A 4-Week Dose-Ranging and Efficacy Trial of KRX-0502 (Ferric Citrate) in Patients With End-Stage Renal Disease

• Sponsor: Keryx Biopharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01074125
• Collaborator: Collaborative Study Group (CSG) (Other)
• Enrollment: 154
• Locations: 16
• Arms: 3
• Duration (Months): 6
• Patients Per Site: 9.6
• Patients Per Site Per Month: 1.6

Study Details

Study Description

Brief Summary

This is a research study for people with high blood phosphorus levels who are on dialysis. This medical condition can cause weakening of the bones and damage other organs. This can lead to many health problems, and sometimes death. Phosphorus is in much of the food we eat, and is helpful to us in small amounts. Patients with kidney failure have trouble getting rid of the phosphorus eaten in food. Dialysis can help remove some of the phosphorus, but often patients must take a phosphate binder like PhosLo®, Renagel®, or Renvela® to bring the blood phosphorus levels back to normal. The purpose of this study is to see if KRX-0502 (ferric citrate) is safe and effective as a phosphate binder.

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

Detailed Description

There will be a screening visit about 4 weeks receiving study drug. Upon qualifying for the study after the screening visit, patients will then be asked to stop taking their current phosphate binder for about 2 weeks. Then, if patients continue to qualify for the study, they will be entered in the study that lasts about 28 days. Study visits will happen every week during the patient's usual dialysis appointments. There will be a total of up to 9 visits for this study, and total participation time could last up to 8 weeks.

Study Design

• Study Type: Interventional
• Actual Enrollment: 154 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A 4-Week Dose-Ranging and Efficacy Trial of KRX-0502 (Ferric Citrate) in Patients With End-Stage Renal Disease (ESRD) Following a Two-Week Washout Period
• Study Start Date: May 1, 2010
• Actual Primary Completion Date: Nov 1, 2010
• Actual Study Completion Date: Nov 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1 g/day 1 g/day KRX-0502 (ferric citrate)	Drug: ferric citrate; 1, 6, or 8 g/day taken within 1 hour of meals or snacks daily for 28 days; Other Names: KRX-0502
Experimental: 6 g/day 6 g/day KRX-0502 (ferric citrate)	Drug: ferric citrate; 1, 6, or 8 g/day taken within 1 hour of meals or snacks daily for 28 days; Other Names: KRX-0502
Experimental: 8 g/day 8 g/day KRX-0502 (ferric citrate)	Drug: ferric citrate; 1, 6, or 8 g/day taken within 1 hour of meals or snacks daily for 28 days; Other Names: KRX-0502

Outcome Measures

Primary Outcome Measures

1. Change in Serum Phosphorus From Baseline to End of Treatment [Baseline and day 28]

   Mean change from baseline was calculated separately for each treatment arm (LOCF)

Secondary Outcome Measures

1. Pairwise Comparison of the Mean Change in Serum Phosphorus From Baseline to the End of Treatment [Baseline and day 28]

   Mean change from baseline was calculated separately for each treatment arm. Only subjects that have both baseline and end of treatment serum phosphorus scores were analyzed for this outcome.

2. Proportion of Patient With a Serum Phosphorus ≤5.5 mg/dL at the End of Treatment [Baseline and day 28]

   proportion was calculated separately for each treatment arm

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Males or non-pregnant, non-lactating females

• Age > 18 years

• On thrice weekly hemodialysis or peritoneal dialysis for at least the previous three months prior to Screening Visit (Visit 0)

• Serum phosphorus levels ≥ 3.5 mg/dL and < 8.0 mg/dL at Screening Visit (Visit 0)

• Serum phosphorus levels > 6.0 mg/dL during the washout period (Visits 2 or 3)

• Taking 3 to 15 tablets/capsules per day of 667mg calcium acetate or 800 mg sevelamer (hydrochloride or carbonate), or any combination of these agents as reported by the patient at Screening Visit (Visit 0)

• Serum ferritin <1000micrograms/L and Transferrin Saturation (TSAT) <50% at the Screening Visit (Visit 0)

• Willingness to be discontinued from current phosphate binder(s) and initiated on KRX-0502 (ferric citrate)

• Willing and able to give informed consent

• Willing and able to stay on a constant dose of Vitamin D (or its analogs) and Sensipar (cinacalcet) for the treatment period, if applicable.

Exclusion Criteria:

• Parathyroidectomy within six months prior to Screening Visit (Visit 0)

• Actively symptomatic gastrointestinal bleeding or inflammatory bowel disease

• Serum phosphorus levels >10.0 mg/dL documented in all of the three monthly laboratories (done routinely in the dialysis unit) in the three months prior to the Screening Visit (Visit 0)

• History of multiple drug allergies or intolerances

• History of malignancy in the last five years (treated cervical or non-melanomatous skin cancer may be permitted if approved by CCC)

• Previous intolerance to oral ferric citrate

• Absolute requirement for oral iron therapy

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

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

• Psychiatric disorder that interferes with the patient's ability to comply with the study protocol

• Inability to tolerate oral drug intake

• Planned surgery or hospitalization during the trial (scheduled outpatient access surgery allowed)

• Any other medical condition that renders the patient unable to or unlikely to complete the trial or that would interfere with optimal participation in the trial or produce significant risk to the patient

• Receipt of any investigational drug within 30 days of Screening Visit (Visit 0)

• Inability to cooperate with study personnel or history of noncompliance

• Unsuitable for this trial per Principal Investigator's clinical judgment

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Western Nephrology	Westminster	Colorado	United States	80031
2	Pines Clinical Research, Inc.	Pembroke Pines	Florida	United States	33028
3	Kidney Care Associates, LLC	Augusta	Georgia	United States	30901
4	Circle Medical Management	Chicago	Illinois	United States	60607
5	Western New England Renal & Transplant Associates	Springfield	Massachusetts	United States	01107
6	Brookdale Physician's Dialysis Associates	Brooklyn	New York	United States	11212
7	DCI	Cincinnati	Ohio	United States	45206
8	Cleveland Clinical Foundation Fresenius East (Fairhill)	Cleveland	Ohio	United States	44104
9	The Ohio State University Cramblett Medical Clinic	Columbus	Ohio	United States	43210
10	Southeast Renal Research Institute	Chattanooga	Tennessee	United States	37404
11	Nephrology Associates, PC	Nashville	Tennessee	United States	37205
12	Meharry Medical College Clinical Research Center	Nashville	Tennessee	United States	37208
13	Vanderbilt University Medical Center Clinical Trials Center	Nashville	Tennessee	United States	37232-1371
14	Kidney Associates	Houston	Texas	United States	77030
15	Centre Point Dialysis	West Allis	Wisconsin	United States	53214
16	RCMI- Clinical Research Center Medical Sciences Campus University of Puerto Rico	Rio Piedras		Puerto Rico	00936-5067

Sponsors and Collaborators

• Keryx Biopharmaceuticals
• Collaborative Study Group (CSG)

Investigators

• Study Chair: Julia B Lewis, MD, Collaborative Study Group (CSG)

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Keryx Biopharmaceuticals
• ClinicalTrials.gov Identifier: NCT01074125
• Other Study ID Numbers: KRX-0502-305
• First Posted: Feb 24, 2010
• Last Update Posted: Dec 4, 2014
• Last Verified: Dec 1, 2014

• Keywords provided by Keryx Biopharmaceuticals: Hyperphosphatemia; ESRD; Dialysis; End Stage Renal Disease; Phosphorus; Renal; Kidney
• Additional relevant MeSH terms: Kidney Diseases; Kidney Failure, Chronic; Hyperphosphatemia

Study Results

Participant Flow

Pre-assignment Detail	3 patients were randomized, but withdrew before initiating study treatment

Arm/Group Title	1 g/Day	6 g/Day	8 g/Day
Arm/Group Description	1 g/day KRX-0502 (ferric citrate) taken within 1 hour of meals or snacks daily for 28 days	6 g/day KRX-0502 (ferric citrate) taken within 1 hour of meals or snacks daily for 28 days	8 g/day KRX-0502 (ferric citrate) taken within 1 hour of meals or snacks daily for 28 days
Period Title: Overall Study
STARTED	51	52	48
COMPLETED	39	47	36
NOT COMPLETED	12	5	12

Baseline Characteristics

Arm/Group Title	1 g/Day	6 g/Day	8 g/Day	Total
Arm/Group Description	1 g/day KRX-0502 (ferric citrate) taken within 1 hour of meals or snacks daily for 28 days	6 g/day KRX-0502 (ferric citrate) taken within 1 hour of meals or snacks daily for 28 days	8 g/day KRX-0502 (ferric citrate) taken within 1 hour of meals or snacks daily for 28 days	Total of all reporting groups
Overall Participants	50	51	45	146
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	39 78%	37 72.5%	39 86.7%	115 78.8%
>=65 years	11 22%	14 27.5%	6 13.3%	31 21.2%
Sex: Female, Male (Count of Participants)
Female	18 36%	21 41.2%	19 42.2%	58 39.7%
Male	32 64%	30 58.8%	26 57.8%	88 60.3%
Region of Enrollment (participants) [Number]
United States	47 94%	49 96.1%	42 93.3%	138 94.5%
Puerto Rico	3 6%	2 3.9%	3 6.7%	8 5.5%

Outcome Measures

1. Primary Outcome

Title	Change in Serum Phosphorus From Baseline to End of Treatment
Description	Mean change from baseline was calculated separately for each treatment arm (LOCF)
Time Frame	Baseline and day 28

Outcome Measure Data

Analysis Population Description

Intent to Treat (ITT) Population

Arm/Group Title	1 g/Day	6 g/Day	8 g/Day
Arm/Group Description	1 g/day KRX-0502 (ferric citrate) ferric citrate: 1, 6, or 8 g/day taken within 1 hour of meals or snacks daily for 28 days	6 g/day KRX-0502 (ferric citrate) ferric citrate: 1, 6, or 8 g/day taken within 1 hour of meals or snacks daily for 28 days	8 g/day KRX-0502 (ferric citrate) ferric citrate: 1, 6, or 8 g/day taken within 1 hour of meals or snacks daily for 28 days
Measure Participants	50	51	45
Mean (Standard Deviation) [mg/dL]	-0.10 (1.285)	-1.86 (1.692)	-2.13 (1.998)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	1 g/Day, 6 g/Day, 8 g/Day
	Comments	To assess dose ranging, the primary efficacy variable will be analyzed via a model with dose effect. Positive dose ranging confirmed if the null hypothesis of slope =0 was rejected at a significance level of 0.05
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Regression, Linear
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.3376
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Pairwise Comparison of the Mean Change in Serum Phosphorus From Baseline to the End of Treatment
Description	Mean change from baseline was calculated separately for each treatment arm. Only subjects that have both baseline and end of treatment serum phosphorus scores were analyzed for this outcome.
Time Frame	Baseline and day 28

Outcome Measure Data

Analysis Population Description

Intent-to-Treat, includes only subjects that had both baseline and end of study actual values

Arm/Group Title	1 g/Day	6 g/Day	8 g/Day
Arm/Group Description	1 g/day KRX-0502 (ferric citrate) taken within 1 hour of meals or snacks daily for 28 days	6 g/day KRX-0502 (ferric citrate) taken within 1 hour of meals or snacks daily for 28 days	8 g/day KRX-0502 (ferric citrate) taken within 1 hour of meals or snacks daily for 28 days
Measure Participants	38	44	34
Mean (Standard Deviation) [mg/dL]	0.04 (1.320)	-1.94 (1.813)	-2.21 (2.097)

3. Secondary Outcome

Title	Proportion of Patient With a Serum Phosphorus ≤5.5 mg/dL at the End of Treatment
Description	proportion was calculated separately for each treatment arm
Time Frame	Baseline and day 28

