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Pilot Study for Patients With Poor Response to Deferasirox

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ClinicalTrials.gov Identifier: NCT00749515
Recruitment Status : Completed
First Posted : September 9, 2008
Results First Posted : February 6, 2019
Last Update Posted : June 25, 2019
Sponsor:
Collaborator:
Novartis
Information provided by (Responsible Party):
Ellis Neufeld, Boston Children's Hospital

Study Type Interventional
Study Design Allocation: N/A;   Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Conditions Transfusion-dependent Hemachromatosis
Thalassemia Major
Sickle Cell Disease
Interventions Drug: Deferoxamine
Drug: Deferasirox
Radiation: HIDA
Enrollment 15
Recruitment Details Between March 2008 and June 2008, 15 patients were recruited who had transfusional iron overload, and had been on deferasirox for at least 6 months at some point in their chelation history. Ten (10) patients were recruited as inadequate responders and 5 were recruited as control patients with adequate response to deferasirox therapy.
Pre-assignment Details  
Arm/Group Title Inadequate Responders Adequate Responders (Control)
Hide Arm/Group Description Patients having a rising ferritin trend over 3 consecutive months, at least one higher than 1500ng/mL (1500 µg/L) or rising liver iron documented by biopsy or change in T2 or Ferriscan magnetic resonance imaging (MRI) and on a dose of more than 30img/kg per day of deferasirox. Patients having a ferritin trend below 1000 ng/mL (1000 µg/L) or documented declining liver iron burden by MRI or biopsy and on a dose of 30img/kg per day or less of deferasirox.
Period Title: Overall Study
Started 10 5
Completed 10 5
Not Completed 0 0
Arm/Group Title Inadequate Responders Adequate Responders (Control) Total
Hide Arm/Group Description Patients having a rising ferritin trend over 3 consecutive months, at least one higher than 1500ng/mL (1500 µg/L) or rising liver iron documented by biopsy or change in T2 or Ferriscan magnetic resonance imaging (MRI) and on a dose of more than 30img/kg per day of deferasirox. Patients having a ferritin trend below 1000 ng/mL (1000 µg/L) or documented declining liver iron burden by MRI or biopsy and on a dose of 30img/kg per day or less of deferasirox. Total of all reporting groups
Overall Number of Baseline Participants 10 5 15
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 10 participants 5 participants 15 participants
<=18 years
7
  70.0%
2
  40.0%
9
  60.0%
Between 18 and 65 years
3
  30.0%
3
  60.0%
6
  40.0%
>=65 years
0
   0.0%
0
   0.0%
0
   0.0%
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 10 participants 5 participants 15 participants
Female
3
  30.0%
2
  40.0%
5
  33.3%
Male
7
  70.0%
3
  60.0%
10
  66.7%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 10 participants 5 participants 15 participants
10 5 15
1.Primary Outcome
Title Area Under the Curve of Deferasirox After a Dose of 35 mg/kg
Hide Description Area Under the Curve (AUC) 0 to 24 hours post dose
Time Frame 0, 1, 2, 4, 6, 8, 12, and 24 hours post dose
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Inadequate Responders Adequate Responders (Control)
Hide Arm/Group Description:
Patients having a rising ferritin trend over 3 consecutive months, at least one higher than 1500ng/mL (1500 µg/L) or rising liver iron documented by biopsy or change in T2 or Ferriscan magnetic resonance imaging (MRI) and on a dose of more than 30img/kg per day of deferasirox.
Patients having a ferritin trend below 1000 ng/mL (1000 µg/L) or documented declining liver iron burden by MRI or biopsy and on a dose of 30img/kg per day or less of deferasirox.
Overall Number of Participants Analyzed 10 5
Mean (Standard Deviation)
Unit of Measure: micromole/liter*hour
479.59  (259.42) 1123.11  (63.4)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Inadequate Responders, Adequate Responders (Control)
Comments [Not Specified]
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <.001
Comments [Not Specified]
Method t-test, 2 sided
Comments [Not Specified]
2.Primary Outcome
Title Half-Life of Deferasirox
Hide Description

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.
