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    Summary
    EudraCT Number:2015-002603-29
    Sponsor's Protocol Code Number:ALN-TTRSC-005
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2015-07-31
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedSpain - AEMPS
    A.2EudraCT number2015-002603-29
    A.3Full title of the trial
    An Open-Label Study To Evaluate The Efficacy And Safety Of Revusiran In Patients With Transthyretin-Mediated Familial Amyloidotic Polyneuropathy With Disease Progression Post Orthotopic Liver Transplant
    Estudio abierto para evaluar la eficacia y la seguridad de revusirán en pacientes con polineuropatía amiloidótica familiar mediada por la transtirretina con progresión de la enfermedad tras trasplante ortotópico de hígado
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to look at the efficacy and safety of an investigational drug, revusiran, in the treatment of patients with Transthyretin-Mediated amyloidosis, whose disease has continued to worsen following liver transplantation
    Estudio para estudiar la eficacia y rseguridad de un medicamento en investigación, el revusirán, en el tratamiento de pacientes con amiloidosis mediada por la transtirretina, cuya enfermedad ha continuado empeorando después de un transplante de hígado
    A.4.1Sponsor's protocol code numberALN-TTRSC-005
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorAlnylam Pharmaceuticals, Inc
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportAlnylam Pharmaceuticals, Inc
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAlnylam Pharmaceuticals Inc
    B.5.2Functional name of contact pointClinical Trial Hotline
    B.5.3 Address:
    B.5.3.1Street Address300 Third Street
    B.5.3.2Town/ cityCambridge
    B.5.3.3Post codeMA 02142
    B.5.3.4CountryUnited States
    B.5.4Telephone number0018663300326
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/14/1267 (EMA/OD/194/13)
    D.3 Description of the IMP
    D.3.1Product nameRevusiran
    D.3.2Product code ALN-TTRSC
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNALN-51547
    D.3.9.2Current sponsor codeALN-51547
    D.3.9.4EV Substance CodeSUB104164
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Transthyretin (TTR)-mediated Familial Amyloidotic Polyneuropathy (FAP)
    Polineuropatía amiloidótica familiar (PAF) mediada por la transtirretina
    E.1.1.1Medical condition in easily understood language
    FAP is a rare hereditary disease caused by the build-up of proteins mainly in the nervous system. It leads to loss of feeling in limbs, limb weakness and eventual inability to walk.
    PAF es una enfermedad hereditaria rara causada por la acumulación de proteínas en el sistema nervioso que lleva a la pérdida de sensibilidad y debilidad de las extremidades e incapacidad para caminar
    E.1.1.2Therapeutic area Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.0
    E.1.2Level PT
    E.1.2Classification code 10019889
    E.1.2Term Hereditary neuropathic amyloidosis
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Assess the efficacy of revusiran in patients with Transthyretin (TTR) -mediated Familial Amyloidotic Polyneuropathy (FAP) with disease progression post-orthotopic liver transplant (OLT) by evaluating the reduction in serum TTR level compared to baseline
    Evaluar la eficacia de revusirán en pacientes con polineuropatía amiloidótica familiar (PAF) mediada por la transtirretina (TTR) con progresión de la enfermedad tras trasplante ortotópico de hígado (TOH) mediante la evaluación de la reducción de la concentración sérica de TTR con respecto al periodo basal.
    E.2.2Secondary objectives of the trial
    ? Evaluate the safety and tolerability of revusiran when administered to TTR-mediated FAP patients with disease progression post-OLT
    ? Characterize the pharmacokinetics (PK) of revusiran
    ? Describe the effect of revusiran on neurologic impairment
    - Evaluar la seguridad y la tolerabilidad de revusirán cuando se administra a pacientes con PAF mediada por la TTR con progresión de la enfermedad tras TOH.
    - Caracterizar la farmacocinética (FC) de revusirán.
