Transfusion-dependent Anemia
Conditions
Keywords
New formulation, deferasirox, chelation, iron overload, compliance, satisfaction, palatability, PRO, PK, safety, PK/PD, ICL670
Brief summary
This was 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 dispersible tablet (DT) formulation in children and adolescents aged ≥ 2 and \< 18 years at enrolment with any transfusion-dependent anemia requiring chelation therapy due to iron overload, to demonstrate the effect of improved compliance on iron burden. Randomization was stratified by age groups (2 to \<10 years, 10 to \<18 years) and prior iron chelation therapy (Yes/ No). There were two study phases which include a 1 year core phase where participants were randomized to a 48 week treatment period to either Deferasirox DT or granules, and an optional extension phase where all participants received the granules up to 5 years. Participants who demonstrated benefit to granules or DT in the core phase, and/or expressed the wish to continue in the optional extension phase on granules, were offered this possibility until there was local access to the new formulation (granules or film-coated tablet (FCT)) or up to 5 years, whichever occurred first.
Interventions
DRUGDeferasirox granule formulation
Deferasirox granules will be provided as stick packs containing 90 mg, 180 mg and 360 mg granules for oral use and will be administered based on body weight.
DRUGDeferasirox DT formulation
Deferasirox DT will be provided as 125 mg, 250 mg and 500 mg dispersible tablets for oral use and will be administered based on body weight.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
2 Years to 17 Years
Healthy volunteers
No
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.. * 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). * Direct (conjugated) bilirubin \>2 x ULN at screening visit 1 or screening visit 2. * Local access to new formulation (granules or FCT) is available (For optional extension phase eligibility only).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Serum Ferritin (SF) for Both Study Drug Formulations in ICT naïve Participants During the Core Phase | From Baseline to Week 25 | 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. |
| Percentage of Overall Compliance Using Stick Pack or Tablet Counts in Iron Chelation Therapy (ICT)-naïve Participants During the Core Phase | 24 weeks | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Serum Ferritin (SF) for Both Study Drug Formulations in ICT naïve Participants During the Core Phase | From Baseline to 48 weeks | 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. |
| Change From Baseline in Serum Ferritin (SF) for Both Study Drug Formulations in Pre-treated Participants During the Core Phase | From Baseline to Week 25 and Week 48 | 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. |
| Change Over-time in Domain Score of Modified Satisfaction With Iron Chelation Therapy (mSICT) Using Patient Reported Outcomes (PRO) Questionnaires | At Week 2, Week 3, 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. |
| Change Over-time in Domain Score of Modified Satisfaction With Iron Chelation Therapy (mSICT) Using Observer Reported Outcomes (ObsRO) Questionnaire (Caregiver's Perspective) | At Week 2, Week 3, Week 25 and Week 48 | 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. |
| Change Over-time in Domain Score of Modified Satisfaction With Iron Chelation Therapy (mSICT) Using Observer Reported Outcomes (ObsRO) Questionnaire (Child's Perspective) | At Week 2, Week 3, Week 25 and Week 48 | 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. |
| Change Over-time in Domain Score of Palatability Using Patient Reported Outcomes (PRO) Questionnaires | At Week 2, Week 3, Week 25 and Week 48 | 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. |
| Change Over-time in Domain Score of Palatability Using Observer Reported Outcomes (ObsRO) Questionnaire | At Week 2, Week 3, Week 25 and Week 48 | 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. |
| Change Over Time in Weekly Dose Violation Rate Using Compliance Observer Reported Outcomes (ObsRO) Questionnaire | At Week 1, Week 13, Week 25, Week 37 and Week 48 | 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. |
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the Core Phase | From Baseline to 48 weeks | 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 Concentrations of Deferasirox to Support the Assessment of Compliance | At Weeks 1, 3, 5, 9, 13, 17, 21, 25, 29, 33, 37, 41, and 45 | 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. |
| Concentrations of Deferasirox Between 2 and 4 Hours Post-dose at Weeks 5 and 9 | At Week 5 and Week 9 | Post-dose pharmacokinetic (PK) data from participants in the Pharmacokinetic Analysis Set 1 (PAS-1) were analyzed along with Pre-dose PK data. |
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the Entire Granule Period | From Baseline to 305 weeks | 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. |
| Number of Participants With Adverse Events of Special Interest (AESI) During the Entire Granule Period | From Baseline to 305 weeks | 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 |
| Change Over Time in Weekly Dose Violation Rate Using Compliance Patient Reported Outcomes (PRO) Questionnaire | At Week 1, Week 13, Week 25, Week 37 and Week 48 | 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. |
| Percentage of Overall Compliance Using Stick Pack or Tablet Counts in ICT-naïve Participants During the Core Phase | 48 weeks | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Exposure-Response Relationship in Relation to Pre- and Post-Dose Deferasirox Concentrations (PK/PD Relationship) | From Baseline to 48 weeks | 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. |
Countries
Belgium, Bulgaria, Egypt, France, Hungary, India, Italy, Lebanon, Malaysia, Oman, Panama, Philippines, Russia, Thailand, Tunisia, Turkey (Türkiye), United States
Participant flow
Pre-assignment details
After enrollment, participants previously treated with iron chelation therapy (ICT) underwent a 5-day chelation washout period prior to the commencement of the 48-week treatment (Core phase).
Participants by arm
| Arm | Count |
|---|---|
| DFX DT Participants received deferasirox (DFX) dispersible tablets (DT) orally once daily based on body weight for 48 weeks in the Core phase. The starting dose was 20mg/kg/day which was then adjusted based on tolerability, safety and efficacy considerations. After the Core phase, participants could enter the Optional Extension phase and cross over to DFX granules administered orally once daily in the form of stick packs for up to 5 years. Participants entering the Optional Extension phase received the equivalent strength-adjusted DFX granules dose corresponding to the last DT dose in the Core phase taking dose adjustment guidelines into account. | 112 |
| DFX Granule Participants received deferasirox (DFX) granules orally once daily based on body weight in the form of stick packs for 48 weeks in the Core phase. The starting dose was 14 mg/kg/day which was then adjusted based on tolerability, safety and efficacy considerations. After the Core phase, participants could enter the Optional Extension phase and continued receiving DFX granules at the same dose as was given at the end of the Core phase taking dose adjustment guidelines into account for up to 5 years. | 112 |
| Total | 224 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Core Phase | Adverse Event | 8 | 5 |
| Core Phase | Lack of Efficacy | 0 | 1 |
| Core Phase | Lost to Follow-up | 0 | 1 |
| Core Phase | Physician Decision | 3 | 0 |
| Core Phase | Protocol Violation | 1 | 2 |
| Core Phase | Recovery | 1 | 0 |
| Core Phase | Withdrawal by parent/guardian | 9 | 4 |
| Core Phase | Withdrawal by Subject | 3 | 0 |
| Optional Extension Phase | Adverse Event | 3 | 9 |
| Optional Extension Phase | Death | 1 | 0 |
| Optional Extension Phase | Lack of Efficacy | 2 | 3 |
| Optional Extension Phase | Physician Decision | 6 | 8 |
| Optional Extension Phase | Protocol Violation | 0 | 1 |
| Optional Extension Phase | Recovery | 1 | 1 |
| Optional Extension Phase | Technical problems | 2 | 0 |
| Optional Extension Phase | Withdrawal by parent/guardian | 10 | 7 |
| Optional Extension Phase | Withdrawal by Subject | 2 | 2 |
Baseline characteristics
| Characteristic | DFX Granule | Total | DFX DT |
|---|---|---|---|
| Age, Continuous | 5.9 years STANDARD_DEVIATION 3.94 | 5.9 years STANDARD_DEVIATION 3.9 | 5.8 years STANDARD_DEVIATION 3.89 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 7 Participants | 14 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 105 Participants | 209 Participants | 104 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 44 Participants | 82 Participants | 38 Participants |
| Race (NIH/OMB) Black or African American | 8 Participants | 19 Participants | 11 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 8 Participants | 14 Participants | 6 Participants |
| Race (NIH/OMB) White | 52 Participants | 109 Participants | 57 Participants |
| Sex/Gender, Customized Female | 56 Participants | 110 Participants | 54 Participants |
| Sex/Gender, Customized Male | 56 Participants | 114 Participants | 58 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 111 | 1 / 69 | 0 / 110 | 0 / 77 |
| other Total, other adverse events | 104 / 111 | 63 / 69 | 97 / 110 | 63 / 77 |
| serious Total, serious adverse events | 23 / 111 | 22 / 69 | 27 / 110 | 20 / 77 |
Outcome results
Primary
Change From Baseline in Serum Ferritin (SF) for Both Study Drug Formulations in ICT naïve Participants During the Core Phase
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.
Time frame: From Baseline to Week 25
Population: The Full Analysis Set 1 (FAS-1) consisted of all ICT naive randomized participants during the core phase.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| DFX DT | Change From Baseline in Serum Ferritin (SF) for Both Study Drug Formulations in ICT naïve Participants During the Core Phase | Baseline | 2063.7 μg/L |
| DFX DT | Change From Baseline in Serum Ferritin (SF) for Both Study Drug Formulations in ICT naïve Participants During the Core Phase | Week 25 | 2216.3 μg/L |
| DFX DT | Change From Baseline in Serum Ferritin (SF) for Both Study Drug Formulations in ICT naïve Participants During the Core Phase | Change from Baseline to Week 25 | 250.5 μg/L |
| DFX Granule | Change From Baseline in Serum Ferritin (SF) for Both Study Drug Formulations in ICT naïve Participants During the Core Phase | Baseline | 1955.5 μg/L |
| DFX Granule | Change From Baseline in Serum Ferritin (SF) for Both Study Drug Formulations in ICT naïve Participants During the Core Phase | Week 25 | 2228.4 μg/L |
| DFX Granule | Change From Baseline in Serum Ferritin (SF) for Both Study Drug Formulations in ICT naïve Participants During the Core Phase | Change from Baseline to Week 25 | 340.0 μg/L |
p-value: 0.254695% CI: [-129, 481.72]ANCOVA
Primary
Percentage of Overall Compliance Using Stick Pack or Tablet Counts in Iron Chelation Therapy (ICT)-naïve Participants During the Core Phase
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.
Time frame: 24 weeks
Population: The Full Analysis Set 1 (FAS-1) consisted of all ICT naive randomized participants during the core phase.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| DFX DT | Percentage of Overall Compliance Using Stick Pack or Tablet Counts in Iron Chelation Therapy (ICT)-naïve Participants During the Core Phase | 89.45 percentage of compliance |
| DFX Granule | Percentage of Overall Compliance Using Stick Pack or Tablet Counts in Iron Chelation Therapy (ICT)-naïve Participants During the Core Phase | 91.78 percentage of compliance |
p-value: 0.359895% CI: [-2.99, 8.15]ANCOVA
Secondary
Change From Baseline in Serum Ferritin (SF) for Both Study Drug Formulations in ICT naïve Participants During the Core Phase
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.
Time frame: From Baseline to 48 weeks
Population: The Full Analysis Set 1 (FAS-1) consisted of all ICT naive randomized participants during the core phase.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| DFX DT | Change From Baseline in Serum Ferritin (SF) for Both Study Drug Formulations in ICT naïve Participants During the Core Phase | 305.8 μg/L |
| DFX Granule | Change From Baseline in Serum Ferritin (SF) for Both Study Drug Formulations in ICT naïve Participants During the Core Phase | 317.0 μg/L |
Secondary
Change From Baseline in Serum Ferritin (SF) for Both Study Drug Formulations in Pre-treated Participants During the Core Phase
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.
Time frame: From Baseline to Week 25 and Week 48
Population: The Full Analysis Set 2 (FAS-2) consisted of all ICT pre-treated randomized participants during the core phase.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| DFX DT | Change From Baseline in Serum Ferritin (SF) for Both Study Drug Formulations in Pre-treated Participants During the Core Phase | Change from Baseline to Week 25 | 59.0 μg/L |
| DFX DT | Change From Baseline in Serum Ferritin (SF) for Both Study Drug Formulations in Pre-treated Participants During the Core Phase | Change from Baseline to Week 48 | 207.7 μg/L |
| DFX Granule | Change From Baseline in Serum Ferritin (SF) for Both Study Drug Formulations in Pre-treated Participants During the Core Phase | Change from Baseline to Week 25 | 150.3 μg/L |
| DFX Granule | Change From Baseline in Serum Ferritin (SF) for Both Study Drug Formulations in Pre-treated Participants During the Core Phase | Change from Baseline to Week 48 | 215.7 μg/L |
Secondary
Change Over-time in Domain Score of Modified Satisfaction With Iron Chelation Therapy (mSICT) Using Observer Reported Outcomes (ObsRO) Questionnaire (Caregiver's Perspective)
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.
Time frame: At Week 2, Week 3, Week 25 and Week 48
Population: The Full Analysis Set 3 (FAS-3) consisted of all randomized participants during the core phase. This includes only the participants aged between 2 years and less than 10 years with a valid assessment for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| DFX DT | Change Over-time in Domain Score of Modified Satisfaction With Iron Chelation Therapy (mSICT) Using Observer Reported Outcomes (ObsRO) Questionnaire (Caregiver's Perspective) | Adherence (Week 48) | 7.5 score on a scale | Standard Deviation 2.53 |
| DFX DT | Change Over-time in Domain Score of Modified Satisfaction With Iron Chelation Therapy (mSICT) Using Observer Reported Outcomes (ObsRO) Questionnaire (Caregiver's Perspective) | Adherence (Week 25) | 7.1 score on a scale | Standard Deviation 2.35 |
| DFX DT | Change Over-time in Domain Score of Modified Satisfaction With Iron Chelation Therapy (mSICT) Using Observer Reported Outcomes (ObsRO) Questionnaire (Caregiver's Perspective) | Concerns (Week 2) | 3.9 score on a scale | Standard Deviation 1.32 |
| DFX DT | Change Over-time in Domain Score of Modified Satisfaction With Iron Chelation Therapy (mSICT) Using Observer Reported Outcomes (ObsRO) Questionnaire (Caregiver's Perspective) | Concerns (Week 3) | 4.1 score on a scale | Standard Deviation 1.31 |
| DFX DT | Change Over-time in Domain Score of Modified Satisfaction With Iron Chelation Therapy (mSICT) Using Observer Reported Outcomes (ObsRO) Questionnaire (Caregiver's Perspective) | Concerns (Week 25) | 4.3 score on a scale | Standard Deviation 1 |
| DFX DT | Change Over-time in Domain Score of Modified Satisfaction With Iron Chelation Therapy (mSICT) Using Observer Reported Outcomes (ObsRO) Questionnaire (Caregiver's Perspective) | Concerns (Week 48) | 4.0 score on a scale | Standard Deviation 1.24 |
| DFX DT | Change Over-time in Domain Score of Modified Satisfaction With Iron Chelation Therapy (mSICT) Using Observer Reported Outcomes (ObsRO) Questionnaire (Caregiver's Perspective) | Adherence (Week 3) | 7.8 score on a scale | Standard Deviation 2.64 |
| DFX DT | Change Over-time in Domain Score of Modified Satisfaction With Iron Chelation Therapy (mSICT) Using Observer Reported Outcomes (ObsRO) Questionnaire (Caregiver's Perspective) | Adherence (Week 2) | 7.7 score on a scale | Standard Deviation 2.84 |
| DFX Granule | Change Over-time in Domain Score of Modified Satisfaction With Iron Chelation Therapy (mSICT) Using Observer Reported Outcomes (ObsRO) Questionnaire (Caregiver's Perspective) | Adherence (Week 2) | 5.8 score on a scale | Standard Deviation 1.32 |
| DFX Granule | Change Over-time in Domain Score of Modified Satisfaction With Iron Chelation Therapy (mSICT) Using Observer Reported Outcomes (ObsRO) Questionnaire (Caregiver's Perspective) | Concerns (Week 25) | 4.5 score on a scale | Standard Deviation 0.89 |
| DFX Granule | Change Over-time in Domain Score of Modified Satisfaction With Iron Chelation Therapy (mSICT) Using Observer Reported Outcomes (ObsRO) Questionnaire (Caregiver's Perspective) | Adherence (Week 25) | 6.5 score on a scale | Standard Deviation 1.69 |
| DFX Granule | Change Over-time in Domain Score of Modified Satisfaction With Iron Chelation Therapy (mSICT) Using Observer Reported Outcomes (ObsRO) Questionnaire (Caregiver's Perspective) | Adherence (Week 48) | 6.8 score on a scale | Standard Deviation 2.57 |
| DFX Granule | Change Over-time in Domain Score of Modified Satisfaction With Iron Chelation Therapy (mSICT) Using Observer Reported Outcomes (ObsRO) Questionnaire (Caregiver's Perspective) | Adherence (Week 3) | 5.8 score on a scale | Standard Deviation 1.43 |
| DFX Granule | Change Over-time in Domain Score of Modified Satisfaction With Iron Chelation Therapy (mSICT) Using Observer Reported Outcomes (ObsRO) Questionnaire (Caregiver's Perspective) | Concerns (Week 2) | 4.5 score on a scale | Standard Deviation 0.94 |
| DFX Granule | Change Over-time in Domain Score of Modified Satisfaction With Iron Chelation Therapy (mSICT) Using Observer Reported Outcomes (ObsRO) Questionnaire (Caregiver's Perspective) | Concerns (Week 48) | 4.6 score on a scale | Standard Deviation 0.77 |
| DFX Granule | Change Over-time in Domain Score of Modified Satisfaction With Iron Chelation Therapy (mSICT) Using Observer Reported Outcomes (ObsRO) Questionnaire (Caregiver's Perspective) | Concerns (Week 3) | 4.7 score on a scale | Standard Deviation 0.71 |
Secondary
Change Over-time in Domain Score of Modified Satisfaction With Iron Chelation Therapy (mSICT) Using Observer Reported Outcomes (ObsRO) Questionnaire (Child's Perspective)
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.
Time frame: At Week 2, Week 3, Week 25 and Week 48
Population: The Full Analysis Set 3 (FAS-3) consisted of all randomized participants during the core phase. This includes only the participants aged between 2 years and less than 10 years with a valid assessment for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| DFX DT | Change Over-time in Domain Score of Modified Satisfaction With Iron Chelation Therapy (mSICT) Using Observer Reported Outcomes (ObsRO) Questionnaire (Child's Perspective) | Concerns (Week 2) | 8.5 score on a scale | Standard Deviation 2.29 |
| DFX DT | Change Over-time in Domain Score of Modified Satisfaction With Iron Chelation Therapy (mSICT) Using Observer Reported Outcomes (ObsRO) Questionnaire (Child's Perspective) | Concerns (Week 3) | 8.7 score on a scale | Standard Deviation 2 |
| DFX DT | Change Over-time in Domain Score of Modified Satisfaction With Iron Chelation Therapy (mSICT) Using Observer Reported Outcomes (ObsRO) Questionnaire (Child's Perspective) | Adherence (Week 2) | 12.1 score on a scale | Standard Deviation 4.57 |
| DFX DT | Change Over-time in Domain Score of Modified Satisfaction With Iron Chelation Therapy (mSICT) Using Observer Reported Outcomes (ObsRO) Questionnaire (Child's Perspective) | Adherence (Week 3) | 11.7 score on a scale | Standard Deviation 3.78 |
| DFX DT | Change Over-time in Domain Score of Modified Satisfaction With Iron Chelation Therapy (mSICT) Using Observer Reported Outcomes (ObsRO) Questionnaire (Child's Perspective) | Adherence (Week 48) | 11.3 score on a scale | Standard Deviation 3.99 |
| DFX DT | Change Over-time in Domain Score of Modified Satisfaction With Iron Chelation Therapy (mSICT) Using Observer Reported Outcomes (ObsRO) Questionnaire (Child's Perspective) | Adherence (Week 25) | 11.1 score on a scale | Standard Deviation 3.82 |
| DFX DT | Change Over-time in Domain Score of Modified Satisfaction With Iron Chelation Therapy (mSICT) Using Observer Reported Outcomes (ObsRO) Questionnaire (Child's Perspective) | Concerns (Week 25) | 8.6 score on a scale | Standard Deviation 1.94 |
| DFX DT | Change Over-time in Domain Score of Modified Satisfaction With Iron Chelation Therapy (mSICT) Using Observer Reported Outcomes (ObsRO) Questionnaire (Child's Perspective) | Concerns (Week 48) | 8.8 score on a scale | Standard Deviation 1.75 |
| DFX Granule | Change Over-time in Domain Score of Modified Satisfaction With Iron Chelation Therapy (mSICT) Using Observer Reported Outcomes (ObsRO) Questionnaire (Child's Perspective) | Adherence (Week 3) | 8.2 score on a scale | Standard Deviation 2.64 |
| DFX Granule | Change Over-time in Domain Score of Modified Satisfaction With Iron Chelation Therapy (mSICT) Using Observer Reported Outcomes (ObsRO) Questionnaire (Child's Perspective) | Concerns (Week 2) | 9.2 score on a scale | Standard Deviation 1.66 |
| DFX Granule | Change Over-time in Domain Score of Modified Satisfaction With Iron Chelation Therapy (mSICT) Using Observer Reported Outcomes (ObsRO) Questionnaire (Child's Perspective) | Adherence (Week 25) | 9.1 score on a scale | Standard Deviation 2.64 |
| DFX Granule | Change Over-time in Domain Score of Modified Satisfaction With Iron Chelation Therapy (mSICT) Using Observer Reported Outcomes (ObsRO) Questionnaire (Child's Perspective) | Concerns (Week 3) | 8.8 score on a scale | Standard Deviation 2.04 |
| DFX Granule | Change Over-time in Domain Score of Modified Satisfaction With Iron Chelation Therapy (mSICT) Using Observer Reported Outcomes (ObsRO) Questionnaire (Child's Perspective) | Concerns (Week 25) | 8.7 score on a scale | Standard Deviation 1.85 |
| DFX Granule | Change Over-time in Domain Score of Modified Satisfaction With Iron Chelation Therapy (mSICT) Using Observer Reported Outcomes (ObsRO) Questionnaire (Child's Perspective) | Concerns (Week 48) | 9.0 score on a scale | Standard Deviation 1.82 |
| DFX Granule | Change Over-time in Domain Score of Modified Satisfaction With Iron Chelation Therapy (mSICT) Using Observer Reported Outcomes (ObsRO) Questionnaire (Child's Perspective) | Adherence (Week 2) | 8.2 score on a scale | Standard Deviation 2.28 |
| DFX Granule | Change Over-time in Domain Score of Modified Satisfaction With Iron Chelation Therapy (mSICT) Using Observer Reported Outcomes (ObsRO) Questionnaire (Child's Perspective) | Adherence (Week 48) | 9.1 score on a scale | Standard Deviation 3 |
Secondary
Change Over-time in Domain Score of Modified Satisfaction With Iron Chelation Therapy (mSICT) Using Patient Reported Outcomes (PRO) Questionnaires
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.
Time frame: At Week 2, Week 3, Week 25 and Week 48
Population: The Full Analysis Set 3 (FAS-3) consisted of all randomized participants during the core phase. This includes only the participants aged between 10 years and less than 18 years with a valid assessment for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| DFX DT | Change Over-time in Domain Score of Modified Satisfaction With Iron Chelation Therapy (mSICT) Using Patient Reported Outcomes (PRO) Questionnaires | Adherence (Week 3) | 10.9 score on a scale | Standard Deviation 4.95 |
| DFX DT | Change Over-time in Domain Score of Modified Satisfaction With Iron Chelation Therapy (mSICT) Using Patient Reported Outcomes (PRO) Questionnaires | Adherence (Week 25) | 11.9 score on a scale | Standard Deviation 3.93 |
| DFX DT | Change Over-time in Domain Score of Modified Satisfaction With Iron Chelation Therapy (mSICT) Using Patient Reported Outcomes (PRO) Questionnaires | Adherence (Week 48) | 12.9 score on a scale | Standard Deviation 4.17 |
| DFX DT | Change Over-time in Domain Score of Modified Satisfaction With Iron Chelation Therapy (mSICT) Using Patient Reported Outcomes (PRO) Questionnaires | Concerns (Week 2) | 13.1 score on a scale | Standard Deviation 2.18 |
| DFX DT | Change Over-time in Domain Score of Modified Satisfaction With Iron Chelation Therapy (mSICT) Using Patient Reported Outcomes (PRO) Questionnaires | Concerns (Week 3) | 13.4 score on a scale | Standard Deviation 2.1 |
| DFX DT | Change Over-time in Domain Score of Modified Satisfaction With Iron Chelation Therapy (mSICT) Using Patient Reported Outcomes (PRO) Questionnaires | Concerns (Week 48) | 12.8 score on a scale | Standard Deviation 2.2 |
| DFX DT | Change Over-time in Domain Score of Modified Satisfaction With Iron Chelation Therapy (mSICT) Using Patient Reported Outcomes (PRO) Questionnaires | Adherence (Week 2) | 9.5 score on a scale | Standard Deviation 2.3 |
| DFX DT | Change Over-time in Domain Score of Modified Satisfaction With Iron Chelation Therapy (mSICT) Using Patient Reported Outcomes (PRO) Questionnaires | Satisfaction/preference (Week 2) | 5.2 score on a scale | Standard Deviation 2.09 |
| DFX DT | Change Over-time in Domain Score of Modified Satisfaction With Iron Chelation Therapy (mSICT) Using Patient Reported Outcomes (PRO) Questionnaires | Satisfaction/preference (Week 3) | 4.0 score on a scale | Standard Deviation 1.32 |
| DFX DT | Change Over-time in Domain Score of Modified Satisfaction With Iron Chelation Therapy (mSICT) Using Patient Reported Outcomes (PRO) Questionnaires | Satisfaction/preference (Week 25) | 5.5 score on a scale | Standard Deviation 2.37 |
| DFX DT | Change Over-time in Domain Score of Modified Satisfaction With Iron Chelation Therapy (mSICT) Using Patient Reported Outcomes (PRO) Questionnaires | Satisfaction/preference (Week 48) | 4.8 score on a scale | Standard Deviation 2.24 |
| DFX DT | Change Over-time in Domain Score of Modified Satisfaction With Iron Chelation Therapy (mSICT) Using Patient Reported Outcomes (PRO) Questionnaires | Concerns (Week 25) | 11.5 score on a scale | Standard Deviation 3.13 |
| DFX Granule | Change Over-time in Domain Score of Modified Satisfaction With Iron Chelation Therapy (mSICT) Using Patient Reported Outcomes (PRO) Questionnaires | Concerns (Week 48) | 13.5 score on a scale | Standard Deviation 2.75 |
| DFX Granule | Change Over-time in Domain Score of Modified Satisfaction With Iron Chelation Therapy (mSICT) Using Patient Reported Outcomes (PRO) Questionnaires | Adherence (Week 3) | 6.6 score on a scale | Standard Deviation 0.79 |
| DFX Granule | Change Over-time in Domain Score of Modified Satisfaction With Iron Chelation Therapy (mSICT) Using Patient Reported Outcomes (PRO) Questionnaires | Satisfaction/preference (Week 3) | 3.1 score on a scale | Standard Deviation 1.22 |
| DFX Granule | Change Over-time in Domain Score of Modified Satisfaction With Iron Chelation Therapy (mSICT) Using Patient Reported Outcomes (PRO) Questionnaires | Adherence (Week 25) | 9.2 score on a scale | Standard Deviation 3.31 |
| DFX Granule | Change Over-time in Domain Score of Modified Satisfaction With Iron Chelation Therapy (mSICT) Using Patient Reported Outcomes (PRO) Questionnaires | Adherence (Week 2) | 7.6 score on a scale | Standard Deviation 1.99 |
| DFX Granule | Change Over-time in Domain Score of Modified Satisfaction With Iron Chelation Therapy (mSICT) Using Patient Reported Outcomes (PRO) Questionnaires | Adherence (Week 48) | 8.4 score on a scale | Standard Deviation 2.29 |
| DFX Granule | Change Over-time in Domain Score of Modified Satisfaction With Iron Chelation Therapy (mSICT) Using Patient Reported Outcomes (PRO) Questionnaires | Satisfaction/preference (Week 48) | 3.1 score on a scale | Standard Deviation 0.92 |
| DFX Granule | Change Over-time in Domain Score of Modified Satisfaction With Iron Chelation Therapy (mSICT) Using Patient Reported Outcomes (PRO) Questionnaires | Concerns (Week 2) | 14.5 score on a scale | Standard Deviation 1.06 |
| DFX Granule | Change Over-time in Domain Score of Modified Satisfaction With Iron Chelation Therapy (mSICT) Using Patient Reported Outcomes (PRO) Questionnaires | Satisfaction/preference (Week 2) | 2.9 score on a scale | Standard Deviation 1.36 |
| DFX Granule | Change Over-time in Domain Score of Modified Satisfaction With Iron Chelation Therapy (mSICT) Using Patient Reported Outcomes (PRO) Questionnaires | Concerns (Week 3) | 14.4 score on a scale | Standard Deviation 0.8 |
| DFX Granule | Change Over-time in Domain Score of Modified Satisfaction With Iron Chelation Therapy (mSICT) Using Patient Reported Outcomes (PRO) Questionnaires | Concerns (Week 25) | 14.5 score on a scale | Standard Deviation 1.21 |
| DFX Granule | Change Over-time in Domain Score of Modified Satisfaction With Iron Chelation Therapy (mSICT) Using Patient Reported Outcomes (PRO) Questionnaires | Satisfaction/preference (Week 25) | 3.0 score on a scale | Standard Deviation 1.1 |
Secondary
Change Over-time in Domain Score of Palatability Using Observer Reported Outcomes (ObsRO) Questionnaire
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.
Time frame: At Week 2, Week 3, Week 25 and Week 48
Population: The Full Analysis Set 3 (FAS-3) consisted of all randomized participants during the core phase. This includes only the participants aged between 2 years and less than 10 years with a valid assessment for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| DFX DT | Change Over-time in Domain Score of Palatability Using Observer Reported Outcomes (ObsRO) Questionnaire | Week 3 | 9.4 score on a scale | Standard Deviation 2.88 |
| DFX DT | Change Over-time in Domain Score of Palatability Using Observer Reported Outcomes (ObsRO) Questionnaire | Week 48 | 9.0 score on a scale | Standard Deviation 3.11 |
| DFX DT | Change Over-time in Domain Score of Palatability Using Observer Reported Outcomes (ObsRO) Questionnaire | Week 2 | 8.9 score on a scale | Standard Deviation 3.13 |
| DFX DT | Change Over-time in Domain Score of Palatability Using Observer Reported Outcomes (ObsRO) Questionnaire | Week 25 | 9.3 score on a scale | Standard Deviation 2.83 |
| DFX Granule | Change Over-time in Domain Score of Palatability Using Observer Reported Outcomes (ObsRO) Questionnaire | Week 48 | 10.9 score on a scale | Standard Deviation 0.96 |
| DFX Granule | Change Over-time in Domain Score of Palatability Using Observer Reported Outcomes (ObsRO) Questionnaire | Week 3 | 10.8 score on a scale | Standard Deviation 0.79 |
| DFX Granule | Change Over-time in Domain Score of Palatability Using Observer Reported Outcomes (ObsRO) Questionnaire | Week 25 | 10.6 score on a scale | Standard Deviation 1.73 |
| DFX Granule | Change Over-time in Domain Score of Palatability Using Observer Reported Outcomes (ObsRO) Questionnaire | Week 2 | 10.9 score on a scale | Standard Deviation 0.9 |
Secondary
Change Over-time in Domain Score of Palatability Using Patient Reported Outcomes (PRO) Questionnaires
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.
Time frame: At Week 2, Week 3, Week 25 and Week 48
Population: The Full Analysis Set 3 (FAS-3) consisted of all randomized participants during the core phase. This includes only the participants aged between 10 years and less than 18 years with a valid assessment for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| DFX DT | Change Over-time in Domain Score of Palatability Using Patient Reported Outcomes (PRO) Questionnaires | Week 2 | 8.8 score on a scale | Standard Deviation 3.32 |
| DFX DT | Change Over-time in Domain Score of Palatability Using Patient Reported Outcomes (PRO) Questionnaires | Week 3 | 9.6 score on a scale | Standard Deviation 2.83 |
| DFX DT | Change Over-time in Domain Score of Palatability Using Patient Reported Outcomes (PRO) Questionnaires | Week 25 | 9.2 score on a scale | Standard Deviation 2.7 |
| DFX DT | Change Over-time in Domain Score of Palatability Using Patient Reported Outcomes (PRO) Questionnaires | Week 48 | 9.4 score on a scale | Standard Deviation 3.07 |
| DFX Granule | Change Over-time in Domain Score of Palatability Using Patient Reported Outcomes (PRO) Questionnaires | Week 48 | 11.0 score on a scale | Standard Deviation 0 |
| DFX Granule | Change Over-time in Domain Score of Palatability Using Patient Reported Outcomes (PRO) Questionnaires | Week 2 | 10.3 score on a scale | Standard Deviation 1.91 |
| DFX Granule | Change Over-time in Domain Score of Palatability Using Patient Reported Outcomes (PRO) Questionnaires | Week 25 | 10.4 score on a scale | Standard Deviation 1.8 |
| DFX Granule | Change Over-time in Domain Score of Palatability Using Patient Reported Outcomes (PRO) Questionnaires | Week 3 | 10.9 score on a scale | Standard Deviation 0.24 |
Secondary
Change Over Time in Weekly Dose Violation Rate Using Compliance Observer Reported Outcomes (ObsRO) Questionnaire
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.
Time frame: At Week 1, Week 13, Week 25, Week 37 and Week 48
Population: The Full Analysis Set 3 (FAS-3) consisted of all randomized participants during the core phase. This includes only the participants aged between 2 years and less than 10 years with a valid assessment for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| DFX DT | Change Over Time in Weekly Dose Violation Rate Using Compliance Observer Reported Outcomes (ObsRO) Questionnaire | Week 13 | 10.38 percentage of days with dose violations | Standard Deviation 27.374 |
| DFX DT | Change Over Time in Weekly Dose Violation Rate Using Compliance Observer Reported Outcomes (ObsRO) Questionnaire | Week 37 | 13.86 percentage of days with dose violations | Standard Deviation 31.769 |
| DFX DT | Change Over Time in Weekly Dose Violation Rate Using Compliance Observer Reported Outcomes (ObsRO) Questionnaire | Week 25 | 7.79 percentage of days with dose violations | Standard Deviation 23.025 |
| DFX DT | Change Over Time in Weekly Dose Violation Rate Using Compliance Observer Reported Outcomes (ObsRO) Questionnaire | Week 48 | 13.56 percentage of days with dose violations | Standard Deviation 32.211 |
| DFX DT | Change Over Time in Weekly Dose Violation Rate Using Compliance Observer Reported Outcomes (ObsRO) Questionnaire | Week 1 | 18.80 percentage of days with dose violations | Standard Deviation 29.912 |
| DFX Granule | Change Over Time in Weekly Dose Violation Rate Using Compliance Observer Reported Outcomes (ObsRO) Questionnaire | Week 48 | 14.50 percentage of days with dose violations | Standard Deviation 31.123 |
| DFX Granule | Change Over Time in Weekly Dose Violation Rate Using Compliance Observer Reported Outcomes (ObsRO) Questionnaire | Week 1 | 27.79 percentage of days with dose violations | Standard Deviation 37.577 |
| DFX Granule | Change Over Time in Weekly Dose Violation Rate Using Compliance Observer Reported Outcomes (ObsRO) Questionnaire | Week 13 | 18.65 percentage of days with dose violations | Standard Deviation 35.513 |
| DFX Granule | Change Over Time in Weekly Dose Violation Rate Using Compliance Observer Reported Outcomes (ObsRO) Questionnaire | Week 25 | 13.72 percentage of days with dose violations | Standard Deviation 31.813 |
| DFX Granule | Change Over Time in Weekly Dose Violation Rate Using Compliance Observer Reported Outcomes (ObsRO) Questionnaire | Week 37 | 20.01 percentage of days with dose violations | Standard Deviation 37.632 |
Secondary
Change Over Time in Weekly Dose Violation Rate Using Compliance Patient Reported Outcomes (PRO) Questionnaire
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.
Time frame: At Week 1, Week 13, Week 25, Week 37 and Week 48
Population: The Full Analysis Set 3 (FAS-3) consisted of all randomized participants during the core phase. This includes only the participants aged between 10 years and less than 18 years with a valid assessment for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| DFX DT | Change Over Time in Weekly Dose Violation Rate Using Compliance Patient Reported Outcomes (PRO) Questionnaire | Week 13 | 12.78 percentage of days with dose violations | Standard Deviation 31 |
| DFX DT | Change Over Time in Weekly Dose Violation Rate Using Compliance Patient Reported Outcomes (PRO) Questionnaire | Week 37 | 18.89 percentage of days with dose violations | Standard Deviation 32.745 |
| DFX DT | Change Over Time in Weekly Dose Violation Rate Using Compliance Patient Reported Outcomes (PRO) Questionnaire | Week 25 | 13.19 percentage of days with dose violations | Standard Deviation 29.614 |
| DFX DT | Change Over Time in Weekly Dose Violation Rate Using Compliance Patient Reported Outcomes (PRO) Questionnaire | Week 48 | 2.86 percentage of days with dose violations | Standard Deviation 7.559 |
| DFX DT | Change Over Time in Weekly Dose Violation Rate Using Compliance Patient Reported Outcomes (PRO) Questionnaire | Week 1 | 26.86 percentage of days with dose violations | Standard Deviation 37.966 |
| DFX Granule | Change Over Time in Weekly Dose Violation Rate Using Compliance Patient Reported Outcomes (PRO) Questionnaire | Week 48 | 52.38 percentage of days with dose violations | Standard Deviation 52.424 |
| DFX Granule | Change Over Time in Weekly Dose Violation Rate Using Compliance Patient Reported Outcomes (PRO) Questionnaire | Week 1 | 26.79 percentage of days with dose violations | Standard Deviation 38.992 |
| DFX Granule | Change Over Time in Weekly Dose Violation Rate Using Compliance Patient Reported Outcomes (PRO) Questionnaire | Week 13 | 23.41 percentage of days with dose violations | Standard Deviation 35.906 |
| DFX Granule | Change Over Time in Weekly Dose Violation Rate Using Compliance Patient Reported Outcomes (PRO) Questionnaire | Week 25 | 25.93 percentage of days with dose violations | Standard Deviation 42.583 |
| DFX Granule | Change Over Time in Weekly Dose Violation Rate Using Compliance Patient Reported Outcomes (PRO) Questionnaire | Week 37 | 30.16 percentage of days with dose violations | Standard Deviation 41.921 |
Secondary
Concentrations of Deferasirox Between 2 and 4 Hours Post-dose at Weeks 5 and 9
Post-dose pharmacokinetic (PK) data from participants in the Pharmacokinetic Analysis Set 1 (PAS-1) were analyzed along with Pre-dose PK data.
Time frame: At Week 5 and Week 9
Population: Pharmacokinetic Analysis Set 1 (PAS-1) consisted of all participants who had at least one evaluable pre- or 3 hours post-dose PK concentration of deferasirox. The analysis included participants only with evaluable values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| DFX DT | Concentrations of Deferasirox Between 2 and 4 Hours Post-dose at Weeks 5 and 9 | Week 5 (3 hour post-dose) | 65.2 μmol/L | Geometric Coefficient of Variation 80.5 |
| DFX DT | Concentrations of Deferasirox Between 2 and 4 Hours Post-dose at Weeks 5 and 9 | Week 9 (3 hour post-dose) | 70.4 μmol/L | Geometric Coefficient of Variation 77 |
| DFX Granule | Concentrations of Deferasirox Between 2 and 4 Hours Post-dose at Weeks 5 and 9 | Week 5 (3 hour post-dose) | 53.2 μmol/L | Geometric Coefficient of Variation 86.2 |
| DFX Granule | Concentrations of Deferasirox Between 2 and 4 Hours Post-dose at Weeks 5 and 9 | Week 9 (3 hour post-dose) | 59.8 μmol/L | Geometric Coefficient of Variation 61.7 |
Secondary
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the Core Phase
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.
Time frame: From Baseline to 48 weeks
Population: The Safety Set consisted of all participants who received at least 1 dose of study drug during the core phase. Three participants did not receive the study drug and hence were excluded from the safety set.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| DFX DT | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the Core Phase | All AEs | 108 Participants |
| DFX DT | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the Core Phase | All SAEs | 23 Participants |
| DFX Granule | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the Core Phase | All AEs | 100 Participants |
| DFX Granule | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the Core Phase | All SAEs | 27 Participants |
Secondary
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the Entire Granule Period
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.
Time frame: From Baseline to 305 weeks
Population: The Safety Set consisted of all participants who received at least 1 dose of granule formulation during the core or extension phase. The participants in the extension phase received granules regardless of which arm they were initially randomized.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| DFX DT | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the Entire Granule Period | AEs | 64 Participants |
| DFX DT | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the Entire Granule Period | Suspected AEs | 48 Participants |
| DFX DT | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the Entire Granule Period | SAEs | 22 Participants |
| DFX DT | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the Entire Granule Period | Suspected SAEs | 4 Participants |
| DFX Granule | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the Entire Granule Period | Suspected SAEs | 7 Participants |
| DFX Granule | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the Entire Granule Period | AEs | 106 Participants |
| DFX Granule | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the Entire Granule Period | SAEs | 38 Participants |
| DFX Granule | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the Entire Granule Period | Suspected AEs | 73 Participants |
Secondary
Number of Participants With Adverse Events of Special Interest (AESI) During the Entire Granule Period
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
Time frame: From Baseline to 305 weeks
Population: The Safety Set consisted of all participants who received at least 1 dose of granule formulation during the core or extension phase. The participants in the extension phase received granules regardless of which arm they were initially randomized.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| DFX DT | Number of Participants With Adverse Events of Special Interest (AESI) During the Entire Granule Period | Hearing loss | 5 Participants |
| DFX DT | Number of Participants With Adverse Events of Special Interest (AESI) During the Entire Granule Period | Lens opacities, Retinal changes and Optic neuritis | 0 Participants |
| DFX DT | Number of Participants With Adverse Events of Special Interest (AESI) During the Entire Granule Period | Liver disorders - Hepatic failure | 1 Participants |
| DFX DT | Number of Participants With Adverse Events of Special Interest (AESI) During the Entire Granule Period | Liver disorders - Increased liver transaminases | 16 Participants |
| DFX DT | Number of Participants With Adverse Events of Special Interest (AESI) During the Entire Granule Period | Peripheral blood cytopenias | 5 Participants |
| DFX DT | Number of Participants With Adverse Events of Special Interest (AESI) During the Entire Granule Period | Renal disorders - Acute renal failure | 1 Participants |
| DFX DT | Number of Participants With Adverse Events of Special Interest (AESI) During the Entire Granule Period | Renal disorders - Increased serum creatinine | 4 Participants |
| DFX DT | Number of Participants With Adverse Events of Special Interest (AESI) During the Entire Granule Period | Renal disorders -Proteinuria | 40 Participants |
| DFX DT | Number of Participants With Adverse Events of Special Interest (AESI) During the Entire Granule Period | Renal disorders - Renal tubular disorders | 4 Participants |
| DFX DT | Number of Participants With Adverse Events of Special Interest (AESI) During the Entire Granule Period | Severe Cutaneous Adverse Reactions (SCARs) | 0 Participants |
| DFX DT | Number of Participants With Adverse Events of Special Interest (AESI) During the Entire Granule Period | Any AESI | 52 Participants |
| DFX DT | Number of Participants With Adverse Events of Special Interest (AESI) During the Entire Granule Period | Gastrointestinal hemorrhages | 3 Participants |
| DFX Granule | Number of Participants With Adverse Events of Special Interest (AESI) During the Entire Granule Period | Any AESI | 79 Participants |
| DFX Granule | Number of Participants With Adverse Events of Special Interest (AESI) During the Entire Granule Period | Hearing loss | 5 Participants |
| DFX Granule | Number of Participants With Adverse Events of Special Interest (AESI) During the Entire Granule Period | Renal disorders - Increased serum creatinine | 8 Participants |
| DFX Granule | Number of Participants With Adverse Events of Special Interest (AESI) During the Entire Granule Period | Lens opacities, Retinal changes and Optic neuritis | 2 Participants |
| DFX Granule | Number of Participants With Adverse Events of Special Interest (AESI) During the Entire Granule Period | Severe Cutaneous Adverse Reactions (SCARs) | 1 Participants |
| DFX Granule | Number of Participants With Adverse Events of Special Interest (AESI) During the Entire Granule Period | Liver disorders - Hepatic failure | 0 Participants |
| DFX Granule | Number of Participants With Adverse Events of Special Interest (AESI) During the Entire Granule Period | Renal disorders -Proteinuria | 49 Participants |
| DFX Granule | Number of Participants With Adverse Events of Special Interest (AESI) During the Entire Granule Period | Liver disorders - Increased liver transaminases | 46 Participants |
| DFX Granule | Number of Participants With Adverse Events of Special Interest (AESI) During the Entire Granule Period | Gastrointestinal hemorrhages | 4 Participants |
| DFX Granule | Number of Participants With Adverse Events of Special Interest (AESI) During the Entire Granule Period | Peripheral blood cytopenias | 7 Participants |
| DFX Granule | Number of Participants With Adverse Events of Special Interest (AESI) During the Entire Granule Period | Renal disorders - Renal tubular disorders | 0 Participants |
| DFX Granule | Number of Participants With Adverse Events of Special Interest (AESI) During the Entire Granule Period | Renal disorders - Acute renal failure | 0 Participants |
Secondary
Percentage of Overall Compliance Using Stick Pack or Tablet Counts in ICT-naïve Participants During the Core Phase
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.
Time frame: 48 weeks
Population: The Full Analysis Set 1 (FAS-1) consisted of all ICT naive randomized participants during the core phase.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| DFX DT | Percentage of Overall Compliance Using Stick Pack or Tablet Counts in ICT-naïve Participants During the Core Phase | 91.57 percentage of compliance |
| DFX Granule | Percentage of Overall Compliance Using Stick Pack or Tablet Counts in ICT-naïve Participants During the Core Phase | 94.80 percentage of compliance |
Secondary
Pre-dose Concentrations of Deferasirox to Support the Assessment of Compliance
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.
Time frame: At Weeks 1, 3, 5, 9, 13, 17, 21, 25, 29, 33, 37, 41, and 45
Population: Pharmacokinetic Analysis Set 1 (PAS-1) consisted of all participants who had at least one evaluable pre- or 3 hours post-dose PK concentration of deferasirox. The analysis included participants only with evaluable values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| DFX DT | Pre-dose Concentrations of Deferasirox to Support the Assessment of Compliance | Week 45 | 28.3 μmol/L | Geometric Coefficient of Variation 141.2 |
| DFX DT | Pre-dose Concentrations of Deferasirox to Support the Assessment of Compliance | Week 13 | 19.7 μmol/L | Geometric Coefficient of Variation 124.2 |
| DFX DT | Pre-dose Concentrations of Deferasirox to Support the Assessment of Compliance | Week 3 | 14.2 μmol/L | Geometric Coefficient of Variation 137 |
| DFX DT | Pre-dose Concentrations of Deferasirox to Support the Assessment of Compliance | Week 17 | 18.4 μmol/L | Geometric Coefficient of Variation 109.4 |
| DFX DT | Pre-dose Concentrations of Deferasirox to Support the Assessment of Compliance | Week 41 | 21.8 μmol/L | Geometric Coefficient of Variation 131.6 |
| DFX DT | Pre-dose Concentrations of Deferasirox to Support the Assessment of Compliance | Week 21 | 19.6 μmol/L | Geometric Coefficient of Variation 120.4 |
| DFX DT | Pre-dose Concentrations of Deferasirox to Support the Assessment of Compliance | Week 5 | 14.4 μmol/L | Geometric Coefficient of Variation 115.7 |
| DFX DT | Pre-dose Concentrations of Deferasirox to Support the Assessment of Compliance | Week 25 | 17.1 μmol/L | Geometric Coefficient of Variation 147.2 |
| DFX DT | Pre-dose Concentrations of Deferasirox to Support the Assessment of Compliance | Week 1 | 2.93 μmol/L | Geometric Coefficient of Variation 369.5 |
| DFX DT | Pre-dose Concentrations of Deferasirox to Support the Assessment of Compliance | Week 29 | 23.8 μmol/L | Geometric Coefficient of Variation 111.3 |
| DFX DT | Pre-dose Concentrations of Deferasirox to Support the Assessment of Compliance | Week 9 | 20.1 μmol/L | Geometric Coefficient of Variation 115.8 |
| DFX DT | Pre-dose Concentrations of Deferasirox to Support the Assessment of Compliance | Week 33 | 21.4 μmol/L | Geometric Coefficient of Variation 184 |
| DFX DT | Pre-dose Concentrations of Deferasirox to Support the Assessment of Compliance | Week 37 | 20.8 μmol/L | Geometric Coefficient of Variation 137.1 |
| DFX Granule | Pre-dose Concentrations of Deferasirox to Support the Assessment of Compliance | Week 33 | 14.1 μmol/L | Geometric Coefficient of Variation 175.6 |
| DFX Granule | Pre-dose Concentrations of Deferasirox to Support the Assessment of Compliance | Week 37 | 14.6 μmol/L | Geometric Coefficient of Variation 135.3 |
| DFX Granule | Pre-dose Concentrations of Deferasirox to Support the Assessment of Compliance | Week 41 | 15.5 μmol/L | Geometric Coefficient of Variation 134.7 |
| DFX Granule | Pre-dose Concentrations of Deferasirox to Support the Assessment of Compliance | Week 45 | 19.0 μmol/L | Geometric Coefficient of Variation 117 |
| DFX Granule | Pre-dose Concentrations of Deferasirox to Support the Assessment of Compliance | Week 1 | 1.40 μmol/L | Geometric Coefficient of Variation 235.4 |
| DFX Granule | Pre-dose Concentrations of Deferasirox to Support the Assessment of Compliance | Week 3 | 11.8 μmol/L | Geometric Coefficient of Variation 117.1 |
| DFX Granule | Pre-dose Concentrations of Deferasirox to Support the Assessment of Compliance | Week 5 | 11.7 μmol/L | Geometric Coefficient of Variation 127.5 |
| DFX Granule | Pre-dose Concentrations of Deferasirox to Support the Assessment of Compliance | Week 9 | 12.1 μmol/L | Geometric Coefficient of Variation 97.1 |
| DFX Granule | Pre-dose Concentrations of Deferasirox to Support the Assessment of Compliance | Week 13 | 13.5 μmol/L | Geometric Coefficient of Variation 107.5 |
| DFX Granule | Pre-dose Concentrations of Deferasirox to Support the Assessment of Compliance | Week 17 | 13.1 μmol/L | Geometric Coefficient of Variation 135.3 |
| DFX Granule | Pre-dose Concentrations of Deferasirox to Support the Assessment of Compliance | Week 21 | 13.4 μmol/L | Geometric Coefficient of Variation 163.6 |
| DFX Granule | Pre-dose Concentrations of Deferasirox to Support the Assessment of Compliance | Week 25 | 15.9 μmol/L | Geometric Coefficient of Variation 108.6 |
| DFX Granule | Pre-dose Concentrations of Deferasirox to Support the Assessment of Compliance | Week 29 | 13.2 μmol/L | Geometric Coefficient of Variation 156.6 |
Other Pre-specified
Exposure-Response Relationship in Relation to Pre- and Post-Dose Deferasirox Concentrations (PK/PD Relationship)
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.
Time frame: From Baseline to 48 weeks