E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Transthyretin mediated amyloidosis (ATTR) |
Amiloidosis TTR. |
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E.1.1.1 | Medical condition in easily understood language |
ATTR is a hereditary disease caused by protein aggregates in the heart and the nervous system. It leads to heart dysfunction , damages to the nerves, and gastrointestinal and bladder dysfunctions. |
ATTR es una enfermedad hereditaria causada por agregados de proteínas en el corazón y el sistema nervioso. Esto conduce a la disfunción del corazón, daño a los nervios, trastornos gastrointestinales. |
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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 | PT |
E.1.2 | Classification code | 10007509 |
E.1.2 | Term | Cardiac amyloidosis |
E.1.2 | System Organ Class | 10007541 - Cardiac disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10019889 |
E.1.2 | Term | Hereditary neuropathic amyloidosis |
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 safety and tolerability of multiple doses of ALN-TTR02. |
Evaluar la seguridad y la tolerabilidad de la administración reiterada de ALN-TTR02. |
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E.2.2 | Secondary objectives of the trial |
To characterize the plasma and urine PK of ALN-TTR02.
To assess preliminary evidence of the PD effect of ALN-TTR02 on serum total TTR levels. |
Caracterizar la FC plasmática y urinaria de ALN-TTR02.
Evaluar los datos preliminares del efecto FD de ALN-TTR02 en las concentraciones séricas totales de TTR.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male or female aged 18 years or older.
2. Patients has a biopsy-proven diagnosis of TTR amyloidosis with documented signs/symptoms of the disease (e.g., sensory, motor, or autonomic neuropathy) that are at least mild to moderate in severity.
3. Body mass index (BMI) of 17?33 kg/m2.
4. Karnofsky performance status of 60% or greater.
5. Absolute neutrophil count (ANC) ?1500 cells/mm³,
platelet count ?100,000 cells/mm³, and hemoglobin ?10 g/dL.
6. Adequate liver function, demonstrated by an aspartate transaminase (AST) and alanine transaminase (ALT) ?2.5 x the upper limit of normal (ULN), total bilirubin within normal limits, albumin >3 g/dL, international normalized ratio (INR) ?1.2.
7. Adequate renal function: serum creatinine ?1.5 x ULN.
8. Seronegative for hepatitis B virus (HBV) and hepatitis C virus (HCV).
9. Women of child-bearing potential must have a negative pregnancy test, cannot be breast feeding, and must be using two highly effective methods of contraception ( hormonal - oral, implantable, injectable, or transdermal contraceptives in conjunction with spermicide, condom, or diaphragm; mechanical - spermicide in conjunction with a barrier such as a condom or diaphragm; intrauterine device (IUD) in conjunction with spermicide or condom; or surgical sterilization of partner in conjunction with spermicide, condom, or diaphragm) prior to screening, throughout study participation, and for 1 month after ending study participation.
10. Males agree to use appropriate contraception throughout study participation and for 1 month after ending study participation.
11. Patient is willing and able to comply with protocol required visit schedule and visit requirements and provide written informed consent. |
1.Varones o mujeres de 18 años de edad en adelante.
2.Diagnóstico de amiloidosis TTR demostrado por biopsia y con signos o síntomas de la enfermedad documentados (p. ej., neuropatía sensitiva, motriz o autónoma) de intensidad leve a moderada, como mínimo.
3.Índice de masa corporal de 17 a 33 kg/m2.
4.Estado funcional de Karnofsky del 60 % o más (véase el apéndice 3).
5.Recuento absoluto de neutrófilos (RAN) ≥1500 células/mm³, recuento de plaquetas ≥100,000 células/mm³ y hemoglobina ≥10 g/dl.
6.Función hepática suficiente, demostrada por valores de aspartato transaminasa (AST) y de alanina transaminasa (ALT) ≤2,5 el límite superior de lo normal (LSN), bilirrubina total dentro de lo normal, albúmina >3 g/dl e índice internacional normalizado (IIN) ≤1,2.
7.Función renal suficiente: creatinina sérica ≤1,5 LSN.
8.Seronegativo para los virus de las hepatitis B (VHB) y C (VHC).
9.Las mujeres en edad fértil deberán dar resultado negativo en una prueba de embarazo, no podrán amamantar y deberán utilizar dos métodos anticonceptivos de gran eficacia antes desde antes del screening hasta 1 mes después de que finalice su participación en el estudio. Se consideran métodos anticonceptivos de gran eficacia los siguientes: hormonales – anticonceptivos orales, implantables, inyectables o transdérmicos junto con espermicida, preservativo o diafragma; mecánicos – espermicida junto con un método de barrera, como el preservativo o el diafragma; dispositivo intrauterino (DIU) junto con espermicida o preservativo; o esterilización quirúrgica de la pareja, junto con espermicida, preservativo o diafragma.
10.Los varones se comprometerán a utilizar métodos anticonceptivos adecuados durante la participación en el estudio y hasta un mes después de que finalice esta.
11.El paciente quiere y puede acudir a las visitas del protocolo, cumplir los requisitos de las mismas y otorgar su consentimiento informado por escrito.
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E.4 | Principal exclusion criteria |
1. Pregnant or nursing.
2. Has had a liver transplant.
3. Has a known surgery planned during any point of the study period.
4. Has known human immunodeficiency virus (HIV) positive status.
5. Has a known or suspected systemic bacterial, viral, parasitic, or fungal infection.
6. Received an investigational agent, other than tafamidis or diflunisal, within 30 days prior to study drug administration.
7. Has a New York Heart Association heart failure classification >2.
8. Has unstable angina.
9. Has uncontrolled clinically significant cardiac arrhythmia.
10. Is considered unfit for the study by the Principal Investigator.
11. Had a prior severe reaction to a liposomal product.
12. Has known hypersensitivity to oligonucleotides.
13. Is an employee or family member of Alnylam, the CRO, or the clinical study site personnel. |
1.Paciente embarazada o en periodo de lactancia.
2.Haber recibido un transplante de hígado.
3.Tener previsto someterse a alguna intervención quirúrgica en algún momento del estudio.
4.Estar infectado por el virus de la inmunodeficiencia humana (VIH).
5.Presentar antecedentes o sospecha de infección sistémica por bacterias, virus, parásitos u hongos.
6.Haber recibido un fármaco en investigación distinto de tafamidis o diflunisal en los 30 días previos a la primera administración del fármaco del estudio.
7.Presentar una insuficiencia cardiaca de grado >2 de la New York Heart Association (véase el apéndice 4).
8.Presentar angina inestable.
9.Presentar una arritmia cardíaca clínicamente significativa y no controlada.
10.El investigador principal considera que el paciente no es adecuado para el ensayo.
11.Haber presentando una reacción grave a un producto liposómico en el pasado.
12.Presentar hipersensibilidad a los oligonucleótidos.
13.Ser empleado o familiar de un empleado de Alnylam, de la CRO o del personal del centro del estudio clínico.
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E.5 End points |
E.5.1 | Primary end point(s) |
To evaluate the safety and tolerability of multiple doses of ALN-TTR02 including:
?assessment of adverse events (AEs),
?12 lead electrocardiograms (ECGs),
?cardiac monitoring (telemetry)
?arterial oxygen saturation (SaO2) using pulse oximetry,
?vital signs (blood pressure, pulse rate, oral body temperature and
respiratory rate),
?clinical laboratory safety tests (hematology, serum chemistry,
coagulation, urinalysis, liver function, lipid panel, thyroid function, complement factor Bb, cytokines, and
?physical examinations. |
Evaluar la seguridad y la tolerabilidad de la administración reiterada de ALN-TTR02 que incluye:
Se evaluarán los acontecimientos adversos.
Se obtendrá un ecocardiograma durante el screening
Se obtendrán ECG de doce derivaciones computadorizados
Se llevará a cabo una monitorización cardiaca continua por telemetría
Se evaluará la oxigenación del oxígeno arterial por pulsioximetría
Las constantes vitales (presión sanguínea, la frecuencia cardiaca y respiratoria y la temperatura corporal)
Análisis de hemograma, bioquímica sérica, función hepática, pruebas de coagulación, PCR, análisis de orina, embarazo (en suero y en orina), serología de las hepatitis B y C, lípidos y función tiroidea.
Exploración física |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The review of AEs will be done at each visit from Day 0 through Day 56.
The other assessments will be carried out at specific timepoints between screening and D208, as descibed in the study schedule. |
La evaluación de acontecimientos adversos se realizará en cada visita, desde el Día 0 hasta el día 56 del estudio.
Las otras evaluaciones se realizarán en diferentes visitas del estudio segun corresponda desde la Visita de Screening hasta la Visita Día 208 tal y como está establecido en el calendario del estudio. |
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E.5.2 | Secondary end point(s) |
PK profile of ALN-TTR02, including:
?plasma-concentration time profiles for ALN-18328 and the novel lipid components DLin-MC3-DMA and PEG2000-C-DMG.
PD effect of ALN-TTR02 on serum TTR, RBP and Vitamin A, including:
?serial assessment of serum concentrations of TTR, TTR mRNA, RBP and Vitamin A. |
Caracterizar la FC plasmática y urinaria de ALN-TTR02 para la que se llevarán a cabo estimaciones de los parámetros FC y se determinarán los perfiles de proporcionalidad de la dosis de ALN-TTR02 para el ARNip de ALN-TTR02 (ALN-18328) y los componentes lipídicos liposómicos, DLin MC3-DMA y PEG2000-C-DMG.
Evaluar los datos preliminares del efecto FD de ALN-TTR02 en las concentraciones séricas totales de TTR, las concentraciones de la vitamina A y la PTR para la que se llevarán a cabo analisis para medir el TTR, el ARNm de la TTR, la PTR y la Vitamina A. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
ALN-18328, PEG2000-C-DMG and DLin-MC3-DMA concentrations will be determined at specified time points between D0 and D208, as described in the study schedule.
An assessment of the concentrations of serum TTR, TTR mRNA, RBP and Vitamin A will be determined at specified time points between screening and D208, as described in the study schedule. |
(ALN-18328) y los componentes lipídicos liposómicos, DLin MC3-DMA y PEG2000-C-DMG se evaluarán en la visitas especificadas en el calendario del estudio entre la visita de Screening y la Visita del Día 208.
Los valores de TTR, el ARNm de la TTR, la PTR y la Vitamina A se evaluarán en la visitas especificadas en el calendario del estudio entre la visita de Screening y la Visita del Día 208.
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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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | No |
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) | 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) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
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 | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 9 |
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 |
Brazil |
France |
Germany |
Portugal |
Spain |
Sweden |
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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 | 1 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |