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

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

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.

Study Overview

• Status: Completed
• Conditions: Transfusion-dependent Anemia
• Intervention / Treatment: Drug: Deferasirox DT formulation; Drug: Deferasirox granule formulation

• Study Type: Interventional
• Enrollment (Actual): 224
• Phase: Phase 2

Contacts and Locations

Study Locations

• Belgium
  • Brussel, Belgium, 1200
    • Novartis Investigative Site
  • Antwerpen
    • Edegem, Antwerpen, Belgium, 2650
      • Novartis Investigative Site
• Bulgaria
  • Plovdiv, Bulgaria, 4002
    • Novartis Investigative Site
  • Sofia, Bulgaria, 1527
    • Novartis Investigative Site
  • Varna, Bulgaria, 9010
    • Novartis Investigative Site
• Egypt
  • Alexandria, Egypt, 21131
    • Novartis Investigative Site
• France
  • Creteil, France, 94000
    • Novartis Investigative Site
  • Paris 15, France, 75015
    • Novartis Investigative Site
• Hungary
  • Debrecen, Hungary, 4032
    • Novartis Investigative Site
• India
  • West Bengal
    • Kolkata, West Bengal, India, 700017
      • Novartis Investigative Site
• Italy
  • Napoli, Italy, 80132
    • Novartis Investigative Site
  • GE
    • Genova, GE, Italy, 16128
      • Novartis Investigative Site
  • PA
    • Palermo, PA, Italy, 90127
      • Novartis Investigative Site
    • Palermo, PA, Italy, 90146
      • Novartis Investigative Site
• Lebanon
  • Beirut
    • Hazmiyeh, Beirut, Lebanon, PO BOX 213
      • Novartis Investigative Site
• Malaysia
  • Kuala Lumpur, Malaysia, 50589
    • Novartis Investigative Site
  • Pulau Pinang, Malaysia, 10990
    • Novartis Investigative Site
  • Perak
    • Ipoh, Perak, Malaysia, 30450
      • Novartis Investigative Site
  • Sarawak
    • Kuching, Sarawak, Malaysia, 93586
      • Novartis Investigative Site
• Oman
  • Muscat, Oman, 123
    • Novartis Investigative Site
• Panama
  • Republica De Panama
    • Panama City, Republica De Panama, Panama, 0801
      • Novartis Investigative Site
• Philippines
  • Quezon City, Philippines, 1100
    • Novartis Investigative Site
• Russian Federation
  • Moscow, Russian Federation, 117198
    • Novartis Investigative Site
• Thailand
  • Bangkok
    • Bangkok noi, Bangkok, Thailand, 10700
      • Novartis Investigative Site
  • Chiangmai
    • Muang, Chiangmai, Thailand, 50200
      • Novartis Investigative Site
• Tunisia
  • Tunis, Tunisia, 1006
    • Novartis Investigative Site
• Turkey
  • Adana, Turkey, 01330
    • Novartis Investigative Site
  • Ankara, Turkey, 06100
    • Novartis Investigative Site
  • Izmir, Turkey, 35040
    • Novartis Investigative Site
• United States
  • California
    • Oakland, California, United States, 94609-1809
      • Novartis Investigative Site
  • Georgia
    • Atlanta, Georgia, United States, 30342
      • Novartis Investigative Site
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Novartis Investigative Site
  • New York
    • Bronx, New York, United States, 10467
      • Childrens Hospital at Montefiore
    • New York, New York, United States, 10021
      • Weill Cornell Medical College SC -
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104 4399
      • Childrens Hospital of Philadelphia Onc. Dept
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical Uni of South Carolina Medical Uni Of South Carolina
  • Tennessee
    • Memphis, Tennessee, United States, 38105
      • St. Jude Children's Research Hospital Memphis St Jude

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 13 years (Child)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm 2	Drug: Deferasirox granule formulation; Deferasirox granules will be provided as stick packs containing 90 mg, 180 mg and 360 mg granules for oral use.; Other Names: ICL670
Active Comparator: Arm 1	Drug: Deferasirox DT formulation; Deferasirox DT will be provided as 125 mg, 250 mg and 500 mg dispersible tablets for oral use; Other Names: ICL670

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Compliance (using stick/pack tablet count).	Evaluate patient compliance measured by stick pack/tablet count in ICT naïve patients during core phase.	24 weeks
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Compliance (using stick/pack tablet count)	Evaluate patient compliance measured by stick pack/tablet count in ICT naïve patients during core phase.	48 weeks
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
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
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
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)
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
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
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
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
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

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Investigators: Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): October 21, 2015
• Primary Completion (Actual): May 31, 2018
• Study Completion (Actual): January 15, 2024

Study Registration Dates

• First Submitted: March 17, 2015
• First Submitted That Met QC Criteria: April 30, 2015
• First Posted (Estimated): May 6, 2015

Study Record Updates

• Last Update Posted (Actual): March 27, 2024
• Last Update Submitted That Met QC Criteria: March 26, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: safety; compliance; satisfaction; PK; iron overload; chelation; deferasirox; palatability; PRO; ICL670; PK/PD; New formulation
• Additional Relevant MeSH Terms: Metabolic Diseases; Iron Metabolism Disorders; Iron Overload; Molecular Mechanisms of Pharmacological Action; Chelating Agents; Sequestering Agents; Iron Chelating Agents; Deferasirox
• Other Study ID Numbers: CICL670F2202; 2013-004739-55 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No