Phase II Study to Investigate the Benefits of an Improved Deferasirox Formulation (Film-coated Tablet)

Study Overview
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Brief Summary
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Assessed the new film-coated tablet formulation to the currently approved dispersible tablet formulation with regards to overall safety, Gastrointestinal (GI) tolerability, palatability, satisfaction and compliance

Official Title
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A Randomized, Open-label, Multicenter, Two Arm, Phase II Study to Investigate the Benefits of an Improved Deferasirox Formulation (Film-coated Tablet)

Conditions
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Chronic Iron Overload Due to Transfusion-dependant Anemias

Intervention / Treatment
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* Drug: Deferasirox dispersible tablet
* Drug: Defearisox film-coated tablet


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Male and female patients aged ≥ 10 years Patients with transfusion-dependent thalassemia and iron overload, requiring deferasirox DT at doses of ≥ 30 mg/kg/day as per the investigator's decision OR Patients with very low, low or intermediate (int) risk myelodysplastic syndrome (MDS) and iron overload, requiring deferasirox DT at doses of ≥ 20 mg/kg/day as per the investigator's decision. History of transfusion of at least 20 PRBC units and anticipated to be transfused with at least 8 units of PRBCs annually during the study Serum ferritin > 1000 ng/mL, measured at screening Visit 1 and screening Visit 2 (the mean value will be used for eligibility criteria). Key Exclusion Criteria: Creatinine clearance below the contraindication limit in the locally approved prescribing information. Creatinine clearance will be estimated from serum creatinine at screening Visit 1 and screening Visit 2 and the mean value will be used for eligibility criteria. Serum creatinine > 1.5 xULN at screening measured at screening Visit 1 and screening Visit 2 (the mean value will be used for eligibility criteria). ALT (SGPT) > 5xULN, unless LIC confirmed as >10 mg Fe/dw within 6 months prior to screening visit 1. Significant proteinuria as indicated by a urinary protein/creatinine ratio > 0.5 mg/mg in a non-first void 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). Liver disease with severity of Child-Pugh Class B or C