Time Frame 0, 1, 2, 4, 6, 8, 12, and 24 hours post dose.
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Inadequate Responders Adequate Responders (Control)
Hide Arm/Group Description:
Patients having a rising ferritin trend over 3 consecutive months, at least one higher than 1500ng/mL (1500 µg/L) or rising liver iron documented by biopsy or change in T2 or Ferriscan magnetic resonance imaging (MRI) and on a dose of more than 30img/kg per day of deferasirox.
Patients having a ferritin trend below 1000 ng/mL (1000 µg/L) or documented declining liver iron burden by MRI or biopsy and on a dose of 30img/kg per day or less of deferasirox.
Overall Number of Participants Analyzed 10 5
Mean (Standard Deviation)
Unit of Measure: hour
6.08  (2.01) 7.83  (2.95)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Inadequate Responders, Adequate Responders (Control)
Comments [Not Specified]
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value .275
Comments [Not Specified]
Method t-test, 2 sided
Comments [Not Specified]
3.Primary Outcome
Title Volume of Distribution/Bioavailability of Deferasirox After a Dose of 35 mg/kg
Hide Description Volume of distribution/bioavailability (Vd/F)
Time Frame 0, 1, 2, 4, 6, 8, 12, and 24 hours post dose
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Inadequate Responders Adequate Responders (Control)
Hide Arm/Group Description:
Patients having a rising ferritin trend over 3 consecutive months, at least one higher than 1500ng/mL (1500 µg/L) or rising liver iron documented by biopsy or change in T2 or Ferriscan magnetic resonance imaging (MRI) and on a dose of more than 30img/kg per day of deferasirox.
Patients having a ferritin trend below 1000 ng/mL (1000 µg/L) or documented declining liver iron burden by MRI or biopsy and on a dose of 30img/kg per day or less of deferasirox.
Overall Number of Participants Analyzed 10 5
Mean (Standard Deviation)
Unit of Measure: liter
10.33  (7.42) 6.5  (2.67)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Inadequate Responders, Adequate Responders (Control)
Comments [Not Specified]
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value .178
Comments [Not Specified]
Method t-test, 2 sided
Comments [Not Specified]
4.Primary Outcome
Title Volume of Distribution/Bioavailability of Deferasirox After a Dose of 35 mg/kg
Hide Description Volume of distribution/bioavailability (Vd/F), adjusted per kilogram body weight
Time Frame 0, 1, 2, 4, 6, 8, 12, and 24 hours post dose
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Inadequate Responders Adequate Responders (Control)
Hide Arm/Group Description:
Patients having a rising ferritin trend over 3 consecutive months, at least one higher than 1500ng/mL (1500 µg/L) or rising liver iron documented by biopsy or change in T2 or Ferriscan magnetic resonance imaging (MRI) and on a dose of more than 30img/kg per day of deferasirox.
Patients having a ferritin trend below 1000 ng/mL (1000 µg/L) or documented declining liver iron burden by MRI or biopsy and on a dose of 30img/kg per day or less of deferasirox.
Overall Number of Participants Analyzed 10 5
Mean (Standard Deviation)
Unit of Measure: liter/kilogram
0.32  (0.25) 0.13  (0.05)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Inadequate Responders, Adequate Responders (Control)
Comments [Not Specified]
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value .062
Comments [Not Specified]
Method t-test, 2 sided
Comments [Not Specified]
5.Primary Outcome
Title Clearance/Bioavailability of Deferasirox in Patients With Poor Response to Deferasirox Compared to Patients With Good Response After a Dose of 35 mg/kg
Hide Description Clearance/bioavailability (CL/F)
Time Frame 0, 1, 2, 4, 6, 8, 12, and 24 hours post dose.
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Inadequate Responders Adequate Responders (Control)
Hide Arm/Group Description:
Patients having a rising ferritin trend over 3 consecutive months, at least one higher than 1500ng/mL (1500 µg/L) or rising liver iron documented by biopsy or change in T2 or Ferriscan magnetic resonance imaging (MRI) and on a dose of more than 30img/kg per day of deferasirox.
