E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Transthyretin amyloidosis |
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E.1.1.1 | Medical condition in easily understood language |
Transthyretin amyloidosis |
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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 | 14.1 |
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 | 10010331 - Congenital, familial and genetic 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 evaluate the efficacy of doxycycline + UDCA on disease progression in ATTR subjects with cardiomyopathy with or without neuropathy. |
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E.2.2 | Secondary objectives of the trial |
1. To evaluate the safety and tolerability of doxycyclin + UDCA in ATTR subjects over 12 months.
2. To evaluate symptoms and signs of peripheral sensorimotor neuropathy when present (Kumamoto Scale).
3. To evaluate disease evolution (maintenance of response, occurrence of disease progression) over 18 months.
4. To evaluate the outcome of the treatment with regard to type of amyloid fibrills
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1) Cardiomyopahty with septal thickness >/= 15 mm and/or S-NT-ProBNP >/=300 ng/L
2) Age >/=50 years
3) Male and females after menopause
4) Written informed consent to be obtained prior to any study procedure
5) Histochemical diagnosis of amyloidosis as based on detection by polarizing microscopy of green birefringent material in Congo red-stained tissue specimens, and typing of amyloid deposits as TTR and identification of amyloid fibril type.
6) Molecular definition of the TTR mutation or immunohistochemical staining of amyloid fibrils with anti TTR antibody
7) NYHA class </=III
8) Systolic blood pressure >/=100 mmHg (standing)
9) Must have symptomatic organ involvement with amyloid to justify therapy
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E.4 | Principal exclusion criteria |
Liver transplantation in the previous 6 months or liver transplantation anticipated in less than 6 months;
2) ALT and/or AST >/= 2 x UNL;
3) Creatinine clearance < 30 ml/min (Cocroft-Gault Formula)
4) Any other lab values, illness or condition that in the opinion of the investigator might place the subject at unacceptable risk for participation in the study;
5) History of hypersensitivity to any of the ingredients of the study therapies;
6) Use of any investigational drug, device (or biologic) within 4 weeks prior to study entry or during the study.
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E.5 End points |
E.5.1 | Primary end point(s) |
Response rate to doxycycline + UDCA treatment at month 12. A responder is an ATTR subject with:
- a reduction of, or an increase in serum NT-proBNP concentration of less than 30% of pre-treatment level will be regarded as consistent with treatment efficacy.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
After 12 month of treatment |
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E.5.2 | Secondary end point(s) |
-mBMI-reduction of less than 10% after 12 months of treatment
- increase of septum thickness ≤ 2 mm during 12 months of treatment.
- to assess the change from baseline in the neurologic Kumamoto Scale at months 6, 12 and 18;
- to assess the tolerability and safety of the treatment, i.e. monitoring and recording all adverse events (AEs) and serious adverse events (SAEs), and the regularly scheduled monitoring of hematology, blood chemistry, physical examinations, and blood pressure over 12 months and 18 months.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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) | 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) | 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 | 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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |