Amlodipine as Adjuvant Treatment to Iron Chelation for Prevention of Cardiac Iron Overload in Thalassemia Patients

Study Overview
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Brief Summary
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This is a randomized, open label, two arms superiority trial of a representative population of patients with a primary diagnosis of transfusion dependent thalassemia with evidence of moderate cardiac iron overload, defined as an average T2* MRI parameter at the mid inter-ventricular septum between 10 and 20ms.

Detailed Description
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Selection of Study Population: The study will enroll 60 adult subjects with transfusion dependent thalassemia receiving deferasirox iron chelation therapy. All eligible subjects will be asked to provide informed consent before participating in the study. Randomization: Subjects will be randomized in a 1:1 ratio to either continuation of their DFX (control arm) or a combination of DFX plus amlodipine (amlodipine arm). Treatment: Subjects randomized to the amlodipine arm will receive open label medication (amlodipine) starting at 2.5mg/day and up-titrated by 2.5mg every 7-14 days with the goal of reaching 10mg/day. DFX dose in either arm will not be adjusted unless it was deemed unsafe to remain on the same dose of DFX by the treating physician (significant side effects, lack of efficacy or over-chelation) or T2* drops below 8 ms. Safety Assessment: Weekly or fortnightly amlodipine titration will be conducted by the research physician in-clinic, based on blood pressure, tolerability, and presence or absence of side-effects. Adverse Events will be assessed at every visit after the first dose through to the last subject visit. Efficacy Assessment: the efficacy of amlodipine combined to standard chelation therapy will be assessed by cardiac T2*MRI, done at baseline and 12 months post treatment.

Official Title
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The Use of the Calcium Channel Blocker Amlodipine as an Adjuvant Treatment to Iron Chelation for the Prevention of Iron Overload Cardiomyopathy in Patients With Thalassemia

Conditions
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Iron Overload, Beta-Thalassemia

Intervention / Treatment
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* Drug: Amlodipine
* Drug: Deferasirox


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of transfusion-dependent Thalassemia being followed by a thalassemia comprehensive care clinic Age 18 or older Taking deferasirox and on a stable dose for >3 months Evidence on cardiac MRI of mild to moderate cardiac iron overload (T2*<20ms but ≥10ms) as measured within 3 months prior to randomization. If a recent cardiac MRI has not been obtained, patients who otherwise meet all eligibility criteria and provide appropriate consent will undergo a cardiac MRI to confirm eligibility Preserved left ventricular ejection fraction (LVEF) >55% as measured by cardiac MRI. If a recent cardiac MRI has not been obtained, patients who otherwise meet all eligibility criteria and provide appropriate consent will undergo a cardiac MRI to confirm eligibility. Agreeable to use an approved method of contraception if female of childbearing potential for the entire duration of the study. Exclusion Criteria: Serum ferritin < 500 ng/mL at screening Liver iron concentration > 30 mg/g dw as measured by liver R2 MRI (FerriScan) Congestive heart failure Severe refractory Hypotension (less than 90 mmHg systolic) Currently taking any calcium channel blockers Pregnancy or nursing (a negative HCG (pregnancy) test must be obtained prior to randomization) As a result of medical review, physical examination or screening investigations, the Principal Investigator (PI) considers the subject unfit for the study No fixed address Hypersensitivity to amlodipine or other dihydropyridines

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Deferasirox<br>deferasirox iron chelation therapy and standard of care by the treating physician | Drug: Deferasirox<br>* Deferasirox administered per standard of care by the treating physician<br>|
| Experimental: Deferasirox plus amlodipine<br>deferasirox iron chelation therapy with amlodipine | Drug: Amlodipine<br>* amlodipine titrated up to 10 mg daily or maximum tolerated dose, whichever comes first<br>Drug: Deferasirox<br>* Deferasirox administered per standard of care by the treating physician<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in cardiac T2* | Change in cardiac T2* as determined by MRI | 12 months following randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in left ventricular ejection fraction | Change in left ventricular ejection fraction (in %) as determined by MRI | 12 months following randomization | 
| Number of Participants with Adverse Events |  | 12 months following randomization |