Efficacy and Safety Study of Deferasirox in Patients With Non-transfusion Dependent Thalassemia

Study Overview
=================
Brief Summary
-----------------
Assessed the efficacy of deferasirox in patients with non-transfusion dependent thalassemia based on change in liver iron concentration from baseline after 52 weeks of treatment. Provided further assessment of the long-term efficacy and safety of deferasirox in NTDT patients with iron overload (LIC ≥ 5 mg Fe/g liver dw and SF ≥ 300 ng/mL) for up to 260 weeks.

Official Title
-----------------
An Open Label, Multi-center, Efficacy and Safety Study of Deferasirox in Iron Overloaded Patients With Non-transfusion Dependent Thalassemia

Conditions
-----------------
Non-transfusion Dependent Thalassemia

Intervention / Treatment
-----------------
* Drug: deferasirox


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Non-transfusion dependent congenital or chronic anemia inclusive of beta-thalassemia intermedia, HbE beta-thalassemia or alpha-thalassemia intermedia (HbH disease)/ Liver iron concentration >/= 5 mg Fe/g dw Serum Ferritin >/= 300 ng/mL Exclusion Criteria: HbS-beta Thalassemia, anticipated regular transfusion program during the study, blood transfusion 6 months prior to study start, significant proteinuria, creatinine clearance </= 40 ml/min, serum creatinine > ULN, ALT >5 x ULN, active hepatitis B or C, cirrhosis Pediatrics Only: A patient's weight of at least 20 kg is required to allow dosing of 5 mg/kg with one tablet of 125 mg

Ages Eligible for Study
-----------------
Minimum Age: 10 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Deferasirox<br>All patients were treated with 10mg/kg/day deferasirox with dose adjustments after 4 weeks of treatment according to baseline Liver Iron Concentration (LIC). | Drug: deferasirox<br>* Deferasirox dispersible tablets at strengths of 125 mg, 250 mg, and 500 mg were administered by oral daily dosing.<br>* Other names: ICL670;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Absolute Change in Liver Iron Content (LIC) at 52 Weeks From Baseline | Absolute change in liver iron concentration measured by MRI from baseline after 52 weeks of treatment | Baseline, 52 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Baseline LIC>15 Achieving LIC<5 mg Fe/g dw | The percentage of participants with baseline LIC>15 mg Fe/g dw achieving an LIC <5 mg Fe/g dw during the study | 5 years | 
| Time to Achieving LIC <5 mg Fe/g dw | Time to achieving LIC <5 mg Fe/g dw for participants with baseline LIC>15 mg Fe/g dw during the study | 5 years | 
| Time From Target LIC of 3 mg Fe/g dw to the First LIC ≥5 mg Fe/g dw in the Follow up Period | Time from the target LIC <3 mg Fe/g dw to the first LIC ≥5 mg Fe/g dw in the follow-up period | post-baseline, up to 260 weeks | 
| Absolute Change in Health-related Outcomes Using Medical Outcomes Study Form 36 (SF-36v2) | The SF-36 is a self-administered questionnaire for adults (from 18 years of age) and contains 36 items which measure: Physical functioning, Role limitation due to physical health problems, Bodily pain, General health perceptions, Vitality, Social functioning, Role limitations due to emotional problems and General mental health . The higher values indicate a better evaluation of health. Range: 0 to 100 [0 (worst possible health state measured by the questionnaire) to 100 (best possible health state)]. | Baseline, 52, 104 & 156 Weeks | 
| Absolute Change in Health-related Outcomes Using the Pediatric Quality of Life Questionnaire (PedsQL™) | The PedsQL™ is a modular approach to measuring health-related quality of life (HRQOL) in children and adolescents. The 23-item PedsQL™ Generic Core Scales encompass the essential core domains for pediatric HRQOL measurement: 1) Physical Functioning (8 items), 2) Emotional Functioning (5 items), 3) Social Functioning (5 items), and 4) School Functioning (5 items). The Generic Core Scales are designed to enable comparisons across patient and healthy populations. The higher values indicate a better evaluation of health. Range: 0 to 100 [0 (worst possible health state measured by the questionnaire) to 100 (best possible health state)]. | Baseline, 52, 104 & 156 Weeks | 
| Absolute Change in LIC From Baseline Over Time | Absolute change in serum ferritin from baseline over time up to 260 weeks | 24, 52, 76, 104, 128, 156, 180, 208, 232, 260 Weeks | 
| Serum Ferritin (SF) vs LIC at Baseline and EOS (Week 260 + 30 Days Follow-up) | Correlation between serum ferritin and LIC is assessed using scatter plots with pearson correlation coefficient and simple linear model. | Baseline, End of Study (EOS): Week 260 + 30 days follow up | 
| Correlation Analysis for Absolute Change in LIC and Serum Ferritin at Week 24 and EOS (Week 260 + 30 Days Follow-up) | Correlation for absolute change between LIC and serum ferritin was assessed using scatter plots with pearson correlation coefficient and simple linear model. | Week 24, End of Study (EOS): Week 260 + 30 days follow up | 
| Absolute Change in LIC From Baseline After 52 Weeks of Treatment by Underlying Non-transfusion Dependent Thalassemia (NTDT) Syndrome | Absolute change in liver iron concentration measured by MRI from baseline after 52 weeks of treatment by underlying NTDT syndrome. The 4 underlying disease types: Beta-thalassemia intermedia (N =69), HbE beta-thalassemia (N = 24), Alpha-thalassemia intermedia (HbH disease) (N = 40), Other, specify (N = 1) | Baseline, 52 Weeks | 
| Absolute Change in Serum Ferritin From Baseline After 52 Weeks | Absolute change in serum ferritin from baseline after 52 weeks of treatment | Baseline, 52 weeks | 
| PK Parameters: AUCtau | The pharmacokinetic parameter, AUCtau was determined using non-compartmental method(s) for deferasirox and its iron complex. AUC=area under the concentration-time curve during a dosing interval at steady state (amount × time × volume). | pre-dose (0 hour), and at 2, and 4 hours at Week 4 | 
| PK Parameters: Cmax | The pharmacokinetic parameter, Cmax, was determined using non-compartmental method(s) for deferasirox and its iron complex. Cmax (maximum/peak plasma drug concentration after drug administration)=amount × volume | pre-dose (0 hour), and at 2, and 4 hours at Week 4 | 
| PK Parameters: Tmax | The pharmacokinetic parameter, Tmax, may be determined using non-compartmental method(s) for deferasirox and its iron complex. Tmax=time to reach maximum/peak concentration following drug administration. | pre-dose (0 hour), and at 2, and 4 hours at Week 4 | 
| Plasma Pharmacokinetics (PK) Deferasirox Concentrations | Blood samples for PK evaluation were collected for a sub-group of patients. The patient had to have been on treatment without dose adjustment or treatment interruption (for any reason) for at least 4 consecutive days prior to scheduled PK sampling visit. If there was a dosage change or interruption within 4 days of the visit, no PK blood samples was collected, and an appropriate comment had to be made on the PK CRF page. | Weeks 12 & 24: pre-dose (0hr), 2hr & 4hr post-dose | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Liver Iron Concentration, Non-transfusion dependent thalassemia, NTDT, deferasirox, ICL670, LIC