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

Transfusion-dependent Anemia Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02435212
• Other study ID #: CICL670F2202
• Secondary ID: 2013-004739-55
• Status: Completed
• Phase: Phase 2
• Start date: October 21, 2015
• Est. completion date: January 15, 2024

Study information

• Verified date: March 2024
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is 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 DT formulation in children and adolescents aged ≥ 2 and < 18 years at enrollment with any transfusion-dependent anemia requiring chelation therapy due to iron overload, to demonstrate the effect of improved compliance on iron burden.

Randomization will be stratified by age groups (2 to <10 years, 10 to <18 years) and prior iron chelation therapy (Yes/ No). There will be two study phases which include a 1 year core phase where patients will be randomized to a 48 week treatment period to either Deferasirox DT or granules, and an optional extension phase where all patients will receive the granules up to 5 years. Patients who demonstrated benefit to granules or DT in the core phase, and/or express the wish to continue in the optional extension phase on granules, will be offered this possibility until there is local access to the new formulation (granules or FCT) or up to 5 years, whichever occurs first.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 224
• Est. completion date: January 15, 2024
• Est. primary completion date: May 31, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 2 Years to 17 Years

Eligibility

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).

Other protocol-defined Inclusion/Exclusion may apply.

Related Conditions & MeSH terms

• Iron Overload
• Transfusion-dependent Anemia

Intervention

Drug:
• Deferasirox granule formulation
Deferasirox granules will be provided as stick packs containing 90 mg, 180 mg and 360 mg granules for oral use.
• Deferasirox DT formulation
Deferasirox DT will be provided as 125 mg, 250 mg and 500 mg dispersible tablets for oral use

Locations

Country	Name	City	State
Belgium	Novartis Investigative Site	Brussel
Belgium	Novartis Investigative Site	Edegem	Antwerpen
Bulgaria	Novartis Investigative Site	Plovdiv
Bulgaria	Novartis Investigative Site	Sofia
Bulgaria	Novartis Investigative Site	Varna
Egypt	Novartis Investigative Site	Alexandria
France	Novartis Investigative Site	Creteil
France	Novartis Investigative Site	Paris 15
Hungary	Novartis Investigative Site	Debrecen
India	Novartis Investigative Site	Kolkata	West Bengal
Italy	Novartis Investigative Site	Genova	GE
Italy	Novartis Investigative Site	Napoli
Italy	Novartis Investigative Site	Palermo	PA
Italy	Novartis Investigative Site	Palermo	PA
Lebanon	Novartis Investigative Site	Hazmiyeh	Beirut
Malaysia	Novartis Investigative Site	Ipoh	Perak
Malaysia	Novartis Investigative Site	Kuala Lumpur
Malaysia	Novartis Investigative Site	Kuching	Sarawak
Malaysia	Novartis Investigative Site	Pulau Pinang
Oman	Novartis Investigative Site	Muscat
Panama	Novartis Investigative Site	Panama City	Republica De Panama
Philippines	Novartis Investigative Site	Quezon City
Russian Federation	Novartis Investigative Site	Moscow
Thailand	Novartis Investigative Site	Bangkok noi	Bangkok
Thailand	Novartis Investigative Site	Muang	Chiangmai
Tunisia	Novartis Investigative Site	Tunis
Turkey	Novartis Investigative Site	Adana
Turkey	Novartis Investigative Site	Ankara
Turkey	Novartis Investigative Site	Izmir
United States	Novartis Investigative Site	Atlanta	Georgia
United States	Childrens Hospital at Montefiore	Bronx	New York
United States	Medical Uni of South Carolina Medical Uni of South Carolina	Charleston	South Carolina
United States	Novartis Investigative Site	Chicago	Illinois
United States	St. Jude Children's Research Hospital Memphis St Jude	Memphis	Tennessee
United States	Weill Cornell Medical College SC -	New York	New York
United States	Novartis Investigative Site	Oakland	California
United States	Childrens Hospital of Philadelphia Onc. Dept	Philadelphia	Pennsylvania

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Belgium,  Bulgaria,  Egypt,  France,  Hungary,  India,  Italy,  Lebanon,  Malaysia,  Oman,  Panama,  Philippines,  Russian Federation,  Thailand,  Tunisia,  Turkey, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Compliance (using stick/pack tablet count).	Evaluate patient compliance measured by stick pack/tablet count in ICT naïve patients during core phase.	24 weeks
Primary	Change in serum ferritin in ICT naive patients.	The comparison of means between the two treatment arms of change from baseline to week 24 of treatment in serum ferritin in pediatric ICT naïve patients with iron overload.	From Baseline to 24 weeks
Secondary	Compliance (using stick/pack tablet count)	Evaluate patient compliance measured by stick pack/tablet count in ICT naïve patients during core phase.	48 weeks
Secondary	Change in serum ferritin in ICT naive patients	The comparison of means between the two treatment arms of change from baseline to week 48 week of treatment in serum ferritin in pediatric ICT naïve patients with iron overload.	From Baseline to 48 weeks
Secondary	Change in serum ferritin in pre-treated patients	The comparison of means between the two treatment arms of change from baseline to week 24 and to 48 weeks of treatment in serum ferritin in pre-treated patients.	From Baseline to 24 weeks and 48 weeks
Secondary	Domain scores of treatment satisfaction and palatability over time	To evaluate both formulations on patient satisfaction and palatability using Patient / Observer Reported Outcomes (PRO/ObsRO) questionnaires	From baseline to 48 weeks
Secondary	Overall safety, as measured by frequency and severity of adverse	This includes active monitoring for renal toxicity; including renal failure, hepatic toxicity; including hepatic failure, and gastrointestinal hemorrhage), and changes in laboratory values from baseline (serum creatinine, creatinine clearance, ALT, AST, RBC and WBC). In addition, vital signs, physical, ophthalmological, audiometric, cardiac, and growth and development evaluations will be assessed.	From Baseline to 48 weeks
Secondary	Rate of dosing instructions deviations ('Compliance', using a questionnaire)	This includes doses missed/not taken at the same time every day, to evaluate the compliance using a daily PRO/ObsRO questionnaire.	From Baseline to 48 weeks
Secondary	Pre-dose deferasirox concentrations in all patients	The pre-dose concentration by incident dose will be plotted for Week 1, Week 3, Week 5, Week 9, Week 13, Week 17, Week 21, Week 25, Week 29, Week 33, Week, 37, Week 41 and Week 45 based on data from all patients. Pre-dose PK data from all patients will be analyzed to support the assessment of compliance.Predicted individual concentrations derived from the compartmental model will be compared to respective observed pre-dose concentrations. Distributions of the difference between predicted and observed values will be shown graphically by boxplots for both treatment groups and visit.	at Weeks 1, 3, 5, 9, 13, 17, 21, 25, 29, 33, 37, 41, and 45 (13 samples)
Secondary	Post-dose deferasirox concentrations between 2 and 4 hours post-dose at Weeks 5 and 9	post-dose PK data to be analyzed along with pre-dose PK data	Week 5, Week 9
Secondary	PK/PD relationship	To explore exposure-response relationships for measures of safety and effectiveness: serum creatinine change from baseline, notable serum creatinine values, serum creatinine clearance change from 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.	From Baseline to 48 weeks
Secondary	Assess additional safety, as measured by frequency and severity of adverse for granules during extension phase	This includesactive monitoring for renal toxicity; including renal failure, hepatic toxicity; including hepatic failure, and gastrointestinal hemorrhage), and changes in laboratory values from baseline (serum creatinine, creatinine clearance, ALT, AST, RBC and WBC). In addition, vital signs, physical, ophthalmological, audiometric, and growth and development evaluations will be assessed.	From Baseline to 305 weeks