Clinical trial NCT02435212: Study to Evaluate Treatment Compliance, Efficacy and Safety of an Improved Deferasirox Formulation (Granules) in Pediatric Patients (2-<18 Years Old) With Iron Overload
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Transfusion-dependent Anemia
Keywords: New formulation
deferasirox
chelation
iron overload
compliance
satisfaction
palatability
PRO
PK
safety
PK/PD
ICL670
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2015-05-06
Enrollment: 224
Sex: ALL
Minimum age (years): 2
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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).

Primary outcomes:
measure: Percentage of Overall Compliance Using Stick Pack or Tablet Counts in Iron Chelation Therapy (ICT)-naïve Participants During the Core Phase
timeFrame: 24 weeks
measure: Change From Baseline in Serum Ferritin (SF) for Both Study Drug Formulations in ICT naïve Participants During the Core Phase
timeFrame: From Baseline to Week 25
Secondary outcomes:
measure: Percentage of Overall Compliance Using Stick Pack or Tablet Counts in ICT-naïve Participants During the Core Phase
timeFrame: 48 weeks
measure: Change From Baseline in Serum Ferritin (SF) for Both Study Drug Formulations in ICT naïve Participants During the Core Phase
timeFrame: From Baseline to 48 weeks
measure: Change From Baseline in Serum Ferritin (SF) for Both Study Drug Formulations in Pre-treated Participants During the Core Phase
timeFrame: From Baseline to Week 25 and Week 48
measure: Change Over-time in Domain Score of Modified Satisfaction With Iron Chelation Therapy (mSICT) Using Patient Reported Outcomes (PRO) Questionnaires
timeFrame: At Week 2, Week 3, Week 25 and Week 48
measure: Change Over-time in Domain Score of Modified Satisfaction With Iron Chelation Therapy (mSICT) Using Observer Reported Outcomes (ObsRO) Questionnaire (Caregiver's Perspective)
timeFrame: At Week 2, Week 3, Week 25 and Week 48
measure: Change Over-time in Domain Score of Modified Satisfaction With Iron Chelation Therapy (mSICT) Using Observer Reported Outcomes (ObsRO) Questionnaire (Child's Perspective)
timeFrame: At Week 2, Week 3, Week 25 and Week 48
measure: Change Over-time in Domain Score of Palatability Using Patient Reported Outcomes (PRO) Questionnaires
timeFrame: At Week 2, Week 3, Week 25 and Week 48
measure: Change Over-time in Domain Score of Palatability Using Observer Reported Outcomes (ObsRO) Questionnaire
timeFrame: At Week 2, Week 3, Week 25 and Week 48
measure: Change Over Time in Weekly Dose Violation Rate Using Compliance Patient Reported Outcomes (PRO) Questionnaire
timeFrame: At Week 1, Week 13, Week 25, Week 37 and Week 48
measure: Change Over Time in Weekly Dose Violation Rate Using Compliance Observer Reported Outcomes (ObsRO) Questionnaire
timeFrame: At Week 1, Week 13, Week 25, Week 37 and Week 48
measure: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the Core Phase
timeFrame: From Baseline to 48 weeks
measure: Pre-dose Concentrations of Deferasirox to Support the Assessment of Compliance
timeFrame: At Weeks 1, 3, 5, 9, 13, 17, 21, 25, 29, 33, 37, 41, and 45
measure: Concentrations of Deferasirox Between 2 and 4 Hours Post-dose at Weeks 5 and 9
timeFrame: At Week 5 and Week 9
measure: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the Entire Granule Period
timeFrame: From Baseline to 305 weeks
measure: Number of Participants With Adverse Events of Special Interest (AESI) During the Entire Granule Period
timeFrame: From Baseline to 305 weeks
Other outcomes:
measure: Exposure-Response Relationship in Relation to Pre- and Post-Dose Deferasirox Concentrations (PK/PD Relationship)
timeFrame: From Baseline to 48 weeks
Locations:
city: Oakland
country: United States
facility: Novartis Investigative Site
state: California
city: Atlanta
country: United States
facility: Novartis Investigative Site
state: Georgia
city: Chicago
country: United States
facility: Novartis Investigative Site
state: Illinois
city: Bronx
country: United States
facility: Childrens Hospital at Montefiore
state: New York
city: Bronx
country: United States
facility: Novartis Investigative Site
state: New York
city: New York
country: United States
facility: Novartis Investigative Site
state: New York
city: New York
country: United States
facility: Weill Cornell Medical College SC -
state: New York
city: Philadelphia
country: United States
facility: Childrens Hospital of Philadelphia Onc. Dept
state: Pennsylvania
city: Philadelphia
country: United States
facility: Novartis Investigative Site
state: Pennsylvania
city: Charleston
country: United States
facility: Medical Uni of South Carolina Medical Uni of South Carolina
state: South Carolina
city: Charleston
country: United States
facility: Novartis Investigative Site
state: South Carolina
city: Memphis
country: United States
facility: Novartis Investigative Site
state: Tennessee
city: Memphis
country: United States
facility: St. Jude Children's Research Hospital Memphis St Jude
state: Tennessee
city: Edegem
country: Belgium
facility: Novartis Investigative Site
state: Antwerpen
city: Brussel
country: Belgium
facility: Novartis Investigative Site
city: Plovdiv
country: Bulgaria
facility: Novartis Investigative Site
city: Sofia
country: Bulgaria
facility: Novartis Investigative Site
city: Varna
country: Bulgaria
facility: Novartis Investigative Site
city: Alexandria
country: Egypt
facility: Novartis Investigative Site
city: Creteil
country: France
facility: Novartis Investigative Site
city: Paris 15
country: France
facility: Novartis Investigative Site
city: Debrecen
country: Hungary
facility: Novartis Investigative Site
city: Kolkata
country: India
facility: Novartis Investigative Site
state: West Bengal
city: Genova
country: Italy
facility: Novartis Investigative Site
state: GE
city: Palermo
country: Italy
facility: Novartis Investigative Site
state: PA
city: Palermo
country: Italy
facility: Novartis Investigative Site
state: PA
city: Napoli
country: Italy
facility: Novartis Investigative Site
city: Hazmiyeh
country: Lebanon
facility: Novartis Investigative Site
state: Beirut
city: Ipoh
country: Malaysia
facility: Novartis Investigative Site
state: Perak
city: Kuching
country: Malaysia
facility: Novartis Investigative Site
state: Sarawak
city: Kuala Lumpur
country: Malaysia
facility: Novartis Investigative Site
city: Pulau Pinang
country: Malaysia
facility: Novartis Investigative Site
city: Muscat
country: Oman
facility: Novartis Investigative Site
city: Panama City
country: Panama
facility: Novartis Investigative Site
state: Republica De Panama
city: Quezon City
country: Philippines
facility: Novartis Investigative Site
city: Quezon
country: Philippines
facility: Novartis Investigative Site
city: Moscow
country: Russian Federation
facility: Novartis Investigative Site
city: Bangkok noi
country: Thailand
facility: Novartis Investigative Site
state: Bangkok
city: Muang
country: Thailand
facility: Novartis Investigative Site
state: Chiangmai
city: Tunis
country: Tunisia
facility: Novartis Investigative Site
city: Adana
country: Turkey
facility: Novartis Investigative Site
city: Ankara
country: Turkey
facility: Novartis Investigative Site
city: Izmir
country: Turkey
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: