E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Familial Amyloid Polyneuropathy |
Polineuropatia Amiloide Familiar |
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E.1.1.1 | Medical condition in easily understood language |
Familial Amyloid Polyneuropathy |
Polineuropatia Amiloide Familiar |
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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 | 16.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10057949 |
E.1.2 | Term | Familial amyloid polyneuropathy |
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 evaluate the efficacy of ISIS 420915 as compared to placebo, given for 65 weeks, as measured by the change from baseline in the modified Neuropathy Impairment Score +7 (mNIS+7) and in the Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) questionnaire total score, in patients with FAP. |
Evaluar la eficacia de ISIS 420915 en comparación con el placebo, administrado durante 65 semanas, medida por el cambio desde el inicio en la puntuación modificada del deterioro de la neuropatía +7 (mNIS+7) y en la puntuación total del cuestionario sobre la calidad de vida con neuropatía diabética de Norfolk (Norfolk QOL-DN), en pacientes con polineuropatía amiloide familiar (FAP). |
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E.2.2 | Secondary objectives of the trial |
To evaluate the efficacy of ISIS 420915 as compared to placebo, based on the change from baseline in the following measures:
- Norfolk QOL-DN questionnaire symptoms domain score in Stage 1 patients and Norfolk QOL-DN questionnaire physical functioning/large fiber neuropathy domain score in Stage 2 patients
- Modified body mass index (mBMI) and body mass index (BMI)
- NIS and modified +7
- NIS+7
To evaluate the pharmacodynamic (PD) effect of ISIS 420915 as compared to placebo, based on the change from baseline in transthyretin (TTR) and retinol binding protein 4 (RBP4).
To evaluate the safety and tolerability of ISIS 420915.
To evaluate the plasma trough levels of ISIS 420915 in all patients and to evaluate the plasma pharmacokinetic parameters of ISIS 420915 in a subset of patients. |
Evaluar la eficacia de ISIS 420915 en comparación con el placebo por el cambio con respecto al inicio en las medidas siguientes:
- La puntuación del dominio de los síntomas del cuestionario Norfolk QOL-DN en pacientes en la Etapa 1 y la puntuación del dominio de la función física/neuropatía de las fibras largas en pacientes en la Etapa 2
- Índice de masa corporal modificado (IMCm) e índice de masa corporal (IMC)
- NIS y +7 modificado
- NIS+7
Evaluar el efecto farmacodinámico (FD) de ISIS 420915 en comparación con el placebo, basado en el cambio con respecto al inicio en la transtiretina (TTR) y la proteína de unión al retinol tipo 4 (RBP4).
Evaluar la seguridad y la tolerabilidad de ISIS 420915.
Evaluar los niveles plasmáticos mínimos de ISIS 420915 en todos los pacientes y evaluar los parámetros farmacocinéticos plasmáticos de ISIS 420915 en un subconjunto de pacientes.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Diagnosed Stage 1 or Stage 2 FAP patient
- Meets NIS requirements
- Male or female aged 18 to 82 years old at the time of informed |
- Pacientes de FAP en fase 1 y en fase 2
- Puntuación NIS ≥ 10 y ≤ 1003.
- Mujeres y Hombres con edad comprendida entre los 18 y los 82 años en el momento del consentimiento informado
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E.4 | Principal exclusion criteria |
- Has inadequate liver, renal or heart function
- Has retinol levels at screen < LLN
- Has human immunodeficiency virus (HIV), hepatitis B or hepatitis C
- Has type 1 or type 2 diabetes mellitus or other cause of sensorimotor
or autonomic neuropathy
- Recently treated with another investigational drug, biological agent or device
- Is currently taking Vyndaqel® or diflunisal
- Prior liver transplant or anticipated liver transplant within 1 year of screening
- Anticipated survival less than 2 years |
- Inadecuada función hepática, renal o cardiaca
- Nivel de retinol en la selección < LIN
- Resultado positivo para virus de la inmunodeficiencia humana (VIH), hepatitis B o hepatitis C
- Presencia de diabetes mellitus tipo 1 o 2 conocida u otras causas de neuropatía autonómica, sensitiva o motora
- Tratamiento reciente con cualquier otro fármaco en investigación, agente biológico o dispositivo
- Actualmente en tratamiento con Vyndaqel® o Diflunisal
- Trasplante hepático previo o previsión de trasplante hepático en un plazo de 1 año desde la selección
- Previsión de supervivencia inferior a 2 años |
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E.5 End points |
E.5.1 | Primary end point(s) |
Change in mNIS+7 score from baseline to Week 66 and the change in the Norfolk QOL-DN questionnaire total score from baseline to Week 66. |
Cambio en la puntuación del mNIS+7 desde el inicio hasta la Semana 66 y el cambio de la puntuación total del cuestionario de Norfolk QOL-DN desde el inicio hasta la Semana 66. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
- Change in the Norfolk QOL-DN questionnaire symptoms domain score (Stage 1 patients only) and Norfolk QOL-DN questionnaire physical functioning/large fiber neuropathy domain score (Stage 2 patients only) from baseline to Week 66
- Change in the mBMI and BMI from baseline to Week 65
- Change in NIS and modified +7 from baseline to Week 66
- Change in NIS+7 score from baseline to Week 66 |
- El cambio en la puntuación del dominio de síntomas del cuestionario de Norfolk QOL-DN (solo pacientes en Etapa 1) y la puntuación del dominio de neuropatía de fibras largas/función física del cuestionario de Norfolk QOL-DN (solo pacientes en Etapa 2) desde el inicio hasta la Semana 66.
- Cambio en el IMC y el IMCm desde el inicio hasta la Semana 65
- Cambio en el NIS y en el +7 modificado desde el inicio hasta la Semana 66
- Cambio en la puntuación del NIS+7 desde el inicio hasta la Semana 66
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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 | Yes |
E.6.7 | Pharmacodynamic | Yes |
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) | 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 | 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 | 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
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 14 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
France |
Italy |
Portugal |
Argentina |
Brazil |
Germany |
Spain |
United Kingdom |
United States |
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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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 2 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 2 |