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Trial registered on ANZCTR


Registration number
ACTRN12610000678099
Ethics application status
Approved
Date submitted
16/08/2010
Date registered
18/08/2010
Date last updated
19/02/2016
Type of registration
Retrospectively registered

Titles & IDs
Public title
HEMATOCRIT Trial: A randomised controlled trial of oral HEMe iron polypeptide Against Treatment with Oral Controlled Release Iron Tablets for the correction of anaemia in peritoneal dialysis patients
Scientific title
A randomised controlled trial of oral HEMe iron polypeptide Against Treatment with Oral Controlled Release Iron Tablets for the correction of anaemia in peritoneal dialysis patients (HEMATOCRIT trial)
Secondary ID [1] 1046 0
CRG110600094 - Cochrane Renal Group
Universal Trial Number (UTN)
Trial acronym
HEMATOCRIT Trial
Linked study record

Health condition
Health condition(s) or problem(s) studied:
darbepoetin-treated peritoneal dialysis patients 243761 0
Anaemia in peritoneal dialysis patients treated with darbepoetin 256594 0
Condition category
Condition code
Renal and Urogenital 256760 256760 0 0
Kidney disease

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Heme iron polypeptide (HIP) (Proferrin ES [registered trademark], Colorado Biolabs, USA) is approved for use as a dietary/nutritional supplement in Canada and the United States of America. The usual dose is 1 tablet (equivalent to 12 mg elemental iron) taken twice or thrice daily, either with or without food. The side effects reported with HIP are similar to those associated with conventional oral iron preparations and include nausea, vomiting and constipation. However, trials in healthy individuals and in haemodialysis patients suggest that the incidence of such adverse drug reactions is relatively low, possibly due to the different absorption characteristics of heme versus non-heme iron. For example, in a study of 37 haemodialysis patients receiving HIP for 6 months, constipation occurred in 3 (8%) patients and was the only observed adverse effect of the agent. The dose of HIP used in that investigation (3 tablets per day) was 50% higher than that proposed in the present study (2 tablets per day). There are no other published data concerning the side effect profile of HIP in end-stage renal failure patients. Concern has previously been expressed about the possibility of transmission of bovine spongiform encephalopathy (BSE) through the consumption of bovine tissue. Currently, HIP is manufactured from red blood cells of cows of American origin, and both the US Department of Agriculture and Food and Drug Administration (FDA) currently maintain that the United States is free of BSE. In addition, the putative infectious agents for BSE, conformationally shifted neuronal membrane copper-binding proteins called prions, usually are not found in blood. Thus, the risk of BSE from taking HIP is negligible. In thus study, the Proferrin will be taken by patients for a period of 6 months.
Intervention code [1] 255848 0
Treatment: Drugs
Comparator / control treatment
Slow-release ferrous sulphate (Ferrogradumet [registered trademark], Abbott, Sydney, Australia) is registered in Australia for use as an oral iron supplement and is one of the most common supplements prescribed in dialysis populations. The usual recommended dose is 2 to 3 tablets a day (equivalent to 210 to 315 mg of elemental iron per day). However, gastrointestinal side effects (especially constipation) usually limit the maximum dosage in end-stage renal failure patients to 2 tablets per day (the dose proposed in the current study). The side effects reported with Ferro-Gradumet are similar to those associated with other conventional oral iron preparations, although the incidence may be lower due to the controlled release nature of the formulation. They are as follows: nausea, vomiting, abdominal pain or discomfort, blackening of stools, diarrhoea and constipation. In a study of 28 peritoneal dialysis patients at Princess Alexandra Hospital, oral Ferrogradumet (registered trademark) administration in a dose of 2 tablets per day for 4 months was associated with significant gastrointestinal side effects in 46% of patients (constipation 38%, nausea 19%, abdominal pain 4%). A randomised, placebo-controlled trial of oral ferrous sulphate in 32 consecutive iron-replete dialysis patients similarly revealed significant gastrointestinal side effects in 50% of subjects. Ferrous sulphate absorption is significantly inhibited by concomitant food and phosphate binder medications. Consequently, subjects participating in the present trial will be instructed to take their study medications on an empty stomach and at least 2 hours apart from phosphate binder ingestion. In this study, the Ferrogradumet will be taken by patients for a period of 6 months.
Control group
Active

Outcomes
Primary outcome [1] 240830 0
The primary outcome measure will be the difference in transferrin saturation (TSAT) values between the HIP and ferrous sulphate groups at the end of the 6 month study period.
Timepoint [1] 240830 0
At the end of the study (6 months)
Secondary outcome [1] 257500 0
The secondary outcome measures will be the differences between the 2 groups at the end of the 6 month study period with respect to serum ferritin concentration, haemoglobin level, darbepoetin (DPO) dosage, Key's index (DPO dosage divided by haemoglobin) and incidence of adverse events.
Timepoint [1] 257500 0
At the end of the study (6 months)

Eligibility
Key inclusion criteria
1. On peritoneal dialysis greater than or equal to 1 month.

2. On darbepoetin for greater than or equal to 1 month

3. 18 years or over.

4. Able to give informed consent.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Patients with a history of psychological illness or condition which interferes with their ability to understand or comply with the requirements of the study.

2. Pregnancy or breast-feeding.

3. Known hypersensitivity to, or intolerance of, oral iron, HIP or DPO.

4. Active peptic ulcer disease.

5. Vitamin B12 or folate deficiency.

6. Recent (within 1 month) acute infection.

7. Parathyroid hormone level greater than 100 pmol/L.

8. Serum aluminium greater than 2 micromol/L.

9. Presence of systemic haematological disease (including antibody-mediated pure red cell aplasia) or known haemoglobinopathy

10. Major surgery, infection, acute myocardial infarction or malignancy within the last 3 months.

11. Intravenous iron therapy, vitamin C therapy, melatonin treatment, androgen therapy or blood transfusion within the previous month.

12. Serum ferritin greater than 500 microg/mL or transferrin saturation (TSAT) greater than 50%.

13. Religious or other objection to consuming product prepared from bovine blood.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
To ensure adequate concealment of allocation, the randomisation will be performed using sequentially numbered, opaque, sealed envelopes, stratified for the presence or absence of a TSAT <= 20%.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The sequence of interventions was obtained from a computer-generated random number list in permuted blocks provided through the Australasian Kidney Trials (AKTN) network.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 4
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD,VIC
Recruitment hospital [1] 5304 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment hospital [2] 5305 0
Princess Alexandra Hospital - Woolloongabba

Funding & Sponsors
Funding source category [1] 243663 0
Commercial sector/Industry
Name [1] 243663 0
Amgen
Address [1] 243663 0
Level 7
123 Epping Road
North Ryde, Sydney
New South Wales 2113
Australia
Country [1] 243663 0
Australia
Funding source category [2] 256344 0
Hospital
Name [2] 256344 0
Princess Alexandra Hospital
Address [2] 256344 0
Ipswich Road
Woolloongabba
Brisbane Qld 4102
Country [2] 256344 0
Australia
Funding source category [3] 256345 0
University
Name [3] 256345 0
University of Queensland
Address [3] 256345 0
Sir Fred Schonell Dr
St Lucia
Brisbane QLD 4072
Australia
Country [3] 256345 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Amgen
Address
Level 7
123 Epping Road
North Ryde, Sydney
New South Wales 2113
Australia
Country
Australia
Secondary sponsor category [1] 251658 0
Hospital
Name [1] 251658 0
Princess Alexandra Hospital
Address [1] 251658 0
Ipswich Road
Woolloongabba
Brisbane Qld 4102
Country [1] 251658 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 258415 0
Princess Alexandra Hospital Human Research Ethics Committee
Ethics committee address [1] 258415 0
Ipswich Road
Woolloongabba
Brisbane Qld 4102
Ethics committee country [1] 258415 0
Australia
Date submitted for ethics approval [1] 258415 0
Approval date [1] 258415 0
10/10/2007
Ethics approval number [1] 258415 0
4/08/2010

Summary
Brief summary
Background: The main hypothesis of this study is that oral heme iron polypeptide (HIP; Proferrin ES [registered trademark]) administration will more effectively augment iron stores in erythropoietic stimulatory agent (ESA)-treated peritoneal dialysis (PD) patients than conventional oral iron supplementation (Ferrogradumet [registered trademark]).
Methods: Inclusion criteria are peritoneal dialysis patients treated with darbepoietin alpha (DPO; Aranesp, Amgen) for at least 1 month. Patients will be randomized 1:1 to receive either slow-release ferrous sulphate (1 tablet twice daily; control) or HIP (1 tablet twice daily) for a period of 6 months. The study will follow an open-label design but outcome assessors will be blinded to study treatment. During the 6-month study period, haemoglobin levels will be measured monthly and iron studies (including transferring saturation [TSAT] measurements) will be performed bi-monthly. The primary outcome measure will be the difference in TSAT levels between the 2 groups at the end of the 6 month study period, adjusted for baseline values using analysis of covariance (ANCOVA). Secondary outcome measures will include serum ferritin concentration, haemoglobin level, DPO dosage, Key’s index (DPO dosage divided by haemoglobin concentration), and occurrence of adverse events (especially gastrointestinal adverse events).
Discussion: This investigator-initiated multicentre study has been designed to provide evidence to help nephrologists and their peritoneal dialysis patients determine whether HIP administration more effectively augments iron stores in ESP-treated PD patients than conventional oral iron supplementation.
Trial website
Trial related presentations / publications
1. Valderrabano F. Erythropoietin in chronic renal failure. Kidney Int 1996;50:1373-91.

2. Benz RL, Pressman MR, Hovick ET, Peterson DD. A preliminary study of the effects of correction of anemia with recombinant human erythropoietin therapy on sleep, sleep disorders, and daytime sleepiness in hemodialysis patients (The SLEEPO study). Am J Kidney Dis 1999;34:1089-95.

