E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Transfusional iron overload |
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E.1.1.1 | Medical condition in easily understood language |
iron overload in the body |
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E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10019613 |
E.1.2 | Term | Hemosiderosis |
E.1.2 | System Organ Class | 10027433 - Metabolism and nutrition disorders |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective is to compare deferasirox to placebo with regard to event-free survival (a composite primary endpoint including death and non-fatal events related to cardiac and liver function and transformation to AML) in low and int-1 risk MDS patients with transfusional iron overload. |
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E.2.2 | Secondary objectives of the trial |
The key secondary objective is to compare overall survival. Other secondary objectives are:
• Change in endocrine function (thyroid and glycemic control)
• Change in hematological function (MDS progression, progression to AML, and transfusion requirements
• Change in serum ferritin level
• Change in cardiac function
• Safety, in particular to assess the levels of increased risk for pre-specified adverse events that would be clinically unacceptable in the context of the level of benefit that is likely to be provided by iron chelation using deferasirox in MDS patients with iron overload
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
-Male or female patients, ≥18 years of age
-Patient must weigh between 35-135 kg
-Patients with low or intermediate (int-1) risk MDS, as determined by IPSS score. This must be confirmed by a bone marrow examination within 6 months prior to study entry and must be hematologically stable
-Ferritin > 1000 mcg/L at screening
-History of transfusion of 15 to 75 PRBC units
-Anticipated to be transfused with at least 8 units of PRBCs annually during the study |
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E.4 | Principal exclusion criteria |
-More than 6 months of cumulative iron chelation therapy (such as daily deferasirox (Exjade®) or deferiprone or 5x/week deferoxamine)
- Intermittent deferoxamine doses in association with blood transfusions are not exclusionary regardless of duration of such treatment.
-More than 3 years since patient began receiving regular transfusions (2 units per 8 weeks or 4 units received in a 3 month period)
-Creatinine clearance <40 mL/min
-Serum creatinine > 1.5 x ULN at screening
- Serum creatinine will be measured at Screening Visit 1 and Screening Visit 2 and the mean value will be used for eligibility criteria.
-Significant proteinuria as indicated by a urinary protein/creatinine ratio > 0.5 mg/mg in a non-first void urine sample at Visit 1 or Visit 2 (or alternatively in two of three samples obtained for screening)
-ECOG performance status > 2
-Left ventricular ejection fraction < 50% by echocardiography as per the central reading assessment
-A history of hospitalization for congestive heart failure
-Systemic diseases which would prevent study treatment (e.g. uncontrolled hypertension, cardiovascular, renal, hepatic, metabolic, etc.)
-Clinical or laboratory evidence of active Hepatitis B or Hepatitis C (HBsAg in the absence of HBsAb OR HCV Ab positive with HCV RNA)
-History of HIV positive test result (ELISA or Western blot)
-Treatment with systemic investigational drug within 4 weeks or topical investigational drug within 7 days of study start
-ALT or AST > 3.5×ULN at screening
-Total bilirubin > 1.5× ULN at screening
-Diagnosis of liver cirrhosis (either established diagnosis or diagnosis by liver biopsy or central ultrasound reading)
-Patients participating in another clinical trial other than an observational registry study
-Patients with a history of another malignancy within the past five years, with the exception of basal cell skin carcinoma or cervical carcinoma in situ or completely resected colonic polyps carcinoma in situ
-History of non-compliance to medical regimens, or patients who are considered potentially unreliable and/or not cooperative
-Presence of a surgical or medical condition which might significantly alter the absorption, distribution, metabolism or excretion of study drug
-Pregnant, intending-to-become pregnant, or breast-feeding patients
-History of drug or alcohol abuse within the 12 months prior to enrollment. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Composite primary endpoint (event-free survival) defined as time from date of randomization to either death or any of the following non-fatal events:
1. Echocardiographic evidence of worsening cardiac function
2. Hospitalization for congestive heart failure
3. Liver function impairment
4. Liver cirrhosis
5. Progression to Acute Myeloid Leukemia (AML) confirmed by bone marrow biopsy |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
From date of randomization to date of death or any of the predefined nonfatal events has been reached |
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E.5.2 | Secondary end point(s) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 19 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Belgium |
Bulgaria |
Canada |
Denmark |
Greece |
Hong Kong |
Italy |
Malaysia |
Mexico |
Netherlands |
New Zealand |
Poland |
Romania |
Russian Federation |
Switzerland |
Thailand |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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Provided in the protocol (treatment period will continue until 244 events have occurred; follow-up will continue for overall survival) |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 7 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 7 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |