Transfusion-dependent HemachromatosisPhase 4NCT00749515

Pilot Study for Patients With Poor Response to Deferasirox

A Phase 4 study testing Deferoxamine, Deferasirox and HIDA in people with Transfusion-dependent Hemachromatosis and Thalassemia Major, run by Boston Children's Hospital at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial 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. Read more about this study

Who is it for?: Ages 6 years and older
Conditions the study is for: Transfusion-dependent Hemachromatosis, Thalassemia Major, Sickle Cell Disease
What is being tested?: Deferoxamine, Deferasirox and HIDA
Type of treatment: Pill or oral medicine, Injection or infusion, Surgery or procedure
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 15 participants
Where: 1 siteUnited States
Study dates: Mar 2008to Nov 2008
Phase: Phase 4
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 6 years and older
All sexes
No healthy volunteers
Child, Adult, Older adult

Who may be able to join

None listed.

Who cannot join

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

Show all 17Show fewer

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.
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

Trial locations and contacts

1 site in 1 country.

United States1 site

Children's Hospital Boston
Boston, Massachusetts, 02115

Other trials in United States

About this study

Official title: Pilot Pharmacokinetic Study In Patients With Inadequate Response To Deferasirox (Exjade)

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.

Read the 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.

Conditions: Transfusion-dependent Hemachromatosis, Thalassemia Major, Sickle Cell Disease
Being tested: Deferoxamine, Deferasirox, HIDA
Keywords: Thalassemia, Iron, Chelation
Medical subject headings: beta-Thalassemia, Anemia, Sickle Cell, Thalassemia

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

DeferoxamineDrug
Also called Desferal
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.
DeferasiroxDrug
Also called Exjade, ICL670
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.
HIDARadiation
All patients had a HIDA scan to assess physiologic liver clearance capacity.

Study groups in NCT00749515
Study group	Role	What they receive
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). Receives: Drug: Deferoxamine; Drug: Deferasirox; Radiation: HIDA

What is being measured

The primary outcome is the main question the study is designed to answer.

Area Under the Curve of Deferasirox After a Dose of 35 mg/kg
Area Under the Curve (AUC) 0 to 24 hours post dose
Measured: 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.
Measured: 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)
Measured: 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
Measured: 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)
Measured: 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
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.
Measured: 3 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

Mar 2008Nov 2008

First posted9 Sep 2008 (estimated)
Study startMar 2008
Primary completionOct 2008
Study completionNov 2008

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Publications (2)Papers the sponsor has linked to this study.
Other trials for Transfusion-dependent HemachromatosisStudies of the same condition, open and under way.
More trials run by Boston Children's HospitalThe sponsor's other registered studies.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 4
Primary purpose: Treatment
Allocation: Not applicable
Intervention model: Single group
Masking: None (open label)
Enrolment: 15 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT00749515
Sponsor's protocol ID: 07090349
Other IDs: NIH/NHLBI 1 K12 HL087164-01
Status last verified: Feb 2024
First submitted: 8 Sep 2008
Last updated: 12 Feb 2024
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: No

Publications

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.
PubMed 19724055
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.
PubMed 37975597

Study at a glance

From the registry record, last updated by the sponsor on 12 Feb 2024. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: Pilot Pharmacokinetic Study In Patients With Inadequate Response To Deferasirox (Exjade)
ClinicalTrials.gov ID: NCT00749515
Acronym / sponsor ID: 07090349
Conditions: Transfusion-dependent Hemachromatosis, Thalassemia Major, Sickle Cell Disease
Keywords: Thalassemia, Iron, Chelation
Phase: Phase 4
Study type: Interventional
Recruitment status: Completed
Enrolment: 15 participants (actual)
Lead sponsor: Boston Children's HospitalUniversity, hospital or other
Collaborators: Novartis
Study start: Mar 2008
Primary completion: Oct 2008 (actual)
Study completion: Nov 2008 (actual)
First posted: 9 Sep 2008 (estimated)
Results: Posted 6 Feb 2019

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Detailed description

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.

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

Study design

Primary purpose: Treatment
Allocation: Not applicable
Intervention model: Single group
Masking: None (open label)
Number of arms: 1

Arm	Type	Receives
Single Arm	Experimental	Drug: Deferoxamine, Drug: Deferasirox, Radiation: HIDAAll 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).

