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

A Randomized, Placebo-Controlled, Phase III Study of Dialysate Containing Soluble Ferric Pyrophosphate (SFP) in Chronic Kidney Disease Patients Receiving Hemodialysis: The Continuous Replacement Using Iron Soluble Equivalents (CRUISE 1) Study

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01320202

Acronym

CRUISE 1

Enrollment

305

Registered

2011-03-22

Start date

2011-03-31

Completion date

2013-11-30

Last updated

2017-04-26

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Renal Failure Chronic Requiring Hemodialysis

Keywords

End Stage Renal Disease, Hemodialysis, SFP, Hemodialysis-dependent chronic renal failure

Brief summary

The purpose of this study is to confirm the safety and efficacy of Soluble Ferric Pyrophosphate (SFP) dialysate solution in maintaining iron delivery for erythropoiesis in anemic adult patients with chronic kidney disease (CKD) receiving hemodialysis. Efficacy will be measured primarily by the change from baseline in hemoglobin (Hgb).

Detailed description

Screening: 2-3 weeks prior to enrollment in Stage 1. Stage 1 (Run-In): 1-4 weeks depending on qualification for Stage 2. Stage 2 (Randomized Blinded Treatment): 12 months unless withdrawn prematurely. Stage 3 (Open-Label Treatment): The duration of Stage 2 plus Stage 3 is intended to be 18 months regardless of treatment assignment in Stage 2.

Interventions

DRUGSoluble Ferric Pyrophosphate (SFP)

Patients to receive 11 micrograms (µg) of iron/ deciliter (dL) of dialysate during dialysis 3 or 4 times/week for up to 18 months.

DEVICEStandard dialysate

Patients to receive standard dialysate (no iron) during dialysis 3 or 4 times/week.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

SINGLE (Subject)

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

Stage 1: Main Inclusion Criteria: * Adult subject ≥ 18 years of age undergoing chronic hemodialysis three or four times per week for chronic kidney disease (CKD) for at least 4 months, and expected to remain on hemodialysis three to four times weekly and be able to complete the duration of the study. * Received IV iron therapy between 6 months and 2 weeks prior to enrollment in order to replace iron losses resulting from hemodialysis procedure. * Mean Screening Hgb ≥ 9.5 to ≤ 11.5 grams per deciliter (g/dL). * Mean Screening Transferrin Saturation (TSAT) ≥ 15% to ≤ 40%. * Mean Screening serum ferritin ≥ 200 to ≤ 800 micrograms per liter (µg/L). * If being administered epoetin, darbepoetin, or CERA, epoetin dose ≤ 45,000 Units (U)/week, darbepoetin dose ≤ 200 micrograms (µg)/week, or CERA dose ≤ 400 micrograms (µg)/month during the four weeks prior to enrollment. Main

Exclusion criteria

* Patient has living kidney donor identified or living-donor kidney transplant scheduled. (Note: Patients awaiting deceased-donor transplant need not be excluded.) * Vascular access for dialysis with femoral catheter or non-tunneled catheter. * Received a total of \> 800 milligrams (mg) IV iron during the 8 weeks prior to enrollment * If being administered an ESA, route of administration change or ESA dose change \> 35% (i.e., \[max - min dose\]/max dose \> 0.35) over the 2 weeks prior to screening. * Serum albumin \< 3.0 grams per deciliter (g/dL) any time over the 8 weeks prior to enrollment. * Red Blood Cell (RBC) or whole blood transfusion within 12 weeks prior to enrollment. Stage 2: Main Inclusion Criteria: * Patient currently enrolled in the Stage 1 run-in period of study. * Undergoing chronic hemodialysis three or four times per week for chronic kidney disease (CKD), and expected to remain on hemodialysis three to four times weekly and be able to complete duration of the study. * Mean Hgb ≥ 9.5 to ≤ 11.5 g/dL over the three most recent consecutive every-week measurements prior to randomization. * Stable Hgb defined as ≤ 1.0 g/dL difference between the maximum and minimum Hgb values over the 3 weeks immediately prior to randomization. * Mean TSAT ≥ 15% to ≤ 40% over the two most recent consecutive every-other-week measurements prior to randomization. * Mean serum ferritin ≥ 200 to ≤ 800 µg/L over the two most recent consecutive every-other-week measurements prior to randomization. * If being administered epoetin, darbepoetin, or CERA, epoetin dose ≤ 45,000 U/week, darbepoetin dose ≤ 200 µg/week, or CERA dose ≤ 400 µg/month during the four weeks prior to randomization. Main

Design outcomes

Primary

Measure	Time frame	Description
Change From Baseline Hemoglobin at End-of-Treatment: Least-Squares Mean	Hgb measured weekly; up to 48 weeks from the date of randomization	Mean change from baseline Hgb (the average of the three most recent Hgb values preceding randomization) assessments during the last one-sixth of the treatment period for patients who prematurely withdraw from study treatment, but will include a minimum of at least the last two Hgb values. Value is expressed as least-squares mean with standard error.
Change From Baseline Hemoglobin at End-of-Treatment: Mean Baseline and End-of-Treatment Hgb	Hgb measured weekly; up to 48 weeks from the date of randomization	Mean change from baseline Hgb (the average of the three most recent Hgb values preceding randomization) assessments during the last one-sixth of the treatment period for patients who prematurely withdraw from study treatment, but will include a minimum of at least the last two Hgb values. Values expressed are mean baseline and end-of-treatment Hgb, along with the mean difference (standard deviation).

Secondary

Measure	Time frame	Description
Mean Change in Unsaturated Iron Binding Capacity (UIBC) From Pre- to Post-dialysis.	Up to 48 weeks from the date of randomization	The mean difference between the pre-dialysis and post-dialysis unsaturated iron binding capacity (UIBC) was calculated, using all post-baseline values obtained during Stage 2. Subjects could participate in Stage 2 for up to 48 weeks, provided that they did not complete Stage 2 early due to a protocol-mandated change in anemia management or withdraw from the study entirely for other reasons.
Red Blood Cell or Whole Blood Transfusion: Number of Patients Receiving Transfusion	up to 48 weeks from the date of randomization	The number of patients requiring red blood cell or whole blood transfusion while in the randomized treatment stage (Stage 2). Patients remained in Stage 2 until they met protocol-defined criteria for Stage 2 completion or until they had participated in Stage 2 for 48 weeks (whichever came sooner). If a patient was transfused, they were withdrawn from Stage 2.
Red Blood Cell or Whole Blood Transfusion: Number of Units Transfused	up to 48 weeks from the date of randomization	The total number of units of red blood cells or whole blood that were received by patients while in the randomized treatment stage (Stage 2). This number is the total number of units received across all randomized patients in each treatment group (it is not the average number of units received per patient). Patients remained in Stage 2 until they met protocol-defined criteria for Stage 2 completion or until they had participated in Stage 2 for 48 weeks (whichever came sooner). If a patient was transfused, they were withdrawn from Stage 2.
Percentage of Change From Baseline to End-of-Treatment (EoT) for: Reticulocyte Hemoglobin Content (CHr), Ferritin, and Pre-Dialysis Serum Iron Panel	Up to 48 weeks from the date of randomization	A comparison of the lab values at the end-of-treatment (EoT) to baseline was performed, and the percentage of change from baseline was calculated for the following lab parameters: reticulocyte hemoglobin content (CHr), Ferritin, pre-dialysis unbound iron-binding capacity (UIBC), pre-dialysis serum iron, pre-dialysis transferrin, pre-dialysis total iron-binding capacity TIBC), and transferrin saturation (TSAT).
Change From Baseline to End-of-Treatment (EoT) in Pre-Dialysis Unsaturated Iron-Binding Capacity (UIBC), Serum Iron, and Total Iron-Binding Capacity (TIBC)	Up to 48 weeks from the date of randomization	The Mean Change from Stage 2 Baseline to End-of-Treatment (EoT) in Pre-Dialysis Unsaturated Iron-Binding Capacity (UIBC), Pre-Dialysis Serum Iron, and Pre-Dialysis Total Iron-Binding Capacity (TIBC) will be quantified.
Mean Change in Serum Iron From Pre-dialysis to Post-dialysis.	Up to 48 weeks from the date of randomization	The mean difference between the pre-dialysis and post-dialysis serum iron was calculated, using all post-baseline values obtained during Stage 2. Subjects could participate in Stage 2 for up to 48 weeks, provided that they did not complete Stage 2 early due to a protocol-mandated change in anemia management or withdraw from the study entirely for other reasons.
Change From Baseline to End-of-Treatment (EoT) in Ferritin	Up to 48 weeks from the date of randomization	The Mean Change from Stage 2 Baseline to End-of-Treatment (EoT) in Ferritin will be quantified.
Change From Baseline to End-of-Treatment (EoT) in Pre-Dialysis Transferrin	Up to 48 weeks from the date of randomization	The Mean Change from Stage 2 Baseline to End-of-Treatment (EoT) in Pre-Dialysis Transferrin will be quantified.
Change From Baseline to End-of-Treatment (EoT) in Pre-Dialysis Transferrin Saturation (TSAT)	Up to 48 weeks from the date of randomization	The Mean Change from Stage 2 Baseline to End-of-Treatment (EoT) in Pre-Dialysis Transferrin Saturation (TSAT) will be quantified.
Variability of Hemoglobin Concentration: Temporal Trend	Hgb measured weekly; up to 48 weeks from the date of randomization	The mean temporal trend of hemoglobin concentration value changes, as measured weekly from baseline until the end of participation in Stage 2.
Variability of Hemoglobin Concentration: Residual Standard Deviation	Hgb measured weekly; up to 48 weeks from the date of randomization	The mean residual standard deviation of hemoglobin concentration value changes, as measured weekly from baseline until the end of participation in Stage 2.
Change From Baseline to End-of-Treatment (EoT) in Reticulocyte Hemoglobin Content (CHr)	Up to 48 weeks from the date of randomization	The Mean Change from Stage 2 Baseline to End-of-Treatment (EoT) in Reticulocyte Hemoglobin Content (CHr) will be quantified.
Mean Change in TSAT (Transferrin) From Pre-dialysis to Post-dialysis.	Up to 48 weeks from the date of randomization	The mean difference between the pre-dialysis and post-dialysis TSAT (transferrin) was calculated, using all post-baseline values obtained during Stage 2. Subjects could participate in Stage 2 for up to 48 weeks, provided that they did not complete Stage 2 early due to a protocol-mandated change in anemia management or withdraw from the study entirely for other reasons.

Countries

Puerto Rico, United States

Participant flow

Participants by arm

Arm	Count
Soluble Ferric Pyrophosphate (SFP) in Dialysate 11 micrograms (µg) of iron / deciliter (dL) of dialysate. Soluble Ferric Pyrophosphate (SFP): Patients to receive 11 micrograms (µg) of iron/ deciliter (dL) of dialysate during dialysis 3 or 4 times/week for up to 18 months.	152
Standard Dialysate 0 micrograms (µg) of iron / deciliter (dL) of dialysate. Standard dialysate: Patients to receive standard dialysate (no iron) during dialysis 3 or 4 times/week for up to 18 months.	153
Total	305

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Adverse Event	5	5
Overall Study	blood transfusion	1	7
Overall Study	Death	5	3
Overall Study	ineligible	3	0
Overall Study	kidney transplant	1	2
Overall Study	Lost to Follow-up	1	0
Overall Study	moved/changed dialysis	5	2
Overall Study	non-protocol change to ESA or IV iron	17	20
Overall Study	Physician Decision	3	1
Overall Study	Protocol Violation	2	1
Overall Study	regained renal function	1	0
Overall Study	sponsor request	2	0
Overall Study	Withdrawal by Subject	10	3

Baseline characteristics

Characteristic	Total	Soluble Ferric Pyrophosphate (SFP) in Dialysate	Standard Dialysate
Age, Continuous	58.3 years STANDARD_DEVIATION 12.87	56.6 years STANDARD_DEVIATION 12.56	59.9 years STANDARD_DEVIATION 13.01
Ethnicity (NIH/OMB) Hispanic or Latino	139 Participants	74 Participants	65 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	166 Participants	78 Participants	88 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
height	168.82 centimeters STANDARD_DEVIATION 9.771	168.48 centimeters STANDARD_DEVIATION 10.197	169.17 centimeters STANDARD_DEVIATION 9.35
post-dialysis body weight	83.61 kilograms STANDARD_DEVIATION 22.685	84.08 kilograms STANDARD_DEVIATION 23.264	83.15 kilograms STANDARD_DEVIATION 22.166
Race (NIH/OMB) American Indian or Alaska Native	18 Participants	6 Participants	12 Participants
Race (NIH/OMB) Asian	13 Participants	8 Participants	5 Participants
Race (NIH/OMB) Black or African American	98 Participants	50 Participants	48 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	2 Participants	2 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	6 Participants	2 Participants	4 Participants
Race (NIH/OMB) White	168 Participants	84 Participants	84 Participants
Region of Enrollment Puerto Rico	17 participants	7 participants	10 participants
Region of Enrollment United States	288 participants	145 participants	143 participants
Sex: Female, Male Female	98 Participants	50 Participants	48 Participants
Sex: Female, Male Male	207 Participants	102 Participants	105 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —
other Total, other adverse events	100 / 151	96 / 149	148 / 205
serious Total, serious adverse events	45 / 151	36 / 149	81 / 205