Outcome Measure Data

Analysis Population Description

Intent-to-Treat

Arm/Group Title	1 g/Day	6 g/Day	8 g/Day
Arm/Group Description	1 g/day KRX-0502 (ferric citrate) ferric citrate: 1, 6, or 8 g/day taken within 1 hour of meals or snacks daily for 28 days	6 g/day KRX-0502 (ferric citrate) ferric citrate: 1, 6, or 8 g/day taken within 1 hour of meals or snacks daily for 28 days	8 g/day KRX-0502 (ferric citrate) ferric citrate: 1, 6, or 8 g/day taken within 1 hour of meals or snacks daily for 28 days
Measure Participants	50	51	45
Number [% of Participants]	12.0 24%	51.0 100%	57.8 128.4%

Adverse Events

Time Frame	Serious Adverse Events (AEs) were recorded up to 30 days post therapy
Arm/Group Title	1g/Day		6g/Day		8g/Day
Arm/Group Description	Participants received 1g tablet of KRX-0502 (ferric citrate) for 4 weeks		Participants received 6g tablet of KRX-0502 (ferric citrate) for 4 weeks		Participants received 8g tablet of KRX-0502 (ferric citrate) for 4 weeks
All Cause Mortality
	1g/Day		6g/Day		8g/Day
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	1g/Day		6g/Day		8g/Day
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/51 (11.8%)		7/52 (13.5%)		9/48 (18.8%)
Blood and lymphatic system disorders
Anaemia	0/51 (0%)	0	1/52 (1.9%)	1	0/48 (0%)	0
Cardiac disorders
Cardiac failure congestive	2/51 (3.9%)	2	0/52 (0%)	0	0/48 (0%)	0
Acute myocardial infarction	0/51 (0%)	0	0/52 (0%)	0	1/48 (2.1%)	1
Hypertensive heart disease	1/51 (2%)	1	0/52 (0%)	0	0/48 (0%)	0
Gastrointestinal disorders
Haematemesis	0/51 (0%)	0	1/52 (1.9%)	1	0/48 (0%)	0
Umbilical hernia, obstructive	0/51 (0%)	0	0/52 (0%)	0	1/48 (2.1%)	1
General disorders
Oedema peripheral	0/51 (0%)	0	1/52 (1.9%)	1	0/48 (0%)	0
Hepatobiliary disorders
Cholelithiasis	0/51 (0%)	0	1/52 (1.9%)	1	0/48 (0%)	0
Infections and infestations
Bacteraemia	0/51 (0%)	0	1/52 (1.9%)	1	0/48 (0%)	0
Cellulitis	0/51 (0%)	0	0/52 (0%)	0	1/48 (2.1%)	1
Device related infection	0/51 (0%)	0	1/52 (1.9%)	1	0/48 (0%)	0
Pneumonia	1/51 (2%)	1	0/52 (0%)	0	0/48 (0%)	0
Subcutaneous absess	0/51 (0%)	0	1/52 (1.9%)	1	0/48 (0%)	0
Injury, poisoning and procedural complications
Arteriovenous fistula aneurysm	1/51 (2%)	1	0/52 (0%)	0	0/48 (0%)	0
Investigations
Blood glucose fluctuation	0/51 (0%)	0	0/52 (0%)	0	1/48 (2.1%)	1
Metabolism and nutrition disorders
Hyperkalaemia	0/51 (0%)	0	1/52 (1.9%)	1	1/48 (2.1%)	1
Musculoskeletal and connective tissue disorders
Pain in extremity	0/51 (0%)	0	1/52 (1.9%)	1	1/48 (2.1%)	1
Nervous system disorders
