Open-label, Multicenter Study Assessing Preference for Deferasirox Film-coated Tablet Compared to Dispersible Tablet

Study Overview
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Brief Summary
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Study to evaluate patient preference of deferasirox film-coated tablet (FCT) or deferasirox dispersible tablet (DT) in patient with transfusion - dependent thalassemia or non-transfusion -dependent thalassemia as measured by preference questionnaire at Week 48

Detailed Description
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This was an open-label, multicenter, single arm, phase II study aimed at collecting data on preference for iron chelation therapy in patients with transfusion-dependent thalassemia (TDT) or non-transfusion-dependent thalassemia (NTDT) throughout a 48 week treatment period. Participants who were either chelator-naïve, or who were previously treated with iron chelators (excluding deferasirox) for at least 6 months continuously, were eligible to participate in this study. The study was divided into 2 phases: Core Phase: Screening phase which lasted for a maximum of 4 weeks to determine patient eligibility followed by Period 1: Participants were treated with deferasirox DT from Baseline visit Day 1 to Week 24 Period 2: Participants were treated with deferasirox FCT from Week 25 to Week 48: At the discretion of the investigator, patients could switch from deferasirox DT to deferasirox FCT at any time during Period 1 of the Core phase, and vice versa, from deferasirox FCT to deferasirox DT at any time during Period 2 of the Core phase. Re-switching treatments was not allowed within each period. Extension Phase: Participants could continue deferasirox FCT formulation as per the judgment of the investigator, through an extension phase for a maximum of 48 weeks months from the last dose of deferasirox FCT received at the end of period 2 in the Core Phase or until one of the end of study criteria defined is met, whichever came first. Participation in the extension phase was optional. The end of study was defined as the earliest occurrence of one of the following: The patient reached Week 96 in the Extension phase. Deferasirox FCT was locally reimbursed for this indication (only applicable for the Extension phase) Another clinical study or post-trial access program became available that could continue to provide deferasirox FCT in this patient population and all patients ongoing were eligible to be transferred to that clinical study.

Official Title
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Open-label, Multicenter, Single Arm, Phase II Study Assessing Treatment Patient Preference for New Deferasirox Formulation (Film-coated Tablet) Compared to the Reference Deferasirox Dispersible Tablet Formulation

Conditions
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Transfusion-dependent Thalassemia, Non-transfusion-dependent Thalassemia

Intervention / Treatment
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* Drug: Deferasirox dispersable tablet (DT)
* Drug: Deferasirox film coated tablet (FCT)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Prior to any screening procedures were performed, written informed consent/assent must be provided. For pediatric patients, consent was obtained from parent(s) or legal patient's representative. Investigators also obtained assent of patients according to local, regional or national guidelines. Male and female patient aged ≥ 2 years Deferasirox naïve patient or chelated naive patient or treated by other chelators for at least 6 months, such as: Deferiprone/ DFP Deferoxamine /DFO Combination (DFO + DFP) Subject was willing to discontinue current iron chelation therapy at least 5 days prior to study day 1 and for the duration of the study Patients with transfusion-dependent thalassemia (independent of underlying condition) with transfusional iron overload as shown by a serum ferritin level of > 1000 ng/ml at screening and if available, LIC > 3 mg Fe/g dw within 6 months prior to screening Patients with non-transfusion-dependent thalassemia with iron overload as shown by a serum ferritin level of ≥ 800 ng/ml at screening and if available, LIC ≥ 5 mg Fe/g dw within 6 months prior to screening Exclusion Criteria: Creatinine clearance below the contraindication limit in the locally approved prescribing information. Serum creatinine level > 1.5 x ULN (upper limit of normal) AST (SGOT) /ALT (SGPT) > 5 x ULN, unless LIC confirmed as >10 mg Fe/dw within 6 months prior to screening visit. Significant proteinuria as indicated by a urinary protein/creatinine ratio > 0.5 mg/mg in a non-first void urine sample. Patients with significant impaired gastrointestinal (GI) function or GI disease that might significantly alter the absorption of oral deferasirox (e.g. ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection). Clinical or laboratory evidence of active Hepatitis B or Hepatitis C (HBsAg in the absence of HBsAb OR HCV Ab positive with HCV RNA positive). Patients with psychiatric or addictive disorders which prevent them from giving their informed consent or undergoing any of the treatment options or patients unwilling or unable to comply with the protocol Patients with a known history of HIV seropositivity (Elisa or Western blot). History of malignancy of any organ system, treated or untreated, within the past 5 years whether or not there is evidence of local recurrence or metastases, with the exception of localized basal cell carcinoma of the skin. Patients participating in another clinical trial or receiving an investigational drug. Patients who have recently completed treatment with an investigational product must have ceased this treatment for at least five times the half-life of the investigational product. History of hypersensitivity to any of the study drug or excipients. Significant medical condition interfering with the ability to partake in this study (e.g. systemic uncontrolled hypertension, unstable cardiac disease not controlled by standard medical therapy, systemic disease (cardiovascular, renal, hepatic, etc.). Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they were using effective methods of contraception during dosing of study treatment Women were considered post-menopausal and not of child bearing potential if they had had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or had had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman had been confirmed by follow up hormone level assessment is she considered not of child bearing potential. Sexually active males unless they used a condom during intercourse while taking drug and for 28 days after stopping study medication and should not father a child in this period. A condom was required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid.

Ages Eligible for Study
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Minimum Age: 2 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Deferasirox DT followed by deferasirox FCT<br>Participants were treated with deferasirox DT followed by deferasirox FCT (core phase). Those who entered the extension phase were treated with deferasirox FCT | Drug: Deferasirox dispersable tablet (DT)<br>* Deferasirox DT was provided as 125 mg, 250 mg, 500 mg dispersible tablets for oral use. The strengths provided in an individual country could differ and reflected the strengths available commercially in each country. For iron chelation naive participants, the starting dose on Baseline Day 1 was 20 mg/kg/day in TDT and 10 mg/kg/day in NTDT. For iron chelation (deferoxamine and/or deferiprone) pre-treated participants, the starting dose was equivalent to the dose of deferoxamine received (for participants pre-treated with deferoxamine) and based on their serum ferritin levels (for participants pre-treated with deferiprone). Participants took deferasirox DT once daily for 24 weeks (core phase). The required number of deferasirox DT tablets were to be dispersed with gentle stirring in a glass of water.<br>Drug: Deferasirox film coated tablet (FCT)<br>* Deferasirox FCT was provided as 90 mg, 180 mg, 360 mg film coated tablets for oral use. The FCT starting dose on Week 25 was 14 mg/kg/day in TDT and 7 mg/kg/day in NTDT. Participants took deferasirox FCT once daily for 24 weeks during the core phase and up to 48 weeks during the extension phase. For patients with difficulties in swallowing deferasirox FCT, it was allowed to crush the film-coated tablets and administer the study drug by sprinkling the full dose on soft food (like yogurt or apple puree).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Preferring Deferasirox FCT or DT at Week 48 Based on Preference Questionnaire (Item 2) | Number of participants preferring deferasirox FCT or DT as measured by preference questionnaire (item 2) at Week 48. The preference questionnaire was a 3-item questionnaire. At Week 48, the second item of the preference questionnaire asked the patients (or parents of young patients from 2 to 9 years old) which medicine did the patient like best: Tablet to dissolve in liquid (=deferasirox DT), Film coated tablet (=deferasirox FCT), Sprinkle powder on food (=deferasirox FCT) and I don't know (=none of the above). The number of participants who selected each response option for item 2 was assessed. The analysis was performed for participants who answered the item 2 of the preference questionnaire. | Week 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Preferring Deferasirox FCT, Deferasirox DT or Previous Iron Chelation Therapy at Week 28 Based on Preference Questionnaire (Item 2) | Number of participants preferring deferasirox FCT, deferasirox DT or previous iron chelation therapy as measured by preference questionnaire (item 2) at Week 28. The preference questionnaire was a 3-item questionnaire. At Week 28, the second item of this questionnaire asked the patients (or parents of young patients from 2 to 9 years old) which medicine did the patient like best: Tablet to dissolve in liquid (=deferasirox DT), Film coated tablet (taken once a day) (=deferasirox FCT), Sprinkle powder on food (=deferasirox FCT), Tablet (taken 3 times a day) (=previous iron chelation therapy), Injection (=previous iron chelation therapy) and I don't know (=none of the above). The number of participants who selected each response option for item 2 was assessed. This analysis was performed only for patients who had received iron chelation therapy prior to enrolling in the study and who answered the item 2 of the preference questionnaire. | Week 28 | 
| Number of Participants Preferring Deferasirox DT or Previous Iron Chelation Therapy at Week 4 and Week 24 Based on Preference Questionnaire (Item 2) | Number of participants preferring deferasirox DT or previous iron chelation therapy as measured by preference questionnaire (item 2) at Week 4 and 24. The preference questionnaire was a 3-item questionnaire. At Week 4 and 24, the second item of the preference questionnaire asked the patients (or parents of young patients from 2 to 9 years old) which medicine did the patient like best: Tablet to dissolve in liquid (=deferasirox DT), Tablet (taken 3 times a day) (=previous iron chelation therapy), Injection (=previous iron chelation therapy) and I don't know (=none of the above). The number of participants who selected each response option for item 2 was assessed. This analysis was performed only for patients who had received iron chelation therapy prior to enrolling in the study and who answered item 2 of the preference questionnaire. | Week 4 and Week 24 | 
| Number of Participants Selecting Each Reason for Treatment Preference as Assessed by the Preference Questionnaire at Week 28 and Week 48 | The preference questionnaire was a 3 item questionnaire. The first item asked the patients (or parents of young patients from 2 to 9 years old) which medicine they were taking. The second item asked which of the medicines did the patient Like best. Finally, the third item asked the patient why he/she preferred the medicine they chose in the second item. The number of participants who selected each response option for item 3 was assessed. Participants could select multiple reasons for treatment preference at each timepoint. | Week 28 and Week 48 | 
| Percentage of Consumed Tablet Counts During Deferasirox DT and Deferasirox FCT Treatment Periods | The percentage of consumed tablet counts (compliance) was calculated for each treatment period in the core phase: deferasirox DT (period 1) and deferasirox FCT (period 2). Compliance was defined as the total tablet count consumed divided by total tablet count prescribed and multiplied by 100. Total tablet count consumed was calculated as total number of tablets dispensed minus total number of tablets lost/wasted or returned. Total tablet count prescribed was calculated as the number of tablets that the patient should have taken during this period. If a patient did not return the study drug, the compliance was not calculated. | Deferasirox DT: From Baseline up to Week 24. Deferasirox FCT: From Week 25 up to Week 48 | 
| Change Over Time in Aftertaste Score of Palatability Questionnaire | The palatability questionnaire consisted of 4 items, three items measuring taste and one item measuring aftertaste. The aftertaste item scored on a 5-point response scale with the response option: Very good = 1, Good = 2, Neither good nor bad = 3, Bad = 4, Very bad = 5. This item offered an additional response option of no aftertaste. The aftertaste score was calculated among participants who had an aftertaste. Higher aftertaste scores indicated a worse aftertaste. For participants less than (<) 10 years old, an observer palatability questionnaire was administered. Items and scoring algorithm remained the same as for participants greater than or equal to (≥) 10 years old. Change in aftertaste score over time was assessed | Week 4, 24, 28 and 48 | 
| Change Over Time in Palatability Score of Palatability Questionnaire | The palatability questionnaire consisted of 4 items, three items measuring taste and one item measuring aftertaste. Among the taste items, first one measured taste on a 5-point response scale. The other two items measured what happened after taking the medicine and how the perceived amount of liquid taken with the medicine was. Responses to these 3 items were combined and converted into a single palatability score using a scoring matrix: each combination of responses on each of 3 items corresponded to a predefined palatability score. E.g. if a participant responded bad to item 1, vomited <30min to item 2 and not enough to item 3, then the palatability score assigned was 0. This score ranged from 0 to 11; higher scores indicated better palatability. For participants <10 years old, an observer palatability questionnaire was administered. Items and scoring algorithm were the same as for participants ≥10 years old. Change in palatability score over time was assessed | Week 4, 24, 28 and 48 | 
| Change From Baseline in Adherence Domain Score of Modified Satisfaction With Iron Chelation (mSICT) Questionnaire | The mSICT patient reported outcome (PRO) consisted of 15 items that represented 3 domains: Adherence, Preference, and Concerns. The adherence domain score consisted of 6 adherence items, measured using a 5-point response scale. The adherence score was calculated by summing these 6 items, with scores ranging from 6 to 30. Higher scores indicated worse adherence. For participants <10 years old, an observer version (ObsRO) was administered. The adherence score remained the same as for participants ≥10 years old. | Baseline (week 2 or, if missing, week 3), week 24, 28 and 48 | 
| Change From Baseline in Preference Domain Score of Modified Satisfaction With Iron Chelation (mSICT) Questionnaire | The mSICT patient reported outcome (PRO) consisted of 15 items that represented 3 domains: Adherence, Preference, and Concerns. The preference/satisfaction domain score consisted of 2 preference/satisfaction items, measured using a 5-point response scale. The preference score was calculated by summing these 2 items, with scores ranging from 2 to 10. Higher scores indicated worse satisfaction. For participants < 10 years old, an observer version (ObsRO) was administered. Preference score remained the same as for participants ≥ 10 years old. | Baseline (week 2 or, if missing, week 3), week 24, 28 and 48 | 
| Change From Baseline in Concerns Domain Score of Modified Satisfaction With Iron Chelation (mSICT) Questionnaire | The mSICT patient reported outcome (PRO) consisted of 15 items that represented 3 domains: Adherence, Preference, and Concerns. The concerns domain score consisted of 3 items to address any concerns or worries with the medication. All 3 items were measured on a 5-point response scale. The concerns score was calculated by summing the 3 items, with scores ranging from 3 to 15. Higher scores indicated fewer concerns. For participants < 10 years old, an observer version (ObsRO) was administered. Concerns score remained the same as for participants ≥ 10 years old. | Baseline (week 2 or, if missing, week 3), week 24, 28 and 48 | 
| Change From Baseline in Gastrointestinal (GI) Symptom Score Based on GI Questionnaire | The GI symptom score was calculated from responses to 5 questions of the GI questionnaire, each with a possible score of 1 to 5, for an overall possible score range of 5 to 25, where a lower score represents a less severe GI symptom and a higher score represents a more severe GI symptom. An observer GI symptom questionnaire was administered to those patients who were < 10 years old. The questionnaire was completed by the parents of the participants. All items and the scoring algorithm remained the same as for participants ≥ 10 years old. | Baseline (week -1 or, if missing, week -2), week 24, 28 and 48 | 
| Change From Baseline in Serum Ferritin Levels | Absolute change from baseline over time in serum ferritin levels | From Baseline (Day 1) up to 96 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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thalassemia, TDT, transfusion-dependent, non-transfusion-dependent, NTDT