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.
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.
Brief Title
Study to Evaluate Treatment Compliance, Efficacy and Safety of an Improved Deferasirox Formulation (Granules) in Pediatric Patients (2-<18 Years Old) With Iron Overload
Completion Date
Completion Date Type
Actual
Conditions
Transfusion-dependent Anemia
Eligibility Criteria
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).
* 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).
Inclusion Criteria
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).
* 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).
Gender
All
Gender Based
false
Keywords
New formulation
deferasirox
chelation
iron overload
compliance
satisfaction
palatability
PRO
PK
safety
PK/PD
ICL670
Healthy Volunteers
No
Last Update Post Date
Last Update Post Date Type
Actual
Last Update Submit Date
Maximum Age
17 Years
Minimum Age
2 Years
NCT Id
NCT02435212
Org Class
Industry
Org Full Name
Novartis
Org Study Id
CICL670F2202
Overall Status
Completed
Phases
Phase 2
Primary Completion Date
Primary Completion Date Type
Actual
Official Title
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
Primary Outcomes
Outcome Description
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.
Outcome Measure
Percentage of Overall Compliance Using Stick Pack or Tablet Counts in Iron Chelation Therapy (ICT)-naïve Participants During the Core Phase
Outcome Time Frame
24 weeks
Outcome Description
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.
Outcome Measure
Change From Baseline in Serum Ferritin (SF) for Both Study Drug Formulations in ICT naïve Participants During the Core Phase
Outcome Time Frame
From Baseline to Week 25
Secondary Ids
Secondary Id
2013-004739-55
Secondary Outcomes
Outcome Description
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.
Outcome Time Frame
48 weeks
Outcome Measure
Percentage of Overall Compliance Using Stick Pack or Tablet Counts in ICT-naïve Participants During the Core Phase
Outcome Description
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.
Outcome Time Frame
From Baseline to 48 weeks
Outcome Measure
Change From Baseline in Serum Ferritin (SF) for Both Study Drug Formulations in ICT naïve Participants During the Core Phase
Outcome Description
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.
Outcome Time Frame
From Baseline to Week 25 and Week 48
Outcome Measure
Change From Baseline in Serum Ferritin (SF) for Both Study Drug Formulations in Pre-treated Participants During the Core Phase
Outcome Description
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.
Outcome Time Frame
At Week 2, Week 3, Week 25 and Week 48
Outcome Measure
Change Over-time in Domain Score of Modified Satisfaction With Iron Chelation Therapy (mSICT) Using Patient Reported Outcomes (PRO) Questionnaires
Outcome Description
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.
Outcome Time Frame
At Week 2, Week 3, Week 25 and Week 48
Outcome Measure
Change Over-time in Domain Score of Modified Satisfaction With Iron Chelation Therapy (mSICT) Using Observer Reported Outcomes (ObsRO) Questionnaire (Caregiver's Perspective)
Outcome Description
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.
Outcome Time Frame
At Week 2, Week 3, Week 25 and Week 48
Outcome Measure
Change Over-time in Domain Score of Modified Satisfaction With Iron Chelation Therapy (mSICT) Using Observer Reported Outcomes (ObsRO) Questionnaire (Child's Perspective)
Outcome Description
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.
Outcome Time Frame
At Week 2, Week 3, Week 25 and Week 48
Outcome Measure
Change Over-time in Domain Score of Palatability Using Patient Reported Outcomes (PRO) Questionnaires
Outcome Description
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.
Outcome Time Frame
At Week 2, Week 3, Week 25 and Week 48
Outcome Measure
Change Over-time in Domain Score of Palatability Using Observer Reported Outcomes (ObsRO) Questionnaire
Outcome Description
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.
\[Number of dose violations / Drug exposure (days)\] \*100. Higher values represent more dose violations.
Outcome Time Frame
At Week 1, Week 13, Week 25, Week 37 and Week 48
Outcome Measure
Change Over Time in Weekly Dose Violation Rate Using Compliance Patient Reported Outcomes (PRO) Questionnaire
Outcome Description
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.
Higher values represent more dose violations.
Outcome Time Frame
At Week 1, Week 13, Week 25, Week 37 and Week 48
Outcome Measure
Change Over Time in Weekly Dose Violation Rate Using Compliance Observer Reported Outcomes (ObsRO) Questionnaire
Outcome Description
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.
Outcome Time Frame
From Baseline to 48 weeks
Outcome Measure
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the Core Phase
Outcome Description
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.
Outcome Time Frame
At Weeks 1, 3, 5, 9, 13, 17, 21, 25, 29, 33, 37, 41, and 45
Outcome Measure
Pre-dose Concentrations of Deferasirox to Support the Assessment of Compliance
Outcome Description
Post-dose pharmacokinetic (PK) data from participants in the Pharmacokinetic Analysis Set 1 (PAS-1) were analyzed along with Pre-dose PK data.
Outcome Time Frame
At Week 5 and Week 9
Outcome Measure
Concentrations of Deferasirox Between 2 and 4 Hours Post-dose at Weeks 5 and 9
Outcome Description
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.
Outcome Time Frame
From Baseline to 305 weeks
Outcome Measure
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the Entire Granule Period
Outcome Description
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
Outcome Time Frame
From Baseline to 305 weeks
Outcome Measure
Number of Participants With Adverse Events of Special Interest (AESI) During the Entire Granule Period
Start Date
Start Date Type
Actual
Status Verified Date
First Post Date
First Post Date Type
Estimated
First Submit Date
First Submit QC Date
Std Ages
Child
Locked Fields
Render the field
Maximum Age Number (converted to Years and rounded down)
17
Minimum Age Number (converted to Years and rounded down)
2
Investigators
Investigator Type
Principal Investigator
Investigator Name
Deepa Manwani
Investigator Email
dmanwani@montefiore.org
Investigator Phone
718-741-2342