Cerebral haemorrhage	0/51 (0%)	0	0/52 (0%)	0	1/48 (2.1%)	1
Haemorrhage intracranial	0/51 (0%)	0	0/52 (0%)	0	1/48 (2.1%)	1
Syncope	0/51 (0%)	0	1/52 (1.9%)	1	0/48 (0%)	0
Renal and urinary disorders
Azotaemia	0/51 (0%)	0	0/52 (0%)	0	1/48 (2.1%)	1
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	0/51 (0%)	0	1/52 (1.9%)	1	0/48 (0%)	0
Hypoxia	0/51 (0%)	0	1/52 (1.9%)	1	0/48 (0%)	0
Pulmonary Hypotension	0/51 (0%)		1/52 (1.9%)	1	0/48 (0%)	0
Pulmonary Odema	0/51 (0%)	0	1/52 (1.9%)	1	0/48 (0%)	0
Surgical and medical procedures
Renal transplant	2/51 (3.9%)	2	0/52 (0%)	0	0/48 (0%)	0
Vascular disorders
Hypertensive crisis	1/51 (2%)	1	0/52 (0%)	0	1/48 (2.1%)	1
Hypertension	0/51 (0%)	0	0/52 (0%)	0	1/48 (2.1%)	1
Hypertensive emergency	1/51 (2%)	1	0/52 (0%)	0	0/48 (0%)	0
Hypotension	0/51 (0%)	0	1/52 (1.9%)	1	0/48 (0%)	0
Other (Not Including Serious) Adverse Events
	1g/Day		6g/Day		8g/Day
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	34/51 (66.7%)		43/52 (82.7%)		41/48 (85.4%)
Gastrointestinal disorders
Diarrhoea	10/51 (19.6%)	10	6/52 (11.5%)	6	13/48 (27.1%)	13
Faeces discoloured	10/51 (19.6%)	10	12/52 (23.1%)	12	7/48 (14.6%)	7
Nausea	4/51 (7.8%)	4	3/52 (5.8%)	3	5/48 (10.4%)	5
Constipation	2/51 (3.9%)	2	1/52 (1.9%)	1	4/48 (8.3%)	4
Vomiting	3/51 (5.9%)	3	1/52 (1.9%)	1	3/48 (6.3%)	3
Abdominal pain upper	0/51 (0%)	0	1/52 (1.9%)	1	4/48 (8.3%)	4
General disorders
Oedema peripheral	1/51 (2%)	1	3/52 (5.8%)	3	1/48 (2.1%)	1
Infections and infestations
Upper respiratory tract infection	1/51 (2%)	1	0/52 (0%)	0	4/48 (8.3%)	4
Injury, poisoning and procedural complications
Fall	3/51 (5.9%)	3	2/52 (3.8%)	2	0/48 (0%)	0
Metabolism and nutrition disorders
Decreased appetite	0/51 (0%)	0	0/52 (0%)	0	3/48 (6.3%)	3
Hypocalcaemia	1/51 (2%)	1	6/52 (11.5%)	6	9/48 (18.8%)	9
Musculoskeletal and connective tissue disorders
Pain in extremity	0/51 (0%)	0	4/52 (7.7%)	4	4/48 (8.3%)	4
Muscle spasms	0/51 (0%)	0	3/52 (5.8%)	3	2/48 (4.2%)	2
Arthralgia	3/51 (5.9%)	3	0/52 (0%)	0	1/48 (2.1%)	1
Nervous system disorders
Dizziness	0/51 (0%)	0	2/52 (3.8%)	2	4/48 (8.3%)	4
Headache	0/51 (0%)	0	1/52 (1.9%)	1	4/48 (8.3%)	4
Respiratory, thoracic and mediastinal disorders
Cough	0/51 (0%)	0	2/52 (3.8%)	2	3/48 (6.3%)	3
Skin and subcutaneous tissue disorders
Pruritus	1/51 (2%)	1	3/52 (5.8%)	3	0/48 (0%)	0
Vascular disorders
Hypertension	2/51 (3.9%)	2	0/52 (0%)	0	5/48 (10.4%)	5
Hypotension	1/51 (2%)	1	2/52 (3.8%)	2	3/48 (6.3%)	3

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.