A Long-Term Safety Extension Trial of Ferric Citrate in Patients With End-Stage Renal Disease (ESRD) on Dialysis

• Sponsor: Keryx Biopharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01554982
• Collaborator: (none)
• Enrollment: 168
• Locations: 34
• Arm: 1
• Duration (Months): 24
• Patients Per Site: 4.9
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

A long-term safety study of ferric citrate (KRX-0502) in renal failure patients who have completed study KRX-0502-304. Only patients who participated in the KRX-0502-304 trial may participate in this trial.

Condition or Disease	Intervention/Treatment	Phase
End Stage Renal Disease; Kidney Failure; Renal Failure; Hyperphosphatemia; ESRD	Drug: ferric citrate	Phase 3

Detailed Description

This study was an open-label, 48-week safety extension of Study KRX-0502-304 (Study 304), to evaluate the safety of long-term use of KRX-0502 in subjects with ESRD for up to 2 years of cumulative exposure. Subjects who completed the Safety Assessment Period (SAP) and, if eligible, the Efficacy Assessment Period (EAP) of Study 304, independent of their assigned treatment arm in the SAP or EAP of Study 304, were eligible for participation in this long-term safety extension study. No new subjects were permitted to enter this study.

Study Design

• Study Type: Interventional
• Actual Enrollment: 168 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Long-Term Safety Extension Trial of KRX-0502 (Ferric Citrate) in Patients With End-Stage Renal Disease (ESRD) on Dialysis
• Study Start Date: Aug 1, 2012
• Actual Primary Completion Date: Jun 1, 2014
• Actual Study Completion Date: Aug 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Other: Ferric Citrate Open label extension of those completing study KRX-0304	Drug: ferric citrate; Dose based on monthly serum phosphorus levels with goal of 3.5-5.5 mg/dL for all patients.; Other Names: Auryxia KRX-0502

Outcome Measures

Primary Outcome Measures

1. Safety Parameters [48 Weeks]

   Safety was assessed by recording and monitoring adverse events (AEs), serious adverse events (SAEs), and sequential laboratory data. Rates of AEs were summarized by system organ class, preferred term, severity, and suspected relationship to KRX-0502 (ferric citrate).

Other Outcome Measures

1. Serum Phosphorus- Baseline [Baseline]

2. Serum Phosphorus- Week 48 [48 weeks]

3. Ferritin- Baseline [Baseline]

4. Ferritin- Week 48 [48 weeks]

5. Transferrin Saturation (TSAT) - Baseline [Baseline]

6. TSAT- Week 48 [48 weeks]

7. Hemoglobin- Baseline [Baseline]

8. Hemoglobin- Week 48 [48 weeks]

9. IV Iron Use [48 weeks]

   Percent of subjects with No IV iron intake from first dose of study drug to Week 48

Eligibility Criteria

Criteria

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

Inclusion Criteria:

1. Males or non-pregnant, non-breast-feeding females who participated in the Safety Assessment Period (SAP), and if eligible, the Efficacy Assessment Period (EAP) of Study KRX-0502-304

2. Willing and able to give informed consent

Exclusion Criteria:

1. Subjects on KRX-0502 (ferric citrate) in KRX-0502-304 who were treatment failures in first period

2. Any subject in Study KRX-0502-304 SAP who early terminated from the trial

3. Any subject who participated in Study KRX-0502-304 but declined EAP

4. Actively symptomatic gastrointestinal bleeding or inflammatory bowel disease

5. History of malignancy in the last five years

6. Previous intolerance to KRX-0502 (ferric citrate)

7. Intolerance to oral iron-containing products

8. Absolute requirement for oral iron therapy

9. Absolute requirement for Vitamin C (multivitamins [Nephrocaps, Renaphro, etc.] allowed)

10. Absolute requirement for calcium-, magnesium-, or aluminum-containing drugs with meals

11. Inability to tolerate oral drug intake

12. Any other medical condition that rendered the subject unable to or unlikely to complete the trial or that would interfere with optimal participation in the trial or produce significant risk to the subject