Outcome results

Primary

Change From Baseline Hemoglobin at End-of-Treatment: Least-Squares Mean

Mean change from baseline Hgb (the average of the three most recent Hgb values preceding randomization) assessments during the last one-sixth of the treatment period for patients who prematurely withdraw from study treatment, but will include a minimum of at least the last two Hgb values. Value is expressed as least-squares mean with standard error.

Time frame: Hgb measured weekly; up to 48 weeks from the date of randomization

Population: modified intent-to-treat populations: all randomized subjects who received at least one dose of study medication and had at least one post-dose hemoglobin measurement obtained.

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Stage 2 Soluble Ferric Pyrophosphate (SFP) in Dialysate	Change From Baseline Hemoglobin at End-of-Treatment: Least-Squares Mean	0.6 grams per liter	Standard Error 1.15
Stage 2 Placebo (Standard Dialysate)	Change From Baseline Hemoglobin at End-of-Treatment: Least-Squares Mean	-3.0 grams per liter	Standard Error 1.14

p-value: 0.011ANCOVA

Primary

Change From Baseline Hemoglobin at End-of-Treatment: Mean Baseline and End-of-Treatment Hgb

Mean change from baseline Hgb (the average of the three most recent Hgb values preceding randomization) assessments during the last one-sixth of the treatment period for patients who prematurely withdraw from study treatment, but will include a minimum of at least the last two Hgb values. Values expressed are mean baseline and end-of-treatment Hgb, along with the mean difference (standard deviation).

Time frame: Hgb measured weekly; up to 48 weeks from the date of randomization

Population: modified intent-to-treat: all randomized patients who received at least one dose of study drug and had at least one post-dose hemoglobin measured.

Arm	Measure	Group	Value (MEAN)	Dispersion
Stage 2 Soluble Ferric Pyrophosphate (SFP) in Dialysate	Change From Baseline Hemoglobin at End-of-Treatment: Mean Baseline and End-of-Treatment Hgb	mean baseline hemoglobin	109.6 grams per liter	Standard Deviation 5.91
Stage 2 Soluble Ferric Pyrophosphate (SFP) in Dialysate	Change From Baseline Hemoglobin at End-of-Treatment: Mean Baseline and End-of-Treatment Hgb	mean end-of-treatment hemoglobin	109.1 grams per liter	Standard Deviation 12.53
Stage 2 Soluble Ferric Pyrophosphate (SFP) in Dialysate	Change From Baseline Hemoglobin at End-of-Treatment: Mean Baseline and End-of-Treatment Hgb	mean change in Hemoglobin at end-of-treatment	-0.4 grams per liter	Standard Deviation 11.67
Stage 2 Placebo (Standard Dialysate)	Change From Baseline Hemoglobin at End-of-Treatment: Mean Baseline and End-of-Treatment Hgb	mean baseline hemoglobin	109.0 grams per liter	Standard Deviation 6.36
Stage 2 Placebo (Standard Dialysate)	Change From Baseline Hemoglobin at End-of-Treatment: Mean Baseline and End-of-Treatment Hgb	mean end-of-treatment hemoglobin	105.2 grams per liter	Standard Deviation 13.65
Stage 2 Placebo (Standard Dialysate)	Change From Baseline Hemoglobin at End-of-Treatment: Mean Baseline and End-of-Treatment Hgb	mean change in Hemoglobin at end-of-treatment	-3.9 grams per liter	Standard Deviation 12.52

Secondary