Pharmacokinetics and Preliminary Bioequivalence of Triferic (Ferric Pyrophosphate Citrate) Administered Via Hemodialysate and Intravenously to Adult CKD-5HD Patients

• Sponsor: Rockwell Medical Technologies, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02739100
• Collaborator: (none)
• Enrollment: 13
• Location: 1
• Arms: 3
• Duration (Months): 3
• Patients Per Site Per Month: 4.3

Study Details

Study Description

Brief Summary

The main purpose is to determine the pharmacokinetics (PK) of Triferic iron administered via hemodialysate and via two different intravenous routes in adult patients with chronic kidney disease on chronic hemodialysis (CKD-5HD). It is an open-label, randomized single dose study.

Condition or Disease	Intervention/Treatment	Phase
End Stage Renal Disease	Drug: Triferic	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 13 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Pharmacokinetics and Preliminary Bioequivalence of Triferic (Ferric Pyrophosphate Citrate) Administered Via Hemodialysate and Intravenously to Adult CKD-5HD Patients
• Study Start Date: Apr 1, 2016
• Actual Primary Completion Date: Jul 1, 2016
• Actual Study Completion Date: Jul 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Triferic via Hemodialysate Triferic will be mixed with the liquid bicarbonate concentrate used in the preparation of the hemodialysate solution. This will result in a final Triferic iron concentration in the dialysate of 2 µM (110 µg/L). The patients will receive Triferic via the hemodialysate over the course of the dialysis treatment. Intervention Drug: Triferic	Drug: Triferic; Other Names: ferric pyrophosphate citrate FPC
Experimental: Triferic via IV infusion Patients will receive a single 6.6-mg dose of Triferic iron administered IV over 4 hrs during hemodialysis via the unused heparin infusion line (pre-dialyzer). Intervention: Drug: Triferic	Drug: Triferic; Other Names: ferric pyrophosphate citrate FPC
Experimental: Triferic IV infusion Patients will receive a single 6.6-mg dose of Triferic iron administered IV over 4 hrs during hemodialysis via an infusion port (post-dialyzer). Intervention: Drug: Triferic	Drug: Triferic; Other Names: ferric pyrophosphate citrate FPC

Outcome Measures

Primary Outcome Measures

1. Pharmacokinetics (PK) of Triferic Iron Administered Via Hemodialysate in Adult CKD-5HD Patients: Cmax. [1, 2, 3, 4, 5, 6, 8, 10, and 12 hours]

   The PK will be done by assessing the mean Cmax of total serum iron from Triferic administered via hemodialysate, compared to Triferic administered at a fixed IV dose of 6.6 mg iron/kg during a single dialysis session.

2. Pharmacokinetics (PK) of Triferic Iron Administered IV in Adult CKD-5HD Patients: Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantified Concentration (AUC(Last)). [1, 2, 3, 4, 5, 6, 8, 10, and 12 hours]

   The PK will be done by assessing the mean area under the serum concentration-time curve from time zero to the time of the last quantified concentration (AUC(last)) and comparing between Triferic administered via hemodialysate and Triferic administered at a fixed IV dose of 6.6 mg iron/kg (pre-dialyzer and post-dialyzer) during a single dialysis session.

Secondary Outcome Measures

1. Number of Participants With Treatment-emergent Adverse Events (TEAEs) [13 days]

   Safety will be documented by recording the incidence of treatment-emergent adverse events (TEAEs)

2. Number of Participants With Treatment-emergent Serious Adverse Events (TEAEs) [13 days]

   Safety will be documented by recording the incidence of treatment-emergent serious adverse events (TESAEs)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. The patient must be able to provide informed consent and have personally signed and dated the written informed consent document before completing any study-related procedures.

2. The patient must have been undergoing chronic hemodialysis for chronic kidney disease for at least 3 months, and is expected to remain on hemodialysis and be able to complete the study.

3. The patient must have a Screening ferritin level of ≥100μg/L.

4. The patient must have a Screening transferrin saturation (TSAT) of 15-45%, inclusive.

5. The patient must have a Screening total iron binding capacity (TIBC) ≥175 μg/dL.

6. The patient must have a Screening hemoglobin (Hgb) concentration ≥9.5 g/dL.

7. The patient must be undergoing hemodialysis at least 3x/week.

8. The patient must have at least a minimally adequate measured dialysis dose defined as single-pool Kt/V (dialyzer clearance of urea multiplied by dialysis time, divided by patient's total body water) ≥1.2, or KIDt/V (online dialyzer clearance measured using ionic dialysance multiplied by dialysis time, divided by patient's total body water) ≥1.2 measured within the 28 days prior to Baseline.