13. Inability to cooperate with study personnel or history of noncompliance

14. Unsuitable for this trial per Principal Investigator's (PI) clinical judgment.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Veterans Administration Greater Los Angeles Health Care System	Los Angeles	California	United States	90073
2	University of Colorado	Aurora	Colorado	United States	80045
3	Western Nephrology and Metabolic Bone Disease, PC	Westminster	Colorado	United States	80031
4	Kidney Care Associates, LLC	Augusta	Georgia	United States	30909
5	Circle Medical Management	Chicago	Illinois	United States	60607
6	DaVita Dialysis Unit 494/Nephrology Specialists, PC	Michigan City	Indiana	United States	46360
7	Dept of Internal Medicine, Nephrology & Hypertension	New Orleans	Louisiana	United States	70112
8	Washington Nephrology Associates	Bethesda	Maryland	United States	20814
9	Tufts Medical Center	Boston	Massachusetts	United States	02111
10	Western New England Renal & Transplant Associates, PC	Springfield	Massachusetts	United States	01107
11	Nephrology Hypertension Clinic, PC	Dearborn,	Michigan	United States	48124
12	Henry Ford Hospital	Detroit	Michigan	United States	48202
13	Rochester Hills DaVita Dialysis	Pontiac	Michigan	United States	48341
14	Asheville Kidney Center	Asheville	North Carolina	United States	28801
15	Metrolina Nephrology Associates, PA	Charlotte	North Carolina	United States	28207
16	Duke University Dept of Medicine/Nephrology	Durham	North Carolina	United States	27705
17	Piedmont Dialysis Center	Winston-Salem	North Carolina	United States	27101
18	Clinical Research Limited	Canton	Ohio	United States	44718
19	University of Cincinnati	Cincinnati	Ohio	United States	45267
20	University of Pennsylvania Health System	Philadelphia	Pennsylvania	United States	19104
21	Southeast Renal Research Institute Nephrology Associates	Chattanooga	Tennessee	United States	37408
22	Nephrology Associates, PC	Nashville	Tennessee	United States	37205
23	Vanderbilt University Medical Center	Nashville	Tennessee	United States	37232
24	UT Southwestern Medical Center at Dallas	Dallas	Texas	United States	75390
25	Kidney Associates, PLLC	Houston	Texas	United States	77030
26	Med Center Dialysis	Houston	Texas	United States	77030
27	Kidney Specialists of North Houston, PLLC	Houston	Texas	United States	77384
28	University of Vermont/ Fletcher Allen Health Care: Renal Services	Burlington	Vermont	United States	05401
29	Nephrology Clinical Research Center	Charlottesville	Virginia	United States	22908
30	Clinical Research & Consulting Center, LLC	Fairfax	Virginia	United States	22030
31	Nephrology Associates of Northern Virginia, Inc.	Fairfax	Virginia	United States	22033
32	Butler Farms Dialysis	Hampton	Virginia	United States	23666
33	Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53226
34	RCMI-Clinical Research Center	Rio Piedras		Puerto Rico

Sponsors and Collaborators

• Keryx Biopharmaceuticals

Investigators

• Study Chair: Julia B Lewis, MD, Collaborative Study Group

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Keryx Biopharmaceuticals
• ClinicalTrials.gov Identifier: NCT01554982
• Other Study ID Numbers: KRX-0502-307
• First Posted: Mar 15, 2012
• Last Update Posted: Jul 13, 2016
• Last Verified: Jun 1, 2016

• Keywords provided by Keryx Biopharmaceuticals: Participation Limited; Long Term; Safety Extension
• Additional relevant MeSH terms: Kidney Diseases; Kidney Failure, Chronic; Renal Insufficiency; Hyperphosphatemia

Study Results

Participant Flow

Arm/Group Title	Ferric Citrate
Arm/Group Description	ferric citrate: Dose based on monthly serum phosphorus levels with goal of 3.5-5.5 mg/dL for all patients.
Period Title: Overall Study
STARTED	168
Received Drug	166
COMPLETED	125
NOT COMPLETED	43

Baseline Characteristics

Arm/Group Title	Ferric Citrate
Arm/Group Description	ferric citrate: Dose based on monthly serum phosphorus levels with goal of 3.5-5.5 mg/dL for all patients.
Overall Participants	166
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	135 81.3%
>=65 years	31 18.7%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	55.1 (11.06)
Sex: Female, Male (Count of Participants)
Female	63 38%
Male	103 62%
Region of Enrollment (participants) [Number]
Puerto Rico	2 1.2%
United States	164 98.8%

Outcome Measures

1. Primary Outcome

Title	Safety Parameters
Description	Safety was assessed by recording and monitoring adverse events (AEs), serious adverse events (SAEs), and sequential laboratory data. Rates of AEs were summarized by system organ class, preferred term, severity, and suspected relationship to KRX-0502 (ferric citrate).
Time Frame	48 Weeks

Outcome Measure Data

Analysis Population Description

Safety Population; Treatment Emergent Adverse Events (TEAEs), not including SAEs, reported include only those occurring at a frequency >5%

Arm/Group Title	Ferric Citrate
Arm/Group Description	ferric citrate: Dose based on monthly serum phosphorus levels with goal of 3.5-5.5 mg/dL for all patients.
Measure Participants	166
Subjects with at least 1 TEAE	142 85.5%
Subjects with at least 1 related TEAE	35 21.1%
Subjects with at least 1 serious TEAE	75 45.2%
Subjects with at least 1 related, serious TEAEa	0 0%
Total # of deaths	10 6%

2. Other Pre-specified Outcome

Title	Serum Phosphorus- Baseline
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ferric Citrate
Arm/Group Description	ferric citrate: Dose based on monthly serum phosphorus levels with goal of 3.5-5.5 mg/dL for all patients.
Measure Participants	166
Mean (Standard Deviation) [mg/dL]	5.7 (1.66)

3. Other Pre-specified Outcome

Title	Serum Phosphorus- Week 48
Time Frame	48 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ferric Citrate
Arm/Group Description	ferric citrate: Dose based on monthly serum phosphorus levels with goal of 3.5-5.5 mg/dL for all patients.
Measure Participants	126
Mean (Standard Deviation) [mg/dL]	5.2 (1.34)

4. Other Pre-specified Outcome

Title	Ferritin- Baseline
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ferric Citrate
Arm/Group Description	ferric citrate: Dose based on monthly serum phosphorus levels with goal of 3.5-5.5 mg/dL for all patients.
Measure Participants	166
Mean (Standard Deviation) [ng/mL]	709.7 (385.11)

5. Other Pre-specified Outcome

Title	Ferritin- Week 48
Time Frame	48 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ferric Citrate
Arm/Group Description	ferric citrate: Dose based on monthly serum phosphorus levels with goal of 3.5-5.5 mg/dL for all patients.
Measure Participants	126
Mean (Standard Deviation) [ng/mL]	821.0 (411.54)

6. Other Pre-specified Outcome

Title	Transferrin Saturation (TSAT) - Baseline
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ferric Citrate
Arm/Group Description	ferric citrate: Dose based on monthly serum phosphorus levels with goal of 3.5-5.5 mg/dL for all patients.
Measure Participants	166
Mean (Standard Deviation) [percentage of saturation]	32.4 (13.51)

7. Other Pre-specified Outcome

Title	TSAT- Week 48
Time Frame	48 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ferric Citrate
Arm/Group Description	ferric citrate: Dose based on monthly serum phosphorus levels with goal of 3.5-5.5 mg/dL for all patients.
Measure Participants	126
Mean (Standard Deviation) [percentage of saturation]	40.3 (19.12)

8. Other Pre-specified Outcome

Title	Hemoglobin- Baseline
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ferric Citrate
Arm/Group Description	ferric citrate: Dose based on monthly serum phosphorus levels with goal of 3.5-5.5 mg/dL for all patients.
Measure Participants	166
Mean (Standard Deviation) [g/dL]	11.1 (1.36)

9. Other Pre-specified Outcome

Title	Hemoglobin- Week 48
Time Frame	48 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ferric Citrate
Arm/Group Description	ferric citrate: Dose based on monthly serum phosphorus levels with goal of 3.5-5.5 mg/dL for all patients.
Measure Participants	126
Mean (Standard Deviation) [g/dL]	11.3 (1.38)

10. Other Pre-specified Outcome

Title	IV Iron Use
Description	Percent of subjects with No IV iron intake from first dose of study drug to Week 48
Time Frame	48 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ferric Citrate
Arm/Group Description	ferric citrate: Dose based on monthly serum phosphorus levels with goal of 3.5-5.5 mg/dL for all patients.
Measure Participants	166
Number [percentage of participants]	59.0 35.5%

Adverse Events

Time Frame	48 weeks
Adverse Event Reporting Description	Treatment-emergent adverse events
Arm/Group Title	Ferric Citrate
Arm/Group Description	ferric citrate: Dose based on monthly serum phosphorus levels with goal of 3.5-5.5 mg/dL for all patients.
All Cause Mortality
	Ferric Citrate
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Ferric Citrate
	Affected / at Risk (%)	# Events
Total	75/166 (45.2%)
Blood and lymphatic system disorders
Leukocytosis	2/166 (1.2%)	2
Thrombocytopenia	1/166 (0.6%)	1
Lymphadenopathy	1/166 (0.6%)	1
Cardiac disorders
Acute myocardial infarction	3/166 (1.8%)	5
Angina pectoris	4/166 (2.4%)	4
Atrial fibrillation	3/166 (1.8%)	3
Bradycardia	1/166 (0.6%)	1
Cardiac arrest	6/166 (3.6%)	6
Cardiac failure congestive	4/166 (2.4%)	4
Ischaemic cardiomyopathy	1/166 (0.6%)	1
Myocardial infarction	1/166 (0.6%)	1
Pericardial effusion	1/166 (0.6%)	1
Pleuropericarditis	1/166 (0.6%)	1
Tachycardia	1/166 (0.6%)	1
Ventricular fibrillation	1/166 (0.6%)	1
Ventricular tachycardia	1/166 (0.6%)	1
Dyspnoea	4/166 (2.4%)	4
Ear and labyrinth disorders
Vertigo positional	1/166 (0.6%)	1
Endocrine disorders
Hyperparathyroidism	2/166 (1.2%)	2
Gastrointestinal disorders
Diarrhoea	1/166 (0.6%)	1
Diverticulitis intestinal haemorrhagic	1/166 (0.6%)	1
Diverticulum intestinal haemorrhagic	1/166 (0.6%)	1
Gastrointestinal haemorrhage	2/166 (1.2%)	2
Haematemesis	1/166 (0.6%)	1
Ileus paralytic	1/166 (0.6%)	1
Lower gastrointestinal haemorrhage	1/166 (0.6%)	1
Peritonitis	2/166 (1.2%)	2
Rectal haemorrhage	1/166 (0.6%)	1
Retroperitoneal haematoma	2/166 (1.2%)	2
Umbilical hernia, obstructive	1/166 (0.6%)	1
Vomiting	1/166 (0.6%)	1
General disorders
Chest pain	2/166 (1.2%)	2
Death	2/166 (1.2%)	2
Necrosis	1/166 (0.6%)	1
Non-cardiac chest pain	3/166 (1.8%)	3
Pyrexia	5/166 (3%)	5
Sudden death	1/166 (0.6%)	1
Infections and infestations
Abscess limb	1/166 (0.6%)	1
Arteriovenous graft site infection	2/166 (1.2%)	2
Bacteraemia	1/166 (0.6%)	1
Bacterial sepsis	1/166 (0.6%)	1
Cellulitis	2/166 (1.2%)	2
Cellulitis streptococcal	1/166 (0.6%)	1
Device related infection	1/166 (0.6%)	1
Furuncle	1/166 (0.6%)	1
Gangrene	1/166 (0.6%)	1
Incision site abscess	1/166 (0.6%)	1
Infected skin ulcer	1/166 (0.6%)	2
Klebsiella bacteraemia	1/166 (0.6%)	1
Liver abscess	1/166 (0.6%)	1
Localised infection	1/166 (0.6%)	1
Meningitis viral	1/166 (0.6%)	1
Osteomyelitis	1/166 (0.6%)	1
Perirectal abscess	1/166 (0.6%)	1
Peritoneal abscess	1/166 (0.6%)	1
Pneumonia	10/166 (6%)	10
Postoperative wound infection	2/166 (1.2%)	2
Sepsis	8/166 (4.8%)	8
Septic shock	1/166 (0.6%)	1
Staphylococcal bacteraemia	1/166 (0.6%)	1
Staphylococcal infection	1/166 (0.6%)	2
Abdominal Abscess	1/166 (0.6%)	1
Pelvic abscess	1/166 (0.6%)	1
Injury, poisoning and procedural complications
Arteriovenous fistula site complication	1/166 (0.6%)	1
Arteriovenous fistula thrombosis	1/166 (0.6%)	1
Humerus fracture	1/166 (0.6%)	1
Joint dislocation	1/166 (0.6%)	1
Postoperative wound complication	1/166 (0.6%)	1
Subdural haematoma	1/166 (0.6%)	2
Vascular graft complication	2/166 (1.2%)	2
Vascular graft thrombosis	2/166 (1.2%)	2
Wound dehiscence	2/166 (1.2%)	3
Wound haemorrhage	1/166 (0.6%)	1
Complications of transplant surgery	1/166 (0.6%)	1
Investigations
Oxygen saturation decreased	1/166 (0.6%)	1
Aspiration pleural cavity	1/166 (0.6%)	1
