Clinical Importance of Treating Iron Overload in Sickle Cell Disease

The recruitment status of this study is unknown because the information has not been verified recently.
Verified September 2009 by Children's Hospital Los Angeles.
Recruitment status was  Recruiting
Sponsor:
Collaborator:
Novartis Pharmaceuticals
Information provided by:
Children's Hospital Los Angeles
ClinicalTrials.gov Identifier:
NCT00981370
First received: September 21, 2009
Last updated: NA
Last verified: September 2009
History: No changes posted
  Purpose

Hypothesis:

The investigators suspect that significant degrees of iron overload in subjects with SCD result in decreased red cell survival, abnormal endothelial function and markedly dysregulated autonomic function. Furthermore, the investigators anticipate that the magnitude of these effects is proportional not only to the magnitude of total body iron stores but also to the duration of exposure to the high iron levels in tissues.

Primary objective To determine if red cell survival as assessed by 51Cr red cell survival analysis, hemoglobin level, reticulocyte count, lactic acid dehydrogenase, and plasma hemoglobin in sickle cell patients is related to the degree of iron overload.

Secondary objective(s)

  1. Determine if the magnitude of endothelial-dependant vasodilation is related to The degree of iron overload.
  2. Determine if the degree of change in cardiac beat to beat variability in response to hypoxic exposure or to cold exposure ("cold-face-test") is related the magnitude of iron overload.

The primary measure of iron overload will be MRI determination of liver iron concentration.


Condition Intervention Phase
Anemia, Sickle Cell
Transfusion Hemochromatosis
Drug: deferasirox
Phase 3

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Clinical Importance of Treating Iron Overload in Sickle Cell Disease

Resource links provided by NLM:


Further study details as provided by Children's Hospital Los Angeles:

Primary Outcome Measures:
  • To determine if red cell survival as assessed by 51Cr red cell survival analysis, hemoglobin level, reticulocyte count, lactic acid dehydrogenase, and plasma hemoglobin in sickle cell patients is related to the degree of iron overload. [ Time Frame: Baseline, 6 months and 12 months (if needed) ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Determine if the magnitude of endothelial-dependant vasodilation measured by flow mediated vasodilation (FMD) is related to the degree of iron overload. [ Time Frame: baseline, 6 months and 12 months (if needed) ] [ Designated as safety issue: Yes ]
  • Determine if the degree of change in cardiac beat to beat variability in response to hypoxic exposure or to cold exposure ("cold-face-test") is related the magnitude of iron overload. [ Time Frame: Baseline, 6 months and 12 months (if needed) ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 20
Study Start Date: April 2009
Estimated Study Completion Date: December 2010
Estimated Primary Completion Date: December 2010 (Final data collection date for primary outcome measure)
Intervention Details:
    Drug: deferasirox
    Treatment starting dose of 20mg/kg/day based on subjects baseline LIC (liver iron concentration) and gradually escalate the dose to a maximum of 35 mg/kg/day based upon toxicity. Duration is up to a max of 12 months.
    Other Name: Exjade
Detailed Description:

Patients with sickle cell anemia often require blood transfusion as part of the treatment for their disease. Since each teaspoon of packed red blood cells contains about 5 mg of iron and humans have no way to get rid of excess iron, the levels of iron in sickle cell patients increase rapidly with each transfusion. Too much iron is extremely dangerous and causes damage to blood vessels, red blood cells, liver, hormone producing glands and heart. It is very difficult to know what damage due to iron overload in sickle cell patients because the sickle cell disease itself causes organ damage to the same organs affected by iron.

The purpose of this project is to demonstrate that iron overload significantly increases the morbidity of sickle cell disease and that treatment of the iron overload with Exjade® prevents or attenuates iron-related morbidity. To accomplish this we will screen sickle cell patients with a history of many blood transfusions to see if they have high iron levels. Then we will treat the patients who have very high iron levels with a drug which will remove the iron. Only patients with a very high iron level will be eligible for the treatment. These patients will have been transfused many times before but cannot currently be on blood transfusions. Before we start the treatment we will test the level of anemia, how fast the red cells are being destroyed, how well their blood vessels work and how well their heart works. When the treatment is over, we will repeat these tests and see if there is an improvement.

To qualify for this study, you must carry the diagnosis of sickle cell anemia and you must have received 10 or more blood transfusions in your life. You also cannot currently be on a regular transfusion program where you are getting blood transfusions regularly planned more than three times a year.

  Eligibility

Ages Eligible for Study:   14 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Male or female patients with sickle cell anemia (SS or SB thalassemia) with transfusional iron overload.
  • Currently not on chronic or frequent transfusion
  • Age equal or greater then 14 years
  • Patients with iron overload from repeated blood transfusion, as defined by one of the following:

    1. For patients greater then 16 years old receiving simple transfusions: estimated lifetime history of receipt of at least 100 ml/kg or 15 adult units of packed red blood cells, OR
    2. For patients equal to or less then 16 years old receiving simple transfusions: estimated lifetime history of receipt of at least 100 ml/kg of packed red blood cells, OR
    3. For any patient: liver iron content equal/greater then 3 mg Fe/g dw as measured by biopsy or magnetic resonance imaging who have not been adequately chelated since that measurement, OR
    4. a serum ferritin equal/greater then 1000 ng/mL on at least two occasions, at least two weeks apart, during the prior year. Samples must be obtained in the absence of concomitant infection
  • Life expectancy equal/greater then 12 months
  • Sexually active women must use an effective method of contraception, or must have undergone clinically documented total hysterectomy and/or oophorectomy, or tubal ligation or be postmenopausal (defined as amenorrhea for at least 12 months)

Inclusion criteria for treatment pilot study

  • Meets all inclusion criteria for screening
  • LIC by MRI greater than or equal to 8 mg/g.

Exclusion Criteria:

  • Blood transfusion within 12 weeks of the day 0 hemolysis labs
  • Currently requires blood transfusion more than three times a year.
  • Contraindication to MRI, including cardiac pacemaker, brain aneurysm clip, implanted neurostimulator, insulin pump, cochlear implant, metal slivers in the eyes, intrauterine device or any other MRI incompatible metal implants or intractable claustrophobia.
  • Serum creatinine above the upper limit of normal
  • Concomitant treatment with erythropoietin or its analogs.
  • AST or ALT greater then 250 U/L during screening (patients may be re-screened at a later date if the cause of the elevation is known to be due to a transient process).
  • Patients receiving currently on chelation will be asked to stop for one week before starting or restarting Exjade. (a equal/greater then 1 week washout period prior to first dose of study drug is required)
  • History of HIV positive test result (ELISA or Western blot)
  • History of drug or alcohol abuse within the 12 months prior to enrollment
  • Patients with uncontrolled systemic hypertension
  • Severe cardiac insufficiency (NYHA III or IV), with uncontrolled and/or unstable cardiac or coronary artery disease not controlled by standard medical therapy
  • Patients with a diagnosis of or history of clinically relevant ocular toxicity related to iron chelation
  • Systemic diseases (cardiovascular, renal, hepatic, etc.) which would prevent study treatment
  • Pregnancy (as documented in required screening laboratory test) or breast feeding
  • Patients who received treatment with systemic investigational drug within the past 4 weeks or topical investigational drug within the past 7 days or are planning to receive other investigational drugs while participating in the study
  • Other surgical or medical condition which might significantly alter the absorption, distribution, metabolism or excretion of study drug
  • History of non-compliance to medical regimens or patients who are considered potentially unreliable and/or not cooperative
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00981370

Contacts
Contact: Anne Nord, RN, BSN,CCRP 323-361-8507 anord@chla.usc.edu
Contact: Jennifer Harrington, RN, BSN 323-361-7319 jharrington@chla.usc.edu

Locations
United States, California
Childrens Hospital Los Angeles Recruiting
Los Angeles, California, United States, 90027
Contact: Anne Nord, RN, BSN, CCRP    323-361-8507    anord@chla.usc.edu   
Contact: Jennifer Harrington, RN, BSN    323-361-7319    jharrington@chla.usc.edu   
Principal Investigator: Thomas D. Coates, M.D.         
Childrens Hospital Los Angeles Recruiting
Los Angeles, California, United States, 90027
Contact: Anne Nord, RN, BSN,CCRP    323-361-8507    anord@chla.usc.edu   
Contact: Jennifer Harrington, RN,, BSN    323-361-7319    jharrington@chla.usc.edu   
Principal Investigator: Thomas D. Coates, M.D.         
Sponsors and Collaborators
Children's Hospital Los Angeles
Novartis Pharmaceuticals
Investigators
Principal Investigator: Thomas D. Coates, M.D. Children's Hospital Los Angeles
  More Information

Publications:

Responsible Party: Thomas D. Coates, M.D., Childrens Hospital Los Angeles
ClinicalTrials.gov Identifier: NCT00981370     History of Changes
Other Study ID Numbers: CICL670AUS30T
Study First Received: September 21, 2009
Last Updated: September 21, 2009
Health Authority: United States: Institutional Review Board

Keywords provided by Children's Hospital Los Angeles:
Sickle Cell Disease
Sickle Cell Anemia
Iron Overload
Chelation Therapy
Iron overload from blood transfusions
Heart rate variability
Autonomic dysfunction

Additional relevant MeSH terms:
Hemochromatosis
Anemia
Anemia, Sickle Cell
Iron Overload
Hematologic Diseases
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Hemoglobinopathies
Genetic Diseases, Inborn
Metal Metabolism, Inborn Errors
Metabolism, Inborn Errors
Iron Metabolism Disorders
Metabolic Diseases
Iron
Deferasirox
Trace Elements
Micronutrients
Growth Substances
Physiological Effects of Drugs
Pharmacologic Actions
Iron Chelating Agents
Chelating Agents
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on July 24, 2014