9. Patient is receiving, or can receive anticoagulation for dialysis by a single dose of unfractionated heparin or low molecular weight heparin pre-dialysis; or by intermittent IV heparin bolus.

10. The patient's vascular access for dialysis that will be used during the study must have stable function in the judgment of the Investigator.

11. The patient must agree to discontinue all iron preparations (oral and IV) for 14 days prior to Baseline.

12. Female patients must not be pregnant or breastfeeding. They must have been amenorrheic for the past year or be surgically sterile or agree to not become pregnant by continuous use of an effective birth control method acceptable to the Investigator for the duration of their participation in the study.

Exclusion Criteria:

1. The patient has had an RBC or whole blood transfusion within 4 weeks prior to Screening.

2. The patient requires a continuous infusion of heparin during standard hemodialysis.

3. The patient has had administration of IV or oral iron supplements (including multivitamins with iron) within 14 days prior to Baseline.

4. The patient has known active bleeding from any site other than AV fistula or graft (e.g., gastrointestinal, hemorrhoidal, nasal, pulmonary, etc.).

5. The patient has a living kidney donor identified or living-donor kidney transplant scheduled to occur during study participation. (Note: Patients awaiting deceased-donor transplant need not be excluded.)

6. The patient's vascular access for hemodialysis is a femoral catheter.

7. The patient is scheduled to have a surgical procedure during the study.

8. The patient has had a hospitalization within the 4 weeks prior to Screening (except for vascular access surgery) that, in the opinion of the Investigator, confers a significant risk of hospitalization during the course of the study.

9. The patient has a history of noncompliance with the dialysis regimen in the opinion of the Investigator

10. The patient has a known ongoing inflammatory disorder (other than CKD), such as systemic lupus erythematosus, rheumatoid arthritis, or other collagen-vascular disease, that currently requires systemic anti-inflammatory or immunomodulatory therapy.

11. The patient has any current febrile illness (e.g., oral temperature ≥100.4°F, 38.0°C). (The patient may subsequently become eligible at least 1 week after resolution of the illness.)

12. The patient has known bacterial, tuberculosis, fungal, viral, or parasitic infection requiring anti-microbial therapy or anticipated to require anti-microbial therapy during the patient's participation in this study.

13. The patient is known to be positive for HIV, hepatitis B, or hepatitis C (viral testing is not required as part of this protocol).

14. The patient has cirrhosis of the liver based on histological criteria or clinical criteria (e.g., presence of ascites, esophageal varices, multiple spider nevi, or history of hepatic encephalopathy).

15. The patient has ALT and/or AST levels consistently greater than twice the upper limit of normal at any time during the two months prior to Baseline.

16. The patient currently has any malignancy other than basal or squamous cell skin cancer.

17. The patient has a history of drug or alcohol abuse within the 6 months prior to Screening.

18. The patient participated in an investigational drug study within 30 days prior to Baseline.

19. The patient has any condition that, in the opinion of the Investigator, would make it unlikely for the patient to complete the study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Orlando Clinical Research Center	Orlando	Florida	United States	32809

Sponsors and Collaborators

• Rockwell Medical Technologies, Inc.

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Rockwell Medical Technologies, Inc.
• ClinicalTrials.gov Identifier: NCT02739100
• Other Study ID Numbers: RMFPC-16
• First Posted: Apr 14, 2016
• Last Update Posted: Feb 1, 2019
• Last Verified: Aug 1, 2018

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Rockwell Medical Technologies, Inc.: pharmacokinetics; bioequivalence
• Additional relevant MeSH terms: Kidney Failure, Chronic

Study Results

Participant Flow

Arm/Group Title	All Participants
Arm/Group Description	In this cross-over study, all enrolled participants underwent blood sampling over 12 hours for pharmacokinetic (PK) purposes on Day 1. On Days 3, 8, and 10 participants received the following three treatments in a randomized sequence (one treatment per study day): Triferic 2 micromolar via hemodialysate, Triferic 6.6. mg intravenously pre-dialyzer over 3 hours, and Triferic 6.6 mg intravenously post-dialyzer over 3 hours. Blood sampling was conducted over a 12 hour period on each treatment day for PK purposes.
Period Title: Overall Study
STARTED	13
Triferic 2 Micromolar Via Hemodialysate	13
Triferic 6.6 mg IV Predialyzer	13
Triferic 6.6. mg IV Post-dialyzer	13
COMPLETED	13
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Safety Population
Arm/Group Description	All 13 participants completed every arm of the study. Therefore, the baseline demographic characteristics of the Safety Population as a whole also reflect the characteristics of each arm of the study.
Overall Participants	13
Age (years) [Median (Standard Deviation) ]
Median (Standard Deviation) [years]	49.2 (8.84)
Sex: Female, Male (Count of Participants)
Female	2 15.4%
Male	11 84.6%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	13 100%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	12 92.3%
White	1 7.7%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	13 100%
Height (centimeters) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [centimeters]	174.3 (9.22)
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	98.7 (19.34)
C-reactive protein (milligram/deciliter) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [milligram/deciliter]	.8 (.81)

Outcome Measures

1. Primary Outcome

Title	Pharmacokinetics (PK) of Triferic Iron Administered Via Hemodialysate in Adult CKD-5HD Patients: Cmax.
Description	The PK will be done by assessing the mean Cmax of total serum iron from Triferic administered via hemodialysate, compared to Triferic administered at a fixed IV dose of 6.6 mg iron/kg during a single dialysis session.
Time Frame	1, 2, 3, 4, 5, 6, 8, 10, and 12 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Triferic Via Hemodialysate	Triferic Via IV Infusion Pre-dialyzer	Triferic IV Infusion Post-dialyzer
Arm/Group Description	Triferic will be mixed with the liquid bicarbonate concentrate used in the preparation of the hemodialysate solution. This will result in a final Triferic iron concentration in the dialysate of 2 µM (110 µg/L). The patients will receive Triferic via the hemodialysate over the course of the dialysis treatment. Triferic	Patients will receive a single 6.6-mg dose of Triferic iron administered IV over 4 hrs during hemodialysis via the unused heparin infusion line (pre-dialyzer).	Patients will receive a single 6.6-mg dose of Triferic iron administered IV over 4 hrs during hemodialysis via an infusion port (post-dialyzer).
Measure Participants	13	13	13
Mean (Standard Deviation) [microgram per deciliter]	124 (49.9)	131 (30.5)	124 (42.4)

2. Primary Outcome

Title	Pharmacokinetics (PK) of Triferic Iron Administered IV in Adult CKD-5HD Patients: Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantified Concentration (AUC(Last)).
Description	The PK will be done by assessing the mean area under the serum concentration-time curve from time zero to the time of the last quantified concentration (AUC(last)) and comparing between Triferic administered via hemodialysate and Triferic administered at a fixed IV dose of 6.6 mg iron/kg (pre-dialyzer and post-dialyzer) during a single dialysis session.
Time Frame	1, 2, 3, 4, 5, 6, 8, 10, and 12 hours

Outcome Measure Data

Analysis Population Description

While all subjects were included in PK analysis, some PK samples were below the lower limit of quantitation (BLQ) of the bioanalytical lab assay. Therefore, the number of subjects analyzed differs from the overall total number of study participants.

Arm/Group Title	Triferic Via Hemodialysate	Triferic Via IV Infusion Pre-dialyzer	Triferic IV Infusion Post-dialyzer
Arm/Group Description	Triferic will be mixed with the liquid bicarbonate concentrate used in the preparation of the hemodialysate solution. This will result in a final Triferic iron concentration in the dialysate of 2 µM (110 µg/L). The patients will receive Triferic via the hemodialysate over the course of the dialysis treatment. Triferic	Patients will receive a single 6.6-mg dose of Triferic iron administered IV over 4 hrs during hemodialysis via the unused heparin infusion line (pre-dialyzer).	Patients will receive a single 6.6-mg dose of Triferic iron administered IV over 4 hrs during hemodialysis via an infusion port (post-dialyzer).
Measure Participants	12	10	13
Mean (Standard Deviation) [hours*microgram/deciliter]	621 (355)	630 (275)	524 (272)

3. Secondary Outcome

Title	Number of Participants With Treatment-emergent Adverse Events (TEAEs)
Description	Safety will be documented by recording the incidence of treatment-emergent adverse events (TEAEs)
Time Frame	13 days

Outcome Measure Data

Analysis Population Description

Safety Population (all enrolled subjects)

Arm/Group Title	Triferic Via Hemodialysate	Triferic Via IV Infusion Pre-dialyzer	Triferic IV Infusion Post-dialyzer
Arm/Group Description	Triferic will be mixed with the liquid bicarbonate concentrate used in the preparation of the hemodialysate solution. This will result in a final Triferic iron concentration in the dialysate of 2 µM (110 µg/L). The patients will receive Triferic via the hemodialysate over the course of the dialysis treatment. Triferic	Patients will receive a single 6.6-mg dose of Triferic iron administered IV over 4 hrs during hemodialysis via the unused heparin infusion line (pre-dialyzer).	Patients will receive a single 6.6-mg dose of Triferic iron administered IV over 4 hrs during hemodialysis via an infusion port (post-dialyzer).
Measure Participants	13	13	13
Count of Participants [Participants]	1 7.7%	2 NaN	0 NaN

4. Secondary Outcome

Title	Number of Participants With Treatment-emergent Serious Adverse Events (TEAEs)
Description	Safety will be documented by recording the incidence of treatment-emergent serious adverse events (TESAEs)
Time Frame	13 days

Outcome Measure Data

Analysis Population Description

Safety Population (all enrolled subjects)

Arm/Group Title	Triferic Via Hemodialysate	Triferic Via IV Infusion Pre-dialyzer	Triferic IV Infusion Post-dialyzer
Arm/Group Description	Triferic will be mixed with the liquid bicarbonate concentrate used in the preparation of the hemodialysate solution. This will result in a final Triferic iron concentration in the dialysate of 2 µM (110 µg/L). The patients will receive Triferic via the hemodialysate over the course of the dialysis treatment. Triferic	Patients will receive a single 6.6-mg dose of Triferic iron administered IV over 4 hrs during hemodialysis via the unused heparin infusion line (pre-dialyzer).	Patients will receive a single 6.6-mg dose of Triferic iron administered IV over 4 hrs during hemodialysis via an infusion port (post-dialyzer).
Measure Participants	13	13	13
Count of Participants [Participants]	0 0%	0 NaN	0 NaN

Adverse Events

Arm/Group Title	Triferic Via Hemodialysate		Triferic Via IV Infusion Pre-dialyzer		Triferic IV Infusion Post-dialyzer
Arm/Group Description	Triferic will be mixed with the liquid bicarbonate concentrate used in the preparation of the hemodialysate solution. This will result in a final Triferic iron concentration in the dialysate of 2 µM (110 µg/L). The patients will receive Triferic via the hemodialysate over the course of the dialysis treatment. Triferic		Patients will receive a single 6.6-mg dose of Triferic iron administered IV over 4 hrs during hemodialysis via the unused heparin infusion line (pre-dialyzer).		Patients will receive a single 6.6-mg dose of Triferic iron administered IV over 4 hrs during hemodialysis via an infusion port (post-dialyzer).
All Cause Mortality
	Triferic Via Hemodialysate		Triferic Via IV Infusion Pre-dialyzer		Triferic IV Infusion Post-dialyzer
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/13 (0%)		0/13 (0%)		0/13 (0%)
Serious Adverse Events
	Triferic Via Hemodialysate		Triferic Via IV Infusion Pre-dialyzer		Triferic IV Infusion Post-dialyzer
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/13 (0%)		0/13 (0%)		0/13 (0%)
Other (Not Including Serious) Adverse Events
	Triferic Via Hemodialysate		Triferic Via IV Infusion Pre-dialyzer		Triferic IV Infusion Post-dialyzer
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/13 (7.7%)		2/13 (15.4%)		0/13 (0%)
Gastrointestinal disorders
vomiting	0/13 (0%)	0	1/13 (7.7%)	1	0/13 (0%)	0
nausea	0/13 (0%)	0	1/13 (7.7%)	1	0/13 (0%)	0
Infections and infestations
upper respiratory tract infection	0/13 (0%)	0	1/13 (7.7%)	1	0/13 (0%)	0
Musculoskeletal and connective tissue disorders
pain in extremity	1/13 (7.7%)	1	0/13 (0%)	0	0/13 (0%)	0

Limitations/Caveats

The bioanalytical (ICP MS) assay used for the primary PK analysis was extremely sensitive to hemolyzed samples. The clinical laboratory assay was a better method of quantification for this study.

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 more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.