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

Sponsor

Novartis Pharmaceuticals (Industry)

Overall Status

Active, not recruiting

CT.gov ID

NCT02435212

Collaborator

(none)

224

Enrollment

Locations

Arms

97.9

Anticipated Duration (Months)

6.1

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Transfusion-dependent Anemia	Drug: Deferasirox granule formulation Drug: Deferasirox DT formulation	Phase 2

Study Design

Study Type:

Interventional

Actual Enrollment :

224 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Oct 21, 2015

Actual Primary Completion Date :

May 31, 2018

Anticipated Study Completion Date :

Dec 19, 2023

Arms and Interventions

Arm	Intervention/Treatment
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
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

Arm

Intervention/Treatment

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

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

Outcome Measures

Primary Outcome Measures

Compliance (using stick/pack tablet count). [24 weeks]
Evaluate patient compliance measured by stick pack/tablet count in ICT naïve patients during core phase.
Change in serum ferritin in ICT naive patients. [Baseline, 24 weeks]
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.

Secondary Outcome Measures

Compliance (using stick/pack tablet count) [48 weeks]
Evaluate patient compliance measured by stick pack/tablet count in ICT naïve patients during core phase.
Change in serum ferritin in ICT naive patients [Baseline, 24 weeks, 48 weeks]
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 pediatric ICT naïve patients with iron overload.
Domain scores of treatment satisfaction and palatability over time [From baseline to 48 weeks]
To evaluate both formulations on patient satisfaction and palatability using Patient / Observer Reported Outcomes (PRO/ObsRO) questionnaires
Overall safety, as measured by frequency and severity of adverse [From Baseline to 48 weeks]
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.
Rate of dosing instructions deviations ('Compliance', using a questionnaire) [From Baseline to 48 weeks]
This includes doses missed/not taken at the same time every day, to evaluate the compliance using a daily PRO/ObsRO questionnaire.
Pre-dose deferasirox concentrations in all patients [at Weeks 1, 3, 5, 9, 13, 17, 21, 25, 29, 33, 37, 41, and 45 (13 samples)]
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.
Post-dose deferasirox concentrations between 2 and 4 hours post-dose at Weeks 5 and 9 [Week 5, Week 9]
post-dose PK data to be analyzed along with pre-dose PK data
PK/PD relationship [From Baseline to 48 weeks]
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.
Assess additional safety, as measured by frequency and severity of adverse for granules during extension phase [From Baseline to 305 weeks]
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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

2 Years to 17 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.
(Criterion no longer applicable, removed as part of Amendment 1): Prior iron chelation therapy.
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).

Other protocol-defined Inclusion/Exclusion may apply.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Children's Hospital Oakland Onc Dept	Oakland	California	United States	94609
2	Childrens Healthcare of Atlanta Onc Dept	Atlanta	Georgia	United States	30342
3	Northwestern University Onc Dept	Chicago	Illinois	United States	60611
4	Children's Hospital at Montefiore	Bronx	New York	United States	10467
5	Weill Cornell Medical College SC -	New York	New York	United States	10021
6	Childrens Hospital of Philadelphia Onc. Dept	Philadelphia	Pennsylvania	United States	19104 4399
7	Medical University of South Carolina Medical Uni of South Carolina	Charleston	South Carolina	United States	29425
8	St. Jude Children's Research Hospital Memphis St Jude	Memphis	Tennessee	United States	38105
9	Novartis Investigative Site	Edegem	Antwerpen	Belgium	2650
10	Novartis Investigative Site	Brussel		Belgium	1200
11	Novartis Investigative Site	Plovdiv		Bulgaria	4002
12	Novartis Investigative Site	Sofia		Bulgaria	1527
13	Novartis Investigative Site	Varna		Bulgaria	9010
14	Novartis Investigative Site	Alexandria		Egypt	21131
15	Novartis Investigative Site	Creteil		France	94000
16	Novartis Investigative Site	Paris		France	75015
17	Novartis Investigative Site	Debrecen		Hungary	4032
18	Novartis Investigative Site	Kolkata	West Bengal	India	700017
19	Novartis Investigative Site	Genova	GE	Italy	16128
20	Novartis Investigative Site	Palermo	PA	Italy	90127
21	Novartis Investigative Site	Palermo	PA	Italy	90146
22	Novartis Investigative Site	Napoli		Italy	80132
23	Novartis Investigative Site	Hazmiyeh	Beirut	Lebanon	PO BOX 213
24	Novartis Investigative Site	Ipoh	Perak	Malaysia	30450
25	Novartis Investigative Site	Kuching	Sarawak	Malaysia	93586
26	Novartis Investigative Site	Kuala Lumpur		Malaysia	50589
27	Novartis Investigative Site	Pulau Pinang		Malaysia	10990
28	Novartis Investigative Site	Muscat		Oman	123
29	Novartis Investigative Site	Panama City	Republica De Panama	Panama	0801
30	Novartis Investigative Site	Quezon City		Philippines	1100
31	Novartis Investigative Site	Moscow		Russian Federation	117198
32	Novartis Investigative Site	Bangkok noi	Bangkok	Thailand	10700
33	Novartis Investigative Site	Muang	Chiangmai	Thailand	50200
34	Novartis Investigative Site	Tunis		Tunisia	1006
35	Novartis Investigative Site	Adana		Turkey	01330
36	Novartis Investigative Site	Ankara		Turkey	06100
37	Novartis Investigative Site	Izmir		Turkey	35040