| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Myelodysplastic syndrome, transfusional iron overload |
|
| E.1.1.1 | Medical condition in easily understood language |
| Myelodysplastic syndrome, transfusional iron overload |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10019613 |
| E.1.2 | Term | Hemosiderosis |
| E.1.2 | System Organ Class | 100000004861 |
|
| 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. |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate:
• Hematologic improvement (HI) in terms of erythroid response
• Overall survival
• Change in endocrine function (thyroid and glycemic control)
• Disease progression (which includes MDS progression and progression
to AML)
• Change in serum ferritin level
• Change in cardiac function
• Frequency of infections requiring intravenous antimicrobials
• Safety, in particular to assess the levels of increased risk for prespecified
adverse events (renal dysfunction, neutropenia,
thrombocytopenia, gastrointestinal bleeding, and laboratory
abnormalities) 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 (see Fleming 2008 for
general approach). |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Male or female , ≥18 years of age, 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.
• Weight between 35-135 kg
• 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. Sexually active pre-menopausal female patients must use double-barrier contraception, oral contraceptive plus barrier contraceptive, or must have undergone clinically documented total hysterectomy and/or oophorectomy, tubal ligation
Additional inclusion criteria as per full protocol may apply. |
|
| E.4 | Principal exclusion criteria |
• More than 6 months of cumulative iron chelation therapy (such as daily
deferasirox (Exjade®) or deferiprone or 5×/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 × ULN at screening
- Serum creatinine will be measured at Screening Visit 1 and Screening
Visit 2 (at least 14 days apart) 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 (including
Child-Pugh Class B and C), 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
positive)
• 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 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, or breast-feeding patients, or patients of child-bearing
potential not employing an effective method of birth control (see Women
of child-bearing potential, below, for further details regarding effective
methods of birth control).
• History of drug or alcohol abuse within the 12 months prior to
enrollment
Additional exclusion criteria as per full protocol may apply. |
|
| 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) |
|
| E.5.2 | Secondary end point(s) |
Main secondary endpoints include:
• Proportion of patients with hematologic improvement in terms of
erythroid response
• Overall survival
• Proportion of patients with hypothyroidism
• Proportion of patients with worsening of glucose metabolism
• Disease progression
• Time to first occurrence of serum ferritin > 2 times the baseline value
• Time to at least a 10% increase from baseline in LVIDD
• Time to at least a 10% increase from baseline in LVISD
• Infections |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
• baseline at D1, bi-weekly during the 1st month, then every 4 w
thereafter until End of Treatment (up to 5 y)
• baseline at D1, bi-weekly during the 1st month, then every 4 w
thereafter until EoT (up to 5 y)
• annually
• annually
• baseline at D1, bi-weekly during the 1st month, then every 4 w
thereafter until EoT (up to 5 y)
• baseline at D1, bi-weekly during the 1st month, then every 4 w
thereafter until EoT (up to 5 y)
• baseline at D1, bi-weekly during the 1st month, then every 4 w
thereafter until EoT (up to 5 y)
• baseline at D1, bi-weekly during the 1st month, then every 4 w
thereafter until EoT (up to 5 y)
• baseline at D1, bi-weekly during the 1st month, then every 4 w
thereafter until EoT (up to 5 y) |
|
| 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) | Yes |
| 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.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| 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 | Information not present in EudraCT |
| 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 |
|
| 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
|
| Provided in the protocol (treatment period will continue until 244 events have occurred; follow-up will continue for overall survival) |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 8 |
| 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 | 8 |
| 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 |
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