E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
transfusional haemosiderosis |
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E.1.1.1 | Medical condition in easily understood language |
iron overload due to multiple blood transfusions |
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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 | PT |
E.1.2 | Classification code | 10019024 |
E.1.2 | Term | Haemosiderosis |
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 |
To compare the gastrointestinal (GI) tolerability of deferasirox administered before and after meals in patients with iron overload due to multiple blood transfusions, on established deferasirox therapy. The primary endpoint is the difference in mean individual Gastrointestinal Quality of Life Index (GIQLI)score change from baseline to end of study in the before-meals arm versus after-meals arm. |
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E.2.2 | Secondary objectives of the trial |
1) To describe the gastrointestinal tolerability of deferasirox administered before and after meals in patients with transfusional iron overload naive to deferasirox therapy. The secondary endpoint is the difference in mean individual GIQLI score change from baseline to 1 month and 2 months of before meal versus after meal deferasirox administration. 2) To compare steady state pharmacokinetics profile characteristics (AUCss, Cmax ss, Cmin ss) following 1 month of deferasirox administered either before or after meals in a crossover design in patients with established deferasirox therapy. where AUCss is Area Under the Curve at steady state (a measure of bioavailability of drug and drug clearance) Cmax ss is the maximum concentration of drug at steady state Cmin ss is the minimum concentration of drug at steady state Exploratory: 1) To investigate the relationship between plasma level of the iron-drug complex and plasma iron parameters. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Adults 18 years and over Ability to provide informed consent Ability to meet all study requirements Adequate renal function (e.g. creatinine clearance≥ 60ml/min), Wllingness to stop other iron chelation therapy, No known allergies to the drug Not pregnant or breast feeding and willing to use effective contraception For non-naive cohort: male or female participants with transfusional iron overload as defined by a minimum of 20 lifetime transfusion episodes and transfusional iron loading with ferritin levels >500 mcg/L and/or liver iron concentration >3 mg of iron/g dry weight (as previously demonstrated by liver biopsy or MRI prior to the study); established on deferasirox therapy for at least 1 year and suffering GI side effects believed to be related to their therapy as suggested by at least one of the following: - The temporal relationship of gastrointestinal side effects occurrence with the administration of deferasirox …. |
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E.4 | Principal exclusion criteria |
Patients with gastrointestinal symptoms assumed or known NOT to be caused by deferasirox. Patients who are treated for any condition with aspirin daily, patients under chronic steroid therapy and patients on anticoagulant therapy that could all lead to potential gastrointestinal symptoms/bleeding. Presence of gastrointestinal disease that may significantly alter the absorption of deferasirox (e.g. ulcerative diseases, uncontrolled nausea, vomiting, diarrhoea, malabsorption syndrome, gastrointestinal or rectal bleeding). History of gastrointestinal surgery (except appendicitis and cholecystectomy) e.g. stomach/bowel surgery or awaiting elective surgery in the next 2 months. Undergoing acute medical intervention or hospitalization. Psychiatric illness (schizophrenia, major depression) which may interfere with study requirements Any other medical condition that, in the opinion of the site investigator would interfere with completing the study (visual problems or cognitive impairment. Platelet count less than 100 000 Currently on treatment for Hepatitis C Patients with severe iron loading in the heart (T2* less than 10 ms) and/or patients with severe total body iron load (liver iron concentration over 30 mg/g dry weight) Patients who have historical evidence of severe iron loading in the heart Women of child-bearing potential who are planning a pregnancy, pregnant, lactating and unwilling to use effective means of contraception. Inadequate renal function (e.g. Creatinine clearance < 60ml/min) Patients unwilling to stop using other iron chelation therapy for the trial duration Known allergy to the drug Patients on aluminium containing antacid preparations Patients who are on Vitamin C at doses higher than 200mg/day Patients receiving or having received any investigational drug within 30 days prior to study enrolment Patients unable to understand oral or written English |
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary endpoint is the between-treatment arm-difference of the mean individual change of Gastrointestinal Quality of Life Index(GIQLI) (follow-up minus baseline) in the non-naive cohort (patients on established deferasirox therapy). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Four weeks after treatment 1 in the non-naive cohort Four weeks after crossover day 1 in the non-naive cohort |
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E.5.2 | Secondary end point(s) |
1) Difference between mean follow-up ( 1 month and 2 months) vs baseline changes of GIQLI per arm in naive cohort 2) Difference of the mean GSRS score changes in both arms of the established cohort and the naive cohort 3) Difference of the mean SF-36 score changes in both arms of the established cohort and the naive cohort 4) Arm difference of geometric mean steady state Cmin at visit 3 and visit 4 in the cross-over group 5) Arm difference of geometric mean AUC and Cmax at Visit 3 and visit 4 in cross-over group 6) Arm difference of geometric mean steady-state Cmin at Visit 3 for all patients (after 1 month of treatment) 7)Effect of food on systemic exposure of deferasirox as assessed by Pharmacokinetics approach. Pooled PK data from all arms will be analysed with a population PK model and appropriate covariates will be examined for clinical and statistical relevance. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
4 weeks and 8 weeks after treatment day 1 |
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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 | No |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | Yes |
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) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
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 | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
Partial parallel and Partial Cross over |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
pre-prandial and post-prandial IMP administration |
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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
| 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 | 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 trial will end 4 weeks after the last visit of the last patient enrolled in the study. This is because patients will be followed up at 28 days from the last visit which was also the day of the last dose of IMP administered on study. |
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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 | 1 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 29 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
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 | 29 |