Erythrocyte Apheresis Versus Phlebotomy in Hemochromatosis

Therapeutic Effect of Erythrocyte Apheresis as Compared to Full Blood Phlebotomy in Patients With Hereditary Hemochromatosis

Primary hemochromatosis is the most frequent hereditary condition in Scandinavia. The condition may result in serious organ damage which can be prevented by therapy, but only few patients develop such organ damage. The optimal treatment, therefore, is still a matter of discussion Prevention of organ damage has traditionally been accomplished by drawing of full blood (phlebotomy), which has to be frequently repeated during the initial phase and then continued indefinitely as a maintenance treatment. The removed amount of iron may be increased two- or threefold for each procedure by using modern equipment for selective removal of red blood cells (red cell apheresis). Possible drawbacks of this technique may be higher costs, prolonged time for each therapeutic procedure, and certain requirements to the patients. The possible advantages are the reduced number of therapeutic procedures and less strain for the patient. No larger, randomized study has been published in order to determine which method should be preferred.

This study is a controlled trial in which participating patients are asked to be randomized to red cell apheresis or traditional phlebotomy. Each group will be followed by means of well-defined assessments in order to explore possible advantages and disadvantages of each method in order to establish what type of treatment should be recommended.

Study Overview

• Status: Unknown
• Conditions: Hemochromatosis
• Intervention / Treatment: Procedure: Arm 1: Erythrocyte apheresis; Procedure: Arm 2: Whole blood phlebotomy

Detailed Description

Introduction Primary hemochromatosis is the most frequent hereditary condition in Scandinavia. The condition may result in serious organ damage which can be prevented by therapy, but only few patients develop such organ damage. Provided the lack of more exact knowledge of which patients should be treated, we have based our inclusion criteria on the guidelines published by the Norwegian Society of Hematology. However, the criteria for ferritin levels have been set at 300 micrograms/L for patients who are homozygous for the C282Y mutation, and also heterozygous individuals will be included if ferritin is higher than 500 micrograms/L.

Furthermore, the optimal treatment method is still a matter of discussion. Prevention of organ damage has traditionally been accomplished by whole blood phlebotomy, which has to be frequently repeated during the initial phase and then continued indefinitely as a maintenance treatment. The removed amount of iron may be increased two- or threefold for each procedure by using modern equipment for selective withdrawal of red blood cells (erythrocyte apheresis). Possible drawbacks of this technique may be higher costs, prolonged time for each therapeutic procedure, and certain requirements to the patients. The possible advantages are the reduced number of therapeutic procedures and less strain for the patient. No larger, randomized study has been published in order to determine which method should be preferred.

Hypothesis: A more rapid decline of primary endpoints (see below) can be achieved by erythrocyte apheresis as compared to traditional phlebotomy, without significant disadvantages.

Design The trial is prospective, randomized and open. Eligible patients are randomized to erythrocyte apheresis and phlebotomy.

Endpoints Primary endpoints Decline of ferritin levels and transferrin saturation.

Secondary endpoints and other variables to be studied Decline in hemoglobin levels. Discomfort during the therapeutic procedure. Any changes in EVF, blood cell counts or albumin and CRP levels. Certain well-defined financial costs: consumed material, technician working time.

Inclusion criteria

1. Diagnosis

   1. Individuals who art homozygous for C282Y or H63D or "compound heterozygous" for these tow variants and have ferritin levels higher than 300 micrograms/L or transferrin saturation higher than 50%.
   2. Individuals heterozygous for C282Y or H63D if ferritin levels higher than 500 micrograms/L or transferrin saturation higher than 50%.
2. Requirements to the patient Body weight higher than 65 kg and initial hemoglobin level higher than 12 g/dL.

Treatment schedule Following randomization to either apheresis or phlebotomy, patients are treated until ferritin levels have declined to below 50 micrograms/L and they are then followed for one year. Patients randomized to apheresis are treated every second week, whereas patients in the phlebotomy group are treated weekly. Prolongation of the interval is permitted in both groups in case of well-defined clinical indications. Any prolongation is to be recorded along with the clinical indication.

Follow-up Clinical symptoms, body weight, laboratory findings (Hemoglobin levels; blood cell counts; levels of iron, transferrin, ferritin, albumin and IgG; serologic assessments for hepatitis viruses, CMV and HIV), discomfort during the therapeutic procedure, duration of each procedure, costs for consumed material, working time of the technician for each procedure.

• Study Type: Interventional
• Enrollment (Anticipated): 67
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Norway
  • Bergen, Norway, N-5021
    • Recruiting
    • Haukeland University Hospital, Department of Transfusion Medicine
    • Contact: Tor Hervig, MD, PhD; Phone Number: +47-55975000; Email: tor.hervig@helse-bergen.no
    • Contact: Signe Hannisdahl; Phone Number: +47-55975000; Email: signe@hannisdahl@helse-bergen.no
  • Haugesund, Norway, N-5504
    • Recruiting
    • Haugesund Hospital, Department of Immunology and Transfusion Medicine
    • Contact: Tatjana Sundic, MD; Phone Number: +47-52732000; Email: tatjana.sundic@helse-fonna.no
    • Contact: Sigbjorn Berentsen, MD, PhD; Phone Number: +47-52732000; Email: s.beren@online.no
  • Nordbyhagen, Norway, N-1474
    • Recruiting
    • Akershus University Hospital (AHUS), Department of Transfusion Medicine
    • Contact: Richard W Olaussen, MD; Phone Number: +47-67928800; Email: richard.olaussen@ahus.no

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Diagnosis

   • Individuals who art homozygous for C282Y or H63D or "compound heterozygous" for these tow variants and have ferritin levels higher than 300 micrograms/L or transferrin saturation higher than 50%.
   • Individuals heterozygous for C282Y or H63D if ferritin levels higher than 500 micrograms/L or transferrin saturation higher than 50%.
2. Requirements to the patient Body weight higher than 65 kg and initial hemoglobin level higher than 12 g/dL.

Exclusion Criteria:

1. Contra-indications to either treatment modality
2. Patients who are not able to co-operate
3. Lack of informed consent

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm 1; Erythrocyte apheresis	Procedure: Arm 1: Erythrocyte apheresis; Erythrocyte apheresis
Active Comparator: Arm 2; Phlebotomy	Procedure: Arm 2: Whole blood phlebotomy; Traditional whole blood phlebotomy

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Decline in ferritin levels and transferrin saturation

Secondary Outcome Measures

Outcome Measure
Costs
Decline in hemoglobin levels
Patient discomfort during therapeutic procedure
Time consumption

Collaborators and Investigators

• Sponsor: University of Bergen
• Collaborators: Haukeland University Hospital; Helse Fonna; University Hospital, Akershus
• Investigators: Principal Investigator: Tatjana Sundic, MD, Department of Immunology and Transfusion Medicine, Haugesund Hospital; Study Chair: Sigbjorn Berentsen, MD, PhD, Department of Medicine, Haugesund Hospital; Study Chair: Tor Hervig, MD, PhD, Department of Transfusion Medicine, Haukeland University Hospital

Publications and helpful links

General Publications

• Asberg A, Hveem K, Thorstensen K, Ellekjter E, Kannelonning K, Fjosne U, Halvorsen TB, Smethurst HB, Sagen E, Bjerve KS. Screening for hemochromatosis: high prevalence and low morbidity in an unselected population of 65,238 persons. Scand J Gastroenterol. 2001 Oct;36(10):1108-15. doi: 10.1080/003655201750422747.
• Muncunill J, Vaquer P, Galmes A, Obrador A, Parera M, Bargay J, Besalduch J. In hereditary hemochromatosis, red cell apheresis removes excess iron twice as fast as manual whole blood phlebotomy. J Clin Apher. 2002;17(2):88-92. doi: 10.1002/jca.10024.
• Rombout-Sestrienkova E, van Noord PA, van Deursen CT, Sybesma BJ, Nillesen-Meertens AE, Koek GH. Therapeutic erythrocytapheresis versus phlebotomy in the initial treatment of hereditary hemochromatosis - A pilot study. Transfus Apher Sci. 2007 Jun;36(3):261-7. doi: 10.1016/j.transci.2007.03.005. Epub 2007 Jun 13.
• Knutsen, H. & Hammerstrom, J. Handlingsprogram for hemokromatose [Norwegian national program for treatment of haemochromatosis]. http://www.legeforeningen.no/asset/22333/1/22333_1.doc . 2003. Norwegian Society of Haematology.
• Telset BIV. Behandling av hereditær hemokromatose: fullblodstapping eller erytrocyttaferese? [Treatment of hereditary haemochromatosis: whole blood phlebotomy or red cell apheresis?] Master Thesis. Bergen: Faculty of Medicine, University of Bergen, 2004

Study record dates

Study Major Dates

• Study Start: January 1, 2006
• Study Completion (Anticipated): December 1, 2009

Study Registration Dates

• First Submitted: July 27, 2007
• First Submitted That Met QC Criteria: July 27, 2007
• First Posted (Estimate): July 31, 2007

Study Record Updates

• Last Update Posted (Estimate): July 31, 2007
• Last Update Submitted That Met QC Criteria: July 27, 2007
• Last Verified: July 1, 2007

More Information

Terms related to this study

• Keywords: Efficacy; Apheresis; Therapy; Phlebotomy; Hemochromatosis; Primary hemochromatosis; Hereditary hemochromatosis; Erythrocyte apheresis
• Additional Relevant MeSH Terms: Metabolic Diseases; Genetic Diseases, Inborn; Iron Metabolism Disorders; Metabolism, Inborn Errors; Metal Metabolism, Inborn Errors; Iron Overload; Hemochromatosis; Hemosiderosis
• Other Study ID Numbers: NSD13903