E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Familial transthyretin amyloidosis complicated by cardiomyopathy |
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E.1.1.1 | Medical condition in easily understood language |
Familial Amyloid Cardiomyopathy (FAC), results from the aggregation of mutant and/or wild-type transthyretin protein in the heart |
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E.1.1.2 | Therapeutic area | Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10019893 |
E.1.2 | Term | Hereditary neuropathic amyloidosis, Swedish type |
E.1.2 | System Organ Class | 100000004850 |
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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 follow the development of neurological, nutritional and cardiac manifestations of transthyretin amyloidosis in patients treated by Diflunisal 250 mg twice daily.
Primary end-points
1. changes in the Kumamoto scale
2. cardiac impairment measured by echocardiographic assessment of global systolic strain
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E.2.2 | Secondary objectives of the trial |
Secondary end points
1. changes in nutritional status measured by the modified body mass index (mBMI)
2. changes in neurological impairment measured by the PND-score.
3. cardiac impairment measured by echocardiographic measurement of septal thickness and blood pro-BNP concentration.
4. Karnofsky performance scale
5. drug safety
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Open to patients that have been participating in the DFNS01 study. All patients will have a biopsy and genetically proven systemic transthyretin amyloidosis caused by a TTR gene mutation. The amyloid shall be proven to be of transthyretin type, and the fibril composition settled.
For patients not previously participating in the DFNS01 trial, the diagnosis shall be proven by biopsy and identification of a TTR-gene mutation. The amyloid shall be proven to be of transthyretin type, and the fibril composition settled. TTTR-amyloid cardiomyopathy shall be confirmed by DPD-scintigraphy, and an increased intra-ventricular septal thickness of > 12 mm and a pro-BNP blood concentration above the normal limit.
2. Age ≥ 18 years.
3. Negative pregnancy test for sexually active women of child bearing potential and willing to comply with effective contraception methods during the course of the trial. Acceptable methods are such as oral contraceptives, contraceptive patches, contraceptive implant, vaginal contraceptive, double-barrier methods (for example, condom and spermicide), intrauterine device (IUD), hormonal IUD.
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E.4 | Principal exclusion criteria |
1. Concomitant use of non-study NSAIDs
2. Heart failure with symptoms at daily activities (NYHA class ≥III)
3. Renal insufficiency (creatinine clearence < 30 ml calculated from the Cockcroft-Gault formula)
4. Active non-haemorrhoidal bleeding within the last 18 month.
5. Non-treated peptic ulcer disease.
6. Anticoagulation therapy, low dose ASA permitted (≤160 mg).
7. Non-steroidal or aspirin allergy/hypersensitivity
8. Thrombocytopenia (< 100,000 platelets/mm3)
9. Inability or unwillingness of subject to give written informed consent
10. By the investigator regarded as unable to follow the study guidelines and scheduled controls.
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary endpoints will be:
1. changes in the Kumamoto scale
2. cardiac impairment measured by echocardiographic assessment of global systolic strain
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Primary and secondary end-points will be evaluated at 12 months and the end of the 24 months study period by descriptive statistical methods.
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E.5.2 | Secondary end point(s) |
Secondary end points will be:
1. changes in nutritional status measured by the modified body mass index (mBMI)
2. changes in neurological impairment measured by the PND-score.
3. cardiac impairment measured by echocardiographic measurement of septal thickness and blood pro-BNP concentration.
4. Karnofsky performance scale
5. drug safety
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary endpoints for effect parameters will be evaluated at 12 months and the end of the 24 months study period by descriptive statistical methods. Safety parameters will be measured at 1 month (± 1 week), 3 months (±2 weeks), 6 months (± 1 month), 9 months (±1 month), 12 months (±1 month) and thereafter every 6 months (± 1month).
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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 | 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) | Yes |
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 | Yes |
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) | No |
E.8.2.2 | Placebo | No |
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 | 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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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 |