Pilot Study for Patients With Poor Response to Deferasirox - Full Text View

Sponsors and Collaborators:	Children's Hospital Boston Novartis
Information provided by:	Children's Hospital Boston
ClinicalTrials.gov Identifier:	NCT00749515

Purpose

This purpose of this study is to understand the differences between people who have a good response to deferasirox (exjade) compared to people who have a poor response to this medication when used for transfusion-dependent iron overload.

The hypothesis is that patients with poor responses have physiologic barriers to deferasirox that may include absorption, pharmacokinetics of drug metabolism, hepatic clearance and/or genetic factors.

Condition	Intervention	Phase
Transfusion-Dependent Hemachromatosis Thalassemia Major Sickle Cell Disease	Drug: Deferoxamine Drug: Deferasirox Radiation: HIDA	Phase IV

Genetics Home Reference related topics: beta thalassemia hemochromatosis sickle cell disease

MedlinePlus related topics: Blood Transfusion and Donation Hemochromatosis Sickle Cell Anemia Thalassemia

Drug Information available for: Deferasirox Deferoxamine Deferoxamine mesylate

U.S. FDA Resources

Study Type:	Interventional
Study Design:	Treatment, Open Label, Uncontrolled, Single Group Assignment, Pharmacokinetics/Dynamics Study
Official Title:	Pilot Pharmacokinetic Study In Patients With Inadequate Response To Deferasirox (Exjade)

Further study details as provided by Children's Hospital Boston:

Primary Outcome Measures:

Pharmacokinetics of deferasirox in patients with poor response to deferasirox compared to patients with good response after a dose of 35 mg/kg. [ Time Frame: 24 hours ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Pharmacogenomics [ Time Frame: 3 months ] [ Designated as safety issue: No ]
Pharmacokinetics of clinical maintenance dose of deferasirox in poor responders to deferasirox compared to good responders. [ Time Frame: 3 months ] [ Designated as safety issue: No ]

Enrollment:	15
Study Start Date:	March 2008
Estimated Study Completion Date:	November 2008
Estimated Primary Completion Date:	October 2008 (Final data collection date for primary outcome measure)

Intervention Details:

After a 3-day washout period from all chelation, all patients have a 12 hour infusion of 50mg/kg of deferoxamine with urine collection and pre and post blood sampling to assess iron and TIBC by atomic absorption.

After a 3-day washout period from all chelation, patients had a desferal challenge which was followed by a single dose of deferasirox, 35mg/kg orally with blood sampling taken pre-deferasirox and at intervals for 24 hours after the dose.

All patients had a HIDA scan to assess physiologic liver clearance capacity.

Detailed Description:

The purpose of this trial is to examine three potential mechanisms of inadequate response to Exjade® in patients with transfusion dependent iron overload including patients with thalassemia syndromes, sickle cell disease and bone marrow failure.

Hypothesis: Patients have physiologic barriers to adequately respond to deferasirox that may include absorption, pharmacokinetics of drug metabolism, hepatic clearance and/or genetic factors.

Study objectives Primary objective

To evaluate three potential mechanisms for inadequate response to deferasirox in a small cohort of patients with hemoglobinopathies.
Oral pharmacokinetics measured with Cmax and AUC following standard dose deferasirox.
Hepatobiliary excretory function
Accessibility of chelatable iron pool by deferoxamine challenge Secondary objective(s)
To identify risk factors that can predict adequate response including demographics, disease status, presence and severity of liver disease, trough levels of deferasirox at outpatient visits and pharmacogenomics.
To investigate usefulness of potential surrogate measures of response including serum deferasirox levels, HIDA-nuclear medicine scan to evaluate hepatic excretory function and urinary iron excretion by deferoxamine challenge.

This is an investigator-initiated, pilot-scale, open-label physiological assessment of patients who respond poorly to deferasirox compared with patients who respond well. We plan to study 2 groups of patients: a)10 patients who have demonstrated poor responses and b) 5 control patients with good responses as defined further in the protocol. The study has two parts.

Part I: Both groups of patients will have inpatient physiological assessments with a dose of 35mg/kg of deferasirox.

Part II: Inadequate responders eligible to continue on deferasirox will continue on a dose of 35 mg/kg for three months during which time serial pharmacokinetic levels will be studied. The control patients will resume their previous clinically appropriate dosing (likely less than 35 mg/kg) and for three months have serial pharmacokinetic levels drawn as well.

The study will begin with an outpatient screening visit when demographics and historical information as well as a physical examination will be obtained and reviewed for eligibility. At that visit patients will be able to sign informed consent. Shortly thereafter patients will be admitted to the GCRC at Children's Hospital Boston for part I of the study, a 2-3 day stay during which PK and nuclear medicine studies will be performed as well as the deferoxamine urinary iron excretion challenge. Patients who are eligible will continue on to part II of the study, and for 3 months and will be monitored for compliance, PK and ferritin changes on appropriate deferasirox doses.

Eligibility

Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Part I: Inclusion criteria for Inadequate responders

Male or female patients with transfusion dependent iron overload including patients with thalassemia syndromes, sickle cell disease and bone marrow failure.
Patients currently on Desferal (desferrioxamine) therapy will require a one day wash out prior to the first dose of study drug.
Dose of deferasirox: >30 mg/kg/day of deferasirox for at least 3 months
No improvement or worsening of liver iron content (LIC) if this has been evaluated on deferasirox in the 3 months preceding the baseline studies.
Age greater than 6 years
Serum Ferritin: Ferritin >1500 ng/ml and rising over three month period while on deferasirox.
Patients had to achieve 'failure' as described above previously and may or may not currently be on deferasirox and may currently be having adequate responses on doses greater than or equal to 35 mg/kg/day of deferasirox.
Life expectancy ≥ 6 months
Written informed consent by the patient or for pediatric patients consent of the patient's legal guardian. The definition of the term 'pediatric' for enrollment and study conduct will be in accordance with Children's Hospital IRB. Parents or the legal guardians will be fully informed by the investigator as to the requirements of the study. Pediatric patients themselves will be informed according to their capabilities in a language and in terms that they are able to understand. Written informed consent will be obtained from their legal guardian on the patient's behalf in accordance with national legislation. If capable, all patients should also personally sign their written informed consent.

Part I: Inclusion criteria for good responders:

Male or female patients with transfusion dependent iron overload including patients with thalassemia syndromes, sickle cell disease and bone marrow failure.
Patients currently on Desferal (desferrioxamine) therapy will require a one day wash out prior to the first dose of study drug.
Serum ferritin less than or equal to 1000 ng/ml or declining over a 3 month period on a dose of less than 30 mg/kg of deferasirox.
Age greater than 6 years
Life expectancy ≥ 6 months
Written informed consent by the patient or for pediatric patients consent of the patient's legal guardian. The definition of the term 'pediatric' for enrollment and study conduct will be in accordance with Children's Hospital IRB. Parents or the legal guardians will be fully informed by the investigator as to the requirements of the study. Pediatric patients themselves will be informed according to their capabilities in a language and in terms that they are able to understand. Written informed consent will be obtained from their legal guardian on the patient's behalf in accordance with national legislation. If capable, all patients should also personally sign their written informed consent.

Exclusion criteria for Part I:

Pregnancy (as documented in required screening laboratory test) or breast feeding
History of non-compliance to medical regimens or patients who are considered potentially unreliable and/or not cooperative
Patients with transfusion requirements equal to or more frequent than every three weeks.
AST or ALT > 400 U/L during screening
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 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
Allergy to deferoxamine
Known contraindication to having a nuclear medicine study
Any other condition which in the opinion of the investigator would prevent completion of the trial.
Prior possible toxicity is not an exclusion criteria for Part I because patients require a chelating agent of which there are only two Patients who are found to be ineligible after screening procedures will have this documented on the screening log. No further data will be collected in the CRF for these patients.

Exclusion criteria for Part II:

Patients with unacceptable toxicity to deferasirox such as renal failure or worsening cardiac function
Patients who have failed to achieve negative iron balance at the maximum tolerated dose of deferasirox
Patients who require an alternative chelator for specific reasons
Patients who are currently enrolled on conflicting therapeutic trials
Patients with serum ferritin less than 500 ng/ml at screening
Any other condition which in the opinion of the investigator would prevent completion of the trial

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00749515

Locations

United States, Massachusetts
Children's Hospital Boston
Boston, Massachusetts, United States, 02115

Sponsors and Collaborators

Children's Hospital Boston

Novartis

Investigators

Principal Investigator:

Deborah Chirnomas, MD

Children's Hospital Boston

More Information

Responsible Party:	Children's Hospital Boston ( Deborah Chirnomas, MD )
Study ID Numbers:	07090349, NIH/NHLBI 1 K12 HL087164-01
Study First Received:	September 8, 2008
Last Updated:	September 8, 2008
ClinicalTrials.gov Identifier:	NCT00749515
Health Authority:	United States: Institutional Review Board

Keywords provided by Children's Hospital Boston:

Thalassemia
Iron
Chelation

Study placed in the following topic categories:

Metabolic Diseases
Deferasirox
Hematologic Diseases
Beta-thalassemia
Anemia
Hemochromatosis, type 3
Anemia, Hemolytic
Iron Metabolism Disorders
Thalassemia
Sickle cell anemia
Anemia, Hemolytic, Congenital
Metabolism, Inborn Errors

Thalassemia minor
Genetic Diseases, Inborn
Beta-Thalassemia
Hemoglobinopathies
Hemochromatosis
Iron Overload
Metabolic disorder
Hemoglobinopathy
Iron
Anemia, Sickle Cell
Deferoxamine

Additional relevant MeSH terms:

Molecular Mechanisms of Pharmacological Action
Iron Chelating Agents
Chelating Agents

Metal Metabolism, Inborn Errors
Pharmacologic Actions
Siderophores

ClinicalTrials.gov processed this record on January 14, 2009