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    Summary
    EudraCT Number:2013-004561-13
    Sponsor's Protocol Code Number:ISIS420915-CS3
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2015-10-30
    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 number2013-004561-13
    A.3Full title of the trial
    An Open-Label Extension Study to Assess the Long-Term Safety and Efficacy of ISIS 420915 in Patients with Familial Amyloid Polyneuropathy (FAP)
    Estudio de extensión abierto para evaluar la seguridad y eficacia a largo plazo de ISIS 420915 en pacientes con polineuropatía amiloide familiar (PAF)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Not available
    No disponible
    A.3.2Name or abbreviated title of the trial where available
    ISIS 420915-CS3
    ISIS 420915-CS3
    A.4.1Sponsor's protocol code numberISIS420915-CS3
    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 SponsorIsis 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 supportIsis Pharmaceuticals
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationIsis Pharmaceuticals, Inc
    B.5.2Functional name of contact pointMatt R. Buck
    B.5.3 Address:
    B.5.3.1Street Address2855 Gazelle Court
    B.5.3.2Town/ cityCarlsbad
    B.5.3.3Post code92010
    B.5.3.4CountryUnited States
    B.5.4Telephone number+34934894257
    B.5.5Fax number0117606033891
    B.5.6E-mailmbuck@isisph.com
    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/3/14/1250
    D.3 Description of the IMP
    D.3.1Product nameHuman Transthyretin Antisense Oligonucleotide
    D.3.2Product code ISIS 420915
    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 INNISIS 420915
    D.3.9.1CAS number 1432726-13-0
    D.3.9.2Current sponsor codeISIS 420915
    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 Yes
    D.3.11.13.1Other medicinal product typeAntisense Oligonucleotide
    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
    Familial Amyloid Polyneuropathy
    Polineuropatía Amiloide Familiar
    E.1.1.1Medical condition in easily understood language
    Familial Amyloid Polyneuropathy
    Polineuropatía Amiloide Familiar
    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 18.1
    E.1.2Level LLT
    E.1.2Classification code 10057949
    E.1.2Term Familial amyloid polyneuropathy
    E.1.2System Organ Class 100000004850
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the safety and tolerability of extended dosing with ISIS 420915 in patients with Familial Amyloid Polyneuropathy.
    Evaluar la seguridad y tolerabilidad de la extensión del tratamiento con ISIS 420915 en pacientes con polineuropatía amiloide familiar
    E.2.2Secondary objectives of the trial
    To evaluate the efficacy of extended dosing with ISIS 420915 based on change from baseline and progression rate, if applicable, in the following measures:
    ? Modified Neuropathy Impairment Score +7 (mNIS+7)
    ? Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) questionnaire:
    o total score (all patients)
    o symptoms domain score (Stage 1 patients)
    o physical functioning/large fiber neuropathy domain score (Stage 2 patients)
    ? Modified body mass index (mBMI) and body mass index (BMI) ? NIS, heat-pain sensory, touch-pressure sensory, nerve conduction, and heart rate to deep breathing tests (components of mNIS+7)
    ? Polyneuropathy disability score (PND score)
    ? To evaluate the pharmacodynamic (PD) effect of extended dosing with ISIS 420915 based on change from baseline in transthyretin (TTR) and retinol binding protein 4 (RBP4)
    ? Global longitudinal strain (GLS) by echocardiogram (ECHO)
    To evaluate the plasma trough levels of ISIS 420915.
    Evaluar la eficacia de la extensión del tratamiento con ISIS 420915 a partir del cambio respecto a la línea basal y las tasas de progresión,en las siguientes mediciones:mNIS+7,Cuestionario Norfolk QOL-DN:punt. total (todos los pacientes),punt.en dominio de síntomas (pac. etapa1),punt.en dominio de funcionamiento físico/neuropatía de fibras grandes (pac.en etapa2),Índice de masa corporal modificado,índice de masa corporal (IMC),NIS, explor.de sensibilidad térmica y dolorosa, explor.de sensibilidad táctil y a la presión,conducción nerviosa y frecuencia cardíaca en respiración profunda (componentes de mNIS+7),Punt.de la discapacidad polineuropática,deformación longitudinal global mediante ECO,Evaluar el efecto farmacodinámico (FD) de la extensión del tratamiento con ISIS 420915 a partir del cambio respecto a la línea basal en la transtirretina (TTR) y en la proteína de fijación del retinol tipo 4 (retinol binding protein 4, RBP4).
