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

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.

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