Ages Eligible for Study
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Minimum Age: 10 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Deferasirox dispersible tablet (DFX-DT)<br>Iron chelation naïve participants received DFX-DT 20 mg/kg/day once daily orally from weeks 1 - 4. After week 4, the dose could be adjusted by +/- 5 to 10 mg/kg/day, with a maximum dose of 40 mg/kg/day. Iron chelation pre-treated participants were supposed to start on a dose that was equivalent to their pre-washout dose. | Drug: Deferasirox dispersible tablet<br>* Deferasirox DT was provided as 125 mg, 250 mg and 500 mg dispersible tablets for oral use.<br>* Other names: ICL670, DT (dispersible tablet);|
| Experimental: Deferasirox film-coated tablet (DFX-FCT)<br>Participants received DFX-FCT 14 mg/kg/day once daily orally from weeks 1 - 4. After week 4, the dose could be adjusted by +/- 3.5 to 7 mg/kg/day, with a maximum dose of 28 mg/kg/day. Iron chelation pre-treated participants were supposed to start on a dose that was equivalent to their pre-washout dose | Drug: Defearisox film-coated tablet<br>* Deferasirox FCT was provided as 90 mg, 180 mg and 360 mg film-coated tablets for oral use.<br>* Other names: ICL670, FCT (film-coated tablet);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Safety as Measured by Frequency of Adverse Events | The percentage of participants with adverse events, serious adverse events and deaths was assessed. | 28 weeks | 
| Overall Safety as Measured by Changes in Laboratory Values From Baseline | The percentage of participants with post-baseline laboratory values meeting specified criteria for notable/extended range was assessed. The following laboratory parameters were measured: platelet count, absolute neutrophils, serum creatinine , creatinine clearance, urinary protein/urinary creatinine ratio, alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Note that within data categories, creat = creatinine, cons = consecutive, ULN = upper limit of normal and urin = urinary. | baseline (BL), 30 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of Selected Gastro-intestinal (GI) Adverse Events | The percentage of participants with any GI adverse event, diarrhea, constipation, nausea, vomiting, abdominal pain was assessed. | 28 weeks | 
| Mean Domain Scores of the Modified Satisfaction With Iron Chelation Therapy (Modified SICT) | The modified SICT consisted of 13 items that represent 3 domains: adherence, satisfaction and concerns. The adherence domain consisted of 7 items, 6 which were measured using a 5-point response scale and was calculated by summing the 6 items. The score range from 6 to 30 and higher scores indicated worse adherence. The satisfaction domain consisted of 3 items, 2 which were measured using a 5-point response scale and was calculated by summing the 2 items. The score range from 2 to 10 and higher scores indicated worse satisfaction. The concerns domain consisted of 3 items to address any concerns or worries with his/her medication. All 3 items were measured on a 5-point response scale and were calculated by summing the 3 items. The score range from 3 to 15 and higher scores indicated fewer concerns. For all three domains, the meaningful difference between two treatment arms was determined to be 1 point. | weeks 2, 3, 13 and 24 (end of treatment or within 7 days of last dose) | 
| Palatability Questionnaire Score | The palatability questionnaire consisted of 4 items. The first item measured the taste and aftertaste of the medication and were scored a on a 5-point response scale. The second item offered an additional response option of no aftertaste. The last 2 items referred to whether the medication was taken, i.e. swallowed or vomited, and how the participant perceived the amount of medication to be taken. The palatability summary score was calculated using a scoring matrix from items 1, 3 and 4 scores and the score ranges from 0 - 11. Higher scores indicated the best palatability. A meaningful difference between two treatment arms was determined to be 1 point. | weeks 2, 3, 13 and 24 (end of treatment or within 7 days of last dose) | 
| Weekly Average of Daily Scores of the Gastrointestinal (GI) Symptom Diary | The GI symptom diary consisted of 6 items, five which were scored using a 0 - 10 rating scale with item appropriate anchors to rate the symptom, for example, Pain in your belly: 0 = no pain and 10 = worst pain. The GI diary summary score was created using the 10 point response scale for the 5 items. The GI symptom daily diary had a minimum score of 0 and a maximum score of 50. The weekly average score for the 7 days was calculated for each individual item and the GI summary score was created from these weekly averages. Higher scores indicated worse symptoms. A meaningful difference between two treatment arms was determined to be 0.3 point. | weeks -1, 4, 8, 12, 16, 20, 24 | 
| Number of Participants With Weekly Average Compliance of Medication Consumption | A compliance questionnaire assessed whether the medication was taken. Weekly average compliance was calculated when there were at least four non-missing daily responses. | Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 | 
| Weekly Dose Violation Rate | The dose violation is defined as a dose either missed completely or not taken in accordance with the timing instruction (no later than 12:00 pm. The rate was calculated as [number of dose violations/drug exposure (days)] x 100. | weeks 1, 4, 8, 12, 16, 20, 24 | 
| Area Under the Plasma Concentration-time Curve From Time Zero to the Last Quantifiable Concentration (AUClast) | Blood samples were collected to assess AUClast. | week 1, day 1: pre-dose (0 hour) and 1, 2, 3, 4, 8 and 24 hours post dose; week 3, day 1: pre-dose (0 hour) and 1, 2, 3, 4, 8 and 24 hours post dose | 
| Observed Maximum Plasma Concentration Following Drug Administration (Cmax) | Blood samples were collected to assess Cmax. | week 1, day 1: pre-dose (0 hour) and 1, 2, 3, 4, 8 and 24 hours post dose; week 3, day 1: pre-dose (0 hour) and 1, 2, 3, 4, 8 and 24 hours post dose | 
| Time to Reach the Maximum Plasma Concentration After Drug Administration (Tmax) | Blood samples were collected to assess Tmax. | week 1, day 1: pre-dose (0 hour) and 1, 2, 3, 4, 8 and 24 hours post dose; week 3, day 1: pre-dose (0 hour) and 1, 2, 3, 4, 8 and 24 hours post dose | 
| Dererasirox Plasma Concentration | Blood samples were collected to assess deferasirox concentration. Dose-adjusted calculations are presented: (concentration/actual dose)*20 for participants on DFX-DT and (concentration/actual dose)*14 for participants on DFX-FCT. | Week 3, day 1, pre-dose (0 hour (h)) and 2 h post-dose; week 13, day 1, pre-dose (0 hour (h)) and 2 h post-dose; and week 21, day 1, pre-dose (0 hour (h)) and 2 h post-dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Iron overload, Chelation, Thalassemia, Myelodysplastic syndrome (MDS), Transfusional hemisiderosis, Deferasirox, ICL670, Dispersible tablet, Film-coated tablet