E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Iron overload in patients being treated for Myelodysplastic syndroms (MDS) by regular blood transfusions |
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E.1.1.1 | Medical condition in easily understood language |
Iron accumulation in patients being treated by regular blood transfusions for a range of conditions in which the bone marrow produces abnormal cells that function poorly(Myelodysplastic syndromes). |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
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 | 10068361 |
E.1.2 | Term | MDS |
E.1.2 | System Organ Class | 100000004864 |
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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 | 10040310 |
E.1.2 | Term | Serum iron increased |
E.1.2 | System Organ Class | 100000004848 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary aim of this study is to assess the activity of the study drug by measuring how long it takes for the levels of iron in the blood to rise to over 1500μg/l (a level associated with a poor prognosis and organ damage) when treated with Deferasirox. |
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E.2.2 | Secondary objectives of the trial |
The secondary aims are to assess the proportion of patients who reach the the 1500μg/l during the 12 months of treatment, the Safety and tolerability of the drug in this population of patients, by collecting data on side effects, as well as measuring the proportion of patients maintaining a serum ferritin level in their blood of less than 1500 μg/l. We will also be measuring the cardiac and hepatic iron loading by MRI scan, in patients willing to undergo imaging, to see if the heart and liver stores of iron have increased during the study as wells as measuring the patients endocrine function to see if this has been altered during treatment. All patients will also be asked to provide blood samples for Biochemical iron parameter tests to look and different iron related proteins in the blood and how they change during treatment. We will be collecting data to measure the proportion of patient achieving a Haematological response, the time to this response and the duration of this respo |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
MRI T* scans will be optional and will therefore be classed as a sub-study. We will be measuring the cardiac and hepatic iron loading by MRI scan, in patients willing to undergo imaging, to see if the heart and liver stores of iron have increased during the study as wells as measuring the patients endocrine function to see if this has been altered during treatment. |
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E.3 | Principal inclusion criteria |
• At least 18 years old. • Written informed consent. • MDS with: o Baseline haemoglobin concentration < 11 g/dl and clinically requiring red cell transfusion with a frequency of at least 2 units every 6 weeks for the receding 12 week period. o Serum ferritin >300μg/l but <1000 μg/l in absence of ongoing inflammation (CRP < 3 x ULN) o Serum creatinine <1.2 x ULN and/or creatinine clearance > 40 mls/min o ALT or AST < 2.5 ULN o IPSS Low/INT-1 previously untreated or having failed a therapeutic trial of erythropoetic stimulating agents (ESA) or other active MDS drug therapy, or alternatively lost their response to such therapy o IPSS INT-2 with < 10% blasts and lacking a complex karyotype or monosomy 7 (and with stable blood counts from diagnosis to study entry).
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E.4 | Principal exclusion criteria |
• Active treatment for MDS, including erythropoetic stimulating agents (ESA), 5-azacitidine, antilymphocyte globulin and low dose chemotherapy such as cytarabine during the trial and within the last 8 weeks • Life expectancy of less than 1 year • Known HIV positive • Active infection • Use of prior investigational agents within 6 weeks • Pregnancy or lactation •Other severe, concurrent medical illness that may affect the patients participation in the study, or psychiatric disorders • Concurrent active or previous malignancy, within the last 3 years, – except controlled, localised prostate cancer on hormone therapy or basal cell carcinoma or cervical carcinoma in situ or completely resected colonic polyps carcinoma in situ • Ongoing inflammation as measured by CRP > 3 x ULN • Serum creatinine >1.2 x ULN and/or creatinine clearance < 40 mls/min • ALT or AST >2.5 ULN • History of drug/alcohol abuse or non-compliance
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E.5 End points |
E.5.1 | Primary end point(s) |
The Primary outcome is Time to mean serum Ferritin > 1500 μg/l, as measured from the time of initiation using the mean serum Ferritin value of 2 consecutive measurements of Ferritin, where the first level is >1500 μg/l and CRP is < 3 times baseline measurement.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary activity outcome measures will be assessed in the full analysis set which includes all patients who have taken at least 1 dose of study drug and have at least one assessment of ferritin level. Analysis will occur when all patients have completed 12months of treatment or discontinued. Patients not reaching mean ferritin level greater than 1500 μg/l at the time of analysis will be censored at the last response assessment. In cases where the second serum ferritin level is not available and the first level is > 1500 μg/l, the first level is used and an event is assumed to have occurred. |
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E.5.2 | Secondary end point(s) |
- Proportion of patients with mean serum Ferritin, of 2 consecutive measurements of Ferritin, >1500 μg/l within 12 months, where the first level is >1500 μg/l and CRP is < 3 times baseline measurement. - Safety and tolerability is defined in terms of the following events deemed to be related to Deferasirox and graded according to the CTCAE Criteria, version 4: a) Grade 3/4 non-haematological toxicity that does not resolve to ≤ Grade 2 within 4 weeks of deferasirox withdrawal, b) unexpected Grade 3/4 non-haematological toxicity, c) ≥Grade 2 auditory or ocular abnormalities associated with chelation therapy. - Proportion of patients maintaining serum ferritin <1500 μg/l at 12 months - Cardiac and hepatic iron loading quantified by MRI R2 and T2* is defined as the mean change in iron concentration pre-treatment and at 12 months or when serum Ferritin levels exceed 2000 μg/l. This will be available for patients treated within a centre offering iron quantitation by MRI, or willing to travel. - Endocrine function is defined as the mean change in the following parameters pre-treatment and at 12 months; diabetes (HbA1c), thyroid (as measured by serum thyroid hormone concentration), sex hormones (measured by serum FSH, LH, testosterone) and adrenal (measured by cortisol). - Proportion of patients achieving hematologic response per IWG2006 criteria - Time to haematological response per IWG2006 criteria - Duration of haematological response per IWG2006 criteria - Biochemical iron parameters including transferrin saturation, hepcidin, non-transferrin bound iron and GDF15 as measure by the central laboratory at UCL. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
The safety outcome measures will be assessed using the safety analysis set. Toxicity will be assessed continuously throughout the study according to CTC version 4. In addition, a three stage design (each of 18 patients) has been planned which incorporates formal early stopping guidelines that meet the error rate criterion of alpha of 0.1 and beta of 0.2 to assess tolerability of treatment (Section 12.4. All other analyses will occur when all patients have completed 12months of treatment or discontinued. |
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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 | No |
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) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
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) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
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 | 16 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
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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The end of trial will be 6 months after the last data capture. This will allow sufficient time for the completion of protocol procedures, data collection and data input. The Trials Office will notify the MHRA and main REC that the trial has ended and will provide them with a summary of the clinical trial report within 12 months of the end of trial. |
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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 | 3 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |