Blinded standard liquid bicarbonate concentrate	Extension Study: Open-label soluble ferric pyrophosphate administered via the liquid bicarbonate concentrate to yield a final dialysate concentration of 2 micromolar (110 micrograms) iron/liter.
Measure Participants	693	687	309
Number [percentage of participants]	0 0%	0.1 0%	1.9 0.3%

7. Secondary Outcome

Title	Incidence of Systemic/Serious Infections
Description	Adverse events for a given intervention (SFP or Placebo) are counted from the date of the first day of dosing of the intervention until 7 days after the last day of dosing of the intervention. Adverse events of systemic/serious infections were defined in the statistical analysis plan for the study to include infections for which the subject was administered at least 3 doses of an IV antibiotic, and infections for which the subject was hospitalized.
Time Frame	Up to 7 weeks for the Parent (Crossover) Study and up to 53 weeks for Extension Study

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of study drug (SFP or placebo, as applicable).

Arm/Group Title	Soluble Ferric Pyrophosphate	Placebo	Open-label Soluble Ferric Pyrophosphate
Arm/Group Description	Parent Study: Blinded soluble ferric pyrophosphate administered via the liquid bicarbonate concentrate to yield a final dialysate concentration of 2 micromolar (110 micrograms) iron/liter.	Parent Study: Blinded standard liquid bicarbonate concentrate	Extension Study: Open-label soluble ferric pyrophosphate administered via the liquid bicarbonate concentrate to yield a final dialysate concentration of 2 micromolar (110 micrograms) iron/liter.
Measure Participants	693	687	309
Number [percentage of participants]	0.4 0.1%	0.9 0.3%	11.3 1.6%

8. Secondary Outcome

Title	Incidence of Serious Adverse Events
Description	Adverse events for a given intervention (SFP or Placebo) are counted from the date of the first day of dosing of the intervention until 7 days after the last day of dosing of the intervention. For each adverse event, investigators assessed whether the event met seriousness criteria.
Time Frame	Up to 7 weeks for the Parent (Crossover) Study and up to 53 weeks for Extension Study

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of study drug (SFP or placebo, as applicable).

Arm/Group Title	Soluble Ferric Pyrophosphate	Placebo	Open-label Soluble Ferric Pyrophosphate
Arm/Group Description	Parent Study: Blinded soluble ferric pyrophosphate administered via the liquid bicarbonate concentrate to yield a final dialysate concentration of 2 micromolar (110 micrograms) iron/liter.	Parent Study: Blinded standard liquid bicarbonate concentrate	Extension Study: Open-label soluble ferric pyrophosphate administered via the liquid bicarbonate concentrate to yield a final dialysate concentration of 2 micromolar (110 micrograms) iron/liter.
Measure Participants	693	687	309
Number [percentage of participants]	4.3 1.2%	5.1 1.4%	46.6 6.6%

9. Other Pre-specified Outcome

Title	Serum Iron Change From Pre-dialysis to Post-dialysis at Week 2
Description	Serum iron was assessed from samples obtained pre-dialysis and post-dialysis at a single hemodialysis during study week 2. Because of the crossover nature of the study, the week 2 values reflect effects of SFP in the SFP/Placebo arm and effects of Placebo in the Placebo/SFP arm.
Time Frame	Pre-dialysis and post-dialysis during study week 2 of the Parent (Crossover) Study

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of study drug (SFP or placebo, as applicable).

Arm/Group Title	SFP/Placebo	Placebo/SFP
Arm/Group Description	Parent Study: Blinded soluble ferric pyrophosphate (SFP) 2 µmoles (110 µg) iron/L of dialysate, then 1 week washout, then blinded standard liquid bicarbonate concentrate without SFP x 2 weeks SFP: Dialysis with SFP administered via the liquid bicarbonate concentrate at a concentration of 2 µmoles (110 µg) iron/L of dialysate Placebo: Dialysis with standard liquid bicarbonate concentrate without iron	Parent Study: Blinded standard liquid bicarbonate concentrate without SFP x 2 weeks, then 1 week washout, then soluble ferric pyrophosphate (SFP) 2 µmoles (110 µg) iron/L of dialysate x 2 weeks. SFP: Dialysis with SFP administered via the liquid bicarbonate concentrate at a concentration of 2 µmoles (110 µg) iron/L of dialysate Placebo: Dialysis with standard liquid bicarbonate concentrate without iron
Measure Participants	307	311
Pre-dialysis	13.66 (5.435)	13.65 (5.299)
Post-dialysis	38.60 (10.151)	14.97 (7.753)
Change from pre-dialysis to post-dialysis	24.91 (9.243)	1.36 (5.447)

10. Other Pre-specified Outcome

Title	Serum Iron Change From Pre-dialysis to Post-dialysis at Week 5
Description	Serum iron was assessed from samples obtained pre-dialysis and post-dialysis at a single hemodialysis during study week 5. Because of the crossover nature of the study, the week 5 values reflect effects of Placebo in the SFP/Placebo arm and effects of SFP in the Placebo/SFP arm.
Time Frame	Pre-dialysis and post-dialysis during study week 5 of the Parent (Crossover) Study

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of study drug (SFP or placebo, as applicable).

Arm/Group Title	SFP/Placebo	Placebo/SFP
Arm/Group Description	Parent Study: Blinded soluble ferric pyrophosphate (SFP) 2 µmoles (110 µg) iron/L of dialysate, then 1 week washout, then blinded standard liquid bicarbonate concentrate without SFP x 2 weeks SFP: Dialysis with SFP administered via the liquid bicarbonate concentrate at a concentration of 2 µmoles (110 µg) iron/L of dialysate Placebo: Dialysis with standard liquid bicarbonate concentrate without iron	Parent Study: Blinded standard liquid bicarbonate concentrate without SFP x 2 weeks, then 1 week washout, then soluble ferric pyrophosphate (SFP) 2 µmoles (110 µg) iron/L of dialysate x 2 weeks. SFP: Dialysis with SFP administered via the liquid bicarbonate concentrate at a concentration of 2 µmoles (110 µg) iron/L of dialysate Placebo: Dialysis with standard liquid bicarbonate concentrate without iron
Measure Participants	299	303
Pre-dialysis	12.97 (4.731)	13.02 (4.856)
Post-dialysis	13.98 (7.884)	37.79 (11.183)
Change from pre-dialysis to post-dialysis	1.12 (6.834)	24.82 (9.827)

11. Other Pre-specified Outcome

Title	Unsaturated Iron-binding Capacity Change From Pre-dialysis to Post-dialysis at Week 2
Description	Unsaturated iron-binding capacity was assessed from samples obtained pre-dialysis and post-dialysis at a single hemodialysis during study week 2. Because of the crossover nature of the study, the week 2 values reflect effects of SFP in the SFP/Placebo arm and effects of Placebo in the Placebo/SFP arm.
Time Frame	Pre-dialysis and post-dialysis during study week 2 of the Parent (Crossover) Study

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of study drug (SFP or placebo, as applicable).

Arm/Group Title	SFP/Placebo	Placebo/SFP
Arm/Group Description	Parent Study: Blinded soluble ferric pyrophosphate (SFP) 2 µmoles (110 µg) iron/L of dialysate, then 1 week washout, then blinded standard liquid bicarbonate concentrate without SFP x 2 weeks SFP: Dialysis with SFP administered via the liquid bicarbonate concentrate at a concentration of 2 µmoles (110 µg) iron/L of dialysate Placebo: Dialysis with standard liquid bicarbonate concentrate without iron	Parent Study: Blinded standard liquid bicarbonate concentrate without SFP x 2 weeks, then 1 week washout, then soluble ferric pyrophosphate (SFP) 2 µmoles (110 µg) iron/L of dialysate x 2 weeks. SFP: Dialysis with SFP administered via the liquid bicarbonate concentrate at a concentration of 2 µmoles (110 µg) iron/L of dialysate Placebo: Dialysis with standard liquid bicarbonate concentrate without iron
Measure Participants	351	352
Pre-dialysis	27.95 (6.310)	28.05 (7.442)
Post-dialysis	11.44 (6.899)	30.49 (8.909)
Change from pre-dialysis to post-dialysis	-16.47 (7.040)	2.49 (4.910)

12. Other Pre-specified Outcome

Title	Unsaturated Iron-binding Capacity Change From Pre-dialysis to Post-dialysis at Week 5
Description	Unsaturated iron-binding capacity was assessed from samples obtained pre-dialysis and post-dialysis at a single hemodialysis during study week 5. Because of the crossover nature of the study, the week 5 values reflect effects of Placebo in the SFP/Placebo arm and effects of SFP in the Placebo/SFP arm.
Time Frame	Pre-dialysis and post-dialysis during study week 5 of the Parent (Crossover) Study

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of study drug (SFP or placebo, as applicable).

Arm/Group Title	SFP/Placebo	Placebo/SFP
Arm/Group Description	Parent Study: Blinded soluble ferric pyrophosphate (SFP) 2 µmoles (110 µg) iron/L of dialysate, then 1 week washout, then blinded standard liquid bicarbonate concentrate without SFP x 2 weeks SFP: Dialysis with SFP administered via the liquid bicarbonate concentrate at a concentration of 2 µmoles (110 µg) iron/L of dialysate Placebo: Dialysis with standard liquid bicarbonate concentrate without iron	Parent Study: Blinded standard liquid bicarbonate concentrate without SFP x 2 weeks, then 1 week washout, then soluble ferric pyrophosphate (SFP) 2 µmoles (110 µg) iron/L of dialysate x 2 weeks. SFP: Dialysis with SFP administered via the liquid bicarbonate concentrate at a concentration of 2 µmoles (110 µg) iron/L of dialysate Placebo: Dialysis with standard liquid bicarbonate concentrate without iron
Measure Participants	351	352
Pre-dialysis	28.80 (6.745)	29.05 (7.311)
Post-dialysis	30.95 (8.488)	12.41 (8.463)
Change from pre-dialysis to post-dialysis	2.05 (5.333)	-16.68 (7.452)

13. Other Pre-specified Outcome

Title	Transferrin Saturation Change From Pre-dialysis to Post-dialysis at Week 2
Description	Transferrin saturation (based on TIBC derived from transferrin levels) was assessed from samples obtained pre-dialysis and post-dialysis at a single hemodialysis during study week 2. Because of the crossover nature of the study, the week 2 values reflect effects of SFP in the SFP/Placebo arm and effects of Placebo in the Placebo/SFP arm.
Time Frame	Pre-dialysis and post-dialysis during study week 2 of the Parent (Crossover) Study

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of study drug (SFP or placebo, as applicable).

Arm/Group Title	SFP/Placebo	Placebo/SFP
Arm/Group Description	Parent Study: Blinded soluble ferric pyrophosphate (SFP) 2 µmoles (110 µg) iron/L of dialysate, then 1 week washout, then blinded standard liquid bicarbonate concentrate without SFP x 2 weeks SFP: Dialysis with SFP administered via the liquid bicarbonate concentrate at a concentration of 2 µmoles (110 µg) iron/L of dialysate Placebo: Dialysis with standard liquid bicarbonate concentrate without iron	Parent Study: Blinded standard liquid bicarbonate concentrate without SFP x 2 weeks, then 1 week washout, then soluble ferric pyrophosphate (SFP) 2 µmoles (110 µg) iron/L of dialysate x 2 weeks. SFP: Dialysis with SFP administered via the liquid bicarbonate concentrate at a concentration of 2 µmoles (110 µg) iron/L of dialysate Placebo: Dialysis with standard liquid bicarbonate concentrate without iron
Measure Participants	351	352
Pre-dialysis	30.31 (11.357)	30.46 (11.849)
Post-dialysis	80.85 (17.646)	30.23 (14.397)
Change from pre-dialysis to post-dialysis	50.44 (17.442)	-0.25 (10.348)

14. Other Pre-specified Outcome

Title	Transferrin Saturation Change From Pre-dialysis to Post-dialysis at Week 5
Description	Transferrin saturation (based on TIBC derived from transferrin levels) was assessed from samples obtained pre-dialysis and post-dialysis at a single hemodialysis during study week 5. Because of the crossover nature of the study, the week 5 values reflect effects of Placebo in the SFP/Placebo arm and effects of SFP in the Placebo/SFP arm.
Time Frame	Pre-dialysis and post-dialysis during study week 5 of the Parent (Crossover) Study

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of study drug (SFP or placebo, as applicable).

Arm/Group Title	SFP/Placebo	Placebo/SFP
Arm/Group Description	Parent Study: Blinded soluble ferric pyrophosphate (SFP) 2 µmoles (110 µg) iron/L of dialysate, then 1 week washout, then blinded standard liquid bicarbonate concentrate without SFP x 2 weeks SFP: Dialysis with SFP administered via the liquid bicarbonate concentrate at a concentration of 2 µmoles (110 µg) iron/L of dialysate Placebo: Dialysis with standard liquid bicarbonate concentrate without iron	Parent Study: Blinded standard liquid bicarbonate concentrate without SFP x 2 weeks, then 1 week washout, then soluble ferric pyrophosphate (SFP) 2 µmoles (110 µg) iron/L of dialysate x 2 weeks. SFP: Dialysis with SFP administered via the liquid bicarbonate concentrate at a concentration of 2 µmoles (110 µg) iron/L of dialysate Placebo: Dialysis with standard liquid bicarbonate concentrate without iron
Measure Participants	351	352
Pre-dialysis	26.75 (10.302)	28.88 (10.585)
Post-dialysis	28.73 (15.818)	79.18 (20.008)
Change from pre-dialysis to post-dialysis	0.10 (13.792)	50.42 (18.163)

15. Other Pre-specified Outcome

Title	Ferritin
Description	The baseline and end of treatment predialysis ferritin levels were evaluated for the 52-week extension study to determine whether soluble ferric pyrophosphate increases iron stores.
Time Frame	Baseline, up to 53 weeks for Extension Study

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of study drug (SFP or placebo, as applicable).

Arm/Group Title	Open-label Soluble Ferric Pyrophosphate
Arm/Group Description	Extension Study: Open-label soluble ferric pyrophosphate administered via the liquid bicarbonate concentrate to yield a final dialysate concentration of 2 micromolar (110 micrograms) iron/liter.
Measure Participants	309
Baseline	653.0 (288.70)
End of Treatment	520.3 (341.84)
Change from Baseline	-132.0 (311.15)

16. Other Pre-specified Outcome

Title	Serum Iron
Description	The baseline and end of treatment predialysis serum iron levels were evaluated for the 52-week extension study to determine the effect of soluble ferric pyrophosphate on serum iron.
Time Frame	Baseline, up to 53 weeks for Extension Study

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of study drug (SFP or placebo, as applicable).

Arm/Group Title	Open-label Soluble Ferric Pyrophosphate
Arm/Group Description	Extension Study: Open-label soluble ferric pyrophosphate administered via the liquid bicarbonate concentrate to yield a final dialysate concentration of 2 micromolar (110 micrograms) iron/liter.
Measure Participants	309
Baseline	12.650 (4.6488)
End of Treatment	11.815 (5.3443)
Change from Baseline	-0.772 (5.2686)

17. Other Pre-specified Outcome

Title	Transferrin Saturation
Description	The baseline and end of treatment predialysis transferrin saturation were evaluated for the 52-week extension study to confirm clearance of iron derived from soluble ferric pyrophosphate.
Time Frame	Baseline, up to 53 weeks for Extension Study

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of study drug (SFP or placebo, as applicable).

Arm/Group Title	Open-label Soluble Ferric Pyrophosphate
Arm/Group Description	Extension Study: Open-label soluble ferric pyrophosphate administered via the liquid bicarbonate concentrate to yield a final dialysate concentration of 2 micromolar (110 micrograms) iron/liter.
Measure Participants	309
Baseline	30.050 (10.0504)
End of Treatment	28.114 (11.5075)
Change from Baseline	-1.835 (11.7221)

18. Other Pre-specified Outcome

Title	Incidence of Patients Meeting Hy's Law Criteria
Description	The peak alanine aminotransferase and the peak total bilirubin levels were evaluated per patient. Laboratory values for a given intervention (SFP or Placebo) are counted from the date of the first day of dosing of the intervention until 7 days after the last day of dosing of the intervention. Patients with alanine aminotransferase more than three times the upper limit of normal and also total bilirubin more than two times the upper limit of normal are counted.
Time Frame	Up to 7 weeks for the Parent (Crossover) Study and up to 53 weeks for Extension Study

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of study drug (SFP or placebo, as applicable).

Arm/Group Title	Soluble Ferric Pyrophosphate	Placebo	Open-label Soluble Ferric Pyrophosphate
Arm/Group Description	Parent Study: Blinded soluble ferric pyrophosphate administered via the liquid bicarbonate concentrate to yield a final dialysate concentration of 2 micromolar (110 micrograms) iron/liter.	Parent Study: Blinded standard liquid bicarbonate concentrate	Extension Study: Open-label soluble ferric pyrophosphate administered via the liquid bicarbonate concentrate to yield a final dialysate concentration of 2 micromolar (110 micrograms) iron/liter.
Measure Participants	693	687	309
Number [participants]	0 0%	0 0%	0 0%

Adverse Events

Time Frame	Up to 7 weeks for the Parent (Crossover) Study and up to 53 weeks for Extension Study
Adverse Event Reporting Description	Adverse events for a given intervention are counted from the first day of dosing of the intervention until 7 days after the last day of dosing of the intervention. Information regarding adverse events was elicited from participants using non-leading questions at each study visit, which generally occurred 3 times per week during the study.
Arm/Group Title	Soluble Ferric Pyrophosphate		Placebo		Open-label Soluble Ferric Pyrophosphate
Arm/Group Description	Parent Study: Blinded soluble ferric pyrophosphate administered via the liquid bicarbonate concentrate to yield a final dialysate concentration of 2 micromolar (110 micrograms) iron/liter.		Parent Study: Blinded standard liquid bicarbonate concentrate		Extension Study: Open-label soluble ferric pyrophosphate administered via the liquid bicarbonate concentrate to yield a final dialysate concentration of 2 micromolar (110 micrograms) iron/liter.
All Cause Mortality
	Soluble Ferric Pyrophosphate		Placebo		Open-label Soluble Ferric Pyrophosphate
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Soluble Ferric Pyrophosphate		Placebo		Open-label Soluble Ferric Pyrophosphate
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	30/693 (4.3%)		35/687 (5.1%)		144/309 (46.6%)
Blood and lymphatic system disorders
Anaemia	0/693 (0%)		1/687 (0.1%)		5/309 (1.6%)
Coagulopathy	0/693 (0%)		0/687 (0%)		1/309 (0.3%)
Haemorrhagic anaemia	0/693 (0%)		0/687 (0%)		1/309 (0.3%)
Cardiac disorders
Acute myocardial infarction	4/693 (0.6%)		1/687 (0.1%)		5/309 (1.6%)
Angina pectoris	0/693 (0%)		1/687 (0.1%)		5/309 (1.6%)
Atrial fibrillation	0/693 (0%)		1/687 (0.1%)		4/309 (1.3%)
Cardiac arrest	0/693 (0%)		1/687 (0.1%)		4/309 (1.3%)
Cardiac failure congestive	1/693 (0.1%)		2/687 (0.3%)		6/309 (1.9%)
Coronary artery disease	0/693 (0%)		2/687 (0.3%)		5/309 (1.6%)
Myocardial infarction	1/693 (0.1%)		3/687 (0.4%)		1/309 (0.3%)
Pericardial effusion	1/693 (0.1%)		0/687 (0%)		2/309 (0.6%)
Sinus tachycardia	0/693 (0%)		1/687 (0.1%)		0/309 (0%)
Angina unstable	0/693 (0%)		0/687 (0%)		3/309 (1%)
Arteriosclerosis coronary artery	0/693 (0%)		0/687 (0%)		2/309 (0.6%)
Ischaemic cardiomyopathy	0/693 (0%)		0/687 (0%)		1/309 (0.3%)
Sick sinus syndrome	0/693 (0%)		0/687 (0%)		1/309 (0.3%)
Tachycardia	0/693 (0%)		0/687 (0%)		1/309 (0.3%)
Ventricular tachycardia	0/693 (0%)		0/687 (0%)		1/309 (0.3%)
Congenital, familial and genetic disorders
Gastrointestinal arteriovenous malformation	0/693 (0%)		0/687 (0%)		1/309 (0.3%)
Eye disorders
Retinal artery embolism	0/693 (0%)		0/687 (0%)		1/309 (0.3%)
Gastrointestinal disorders
Anal fistula	0/693 (0%)		1/687 (0.1%)		0/309 (0%)
Duodenal ulcer haemorrhage	1/693 (0.1%)		0/687 (0%)		0/309 (0%)
Dysphagia	1/693 (0.1%)		0/687 (0%)		0/309 (0%)
Enterovesical fistula	0/693 (0%)		1/687 (0.1%)		0/309 (0%)
Impaired gastric emptying	1/693 (0.1%)		1/687 (0.1%)		0/309 (0%)
Lower gastrointestinal haemorrhage	0/693 (0%)		1/687 (0.1%)		1/309 (0.3%)
Pancreatitis	1/693 (0.1%)		0/687 (0%)		0/309 (0%)
Upper gastrointestinal haemorrhage	0/693 (0%)		1/687 (0.1%)		2/309 (0.6%)
Gastrointestinal haemorrhage	0/693 (0%)		0/687 (0%)		8/309 (2.6%)
Abdominal pain	0/693 (0%)		0/687 (0%)		2/309 (0.6%)
Small intestinal obstruction	0/693 (0%)		0/687 (0%)		2/309 (0.6%)
Abdominal pain lower	0/693 (0%)		0/687 (0%)		1/309 (0.3%)
Colitis	0/693 (0%)		0/687 (0%)		1/309 (0.3%)
Duodenitis	0/693 (0%)		0/687 (0%)		1/309 (0.3%)
Gastric ulcer	0/693 (0%)		0/687 (0%)		1/309 (0.3%)
Intestinal perforation	0/693 (0%)		0/687 (0%)		1/309 (0.3%)
Oesophagitis	0/693 (0%)		0/687 (0%)		1/309 (0.3%)
Rectal haemorrhage	0/693 (0%)		0/687 (0%)		1/309 (0.3%)
General disorders
Gait disturbance	1/693 (0.1%)		0/687 (0%)		0/309 (0%)
Systemic inflammatory response syndrome	0/693 (0%)		1/687 (0.1%)		0/309 (0%)
Non-cardiac chest pain	0/693 (0%)		0/687 (0%)		4/309 (1.3%)
Asthenia	0/693 (0%)		0/687 (0%)		2/309 (0.6%)
Chest pain	0/693 (0%)		0/687 (0%)		2/309 (0.6%)
Medical device complication	0/693 (0%)		0/687 (0%)		2/309 (0.6%)
Pyrexia	0/693 (0%)		0/687 (0%)		2/309 (0.6%)
Adverse drug reaction	0/693 (0%)		0/687 (0%)		1/309 (0.3%)
Device pacing issue	0/693 (0%)		0/687 (0%)		1/309 (0.3%)
Malaise	0/693 (0%)		0/687 (0%)		1/309 (0.3%)
Sudden death	0/693 (0%)		0/687 (0%)		1/309 (0.3%)
Hepatobiliary disorders
Cholecystitis acute	1/693 (0.1%)		0/687 (0%)		0/309 (0%)
Cholelithiasis	0/693 (0%)		0/687 (0%)		3/309 (1%)
Biliary dyskinesia	0/693 (0%)		0/687 (0%)		2/309 (0.6%)
Cholecystitis	0/693 (0%)		0/687 (0%)		2/309 (0.6%)
Bile duct obstruction	0/693 (0%)		0/687 (0%)		1/309 (0.3%)
Biliary colic	0/693 (0%)		0/687 (0%)		1/309 (0.3%)
Hepatic necrosis	0/693 (0%)		0/687 (0%)		1/309 (0.3%)
Immune system disorders
Anaphylactic reaction	0/693 (0%)		0/687 (0%)		1/309 (0.3%)
Drug hypersensitivity	0/693 (0%)		0/687 (0%)		1/309 (0.3%)
Infections and infestations
Bacteraemia	0/693 (0%)		1/687 (0.1%)		4/309 (1.3%)
Bronchitis	0/693 (0%)		2/687 (0.3%)		6/309 (1.9%)
Cholecystitis infective	0/693 (0%)		1/687 (0.1%)		0/309 (0%)
Device related infection	0/693 (0%)		1/687 (0.1%)		1/309 (0.3%)
Gastroenteritis	1/693 (0.1%)		1/687 (0.1%)		2/309 (0.6%)
Lobar pneumonia	0/693 (0%)		1/687 (0.1%)		0/309 (0%)
Pneumonia	0/693 (0%)		5/687 (0.7%)		7/309 (2.3%)
Pneumonia primary atypical	1/693 (0.1%)		0/687 (0%)		0/309 (0%)
Streptococcal sepsis	1/693 (0.1%)		0/687 (0%)		0/309 (0%)
Viral infection	1/693 (0.1%)		0/687 (0%)		1/309 (0.3%)
Sepsis	0/693 (0%)		0/687 (0%)		6/309 (1.9%)
Cellulitis	0/693 (0%)		0/687 (0%)		5/309 (1.6%)
Gangrene	0/693 (0%)		0/687 (0%)		4/309 (1.3%)
Septic shock	0/693 (0%)		0/687 (0%)		4/309 (1.3%)
Diabetic foot infection	0/693 (0%)		0/687 (0%)		3/309 (1%)
Urinary tract infection	0/693 (0%)		0/687 (0%)		3/309 (1%)
Arteriovenous fistula site infection	0/693 (0%)		0/687 (0%)		2/309 (0.6%)
Staphylococcal bacteraemia	0/693 (0%)		0/687 (0%)		2/309 (0.6%)
Abscess limb	0/693 (0%)		0/687 (0%)		1/309 (0.3%)
Arteriovenous graft site infection	0/693 (0%)		0/687 (0%)		1/309 (0.3%)
Chest wall abscess	0/693 (0%)		0/687 (0%)		1/309 (0.3%)
Clostridium difficile colitis	0/693 (0%)		0/687 (0%)		1/309 (0.3%)
Escherichia urinary tract infection	0/693 (0%)		0/687 (0%)		1/309 (0.3%)
Gastroenteritis viral	0/693 (0%)		0/687 (0%)		1/309 (0.3%)
Nasal abscess	0/693 (0%)		0/687 (0%)		1/309 (0.3%)
Necrotising fasciitis	0/693 (0%)		0/687 (0%)		1/309 (0.3%)
Osteomyelitis	0/693 (0%)		0/687 (0%)		1/309 (0.3%)
Pharyngitis	0/693 (0%)		0/687 (0%)		1/309 (0.3%)
Pneumonia influenzal	0/693 (0%)		0/687 (0%)		1/309 (0.3%)
Streptococcal bacteraemia	0/693 (0%)		0/687 (0%)		1/309 (0.3%)
Wound sepsis	0/693 (0%)		0/687 (0%)		1/309 (0.3%)
Injury, poisoning and procedural complications
Arteriovenous fistula site haemorrhage	1/693 (0.1%)		0/687 (0%)		1/309 (0.3%)
Arteriovenous fistula thrombosis	1/693 (0.1%)		1/687 (0.1%)		5/309 (1.6%)
Hip fracture	1/693 (0.1%)		2/687 (0.3%)		2/309 (0.6%)
Humerus fracture	0/693 (0%)		1/687 (0.1%)		1/309 (0.3%)
Postoperative ileus	0/693 (0%)		1/687 (0.1%)		0/309 (0%)
Procedural hypotension	0/693 (0%)		1/687 (0.1%)		0/309 (0%)
Subdural haematoma	0/693 (0%)		1/687 (0.1%)		1/309 (0.3%)
Vascular graft thrombosis	1/693 (0.1%)		1/687 (0.1%)		7/309 (2.3%)
Areriovenous fistula aneurysm	0/693 (0%)		0/687 (0%)		2/309 (0.6%)
Arteriovenous fistula site complication	0/693 (0%)		0/687 (0%)		2/309 (0.6%)
Ankle fracture	0/693 (0%)		0/687 (0%)		1/309 (0.3%)
Arteriovenous graft site haemorrhage	0/693 (0%)		0/687 (0%)		1/309 (0.3%)
Burns third degree	0/693 (0%)		0/687 (0%)		1/309 (0.3%)
Contusion	0/693 (0%)		0/687 (0%)		1/309 (0.3%)
Fall	0/693 (0%)		0/687 (0%)		1/309 (0.3%)
Muscle strain	0/693 (0%)		0/687 (0%)		1/309 (0.3%)
Post procedural myocardial infarction	0/693 (0%)		0/687 (0%)		1/309 (0.3%)
Toxicity to various agents	0/693 (0%)		0/687 (0%)		1/309 (0.3%)
Vascular graft complication	0/693 (0%)		0/687 (0%)		1/309 (0.3%)
Wrist fracture	0/693 (0%)		0/687 (0%)		1/309 (0.3%)
Investigations
International normalised ratio increased	0/693 (0%)		0/687 (0%)		1/309 (0.3%)
Metabolism and nutrition disorders
Hyperkalaemia	2/693 (0.3%)		1/687 (0.1%)		7/309 (2.3%)
Hypoglycaemia	2/693 (0.3%)		0/687 (0%)		3/309 (1%)
Fluid overload	0/693 (0%)		0/687 (0%)		9/309 (2.9%)
Diabetic foot	0/693 (0%)		0/687 (0%)		1/309 (0.3%)
Failure to thrive	0/693 (0%)		0/687 (0%)		1/309 (0.3%)
Hypocalcaemia	0/693 (0%)		0/687 (0%)		1/309 (0.3%)
Hypokalaemia	0/693 (0%)		0/687 (0%)		1/309 (0.3%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/693 (0%)		0/687 (0%)		1/309 (0.3%)
Bone cyst	0/693 (0%)		0/687 (0%)		1/309 (0.3%)
Muscular weakness	0/693 (0%)		0/687 (0%)		1/309 (0.3%)
Osteoarthritis	0/693 (0%)		0/687 (0%)		1/309 (0.3%)
Plantar fasciitis	0/693 (0%)		0/687 (0%)		1/309 (0.3%)
Rhabdomyolysis	0/693 (0%)		0/687 (0%)		1/309 (0.3%)
Systemic lupus erythematosus	0/693 (0%)		0/687 (0%)		1/309 (0.3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bladder cancer	0/693 (0%)		0/687 (0%)		1/309 (0.3%)
Breast cancer in situ	0/693 (0%)		0/687 (0%)		1/309 (0.3%)
Metastatic renal cell carcinoma	0/693 (0%)		0/687 (0%)		1/309 (0.3%)
Nervous system disorders
Cerebrovascular accident	1/693 (0.1%)		0/687 (0%)		1/309 (0.3%)
Convulsion	0/693 (0%)		1/687 (0.1%)		0/309 (0%)
Metabolic encephalopathy	0/693 (0%)		1/687 (0.1%)		3/309 (1%)
Syncope	2/693 (0.3%)		1/687 (0.1%)		5/309 (1.6%)
Transient ischaemic attack	1/693 (0.1%)		0/687 (0%)		3/309 (1%)
Hepatic encephalopathy	0/693 (0%)		0/687 (0%)		3/309 (1%)
Uraemic encephalopathy	0/693 (0%)		0/687 (0%)		2/309 (0.6%)
Haemorrhage intracranial	0/693 (0%)		0/687 (0%)		1/309 (0.3%)
Subarachnoid haemorrhage	0/693 (0%)		0/687 (0%)		1/309 (0.3%)
Vascular dementia	0/693 (0%)		0/687 (0%)		1/309 (0.3%)
Psychiatric disorders
Bipolar disorder	1/693 (0.1%)		0/687 (0%)		0/309 (0%)
Mental status changes	0/693 (0%)		0/687 (0%)		1/309 (0.3%)
Renal and urinary disorders
Azotaemia	0/693 (0%)		0/687 (0%)		1/309 (0.3%)
Nephrolithiasis	0/693 (0%)		0/687 (0%)		1/309 (0.3%)
Respiratory, thoracic and mediastinal disorders
Acute pulmonary oedema	1/693 (0.1%)		0/687 (0%)		0/309 (0%)
Acute respiratory failure	0/693 (0%)		2/687 (0.3%)		3/309 (1%)
Chronic obstructive pulmonary disease	1/693 (0.1%)		0/687 (0%)		3/309 (1%)
Dyspnoea	1/693 (0.1%)		0/687 (0%)		2/309 (0.6%)
Epistaxis	0/693 (0%)		1/687 (0.1%)		0/309 (0%)
Pleural effusion	0/693 (0%)		1/687 (0.1%)		3/309 (1%)
Pulmonary oedema	3/693 (0.4%)		1/687 (0.1%)		4/309 (1.3%)
Respiratory arrest	0/693 (0%)		1/687 (0.1%)		1/309 (0.3%)
Pulmonary oedema	0/693 (0%)		0/687 (0%)		4/309 (1.3%)
Respiratory failure	0/693 (0%)		0/687 (0%)		2/309 (0.6%)
Asthma	0/693 (0%)		0/687 (0%)		1/309 (0.3%)
Mediastinal haemorrhage	0/693 (0%)		0/687 (0%)		1/309 (0.3%)
Pleurisy	0/693 (0%)		0/687 (0%)		1/309 (0.3%)
Skin and subcutaneous tissue disorders
Rash macular	0/693 (0%)		0/687 (0%)		1/309 (0.3%)
Skin ulcer	0/693 (0%)		0/687 (0%)		1/309 (0.3%)
Vascular disorders
Deep vein thrombosis	0/693 (0%)		1/687 (0.1%)		1/309 (0.3%)
Hypertensive crisis	1/693 (0.1%)		0/687 (0%)		2/309 (0.6%)
Peripheral vascular disorder	0/693 (0%)		1/687 (0.1%)		4/309 (1.3%)
Peripheral arterial occlusive disease	0/693 (0%)		0/687 (0%)		2/309 (0.6%)
Haematoma	0/693 (0%)		0/687 (0%)		1/309 (0.3%)
Hypertension	0/693 (0%)		0/687 (0%)		1/309 (0.3%)
Hypotension	0/693 (0%)		0/687 (0%)		1/309 (0.3%)
Peripheral embolism	0/693 (0%)		0/687 (0%)		1/309 (0.3%)
Peripheral ischaemia	0/693 (0%)		0/687 (0%)		1/309 (0.3%)
Steal syndrome	0/693 (0%)		0/687 (0%)		1/309 (0.3%)
Subclavian vein thrombosis	0/693 (0%)		0/687 (0%)		1/309 (0.3%)
Superior vena cava syndrome	0/693 (0%)		0/687 (0%)		1/309 (0.3%)
Venous occlusion	0/693 (0%)		0/687 (0%)		1/309 (0.3%)
Other (Not Including Serious) Adverse Events
	Soluble Ferric Pyrophosphate		Placebo		Open-label Soluble Ferric Pyrophosphate
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	123/693 (17.7%)		131/687 (19.1%)		253/309 (81.9%)
Blood and lymphatic system disorders
Anaemia	8/693 (1.2%)		6/687 (0.9%)		20/309 (6.5%)
Gastrointestinal disorders
Diarrhoea	9/693 (1.3%)		15/687 (2.2%)		53/309 (17.2%)
Nausea	12/693 (1.7%)		12/687 (1.7%)		61/309 (19.7%)
Vomiting	8/693 (1.2%)		8/687 (1.2%)		37/309 (12%)
Abdominal pain	3/693 (0.4%)		0/687 (0%)		24/309 (7.8%)
General disorders
Oedema peripheral	5/693 (0.7%)		8/687 (1.2%)		36/309 (11.7%)
Pyrexia	1/693 (0.1%)		1/687 (0.1%)		27/309 (8.7%)
Infections and infestations
Upper respiratory tract infection	4/693 (0.6%)		9/687 (1.3%)		26/309 (8.4%)
Nasopharyngitis	4/693 (0.6%)		1/687 (0.1%)		16/309 (5.2%)
Urinary tract infection	2/693 (0.3%)		3/687 (0.4%)		21/309 (6.8%)
Injury, poisoning and procedural complications
Arteriovenous fistula site complication	11/693 (1.6%)		9/687 (1.3%)		56/309 (18.1%)
Procedural hypotension	32/693 (4.6%)		32/687 (4.7%)		39/309 (12.6%)
Arteriovenous fistula thrombosis	3/693 (0.4%)		3/687 (0.4%)		24/309 (7.8%)
Haemodialysis-induced symptom	4/693 (0.6%)		3/687 (0.4%)		49/309 (15.9%)
Vascular graft complication	2/693 (0.3%)		2/687 (0.3%)		27/309 (8.7%)
Vascular graft thrombosis	2/693 (0.3%)		3/687 (0.4%)		23/309 (7.4%)
Metabolism and nutrition disorders
Fluid overload	5/693 (0.7%)		1/687 (0.1%)		18/309 (5.8%)
Hyperkalaemia	1/693 (0.1%)		4/687 (0.6%)		20/309 (6.5%)
Musculoskeletal and connective tissue disorders
Muscle spasms	17/693 (2.5%)		15/687 (2.2%)		20/309 (6.5%)
Back pain	3/693 (0.4%)		1/687 (0.1%)		32/309 (10.4%)
Pain in extremity	2/693 (0.3%)		4/687 (0.6%)		32/309 (10.4%)
Nervous system disorders
Dizziness	5/693 (0.7%)		7/687 (1%)		37/309 (12%)
Respiratory, thoracic and mediastinal disorders
Cough	4/693 (0.6%)		10/687 (1.5%)		25/309 (8.1%)
Dyspnoea	8/693 (1.2%)		2/687 (0.3%)		27/309 (8.7%)
Vascular disorders
Hypertension	7/693 (1%)		5/687 (0.7%)		26/309 (8.4%)

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 less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.