Myelodysplastic Syndromes (MDS) Event Free Survival With Iron Chelation Therapy Study

Study Overview
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Brief Summary
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This was a randomized, double-blind trial to evaluate deferasirox vs placebo in patients with myelodysplastic syndromes (low/int-1 risk) and transfusional iron overload .The trial was conducted in 17 countries, started in 2010 and ended in 2018.

Detailed Description
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This randomized, double blind trial to evaluate deferasirox vs placebo in patients with myelodysplastic syndromes (low/int-1 risk) and transfusional iron overload consisted of four periods, a screening period, a treatment period, a post treatment follow-up period and a survival period. The trial recruitment period lasted until December 2014 and the trial continued for three years from the date the last patient enrolled until February 2018 (last patient last visit date). Screening period: The screening period lasting up to 35 days with two screening visits, at least 14 days apart, used to assess patient eligibility. Eligible patients with low or int-1 risk myelodysplastic syndromes (MDS) with transfusional iron overload were randomized in a 2:1 ratio to deferasirox or placebo respectively. Randomization was also stratified using the International prognostic scoring system of low or int-1 MDS and by geographical region (Asian vs non-Asian countries) since the Asian population has been reported to have a longer survival. The following concomitant medications could be permitted for use while the patient was on study, and information outlining start date(s) and end date(s) of each medication taken were to be recorded on the appropriate eCRF: Erythropoietin (growth factor), G-CSF (growth factor), GM-CSF growth factor), Azacitidine, Thalidomide, Arsenic trioxide, Lenalidomide, Decitabine, Cyclosporine A, Vitamin C supplements (≤ 200 mg/day) Treatment period: The dosing schedule was 10 mg/kg/day (once daily) for the first 2 weeks, followed by 20 mg/kg/day (once daily). After 3 months of treatment at the dose of 20mg/kg/day, the dose could be adjusted by 5 or 10 mg/kg/day up to 40 mg/kg/day based on the serum ferritin response. Placebo matching to each strength of the active deferasirox was utilized to maintain the double-blind trial design. During the treatment period patients returned to the investigational site every four weeks for routine procedures and to monitor safety, efficacy and compliance to treatment. An external Data Monitoring Committee (DMC) monitored patient safety and trial conduct and received a blinded summary of serious adverse events. All suspected endpoint events were reviewed and adjudicated by the Endpoint Adjudication Committee (EAC) to ensure that all events that were reported were judged uniformly using the same criteria. The first confirmed suspected endpoint event for a patient was counted for the trial's composite primary endpoint, event free survival. The composite primary endpoint, event free survival, was defined for a patient as the date randomized to trial treatment to the date of the first documented non-fatal event, related to cardiac and liver function, transformation to AML, or death due to any cause. When a patient had a non-fatal event, related to cardiac and liver function, and transformation to AML, the trial treatment (deferasirox or placebo) was discontinued. After trial treatment was discontinued, a 28 days post treatment safety assessment for AEs and SAEs was completed. Any patient who died during the treatment or 28 day post treatment safety assessment is represented in the all-cause mortality table in the safety section of this result. After trial treatment was discontinued for a patient, their treatment was un-blinded. Subsequent iron chelation treatment was subject to the patient's and investigator's decision. Patients continued to be followed during the post-treatment evaluation or survival follow up period, depending on their choice. For patients who did not meet a non-fatal event, study treatment was continued as long as the patient and the treating physician felt it was in the best interest for the patient or until the trial terminated/completed. There was no un-blinding of the trial treatment for patients who terminated trial treatment without meeting a non-fatal event. Patients continued to be followed during the post-treatment evaluation or survival follow up period, depending on their choice. A patient who discontinued study treatment without meeting a non-fatal component of the composite primary endpoint continued to be evaluated every 3 months. Once a patient stopped study evaluations they were followed for at least every 6 months for overall survival and any iron chelation therapies they are receiving up to the end of study. Post-treatment evaluation period: For patients who had a non-fatal event: After treatment termination, all patients were followed for safety (28 days) and then evaluated with visits every three months if they agreed to move into the post treatment evaluation phase. For patients who did not meet a non-fatal event: After termination of study treatment, if a patient and investigator chose the post-treatment evaluation period, the patient was followed for safety and endpoints at visits occurring every three months. Survival Follow Up period: Subsequent to the post treatment evaluation period, or at the end of treatment period, if a patient and treating physician decided that the patient would not participate in the post treatment evaluation period, the patient was followed every 6 months for overall survival and iron chelation therapies. The end of the study was defined as three years from the date the last patient was enrolled (last patient first visit). The sample size of 210 patients did not provide sufficient power for testing statistical hypotheses. The statistical analysis was revised accordingly to concentrate on evaluating the treatment effect of deferasirox relative to placebo, and the study phase designation was changed from Phase lll to Phase II. Amendment 4 of the study adjusted the sample size, statistical analysis, and duration of the study and added two secondary endpoints: Hematologic improvement (HI) in terms of erythroid response and Frequency and rate of infections requiring intravenous (IV) antimicrobials. Upon approval of the amendment, patients signed a new consent form and continued the appropriate visit schedule.

Official Title
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A Multi-center, Randomized, Double-blind, Placebo-controlled Clinical Trial of Deferasirox in Patients With Myelodysplastic Syndromes (Low/Int-1 Risk) and Transfusional Iron Overload

Conditions
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Myelodysplastic Syndromes

Intervention / Treatment
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* Drug: Deferasirox
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Weigh between 35-135 kilograms Low or int-1 risk MDS Ferritin >1000 micrograms/liter at screening History of transfusion of 15 to 75 Packed Red Blood Cells (PRBC) units Anticipated to be transfused with at least 8 units of PRBCs annually during the study Women of child-bearing potential using effective methods of contraception during dosing of study treatment Exclusion Criteria: More than 6 months of cumulative ICT (such as daily deferasirox (Exjade®) or deferiprone or 5×/week deferoxamine) More than 3 years since patient began receiving regular transfusions (2 units per 8 weeks or 4 units received in a 3 month period) Significant proteinuria History of hospitalization for congestive heart failure; other heart conditions as specified in the protocol Systemic diseases which would prevent study treatment Hepatitis B; Hepatitis C; HIV Liver cirrhosis Pregnant, or breast-feeding patients, or patients of child-bearing potential not employing an effective method of birth control History of drug or alcohol abuse within the 12 months prior to enrollment

Ages Eligible for Study
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Minimum Age: 18 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Deferasirox<br>10 mg/kg/day (once daily) for the first 2 weeks of treatment, followed by 20 mg/kg/day (once daily) from Week 2 to End of Treatment. After 3 months of treatment at 20 mg/kg/day, the dose was allowed to be adjusted by 5 or 10 mg/kg/day up to 40 mg/kg/day based on serum ferritin responses. When a target serum ferritin level was reached (usually between 500 and 1000 µg/L), the dose could be reduced by 50% to maintain the serum ferritin within the target range. | Drug: Deferasirox<br>* Deferasirox provided as 125 mg, 250 mg, and 500 mg dispersible tablets for oral use<br>* Other names: ICL670, Exjade®;|
| Placebo Comparator: Placebo<br>10 mg/kg/day (once daily) for the first 2 weeks of treatment, followed by 20 mg/kg/day (once daily) from Week 2 to End of Treatment. After 3 months of treatment at 20 mg/kg/day, the dose was allowed to be adjusted by 5 or 10 mg/kg/day up to 40 mg/kg/day based on serum ferritin responses. When a target serum ferritin level was reached (usually between 500 and 1000 µg/L), the dose could be reduced by 50% to maintain the serum ferritin within the target range. | Drug: Placebo<br>* Inactive ingredients used as a placebo comparator, provided as 125 mg, 250 mg, and 500 mg dispersible tablets for oral use<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free Survival | Event-free survival was defined as the time from the date of randomization to the date of the first documented non-fatal event (worsening cardiac function, hospitalization for congestive heart failure, liver function impairment, liver cirrhosis, transformation to AML, as defined in the protocol), or death, whichever occurred first. Participants who did not experience a non-fatal event as of the time of data cut-off (end of study), as well as participants who did not experience a non-fatal event and stopped study participation before the data cut-off, were censored as specified in the protocol. | Day 1 to end of treatment period, approx. 7 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Hematologic Improvement (HI) in Terms of Erythroid Response | HI in terms of erythroid responses was assessed based on International Working Group (IWG) criteria, with improvement defined as follows: Hemoglobin increase of ≥ 1.5 g/dL OR Reduction of ≥ 4 RBC transfusions/8 weeks in comparison to pre-treatment values and lasting at least 8 weeks. The last hemoglobin value measured prior to randomization was used as the pre-treatment value. The last available lab assessment date was used as the cut-off date for the analysis. | Day 1 to end of treatment period, approx. 7 years | 
| Overall Survival | Overall survival was calculated as the date of death (irrespective of cause) minus date of randomization plus 1. | Day 1 to end of treatment period, approx. 7.4 years | 
| Percentage of Participants With Newly Occurring Hypothyroidism Compared to Baseline | As assessed by annual measurement of Thyroid Stimulating Hormone (TSH) and free T4. Hypothyroidism was defined as follows and is inclusive of: Primary hypothyroidism: serum TSH >upper limit of normal (ULN) and free T4 <lower limit of normal (LLN); Secondary hypothyroidism: serum TSH <ULN and free T4 <lower limit of normal; Subclinical hypothyroidism: TSH >ULN and a free T4 within normal limits. The last available lab assessment date was used as the cut-off date for the analysis. | Day 1 to end of treatment period, approx. 7 years | 
| Percentage of Participants With Worsening Glucose Metabolism Compared to Baseline | As assessed by an annual glucose tolerance test (OGTT). Worsening glucose metabolism was defined as an increase in glucose metabolism category (normal, impaired glucose metabolism, diabetes mellitus) based on the American Diabetes Association criteria (American Diabetes Association 2009) compared to the baseline result. The last available lab assessment date was used as the cut-off date for the analysis. | Day 1 to end of treatment period, approx. 7 years | 
| Time to Disease Progression | Disease progression was defined as follows: MDS progression: Transition into a higher MDS risk group based on IPSS scoring Progression to AML: 20 percent or more blasts seen in the bone marrow collected by biopsy or aspirate. Disease progression was calculated as follows: Date of diagnosis of MDS progression or date of first diagnosis of AML, minus date of randomization plus 1. Participants who neither experienced MDS progression nor progression to AML were censored at the last contact date. | Day 1 to end of treatment period, approx. 7 years | 
| Time to First Occurrence of Serum Ferritin Level >2 Times the Baseline Value at Two Consecutive Assessments (at Least Two Weeks Apart) | Assessed by blood draw and calculated as follows: Date of first occurrence of serum ferritin >2 times the baseline value at two consecutive assessments (at least two weeks apart), minus date of randomization plus 1. Participants who did not experience such an increase were censored at the last date when serum ferritin was available. | Day 1 to end of treatment period, approx. 7 years | 
| Time to at Least a 10% Increase From Baseline in Left Ventricular End-diastolic Internal (LVIDD) at Two Consecutive Assessments at Least Two Weeks Apart | Assessed by echocardiography and calculated as follows: Date of echocardiography assessment where a minimum of 10% increase of LVIDD first occurred, minus date of randomization plus 1. Participants who did not experience such an increase were censored at the last date when LVIDD was available. | Day 1 to end of treatment period, approx. 7 years | 
| Time to at Least a 10% Increase From Baseline in Left Ventricular Internal Systolic Diameter (LVISD) at Two Consecutive Assessments at Least Two Weeks Apart | Assessed by echocardiography and calculated as follows: Date of echocardiography assessment where a minimum of 10% increase of LVISD first occurred, minus date of randomization plus 1. Participants who did not experience such an increase were censored at the last date when LVISD was available. | Day 1 to end of treatment period, approx. 7 years | 
| Total Number of Infections Requiring Intravenous Antimicrobials | The total number of infections were counted and summarized per treatment group. For this number, one participant can contribute more than one infection event. Infections were determined from the reported AEs with system organ class Infections and infestations and action taken Concomitant medication taken. Antimicrobial therapy was determined from the reported concomitant medications for participants who had an infection AE. The route of administration needed to be specified as intravenous (i.v.). End of treatment period was defined as the treatment period plus 28 days. | Day 1 to end of treatment period, approx. 7 years | 
| Percentage of Participants With Major Gastrointestinal Bleeding | Major gastrointestinal bleeding was defined as an AE that could include one of the following MedDRA preferred terms: gastric hemorrhage, gastrointestinal hemorrhage, small intestinal hemorrhage, esophageal hemorrhage, large intestinal hemorrhage, rectal hemorrhage, melaena, duodenal ulcer hemorrhage, gastric ulcer hemorrhage, peptic ulcer hemorrhage, large intestinal ulcer hemorrhage, esophageal ulcer hemorrhage, and hematochezia. The end of treatment period was defined as the treatment period plus 28 days. | Day 1 to end of treatment period, approx. 7 years | 
| Percentage of Participants With Significant Renal Dysfunction | Significant renal dysfunction was defined as a serum creatinine value ≥ 2 times upper limit of normal (ULN) at two consecutive assessments at least 7 days apart | Day 1 to end of treatment period, approx. 7 years | 
| Percentage of Participants With Newly Occurring Moderate or Severe Neutropenia | Moderate or severe neutropenia was defined as neutrophil counts less than 1.0×10E9/L. | Day 1 to end of treatment period, approx. 7 years | 
| Percentage of Participants With Newly Occurring Severe Thrombocytopenia | Severe thrombocytopenia was defined as platelets counts less than 50×10E9/L. | Day 1 to end of treatment period, approx. 7 years | 
| Time to Study Drug Discontinuation Due to an AE or Laboratory Abnormality | As recorded on the Study Treatment Completion electronic Case Report Form (eCRF), date and reason given.Only participants for whom the reason for stopping study medication was entered as AE or laboratory abnormality were considered. This time to event endpoint was calculated as the date of study drug discontinuation due to an AE or laboratory abnormality minus date of randomization plus 1. Participants who did not discontinue study medication due to an AE or laboratory abnormality were censored at the date of study drug discontinuation. | Day 1 to end of treatment period, approx. 7 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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TELESTO, MDS Study, Myelodysplastic Syndromes, Myelodysplastic Syndromes (low-int-1 risk)