Who may qualify

Ages: 6 years and older
Sex: All
Healthy volunteers: Not accepted
Age groups: Child, Adult, Older adult

Key inclusion criteria (0 listed)

Key exclusion criteria (17 listed)

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

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
DeferoxamineAlso: DesferalAfter 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.	Drug	Single Arm
DeferasiroxAlso: Exjade, ICL670After 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.	Drug	Single Arm
HIDAAll patients had a HIDA scan to assess physiologic liver clearance capacity.	Radiation	Single Arm

Primary outcome

Area Under the Curve of Deferasirox After a Dose of 35 mg/kg
Time frame: 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
Time frame: 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
Time frame: 0, 1, 2, 4, 6, 8, 12, and 24 hours post dose
Volume of distribution/bioavailability (Vd/F)
Volume of Distribution/Bioavailability of Deferasirox After a Dose of 35 mg/kg
Time frame: 0, 1, 2, 4, 6, 8, 12, and 24 hours post dose
Volume of distribution/bioavailability (Vd/F), adjusted per kilogram body weight
Clearance/Bioavailability of Deferasirox in Patients With Poor Response to Deferasirox Compared to Patients With Good Response After a Dose of 35 mg/kg
Time frame: 0, 1, 2, 4, 6, 8, 12, and 24 hours post dose.
Clearance/bioavailability (CL/F)

1 secondary outcome

Number of Participants With Polymorphisms in Genes Known to be, or Potentially Involved, in Deferasirox Disposition
Time frame: 3 months

Results and safety

Results posted to the registry on 6 Feb 2019, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Inadequate Responders	10	10
Adequate Responders (Control)	5	5

Primary outcome: Area Under the Curve of Deferasirox After a Dose of 35 mg/kg

Time frame: 0, 1, 2, 4, 6, 8, 12, and 24 hours post dose. Mean (Standard Deviation). Unit: micromole/liter*hour

Measure	Inadequate Responders n = 10	Adequate Responders (Control) n = 5
Value	479.59 (259.42)	1123.11 (63.4)

Inadequate Responders vs Adequate Responders (Control): p <.001, t-test, 2 sided

Primary outcome: Half-Life of Deferasirox

Time frame: 0, 1, 2, 4, 6, 8, 12, and 24 hours post dose.. Mean (Standard Deviation). Unit: hour

Measure	Inadequate Responders n = 10	Adequate Responders (Control) n = 5
Value	6.08 (2.01)	7.83 (2.95)

Inadequate Responders vs Adequate Responders (Control): p = .275, t-test, 2 sided

Primary outcome: Volume of Distribution/Bioavailability of Deferasirox After a Dose of 35 mg/kg

Time frame: 0, 1, 2, 4, 6, 8, 12, and 24 hours post dose. Mean (Standard Deviation). Unit: liter

Measure	Inadequate Responders n = 10	Adequate Responders (Control) n = 5
Value	10.33 (7.42)	6.5 (2.67)

Inadequate Responders vs Adequate Responders (Control): p = .178, t-test, 2 sided

Primary outcome: Volume of Distribution/Bioavailability of Deferasirox After a Dose of 35 mg/kg

Time frame: 0, 1, 2, 4, 6, 8, 12, and 24 hours post dose. Mean (Standard Deviation). Unit: liter/kilogram

Measure	Inadequate Responders n = 10	Adequate Responders (Control) n = 5
Value	0.32 (0.25)	0.13 (0.05)

Inadequate Responders vs Adequate Responders (Control): p = .062, t-test, 2 sided

1 secondary outcome is reported in the full results.

Adverse events

Time frame: Adverse event are reported for at least 28 days following the last dose of study drug.. Other adverse events reported at 0% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Inadequate Responders	0 of 10 (0%)	0 of 10 (0%)	0 of 10
Adequate Responders (Control)	0 of 5 (0%)	0 of 5 (0%)	0 of 5

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 12 Feb 2024.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Results publication: PubMed 19724055Chirnomas 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.
Derived from this study: PubMed 37975597Padhani 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.

Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Deborah Chirnomas, MD principal investigator

Boston Children's Hospital

1 site in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing Deferoxamine, Deferasirox and HIDA in people with Transfusion-dependent Hemachromatosis and Thalassemia Major, run by Boston Children's Hospital at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 0 inclusion and 17 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 12 Feb 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 6 Feb 2019). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Area Under the Curve of Deferasirox After a Dose of 35 mg/kg (time frame: 0, 1, 2, 4, 6, 8, 12, and 24 hours post dose). The study lists 5 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00749515, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 12 Feb 2024.