E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Iron overload (secondary hemochromatosis) in non-transfusion dependent forms of hereditary anemias. Iron overload and hereditary anemia are a growing, underestimated emerging health care problem. |
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E.1.1.1 | Medical condition in easily understood language |
Iron overload in patients with a form of hereditary anemia not requiring 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 | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10002272 |
E.1.2 | Term | Anemia |
E.1.2 | System Organ Class | 100000004851 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10057875 |
E.1.2 | Term | Secondary haemochromatosis |
E.1.2 | System Organ Class | 100000004861 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | HLT |
E.1.2 | Classification code | 10022979 |
E.1.2 | Term | Iron excess |
E.1.2 | System Organ Class | 100000004861 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10055610 |
E.1.2 | Term | Hemoglobinopathy |
E.1.2 | System Organ Class | 100000004850 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10074356 |
E.1.2 | Term | Non-transfusion dependent thalassemia |
E.1.2 | System Organ Class | 100000004850 |
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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 |
To show that PPIs compared to placebo are an effective treatment of secondary hemochromatosis in a relative large number of patients with hereditary anemia and mild iron overload. |
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E.2.2 | Secondary objectives of the trial |
To assess the safety and side effects of treatment with esomeprazole. To assess quality of life during treatment with esomeprazole compared with placebo. To evaluate cost-effectiveness of esomeprazole in treatment of iron overload in hereditary anemia. To assess the changes in ‘iron markers’ during treatment with esomeprazole compared with placebo. To assess the need for chelation therapy after one year of treatment with esomeprazole compared with placebo. To assess the adherence to therapy in a real life setting.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
o Diagnosis of hereditary anemia: hemoglobinopathy (including all sickle cell syndromes and beta-thalassemia), sideroblastic anemia, congenital dyserythropoietic anemia or an erythrocyte enzyme deficiency. o Hemoglobin before study inclusion <7.0 mmol/L o Clinically stable and relevant iron overload defined as either one of: - a baseline LIC measurement by MRI between 3 and 15 mg Fe/g without having received iron chelation 2 months prior to entering the study. - OR a baseline LIC measurement by MRI between 3 and 15 mg Fe/g on stable chelation therapy (deferasirox, deferoxamine or deferiprone), with documented stable dosage the preceding 2 months and no expected dose reductions or increases the next two years. o Aged more than 18 years and able to sign informed consent. o Serum transferrin saturation higher than 0.40 once during the preceding 24 months. o Received less than 10 units of blood during the preceding 12 months. o Is expected to receive less than 4 units fo blood during the following 12 months o Is not splenectomized during the preceding 24 months. |
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E.4 | Principal exclusion criteria |
o Pregnancy. o Liver cirrhosis. o Heart failure. o Severe cardiac iron overload defined as MRI T2* < 20 ms. o Severe liver iron overload defined as MRI LIC > 15 mg Fe/g dw. o Expected poor compliance. o Currently taking PPI and not able to stop for personal or medical reasons. o Patients that are being phlebotomized as treatment for iron overload. o Current peptic ulcer disease, gastro-intestinal bleeding or other causes of blood loss. o Contra-indication for esomeprazole use. o Concomitant use of clopidogrel. o Contra-indication for MRI. o Received more than 4 units blood during one of the treatment periods of 12 months. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The main endpoint of this study, is the change in LIC from baseline (start of treatment) to 12 months measured by MRI of the liver. This endpoint will be used in the primary analysis to compare treatment with esomeprazole to treatment with placebo. The LIC will be expressed in mg Fe/g dw after data analysis of the T2* and T1 images of the MRI. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
MRI 1: baseline. The maximum time interval between start of study medication and the baseline MRI will be 14 days. MRI 2: after the first treatment year (T=12 months). The maximum time interval between the cross-over point and the MRI will be 7 days. MRI 3: after the second treatment year (T=24 months). The maximum time interval between the end of study treatment and the MRI will be 7 days.
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E.5.2 | Secondary end point(s) |
1. Tolerability of esomeprazole: the incidence of side effect / adverse events will be monitored every 3 months during study visits. Measurement of vitamin B12, zinc and magnesium, T0, T12 and T24. Report of airway infections. 2. Quality of life: this will be assessed with EQ5D-forms, with time intervals of 3 months. 3. Cost-effectiveness analysis of esomeprazole in treatment of iron overload in hereditary anemia. This will be assessed by a prospective cost-effectiveness analysis. IMCQ and iPCQ questionnaires will be filled in with time intervals of 3 months. 4. Related changes in markers of iron metabolism: a. Plasma hepcidin T0. b. Serum ferritin T0, T12, T24. 5. Compliance to study drug a. Plasma gastrin T0, T6, T12, T18, T24. b. Counting of the capsules. 6. Need for chelation therapy |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Timepoints outlined in E.5.5. T0 = start of stdy. T6 = 6 months after start first treatment period. T12 = 12 months after start first treatment period. |
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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 | Yes |
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 | No |
E.8.1.6 | Cross over | Yes |
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
| 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 | 3 |
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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Last visit of the last subject undergoing the trial. The last visit is planned after the second treatment period of 12 months. |
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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 | |
E.8.9.1 | In the Member State concerned days | |