Pilot Study for Patients With Poor Response to Deferasirox

NCT00749515 | Completed Phase 4 Results

• 2 other identifiers: 07090349NIH/NHLBI 1 K12 HL087164-01
• Study Type: interventional
• Target: 15
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Transfusion-dependent Hemachromatosis; Thalassemia Major; Sickle Cell Disease

Keywords

Thalassemia; Iron; Chelation

Outcome Measures

Primary Outcomes (5)

• Area Under the Curve of Deferasirox After a Dose of 35 mg/kg

  Area Under the Curve (AUC) 0 to 24 hours post dose

  0, 1, 2, 4, 6, 8, 12, and 24 hours post dose

• Half-Life of Deferasirox

  All patients received the same interventions of deferoxamine challenge, deferasirox dose with pharmacokinetic monitoring. Then we compared responses between patients who were known to be slow responders to deferasirox and those who were known to be rapid responders (chelated well). Deferoxamine: 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 Total Iron Binding Capacity (TIBC) by atomic absorption.

  0, 1, 2, 4, 6, 8, 12, and 24 hours post dose.

• Volume of Distribution/Bioavailability of Deferasirox After a Dose of 35 mg/kg

  Volume of distribution/bioavailability (Vd/F)

  0, 1, 2, 4, 6, 8, 12, and 24 hours post dose

• Volume of Distribution/Bioavailability of Deferasirox After a Dose of 35 mg/kg

  Volume of distribution/bioavailability (Vd/F), adjusted per kilogram body weight

  0, 1, 2, 4, 6, 8, 12, and 24 hours post dose

• Clearance/Bioavailability of Deferasirox in Patients With Poor Response to Deferasirox Compared to Patients With Good Response After a Dose of 35 mg/kg

  Clearance/bioavailability (CL/F)

  0, 1, 2, 4, 6, 8, 12, and 24 hours post dose.

Secondary Outcomes (1)

• Number of Participants With Polymorphisms in Genes Known to be, or Potentially Involved, in Deferasirox Disposition

  3 months

Study Arms (1)

Single Arm

EXPERIMENTAL

All patients received the same interventions of deferoxamine challenge, deferasirox dose with pharmacokinetic monitoring and HIDA scan. Then we compared responses between patients who were known to be slow responders to deferasirox and those who were known to be rapid responders (chelated well).

Drug: Deferoxamine; Drug: Deferasirox; Radiation: HIDA

Interventions

Deferoxamine DRUG

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 Total Iron Binding Capacity (TIBC) by atomic absorption.

Also known as: Desferal

Single Arm

Deferasirox DRUG

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.

Also known as: Exjade, ICL670

Single Arm

HIDA RADIATION

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

Single Arm

Eligibility Criteria

• Age: 6 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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.

You may not qualify if:

• 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.
• 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

Sponsors & Collaborators

• Boston Children's Hospital: lead
• Novartis: collaborator

Study Sites (1)

Children's Hospital Boston

Boston, Massachusetts, 02115, United States

Location

Related Publications (2)

• Chirnomas D, Smith AL, Braunstein J, Finkelstein Y, Pereira L, Bergmann AK, Grant FD, Paley C, Shannon M, Neufeld EJ. Deferasirox pharmacokinetics in patients with adequate versus inadequate response. Blood. 2009 Nov 5;114(19):4009-13. doi: 10.1182/blood-2009-05-222729. Epub 2009 Sep 1.

  PMID: 19724055 RESULT

• Padhani ZA, Gangwani MK, Sadaf A, Hasan B, Colan S, Alvi N, Das JK. Calcium channel blockers for preventing cardiomyopathy due to iron overload in people with transfusion-dependent beta thalassaemia. Cochrane Database Syst Rev. 2023 Nov 17;11(11):CD011626. doi: 10.1002/14651858.CD011626.pub3.

  PMID: 37975597 DERIVED

MeSH Terms

Conditions

beta-Thalassemia; Anemia, Sickle Cell; Thalassemia

Interventions

Deferoxamine; Deferasirox; lidofenin

Condition Hierarchy (Ancestors)

Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemoglobinopathies; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Hydroxamic Acids; Hydroxylamines; Amines; Organic Chemicals; Hydroxy Acids; Carboxylic Acids; Benzoates; Acids, Carbocyclic; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Ellis Neufeld, MD, PhD
• Organization: St. Jude Children's Research Hospital

ellis.neufeld@stjude.org

901-595-7509

Study Officials

• Deborah Chirnomas, MD

  Boston Children's Hospital

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Pediatrics

Study Record Dates

• First Submitted: September 8, 2008
• First Posted: September 9, 2008
• Study Start: March 1, 2008
• Primary Completion: October 1, 2008
• Study Completion: November 1, 2008
• Last Updated: February 12, 2024
• Results First Posted: February 6, 2019

Record last verified: 2024-02

Locations

US (1)