    - Describir el efecto de revusirán en el deterioro neurológico.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Male or female ?18 years of age
    2. Diagnosis of FAP with documented TTR mutation
    3. Received an OLT ?12 months before the date of informed consent
    4. An increase in polyneuropathy disability (PND) score compared to a preliver transplant assessment OR increase in PND score between any 2 assessments postliver transplant, which in the opinion of the Investigator is due to underlying FAP progression
    5. On stable immunosuppressive regimen with ?10 mg/day of prednisone for at least 3 months before the date of informed consent
    6. Neurological impairment score (NIS) of 5 to 130 (inclusive)
    7. Polyneuropathy Disability score of ?3b
    8. Karnofsky Performance Status ?60%
    9. No liver allograft rejection episodes (chronic, acute, or subacute) in the past 6 months before the date of informed consent
    10. Normal liver function, including aspartate transaminase, alanine transaminase, and total bilirubin, unless elevation in total bilirubin is due to Gilbert?s syndrome based on central laboratory evaluation
    11. Adequate renal function demonstrated by estimated glomerular filtration rate ?45 mL/min/1.73 m2 (calculated by a central laboratory using the Modification of Diet in Renal Disease formula)
    12. Women of child-bearing potential must have a negative pregnancy test, cannot be breast feeding, and must be willing to use 1 highly effective method of contraception throughout study participation and for 28 days after last dose administration
    13. Males who agree to use appropriate means of contraception throughout study participation until 28 days after last dose administration
    14. Patient, or patient?s legal representative, is able and willing to provide written informed consent and the patient is willing to comply with the study requirements
    1. Pacientes de ambos sexos ? 18 años.
    2. Presentar diagnóstico de PAF con mutación en el gen TTR documentada.
    3. Haber recibido un TOH ? 12 meses antes de la fecha del consentimiento informado.
    4. Presentar un aumento en la puntuación de la discapacidad debida a la polineuropatía (PND) (p. ej., un cambio en la PND de 1 a 2 o de 3a a 3b) con respecto a la evaluación previa al trasplante de hígado O un aumento de la puntuación de la PND entre 2 evaluaciones cualesquiera después del trasplante que, en opinión del investigador, se deba a progresión de la PAF subyacente.
    5. Llevar en tratamiento inmunosupresor estable con ? 10 mg/día de prednisona durante un mínimo de 3 meses antes de la fecha del consentimiento informado.
    6. Presentar una puntuación en la escala de deterioro neurológico (NIS) de 5 a 130 (inclusive).
    7. Presentar una puntuación de la discapacidad debida a la polineuropatía de ? 3b.
    8. Presentar una valoración en la Escala del estado funcional de Karnofsky ? 60 %.
    9. No haber tenido episodios (crónicos, agudos o subagudos) de rechazo del aloinjerto de hígado en los 6 meses anteriores a la fecha del consentimiento informado.
    10. Presentar una función hepática normal, incluidos los valores de aspartato-transferasa, alaninatransferasa y bilirrubina total, salvo que la elevación de la bilirrubina total se deba al síndrome de Gilbert según la evaluación del laboratorio central.
    11. Presentar una función renal aceptable confirmada mediante una filtración glomerular (FG) estimada ? 45 ml/min/1,73 m2 (calculada por el laboratorio central usando la ecuación utilizada en el estudio de modificación de la dieta en la enfermedad renal [Modification of Diet in Renal Disease]).
    12. Las mujeres potencialmente fértiles deberán dar resultado negativo en una prueba de embarazo, no podrán amamantar y deberán aceptar el uso de 1 método anticonceptivo de gran eficacia durante toda su participación en el estudio y hasta 28 días después de haber recibido la última dosis del fármaco del estudio.
    13. Los varones deben aceptar el uso de métodos anticonceptivos adecuados durante toda su participación en el estudio y hasta transcurridos 28 días de la administración de la última dosis del fármaco del estudio.
    14. El paciente o su representante legal deben querer y poder proporcionar el consentimiento informado por escrito y el paciente debe estar dispuesto a cumplir las obligaciones del estudio.
    E.4Principal exclusion criteria
    1. Untreated hypo- or hyperthyroidism
    2. Active infection requiring systemic antiviral or antimicrobial therapy that will not be completed before the first dose of study drug administration
    3. Active infection with hepatitis B or hepatitis C (based on serology)
    4. Known human immunodeficiency virus infection
    5. New York Heart Association (NYHA) classification of >2
    6. Known leptomeningeal amyloidosis
    7. Other known causes of sensorimotor or autonomic neuropathy (eg, autoimmune disease)
    8. Known type I diabetes
    9. Type II diabetes mellitus for ?5 years from the time of informed consent
    10. Vitamin B12 levels below the lower limit of normal
    11. Known history of alcohol abuse within the last 2 years from the time of informed consent
    12. Received an investigational agent or device within 30 days of anticipated study drug administration or 5 half-lives of the study drug, whichever is longer
    13. Currently taking diflunisal, tafamidis, doxycycline, or tauroursodeoxycholic acid; if previously on any of these agents, must have completed a 14-day washout before start of study drug administration in this study
    14. Malignancy within the last 2 years from the time of informed consent, except for basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix that has been successfully treated
    15. History of allergic reaction to an oligonucleotide or N-acetylgalactosamine (GalNAc)
    16. History of intolerance to subcutaneous (SC) injection
    17. Other medical conditions or comorbidities which, in the opinion of the Investigator, would interfere with study compliance or data interpretation
    1. Hipotiroidismo o hipertiroidismo no tratado.
    2. Infección activo que requiera tratamiento antibiótico o antiviral que no habrá finalizado antes de la administración de la primera dosis del fármaco del estudio.
    3. Infección activa por el virus de la hepatitis B o de la hepatitis C (según la serología).
    4. Infección confirmada por el virus de la inmunodeficiencia humana.
    5. Puntuación > 2 según la clasificación de la New York Heart Association (NYHA).
    6. Amiloidosis leptomeníngea diagnosticada.
    7. Otras causas conocidas de neuropatía sensitivomotora o autónoma (p. ej., enfermedad autoinmunitaria).
    8. Diabetes de tipo I diagnosticada.
    9. Diabetes mellitus de tipo II durante ? 5 años desde el momento del consentimiento informado.
    10. Concentración de vitamina B12 por debajo del límite inferior de la normalidad.
    11. Antecedentes conocidos de consumo de alcohol en los 2 últimos años desde el momento del consentimiento informado.
    12. Haber recibido un medicamento o un producto sanitario en investigación en los 30 días previos a la fecha prevista para la administración del fármaco del estudio o en las 5 semividas siguientes a la administración de dicho fármaco en investigación, lo que suponga más tiempo.
    13. Estar recibiendo en la actualidad diflunisal, tafamidis, doxiciclina o ácido tauroursodesoxicólico; si ha recibido alguno de ellos, deberá haber un período de lavado de 14 días antes de empezar a recibir el fármaco de este estudio.
    14. Neoplasia maligna en los 2 últimos años desde el momento del consentimiento informado, excepto en caso de carcinoma cutáneo basocelular o epidermoide o carcinoma in situ del cuello del útero tratado de manera satisfactoria.
    15. Antecedentes de reacción alérgica a un oligonucleótido o a N-acetilgalactosamina (GalNAc).
    16. Antecedentes de intolerancia a la inyección subcutánea (s.c.).
    17. Otros procesos patológicos o enfermedades concomitantes que, en opinión del investigador,
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is the percent reduction from baseline in serum TTR level at 6 months.
    El criterio principal de valoración es el porcentaje de reducción respecto al periodo basal de la concentración de TTR sérica a los 6 meses.
    E.5.1.1Timepoint(s) of evaluation of this end point
    6 months
    6 meses
    E.5.2Secondary end point(s)
    The secondary endpoints of the study are the change from baseline over 18 months for the following:
    ? Serum TTR
    ? Modified (m)NIS+7
    ? Norfolk Quality of Life-Diabetic Neuropathy questionnaire
    ? PND Score
    Los criterios secundarios de valoración del estudio son el cambio respecto al periodo basal a lo largo de 18 meses en:
    - La concentración sérica de TTR
    - La puntuación NIS+7 modificada
    - El cuestionario de Norfolk sobre calidad de vida con neuropatía periférica (Norfolk Quality of Life-Diabetic Neuropathy)
    - La puntuación PND
    E.5.2.1Timepoint(s) of evaluation of this end point
    18 months
    18 meses
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    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.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA5
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial 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
    LVLS
    Última visita del ultimo paciente
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months21
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial months21
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 12
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state2
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 12
    F.4.2.2In the whole clinical trial 12
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Consistent with standard of care
    Consistente con el tratamiento estándar
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2015-10-13
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-10-02
    P. End of Trial
    P.End of Trial StatusCompleted
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