Patients having a ferritin trend below 1000 ng/mL (1000 µg/L) or documented declining liver iron burden by MRI or biopsy and on a dose of 30img/kg per day or less of deferasirox.
Overall Number of Participants Analyzed 10 5
Mean (Standard Deviation)
Unit of Measure: liter/hour
1.30  (.18) 0.61  (0.22)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Inadequate Responders, Adequate Responders (Control)
Comments [Not Specified]
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value .104
Comments [Not Specified]
Method t-test, 2 sided
Comments [Not Specified]
6.Secondary Outcome
Title Number of Participants With Polymorphisms in Genes Known to be, or Potentially Involved, in Deferasirox Disposition
Hide Description Polymorphisms in genes known to be, or potentially involved, in deferasirox disposition: UGT1a1 (including the Gilbert syndrome promoter polymorphism, (TA)nTAA),UGT1a3, BRCP/ABCG2, MRP2/ABCC2. These genes were chosen because deferasirox is primarily eliminated by glucuronidation and subsequent biliary excretion.
Time Frame 3 months
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Inadequate Responders Adequate Responders (Control)
Hide Arm/Group Description:
Patients having a rising ferritin trend over 3 consecutive months, at least one higher than 1500ng/mL (1500 µg/L) or rising liver iron documented by biopsy or change in T2 or Ferriscan magnetic resonance imaging (MRI) and on a dose of more than 30img/kg per day of deferasirox.
Patients having a ferritin trend below 1000 ng/mL (1000 µg/L) or documented declining liver iron burden by MRI or biopsy and on a dose of 30img/kg per day or less of deferasirox.
Overall Number of Participants Analyzed 10 5
Measure Type: Count of Participants
Unit of Measure: Participants
UGT1a1
10
 100.0%
5
 100.0%
UGT1a3
10
 100.0%
5
 100.0%
BCRP/ABCG2
10
 100.0%
5
 100.0%
MRP2/ABCC2
10
 100.0%
5
 100.0%
Time Frame Adverse event are reported for at least 28 days following the last dose of study drug.
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Inadequate Responders Adequate Responders (Control)
Hide Arm/Group Description Patients having a rising ferritin trend over 3 consecutive months, at least one higher than 1500ng/mL (1500 µg/L) or rising liver iron documented by biopsy or change in T2 or Ferriscan magnetic resonance imaging (MRI) and on a dose of more than 30img/kg per day of deferasirox. Patients having a ferritin trend below 1000 ng/mL (1000 µg/L) or documented declining liver iron burden by MRI or biopsy and on a dose of 30img/kg per day or less of deferasirox.
All-Cause Mortality
Inadequate Responders Adequate Responders (Control)
Affected / at Risk (%) Affected / at Risk (%)
Total   0/10 (0.00%)   0/5 (0.00%) 
Hide Serious Adverse Events
Inadequate Responders Adequate Responders (Control)
Affected / at Risk (%) Affected / at Risk (%)
Total   0/10 (0.00%)   0/5 (0.00%) 
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Inadequate Responders Adequate Responders (Control)
Affected / at Risk (%) Affected / at Risk (%)
Total   0/10 (0.00%)   0/5 (0.00%) 
[Not Specified]
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Ellis Neufeld, MD, PhD
Organization: St. Jude Children's Research Hospital
Phone: 901-595-7509
EMail: ellis.neufeld@stjude.org
Publications of Results:
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.
Layout table for additonal information
Responsible Party: Ellis Neufeld, Boston Children's Hospital
ClinicalTrials.gov Identifier: NCT00749515    
Other Study ID Numbers: 07090349
NIH/NHLBI 1 K12 HL087164-01
First Submitted: September 8, 2008
First Posted: September 9, 2008
Results First Submitted: June 21, 2011
Results First Posted: February 6, 2019
Last Update Posted: June 25, 2019