Study to Evaluate Treatment Compliance, Efficacy and Safety of an Improved Deferasirox Formulation (Granules) in Pediatric Patients (2-<18 Years Old) With Iron Overload

Study Overview
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Brief Summary
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This is a randomized, open-label, multicenter, two arm, phase II study to evaluate treatment compliance and change in serum ferritin of a deferasirox granule formulation and a deferasirox DT formulation in children and adolescents aged ≥ 2 and < 18 years at enrollment with any transfusion-dependent anemia requiring chelation therapy due to iron overload, to demonstrate the effect of improved compliance on iron burden. Randomization will be stratified by age groups (2 to <10 years, 10 to <18 years) and prior iron chelation therapy (Yes/ No). There will be two study phases which include a 1 year core phase where patients will be randomized to a 48 week treatment period to either Deferasirox DT or granules, and an optional extension phase where all patients will receive the granules up to 5 years. Patients who demonstrated benefit to granules or DT in the core phase, and/or express the wish to continue in the optional extension phase on granules, will be offered this possibility until there is local access to the new formulation (granules or FCT) or up to 5 years, whichever occurs first.

Official Title
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A Randomized, Open-label, Multicenter, Two Arm, Phase II Study to Evaluate Treatment Compliance, Efficacy and Safety of an Improved Deferasirox Formulation (Granules) in Pediatric Patients With Iron Overload

Conditions
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Transfusion-dependent Anemia

Intervention / Treatment
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* Drug: Deferasirox granule formulation
* Drug: Deferasirox DT formulation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent/assent before any study-specific procedures. Consent will be obtained from parent(s) or legal guardians. Investigators will also obtain assent of patients according to local guidelines. Male and female children and adolescents aged ≥ 2 and < 18 years. [France: Male and female children and adolescent aged ≥ 2 and < 18 years old, however children aged ≥ 2 and ≤ 6years can be enrolled only when deferoxamine treatment is contraindicated or inadequate in these patients as per investigator decision. Applicable to core phase only. Once in the core phase patients can turn 18 years and still be considered eligible, also for participation in the optional extension phase. Any transfusion-dependent anemia associated with iron overload requiring iron chelation therapy and with a history of transfusion of approximately 20 PRBC units and a treatment goal to reduce iron burden (300mL PRBC = 1 unit in adults whereas 4 ml/kg PRBC is considered 1 unit for children). Serum ferritin > 1000 ng/mL, measured at screening Visit 1 and screening Visit 2 (the mean value will be used for eligibility criteria). Patient has to have participated and completed the 48 weeks core phase treatment as per protocol (For optional extension phase eligibility only). Exclusion Criteria: Creatinine clearance below the contraindication limit in the locally approved prescribing information (using Schwartz formula) at screening visit 1 or screening visit 2. Serum creatinine > 1.5 xULN at screening measured at screening Visit 1 and or screening Visit 2 ALT and/or AST > 3.0 x ULN at screening visit 1 or screening visit 2. (Criterion no longer applicable, removed as part of Amendment 1): Prior iron chelation therapy. Liver disease with severity of Child-Pugh class B or C. Significant proteinuria as indicated by a urinary protein/creatinine ratio > 0.5 mg/mg in a second morning urine sample at screening Visit 1 or screening Visit 2. Patients with significant impaired gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral deferasirox (e.g. ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection). Other protocol-defined Inclusion/Exclusion may apply.

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 17 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm 1<br> | Drug: Deferasirox DT formulation<br>* Deferasirox DT will be provided as 125 mg, 250 mg and 500 mg dispersible tablets for oral use<br>* Other names: ICL670;|
| Experimental: Arm 2<br> | Drug: Deferasirox granule formulation<br>* Deferasirox granules will be provided as stick packs containing 90 mg, 180 mg and 360 mg granules for oral use.<br>* Other names: ICL670;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Compliance (using stick/pack tablet count). | Evaluate patient compliance measured by stick pack/tablet count in ICT naïve patients during core phase. | 24 weeks | 
| Change in serum ferritin in ICT naive patients. | The comparison of means between the two treatment arms of change from baseline to week 24 of treatment in serum ferritin in pediatric ICT naïve patients with iron overload. | Baseline, 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Compliance (using stick/pack tablet count) | Evaluate patient compliance measured by stick pack/tablet count in ICT naïve patients during core phase. | 48 weeks | 
| Change in serum ferritin in ICT naive patients | The comparison of means between the two treatment arms of change from baseline to week 24 and to 48 weeks of treatment in serum ferritin in pediatric ICT naïve patients with iron overload. | Baseline, 24 weeks, 48 weeks | 
| Domain scores of treatment satisfaction and palatability over time | To evaluate both formulations on patient satisfaction and palatability using Patient / Observer Reported Outcomes (PRO/ObsRO) questionnaires | From baseline to 48 weeks | 
| Overall safety, as measured by frequency and severity of adverse | This includes active monitoring for renal toxicity; including renal failure, hepatic toxicity; including hepatic failure, and gastrointestinal hemorrhage), and changes in laboratory values from baseline (serum creatinine, creatinine clearance, ALT, AST, RBC and WBC). In addition, vital signs, physical, ophthalmological, audiometric, cardiac, and growth and development evaluations will be assessed. | From Baseline to 48 weeks | 
| Rate of dosing instructions deviations ('Compliance', using a questionnaire) | This includes doses missed/not taken at the same time every day, to evaluate the compliance using a daily PRO/ObsRO questionnaire. | From Baseline to 48 weeks | 
| Pre-dose deferasirox concentrations in all patients | The pre-dose concentration by incident dose will be plotted for Week 1, Week 3, Week 5, Week 9, Week 13, Week 17, Week 21, Week 25, Week 29, Week 33, Week, 37, Week 41 and Week 45 based on data from all patients. Pre-dose PK data from all patients will be analyzed to support the assessment of compliance.Predicted individual concentrations derived from the compartmental model will be compared to respective observed pre-dose concentrations. Distributions of the difference between predicted and observed values will be shown graphically by boxplots for both treatment groups and visit. | at Weeks 1, 3, 5, 9, 13, 17, 21, 25, 29, 33, 37, 41, and 45 (13 samples) | 
| Post-dose deferasirox concentrations between 2 and 4 hours post-dose at Weeks 5 and 9 | post-dose PK data to be analyzed along with pre-dose PK data | Week 5, Week 9 | 
| PK/PD relationship | To explore exposure-response relationships for measures of safety and effectiveness: serum creatinine change from baseline, notable serum creatinine values, serum creatinine clearance change from baseline and notable serum creatinine clearance categories, serum ferritin change from baseline, in relationship to derived PK parameters for pre- and post-dose deferasirox concentrations. | From Baseline to 48 weeks | 
| Assess additional safety, as measured by frequency and severity of adverse for granules during extension phase | This includesactive monitoring for renal toxicity; including renal failure, hepatic toxicity; including hepatic failure, and gastrointestinal hemorrhage), and changes in laboratory values from baseline (serum creatinine, creatinine clearance, ALT, AST, RBC and WBC). In addition, vital signs, physical, ophthalmological, audiometric, and growth and development evaluations will be assessed. | From Baseline to 305 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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New formulation, deferasirox, chelation, iron overload, compliance, satisfaction, palatability, PRO, PK, safety, PK/PD, ICL670