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

Compliance was calculated as the ratio of total count consumed to total count prescribed of deferasirox granule stick packs or dispersible tablets, where total count consumed was derived from cumulative dispensed, returned and lost/wasted counts over 24 weeks of treatment and total count prescribed was derived from cumulative prescribed count over 24 weeks of treatment.

The analysis included the comparison of means between the two treatment arms of change from baseline after 24 weeks of treatment in serum ferritin in pediatric ICT naïve participants with iron overload. The endpoint was assessed at Week 25 visit.

Compliance was calculated as the ratio of total count consumed to total count prescribed of deferasirox granule stick packs or dispersible tablets over 48 weeks of treatment.

The analysis included the comparison of means between the two treatment arms of change from baseline after 48 weeks of treatment in serum ferritin in pediatric ICT naïve participants with iron overload.

The analysis included the comparison of means between the two treatment arms of change from baseline after 25 weeks and after 48 weeks of treatment in serum ferritin in pre-treated participants. The analyses were performed at Week 25 and Week 48.

Participants aged between 10 years and less than 18 years at enrollment completed PRO questionnaires by themselves. The mSICT questionnaire for PRO consisted of 3 domains: adherence, satisfaction/preference, and concerns. The adherence domain had a minimum score of 6 and maximum score of 30; a lower score for adherence indicates better adherence. Satisfaction/preference domain had a minimum score of 2 and maximum score of 10; a lower score for satisfaction/preference indicates better satisfaction/preference. Concerns domain had a minimum score of 3 and maximum score of 15; a higher score for concerns indicate fewer concerns.

The ObsRO questionnaires for participants aged between 2 years and less than 10 years were designed as observations made by caregivers such as the parent or legal guardian. The caregivers continued completing the ObsRO questionnaires even after the participant turned 10 years for consistency in responses. The mSICT questionnaire consisted of 2 domains: adherence and concerns per caregiver's perspective. The adherence domain had a minimum score of 5 and a maximum score of 25; a lower score for adherence indicates better adherence. The concerns domain had a minimum score of 1 and a maximum score of 5; a higher score for concerns indicates fewer concerns.

The ObsRO questionnaires for participants aged between 2 years and less than 10 years were designed as observations made by caregivers such as the parent or legal guardian. The caregivers continued completing the ObsRO questionnaires even after the participant turned 10 years for consistency in responses. The mSICT questionnaire is presented for 2 domains: adherence and concerns per child's perspective. The adherence domain had a minimum score of 6 and a maximum score of 30; a lower score for adherence indicates better adherence. The concerns domain had a minimum score of 2 and a maximum score of 10; a higher score for concerns indicates fewer concerns.

The palatability questionnaire was used to measure: taste, aftertaste, whether medication was taken and how the participant perceived the amount of medication taken. This questionnaire had a minimum score of 0 and maximum score of 11; a higher score means better palatability. Participants aged between 10 years and less than 18 years at enrollment completed the PRO questionnaire by themselves.

The palatability questionnaire was used to measure: taste, aftertaste, whether medication was taken and how the participant perceived the amount of medication taken. This questionnaire had a minimum score of 0 and maximum score of 11; a higher score means better palatability. The ObsRO questionnaires for participants aged between 2 years and less than 10 years were designed as observations made by caregivers such as the parent or legal guardian. The caregivers continued completing the ObsRO questionnaires even after the participant turned 10 years for consistency in responses.

The compliance questionnaire consisted of 2 items: 1. To assess if the medication was taken (yes/no) and 2. To record of the time when the medication was taken (with a not applicable option for participants who did not take their medication). Daily diary records were used to calculate the rate of dose violation in each study arm (doses missed completely or not taken before 12 PM). The dose violation rate was calculated as:

[Number of dose violations / Drug exposure (days)] *100. Higher values represent more dose violations.

The compliance questionnaire consisted of 2 items: 1. To assess if the medication was taken (yes/no) and 2. To record the time when the medication was taken (with a not applicable option for participants who did not take their medication). Daily diary records were used to calculate the rate of dose violation in each treatment arm (doses missed completely or not taken before 12 PM). The ObsRO questionnaires for participants aged between 2 years and less than 10 years were designed as observations made by caregivers such as the parent or legal guardian. The caregivers continued completing the ObsRO questionnaires even after the participant turned 10 years for consistency in responses. The dose violation rate was calculated as: [Number of dose violations / Drug exposure (days)] *100.

Higher values represent more dose violations.

An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and unintended sign [including abnormal laboratory findings], symptom or disease) in a clinical investigation participant after providing written informed consent for participation in the study.

Pre-dose pharmacokinetic (PK) data from participants in the Pharmacokinetic Analysis Set 1 (PAS-1) were analyzed to assess variability of individual participant's compliance. A linear mixed effect power model to pre-dose samples which fulfill compliance criteria in terms of steady state (4 consecutive same doses prior to the PK sample drawn), time-windows (PK sample drawn 20 to 28 hours after previous dose) and without any vomiting episodes within the 4 hours prior to the PK sample were fitted. The model considered dose, treatment group, stratification factors and potential other factors, such as body weight as covariates.

Post-dose pharmacokinetic (PK) data from participants in the Pharmacokinetic Analysis Set 1 (PAS-1) were analyzed along with Pre-dose PK data.

An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and unintended sign [including abnormal laboratory findings], symptom or disease) in a clinical investigation after participant providing written informed consent for participation in the study. In the DFX Granules arm, AEs are reported since the initial randomization to the arm in the core phase and continuing in the extension phase. In the DFX cross-over arm, AEs are reported for participants since the participant crossed-over from dispersible tablet to granules in the extension phase only.

An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and unintended sign [including abnormal laboratory findings], symptom or disease) in a clinical investigation after participant providing written informed consent for participation in the study. In the DFX Granules arm, AEs are reported since the initial randomization to the arm in the core phase and continuing in the extension phase. In the DFX cross-over arm, AEs are reported for participants since the participant crossed-over from dispersible tablet to granules in the extension phase only. AESI included active monitoring for renal toxicity; including renal failure, hepatic toxicity; including hepatic failure, and gastrointestinal hemorrhage

This outcome measure explores exposure-response relationships for measures of safety and effectiveness through serum creatinine change from baseline, notable serum creatinine values, serum creatinine clearance change form 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.