Trial Outcomes & Findings for Myelodysplastic Syndromes (MDS) Event Free Survival With Iron Chelation Therapy Study (NCT NCT00940602)

Last Updated: 2020-11-23

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

225 participants

Primary outcome timeframe

Day 1 to end of treatment period, approx. 7 years

Results posted on

2020-11-23

Participant Flow

1 patient rand. to deferasirox arm did not receive study drug \& was excl. from the Safety set. Terminated by Sponsor: Patients who had completed at least 3 years of on-treatment period including 28-day follow-up \& were still on trial when end-of-study definition (3 years after LPFV) was reached \& therefore, the study was terminated as per protocol

The planned sample size of 210 patients randomized in a ratio of 2:1 in favor of deferasirox was based on the feasibility of enrolling the patients and consultations with the Health Authorities.

Participant milestones

Participant milestones
Measure	Deferasirox 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	Placebo 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
Overall Study STARTED	149	76
Overall Study Safety Analysis Set	148	76
Overall Study Full Analysis Set	149	76
Overall Study Treated	148	76
Overall Study Untreated	1	0
Overall Study COMPLETED	0	0
Overall Study NOT COMPLETED	149	76

Reasons for withdrawal

Reasons for withdrawal
Measure	Deferasirox 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	Placebo 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
Overall Study Administrative problems	1	1
Overall Study Patient/guardian decision	13	28
Overall Study Physician Decision	8	5
Overall Study Pregnancy	1	0
Overall Study Protocol Deviation (untreated)	1	0
Overall Study Disease progression	8	2
Overall Study Death	38	19
Overall Study Lost to Follow-up	3	1
Overall Study Patient withdrew consent	26	13
Overall Study Adverse Event	7	2
Overall Study Study terminated by Sponsor = trial was to continue for 3 years from date the last patient enrolled	43	5

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Deferasirox n=149 Participants 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	Placebo n=76 Participants 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	Total n=225 Participants Total of all reporting groups
Age, Continuous	61.2 years STANDARD_DEVIATION 16.13 • n=5 Participants	60.7 years STANDARD_DEVIATION 15.05 • n=7 Participants	61.0 years STANDARD_DEVIATION 15.74 • n=5 Participants
Sex: Female, Male Female	56 Participants n=5 Participants	32 Participants n=7 Participants	88 Participants n=5 Participants
Sex: Female, Male Male	93 Participants n=5 Participants	44 Participants n=7 Participants	137 Participants n=5 Participants
Race/Ethnicity, Customized Hispanic/latino	14 participants n=5 Participants	5 participants n=7 Participants	19 participants n=5 Participants
Race/Ethnicity, Customized Chinese	61 participants n=5 Participants	29 participants n=7 Participants	90 participants n=5 Participants
Race/Ethnicity, Customized Mixed ethnicity	1 participants n=5 Participants	0 participants n=7 Participants	1 participants n=5 Participants
Race/Ethnicity, Customized Other	73 participants n=5 Participants	42 participants n=7 Participants	115 participants n=5 Participants
MDS risk category Low (combined score 0)	41 participants n=5 Participants	21 participants n=7 Participants	62 participants n=5 Participants
MDS risk category Intermediate 1 (combined score 0.5 - 1.0)	108 participants n=5 Participants	55 participants n=7 Participants	163 participants n=5 Participants

PRIMARY outcome

Timeframe: Day 1 to end of treatment period, approx. 7 years

Population: FAS: the FAS comprised all patients to whom study treatment had been assigned by randomization. According to the intention to treat principle, patients were analyzed according to the study treatment and strata they were assigned to during the randomization procedure.

Outcome measures

Outcome measures
Measure	Deferasirox n=149 Participants 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	Placebo n=76 Participants 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
Event-free Survival	1440 days Interval 1167.0 to 1559.0	1091 days Interval 820.0 to 1348.0

SECONDARY outcome

Timeframe: Day 1 to end of treatment period, approx. 7 years

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.

Outcome measures

Outcome measures
Measure	Deferasirox n=149 Participants 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	Placebo n=76 Participants 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
Percentage of Participants With Hematologic Improvement (HI) in Terms of Erythroid Response	39.6 percentage of participants Interval 31.4 to 47.6	27.6 percentage of participants Interval 16.9 to 38.3

SECONDARY outcome

Timeframe: Day 1 to end of treatment period, approx. 7.4 years

Overall survival was calculated as the date of death (irrespective of cause) minus date of randomization plus 1.

Outcome measures

Outcome measures
Measure	Deferasirox n=149 Participants 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	Placebo n=76 Participants 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
Overall Survival	1907 days Interval 1440.0 to NA = Not evaluable as insufficient number of events	1509 days Interval 1095.0 to 1804.0

SECONDARY outcome

Timeframe: Day 1 to end of treatment period, approx. 7 years

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.

Outcome measures

Outcome measures
Measure	Deferasirox n=149 Participants 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	Placebo n=76 Participants 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
Percentage of Participants With Newly Occurring Hypothyroidism Compared to Baseline	5.4 percentage of participants Interval 1.4 to 9.3	3.9 percentage of participants Interval 0.0 to 9.0

SECONDARY outcome

Timeframe: Day 1 to end of treatment period, approx. 7 years

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.

Outcome measures

Outcome measures
Measure	Deferasirox n=149 Participants 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	Placebo n=76 Participants 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
Percentage of Participants With Worsening Glucose Metabolism Compared to Baseline	18.1 percentage of participants Interval 11.6 to 24.6	18.4 percentage of participants Interval 9.0 to 27.8

SECONDARY outcome

Timeframe: Day 1 to end of treatment period, approx. 7 years

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.

Outcome measures

Outcome measures
Measure	Deferasirox n=149 Participants 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	Placebo n=76 Participants 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
Time to Disease Progression	NA days NA = Not evaluable as insufficient number of events	NA days NA = Not evaluable as insufficient number of events

SECONDARY outcome

Timeframe: Day 1 to end of treatment period, approx. 7 years

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.

Outcome measures

Outcome measures
Measure	Deferasirox n=149 Participants 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	Placebo n=76 Participants 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
Time to First Occurrence of Serum Ferritin Level >2 Times the Baseline Value at Two Consecutive Assessments (at Least Two Weeks Apart)	NA days NA = Not evaluable as insufficient number of events	592 days Interval 397.0 to 877.0

SECONDARY outcome

Timeframe: Day 1 to end of treatment period, approx. 7 years

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.

Outcome measures

Outcome measures
Measure	Deferasirox n=149 Participants 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	Placebo n=76 Participants 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
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	NA days Interval 871.0 to NA = Not evaluable as insufficient number of events	NA days Interval 732.0 to NA = Not evaluable as insufficient number of events

SECONDARY outcome

Timeframe: Day 1 to end of treatment period, approx. 7 years

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.

Outcome measures

Outcome measures
Measure	Deferasirox n=149 Participants 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	Placebo n=76 Participants 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
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	1179.0 days Interval 532.0 to NA = Not evaluable as insufficient number of events	NA days Interval 502.0 to NA = Not evaluable as insufficient number of events

SECONDARY outcome

Timeframe: Day 1 to end of treatment period, approx. 7 years

Population: SAS: the safety set included all randomized patients who received at least one dose of study medication. Patients were analyzed according to the study treatment they actually received and the strata they were assigned. No Statistical Analysis was performed

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.

Outcome measures

Outcome measures
Measure	Deferasirox n=148 Participants 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	Placebo n=76 Participants 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
Total Number of Infections Requiring Intravenous Antimicrobials	253 infections	111 infections

SECONDARY outcome

Timeframe: Day 1 to end of treatment period, approx. 7 years

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.

Outcome measures

Outcome measures
Measure	Deferasirox n=148 Participants 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	Placebo n=76 Participants 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
Percentage of Participants With Major Gastrointestinal Bleeding	5.4 percentage of participants Interval 1.4 to 9.4	3.9 percentage of participants Interval 0.0 to 9.0

SECONDARY outcome

Timeframe: Day 1 to end of treatment period, approx. 7 years

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

Outcome measures

Outcome measures
Measure	Deferasirox n=148 Participants 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	Placebo n=76 Participants 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
Percentage of Participants With Significant Renal Dysfunction	0.7 percentage of participants Interval 0.0 to 2.3	0 percentage of participants Interval 0.0 to 0.7

SECONDARY outcome

Timeframe: Day 1 to end of treatment period, approx. 7 years

Moderate or severe neutropenia was defined as neutrophil counts less than 1.0×10E9/L.

Outcome measures

Outcome measures
Measure	Deferasirox n=148 Participants 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	Placebo n=76 Participants 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
Percentage of Participants With Newly Occurring Moderate or Severe Neutropenia	27.7 percentage of participants Interval 20.2 to 35.5	26.3 percentage of participants Interval 15.8 to 36.9

SECONDARY outcome

Timeframe: Day 1 to end of treatment period, approx. 7 years

Severe thrombocytopenia was defined as platelets counts less than 50×10E9/L.

Outcome measures

Outcome measures
Measure	Deferasirox n=148 Participants 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	Placebo n=76 Participants 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
Percentage of Participants With Newly Occurring Severe Thrombocytopenia	10.1 percentage of participants Interval 4.9 to 15.3	19.7 percentage of participants Interval 10.1 to 29.3

SECONDARY outcome

Timeframe: Day 1 to end of treatment period, approx. 7 years

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.

Outcome measures

Outcome measures
Measure	Deferasirox n=148 Participants 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	Placebo n=76 Participants 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
Time to Study Drug Discontinuation Due to an AE or Laboratory Abnormality	NA days Interval 1486.0 to NA = Not evaluable as insufficient number of events	1022 days Interval 904.0 to NA = Not evaluable as insufficient number of events

POST_HOC outcome

Timeframe: 2627 days, approx. 7.4 years

On-treatment deaths were collected from FPFT up to 28 days after study drug discontinuation, for a maximum duration of 2627 days (2599 plus 28 days) (treatment duration ranged from 1 day to 2599 days). Deaths post treatment survival follow up were collected after the on treatment period, up to approx. 7.4 years. Patients who had not experienced any of the non-fatal events from the composite primary endpoint and had not stopped study participation at the time of data cut-off (end of study) were censored.

Outcome measures

Outcome measures
Measure	Deferasirox n=149 Participants 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	Placebo n=76 Participants 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
All Collected Deaths Total deaths	57 Participants	33 Participants
All Collected Deaths Deaths on-treatment	24 Participants	10 Participants
All Collected Deaths Deaths post-treatment survival follow up	33 Participants	23 Participants

Adverse Events

Deferasirox

Serious events: 80 serious events

Other events: 135 other events

Deaths: 24 deaths

Placebo

Serious events: 38 serious events

Other events: 65 other events

Deaths: 10 deaths

All Patients

Serious events: 118 serious events

Other events: 200 other events

Deaths: 34 deaths

Serious adverse events

Other adverse events

Additional Information

Study Director

Novartis Pharmaceuticals

Phone: 862-778-8300

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (ie, data from all sites) in the clinical trial.
Publication restrictions are in place

Restriction type: OTHER