E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Chronic iron overload in patients cardiac iron overload and β thalassemia |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10043389 |
E.1.2 | Term | <Manually entered code. Term in E.1.1> |
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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 evaluate, over the 24 months of study treatment, the efficacy of: 1. Intensive chelation with once a day oral deferasirox (20-40mg/kg/day) plus parenteral infusion of DFO (40 mg/kg/day) for 3-4 days in patients with severe cardiac iron (cardiac T2* ranging from 5 to <10 ms) 2. Once a day oral deferasirox (30-40 mg/kg/day) treatment as monotherapy in patients that have mild/moderate cardiac iron overload.
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E.2.2 | Secondary objectives of the trial |
• To evaluate during the 24 months of study the safety and tolerability of intensive iron chelation with once a day deferasirox in combination with DFO (phase A); and a once a day deferasirox as monotherapy (phase B). • To evaluate the reduction in cardiac iron overload when patients are treated with intensive iron chelation therapy and when the patients transition to deferasirox monotherapy. • To assess the time needed for patients receiving intensive iron chelation therapy, to achieve a cardiac MRI T2* > 10 ms. • To evaluate the improvement in cardiac function during the 24 months of study when patients are treated with intensive iron chelation therapy consisting deferasirox–DFO combination regimen and when the patients transition to deferasirox monotherapy.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Male or female patients with β-thalassemia major, at least 18 years old, having given written consent to participate in the study. • Cardiac MRI T2* value ranging from 5 to <10 ms. • LVEF ≥ 56 % as determined by CMR. • Patients with LIC > 10 mg Fe/g dw will be included in the protocol. Study will evaluate the first 10 patients at 6 months, and if no safety signals are present, patients with LIC>7 mg Fe/g dw will be allowed to be included. • Prior iron chelation treatment with DFO, DFP, DFX or combination DFO-DFP.
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E.4 | Principal exclusion criteria |
•Patients with symptoms of cardiac dysfunction symptoms • Patients with cardiac T2* MRI < 5 or > 10 ms. • Patients not responding to intensive iron chelation therapy regimens such i.v DFO 24 hr infusions or DFO-DFP combination. Non response being defined as patients who have not achieved an improvement in cardiac MRI T2* of at least 2 ms within the prior year or have had a deterioration in LVEF ≤ 56% in the year prior to study start. • Patients with documented liver failure • Patients with serum creatinine > ULN or with significant proteinuria as indicated by a urinary protein/creatinine ratio ≥ 1.0 in a non-first void urine sample at baseline. • Patients with ALT (SGPT) levels > 5 x ULN. • Patients with considerable impaired gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral deferasirox / ICL670 (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection. • History or clinical evidence of pancreatic injury or pancreatitis. • Patients with a known hypersensitivity to any of the study drugs or the drug’s excipients. • History of clinically relevant ocular and/or auditor toxicity related to iron chelation therapy. • Patients with psychiatric or addictive disorders which prevent them from giving their informed consent or undergoing any of the treatment options or patients unwilling or unable to comply with the protocol. • Patients with a known history of HIV seropositivity (Elisa or Western blot). • History of malignancy of any organ system, treated or untreated, within the past 5 years whether or not there is evidence of local recurrence or metastases, with the exception of localized basal cell carcinoma of the skin. • Female patients who are pregnant or breast feeding. • Female patients of reproductive potential not employing an effective method of birth control. Women of childbearing potential must have a negative serum pregnancy test ≤ 48 hours prior to the study drugs. • Patients participating in another clinical trial or receiving an investigational drug. • History of non-compliance with medical regimens or patients who are considered potentially unreliable and/or not cooperative, unwilling or unable to comply with the protocol.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint will be treatment response (Complete Response, Partial Response, Stable Disease). The primary efficacy endpoint will be to evaluate: • The number of patients achieving a complete response (CR), defined as patients that stop intensive deferasirox -DFO treatment, at any time point during the 24 months of study, based on an improvement in the cardiac MRI T2* value being >10ms, and continue to be treated with deferasirox monotherapy without any further need for reverting back to intensive iron chelation treatment during the 24 months of study. • The number of patients achieving a partial response (PR), defined as patients that stop intensive deferasirox -DFO treatment at any time point during the 24 months study and transition to receive deferasirox onotherapy, but due to a deterioration in cardiac MRI T2* to a value < 10 ms revert back to intensive deferasirox -DFO iron chelation therapy during the 24 months of study. • The number of patients with stable disease (SD), defined as those patients that never achieved an improvement in the cardiac MRI T2* to values >10ms during the 24 months of study.
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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 | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
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 | Information not present in EudraCT |
E.8.1.2 | Open | Information not present in EudraCT |
E.8.1.3 | Single blind | Information not present in EudraCT |
E.8.1.4 | Double blind | Information not present in EudraCT |
E.8.1.5 | Parallel group | Information not present in EudraCT |
E.8.1.6 | Cross over | Information not present in EudraCT |
E.8.1.7 | Other | Information not present in EudraCT |
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 | 7 |
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 | Information not present in EudraCT |
E.8.7 | Trial has a data monitoring committee | Yes |
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 |
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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 | 0 |
E.8.9.1 | In the Member State concerned days | 0 |