3. Macdougall IC. Strategies for iron supplementation: oral versus intravenous. Kidney Int 1999;55 Suppl 69:S61-6.

4. Nyvad O, Danielsen H, Madsen S. Intravenous iron-sucrose complex to reduce epoetin demand in dialysis patients [letter]. Lancet 1994;344:1305-6.

5. Silverberg DS, Blum M, Peer G, Kaplan E, Iaina A. Intravenous ferric saccharate as an iron supplement in dialysis patients. Nephron 1996;72:413-7.

6. Johnson DW, Herzig KA, Gissane R, Campbell SB, Hawley CM, Isbel NM. A prospective cross-over trial comparing intermittent intravenous and continuous oral iron supplementation in peritoneal dialysis patients. Nephrol Dial Transplant 2001;16:1879-84.

7. Markowitz GS, Kahn GA, Feingold RE, Coco M, Lynn RI. An evaluation of the effectiveness of oral iron therapy in hemodialysis patients receiving recombinant human erythropoietin. Clin Nephrol 1997;48:34-40.

8. Schaefer RM, Schaefer L. Management of iron substitution during r-HuEPO therapy in chronic renal failure patients. Erythropoiesis 1992;3:71-5.

9. Drueke TB, Barany P, Cazzola M, et al. Management of iron deficiency in renal anemia: guidelines for the optimal therapeutic approach in erythropoietin-treated patients. Clin Nephrol 1997;48:1-8.

10. Muirhead N, Bargman J, Burgess E, et al. Evidence-based recommendations for the clinical use of recombinant human erythropoietin. Am J Kidney Dis 1995;26:S1-24.

11. European best practice guidelines for the management of anaemia in patients with chronic renal failure. Working Party for European Best Practice Guidelines for the Management of Anaemia in Patients with Chronic Renal Failure. Nephrol Dial Transplant 1999;14 Suppl 5:1-50.

12. Pollock CA, Saltissi D, Roger S, et al. Biochemical and haematological targets. In: Knight J, Chu R, Smith J, Gerard J. (ed.) The CARI Guidelines. 1 edn. Excerpta Medica Communications, Sydney, 2000; 19-26.

13. Barrett BJ, Fenton SS, Ferguson B, et al. Clinical practice guidelines for the management of anemia coexistent with chronic renal failure. J Am Soc Nephrol 1999;10 Suppl 13:S292-6.

14. Grasbeck R, Kouvonen I, Lundberg M, Tenhunen R. An intestinal receptor for heme. Scand J Haematol 1979;23:5-9.

15. Hallberg L, Ryttinger L, Solvell L. Side-effects of oral iron therapy. A double-blind study of different iron compounds in tablet form. Acta Med Scand Suppl 1966;459:3-10.

16. Seligman PA, Moore GM, Schleicher RB. Clinical studies of HIP: An oral heme-iron product. Nutr Res 2000;20:1279-86.

17. Hallberg L, Hulten L, Gramatkovski E. Iron absorption from the whole diet in men: how effective is the regulation of iron absorption? Am J Clin Nutr 1997;66:347-56.

18. Skikne BS, Ahluwalia N, Fergusson B, Chonko A, Cook JD. Effects of erythropoietin therapy on iron absorption in chronic renal failure. J Lab Clin Med 2000;135:452-8.

19. Nissenson AR, Berns JS, Sakiewicz P, et al. Clinical evaluation of heme iron polypeptide: sustaining a response to rHuEPO in hemodialysis patients. Am J Kidney Dis 2003;42:325-30.

20. Fishbane S, Goreja MAJ, Maesaka JK. Reduced nPCR in patients with gastrointestinal side effects due to ferrous sulfate. [Abstract] J Am Soc Nephrol 1998;9:248A
Public notes

Contacts
Principal investigator
Name 30215 0
Prof David Johnson
Address 30215 0
Dept of Nephrology
Princess Alexandra Hospital
199 Ipswich Rd
Woolloongabba
Brisbane Qld 4102
Country 30215 0
Australia
Phone 30215 0
+61 7 3176 5080
Fax 30215 0
Email 30215 0
david.johnson2@health.qld.gov.au
Contact person for public queries
Name 13462 0
Prof Prof, David Wayne, Johnson
Address 13462 0
Director, Nephrology, Princess Alexandra Hospital, Ipswich Road, Woolloongabba, Brisbane, Qld AUSTRALIA 4152
Country 13462 0
Australia
Phone 13462 0
+61 7 31765080
Fax 13462 0
+61 7 31765480
Email 13462 0
david_johnson@health.qld.gov.au
Contact person for scientific queries
Name 4390 0
Ms Ms, Jean, Helyar
Address 4390 0
Senior Clinical Research Nurse, Renal Medicine, Princess Alexandra Hospital, Ipswich Road, Woolloongabba, Brisbane, Qld AUSTRALIA 4152
Country 4390 0
Australia
Phone 4390 0
+61 7 31765080
Fax 4390 0
Email 4390 0
alison_martin@health.qld.gov.au

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary