Sickle Cell Disease, Thalassemia Major, Transfusion-dependent Hemachromatosis
Conditions
Keywords
Thalassemia, Iron, Chelation
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.
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, Hepatobiliary Iminodiacetic Acid (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.
Interventions
DRUGDeferoxamine
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.
DRUGDeferasirox
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.
RADIATIONHIDA
All patients had a HIDA scan to assess physiologic liver clearance capacity.
Sponsors
Novartis
Boston Children's Hospital
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
6 Years to No maximum
Healthy volunteers
No
Inclusion 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Curve of Deferasirox After a Dose of 35 mg/kg | 0, 1, 2, 4, 6, 8, 12, and 24 hours post dose | Area Under the Curve (AUC) 0 to 24 hours post dose |
| Half-Life of Deferasirox | 0, 1, 2, 4, 6, 8, 12, and 24 hours post dose. | 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. |
| Volume of Distribution/Bioavailability of Deferasirox After a Dose of 35 mg/kg | 0, 1, 2, 4, 6, 8, 12, and 24 hours post dose | Volume of distribution/bioavailability (Vd/F) |
| Clearance/Bioavailability of Deferasirox in Patients With Poor Response to Deferasirox Compared to Patients With Good Response After a Dose of 35 mg/kg | 0, 1, 2, 4, 6, 8, 12, and 24 hours post dose. | Clearance/bioavailability (CL/F) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Polymorphisms in Genes Known to be, or Potentially Involved, in Deferasirox Disposition | 3 months | 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. |
Countries
United States
Participant flow
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.
Participants by arm
| Arm | Count |
|---|---|
| Inadequate Responders 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. | 10 |
| Adequate Responders (Control) 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. | 5 |
| Total | 15 |
Baseline characteristics
| Characteristic | Inadequate Responders | Adequate Responders (Control) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 7 Participants | 2 Participants | 9 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 3 Participants | 6 Participants |
| Region of Enrollment United States | 10 participants | 5 participants | 15 participants |
| Sex: Female, Male Female | 3 Participants | 2 Participants | 5 Participants |
| Sex: Female, Male Male | 7 Participants | 3 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 5 |
| other Total, other adverse events | 0 / 10 | 0 / 5 |
| serious Total, serious adverse events | 0 / 10 | 0 / 5 |
Outcome results
Primary
Area Under the Curve of Deferasirox After a Dose of 35 mg/kg
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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Inadequate Responders | Area Under the Curve of Deferasirox After a Dose of 35 mg/kg | 479.59 micromole/liter*hour | Standard Deviation 259.42 |
| Adequate Responders (Control) | Area Under the Curve of Deferasirox After a Dose of 35 mg/kg | 1123.11 micromole/liter*hour | Standard Deviation 63.4 |
p-value: <0.001t-test, 2 sided
Primary
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)
Time frame: 0, 1, 2, 4, 6, 8, 12, and 24 hours post dose.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Inadequate Responders | Clearance/Bioavailability of Deferasirox in Patients With Poor Response to Deferasirox Compared to Patients With Good Response After a Dose of 35 mg/kg | 1.30 liter/hour | Standard Deviation 0.18 |
| Adequate Responders (Control) | Clearance/Bioavailability of Deferasirox in Patients With Poor Response to Deferasirox Compared to Patients With Good Response After a Dose of 35 mg/kg | 0.61 liter/hour | Standard Deviation 0.22 |
p-value: 0.104t-test, 2 sided
Primary
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.
Time frame: 0, 1, 2, 4, 6, 8, 12, and 24 hours post dose.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Inadequate Responders | Half-Life of Deferasirox | 6.08 hour | Standard Deviation 2.01 |
| Adequate Responders (Control) | Half-Life of Deferasirox | 7.83 hour | Standard Deviation 2.95 |
p-value: 0.275t-test, 2 sided
Primary
Volume of Distribution/Bioavailability of Deferasirox After a Dose of 35 mg/kg
Volume of distribution/bioavailability (Vd/F)
Time frame: 0, 1, 2, 4, 6, 8, 12, and 24 hours post dose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Inadequate Responders | Volume of Distribution/Bioavailability of Deferasirox After a Dose of 35 mg/kg | 10.33 liter | Standard Deviation 7.42 |
| Adequate Responders (Control) | Volume of Distribution/Bioavailability of Deferasirox After a Dose of 35 mg/kg | 6.5 liter | Standard Deviation 2.67 |
p-value: 0.178t-test, 2 sided
Primary
Volume of Distribution/Bioavailability of Deferasirox After a Dose of 35 mg/kg
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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Inadequate Responders | Volume of Distribution/Bioavailability of Deferasirox After a Dose of 35 mg/kg | 0.32 liter/kilogram | Standard Deviation 0.25 |
| Adequate Responders (Control) | Volume of Distribution/Bioavailability of Deferasirox After a Dose of 35 mg/kg | 0.13 liter/kilogram | Standard Deviation 0.05 |
p-value: 0.062t-test, 2 sided
Secondary
Number of Participants With Polymorphisms in Genes Known to be, or Potentially Involved, in Deferasirox Disposition
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
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Inadequate Responders | Number of Participants With Polymorphisms in Genes Known to be, or Potentially Involved, in Deferasirox Disposition | UGT1a1 | 10 Participants |
| Inadequate Responders | Number of Participants With Polymorphisms in Genes Known to be, or Potentially Involved, in Deferasirox Disposition | UGT1a3 | 10 Participants |
| Inadequate Responders | Number of Participants With Polymorphisms in Genes Known to be, or Potentially Involved, in Deferasirox Disposition | BCRP/ABCG2 | 10 Participants |
| Inadequate Responders | Number of Participants With Polymorphisms in Genes Known to be, or Potentially Involved, in Deferasirox Disposition | MRP2/ABCC2 | 10 Participants |
| Adequate Responders (Control) | Number of Participants With Polymorphisms in Genes Known to be, or Potentially Involved, in Deferasirox Disposition | MRP2/ABCC2 | 5 Participants |
| Adequate Responders (Control) | Number of Participants With Polymorphisms in Genes Known to be, or Potentially Involved, in Deferasirox Disposition | UGT1a1 | 5 Participants |
| Adequate Responders (Control) | Number of Participants With Polymorphisms in Genes Known to be, or Potentially Involved, in Deferasirox Disposition | BCRP/ABCG2 | 5 Participants |
| Adequate Responders (Control) | Number of Participants With Polymorphisms in Genes Known to be, or Potentially Involved, in Deferasirox Disposition | UGT1a3 | 5 Participants |