Metabolism and nutrition disorders
Diabetic foot	1/166 (0.6%)	1
Fluid overload	5/166 (3%)	5
Hyperkalaemia	3/166 (1.8%)	3
Hypocalcaemia	1/166 (0.6%)	1
Lactic acidosis	1/166 (0.6%)	1
Metabolic encephalopathy	1/166 (0.6%)	1
Hypoglycemia	2/166 (1.2%)	2
Dehydration	1/166 (0.6%)	1
Musculoskeletal and connective tissue disorders
Arthritis	1/166 (0.6%)	1
Back pain	2/166 (1.2%)	2
Lumbar spinal stenosis	1/166 (0.6%)	1
Musculoskeletal chest pain	1/166 (0.6%)	1
Neuropathic arthropathy	1/166 (0.6%)	1
Osteoarthritis	2/166 (1.2%)	2
Spinal osteoarthritis	1/166 (0.6%)	1
Systemic lupus erythematosus	1/166 (0.6%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lung neoplasm malignant	1/166 (0.6%)	1
Nervous system disorders
Syncope	4/166 (2.4%)	4
Unresponsive to stimuli	1/166 (0.6%)	1
Cerebral thrombosis	1/166 (0.6%)	1
Transient ischaemic attack	1/166 (0.6%)	1
Paraparesis	1/166 (0.6%)	1
Dizziness	1/166 (0.6%)	1
Psychiatric disorders
Disorientation	1/166 (0.6%)	1
Mental disorder	3/166 (1.8%)	3
Confusional state	1/166 (0.6%)	1
Renal and urinary disorders
Azotaemia	1/166 (0.6%)	1
Reproductive system and breast disorders
Postmenopausal haemorrhage	1/166 (0.6%)	1
Respiratory, thoracic and mediastinal disorders
Acute pulmonary oedema	2/166 (1.2%)	2
Acute respiratory distress syndrome	1/166 (0.6%)	1
Acute respiratory failure	1/166 (0.6%)	1
Asthma	1/166 (0.6%)	1
Dyspnoea	1/166 (0.6%)	2
Pleural effusion	3/166 (1.8%)	4
Pneumonia aspiration	1/166 (0.6%)	1
Pulmonary embolism	1/166 (0.6%)	1
Pulmonary oedema	3/166 (1.8%)	3
Respiratory distress	1/166 (0.6%)	2
Respiratory failure	2/166 (1.2%)	2
Skin and subcutaneous tissue disorders
Angioedema	1/166 (0.6%)	1
Surgical and medical procedures
Cardiac pacemaker insertion	1/166 (0.6%)	1
Catheter placement	2/166 (1.2%)	2
Leg amputation	2/166 (1.2%)	2
Parathyroidectomy	1/166 (0.6%)	1
Peritoneal dialysis	1/166 (0.6%)	1
Renal transplant	10/166 (6%)	10
Spinal fusion surgery	1/166 (0.6%)	2
Vascular disorders
Aneurysm	1/166 (0.6%)	1
Brachiocephalic vein stenosis	1/166 (0.6%)	1
Deep vein thrombosis	2/166 (1.2%)	2
Hypertension	2/166 (1.2%)	2
Hypertensive crisis	2/166 (1.2%)	2
Hypertensive emergency	1/166 (0.6%)	1
Hypotension	5/166 (3%)	6
Peripheral vascular disorder	1/166 (0.6%)	1
Other (Not Including Serious) Adverse Events
	Ferric Citrate
	Affected / at Risk (%)	# Events
Total	142/166 (85.5%)
Cardiac disorders
Dyspnoea	13/166 (7.8%)	16
Gastrointestinal disorders
Constipation	9/166 (5.4%)	11
Diarrhoea	26/166 (15.7%)	29
Faeces discoloured	14/166 (8.4%)	14
Nausea	17/166 (10.2%)	20
Oedema peripheral	10/166 (6%)	15
Vomiting	16/166 (9.6%)	23
General disorders
Pyrexia	9/166 (5.4%)	9
Infections and infestations
Nasopharyngitis	10/166 (6%)	11
Injury, poisoning and procedural complications
Arteriovenous fistula site complication	12/166 (7.2%)	17
Fall	9/166 (5.4%)	14
Vascular graft complication	9/166 (5.4%)	10
Musculoskeletal and connective tissue disorders
Musculoskeletal pain	10/166 (6%)	16
Pain in extremity	11/166 (6.6%)	28
Nervous system disorders
Dizziness	9/166 (5.4%)	13
Headache	14/166 (8.4%)	23
Respiratory, thoracic and mediastinal disorders
Cough	11/166 (6.6%)	14
Vascular disorders
Hypertension	9/166 (5.4%)	11
Hypotension	10/166 (6%)	66

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

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