    Evaluar la concentración mínima de ISIS 420915 en plasma
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Completion of ISIS 420915-CS2 with the following as judged by the Investigator and Sponsor:
    a. Satisfactory completion of dosing and end of treatment (EOT) efficacy assessments
    b. No significant tolerability issues
    c. Satisfactory compliance to the ISIS 420915-CS2 protocol requirements
    2. Willingness to take vitamin A supplements
    3. Satisfy one of the following:
    a. Females: Non-pregnant and non-lactating; surgically sterile, postmenopausal, abstinent, or if engaged in sexual relations of childbearing potential, patient is using an acceptable contraceptive method (refer to Section 6.3.1) from the time of signing the informed consent form until at least 3 months after the last dose of ISIS 420915.
    b. Males: Surgically sterile, abstinent, or if engaged in sexual relations with a female of childbearing potential, patient is utilizing an acceptable contraceptive method (refer to Section 6.3.1) during and for 3 months after the last dose of ISIS 420915.
    4. Must have given written informed consent (signed and dated) and any authorization required by local law and be able to comply with all study requirements
    1.Completar el tratamiento de ISIS 420915-CS2 junto con los siguientes criterios según estimen el investigador y el promotor:
    a.Finalizar la administración y las evaluaciones de la eficacia de FdT (final de tratamiento) de manera satisfactoria
    b.Sin problemas de tolerabilidad significativos
    c.Cumplir los requisitos del protocolo ISIS 420915-CS2 de manera satisfactoria
    En circunstancias especiales, los pacientes que participaron en el estudio ISIS 420915-CS2 pero que no completaron todo el periodo de tratamiento pueden participar en este estudio previa aprobación del promotor.
    2.Estar dispuestos a tomar suplementos de vitamina A
    3.Satisfacer uno de los siguientes criterios:
    a.Mujeres: no estar embarazadas ni en periodo de lactancia; esterilizadas quirúrgicamente, posmenopáusicas, abstinentes o, si son fértiles y mantienen relaciones sexuales, que utilicen un método anticonceptivo aceptable desde el momento en que firmen el consentimiento informado y durante al menos los 3 meses posteriores a la última dosis de ISIS 420915
    b.Hombres: esterilizados quirúrgicamente, abstinentes o, si son fértiles y mantienen relaciones sexuales con mujeres en edad fértil, que utilicen un método anticonceptivo aceptable durante el tratamiento y los 3 meses posteriores a la última dosis de ISIS 420915
    4.Haber dado su consentimiento informado por escrito (firmado y fechado) y presentado cualquier autorización exigida por la legislación local y haber sido capaces de cumplir todos los requisitos del estudio
    E.4Principal exclusion criteria
    Have any new condition or worsening of existing condition that in the opinion of the Investigator or Sponsor would make the patient unsuitable for enrollment, or could interfere with the patient participating in or completing the study.
    Presentar cualquier otra enfermedad o empeoramiento de la enfermedad existente que, en opinión del investigador o del promotor, haría que el paciente no fuera apto para su inscripción, o que pudiera interferir en la participación del paciente en el estudio o en su capacidad para completarlo.
    E.5 End points
    E.5.1Primary end point(s)
    Safety Endpoints
    ? Adverse events
    ? Vital signs and weight
    ? Physical examination
    ? Clinical laboratory tests
    ? ECG
    ? Use of concomitant medication
    ? Ophthalmology and ERG examinations
    Criterios de valoración de seguridad:
    ?Acontecimientos adversos
    ?Constantes vitales y peso
    ?Exploración física
    ?Pruebas analíticas clínicas
    ?ECG
    ?Uso de medicación concomitante
    ?ERG y exploraciones oftalmológicas
    E.5.1.1Timepoint(s) of evaluation of this end point
    Through the course of the study.
    Durante el transcurso del estudio
    E.5.2Secondary end point(s)
    Efficacy Endpoints
    ? Change in the mNIS+7 score and components from baseline to Week 78 and Week 156
    ? Change in the Norfolk QOL-DN questionnaire scores from baseline to Week 78 and Week 156
    ? Change in the mBMI and BMI from baseline to Week 78 and Week 156
    ? Change in PND score from baseline to Week 78 and Week 156
    ? Changes in Global longitudinal strain (GLS) by echocardiogram (ECHO)from baseline to Week 78 and Week 156 in the ISIS 420915-CS2 ECHO subgroup and in the Cardiomyopathy-ECHO (CM-ECHO) Set
    Criterios de valoración de la eficacia:
    ?Cambio en la puntuación y componentes de mNIS+7 desde la línea basal hasta las semanas 78 y 156
    ?Cambio en la puntuación del cuestionario Norfolk QOL-DN desde la línea basal hasta las semanas 78 y 156
    ?Cambio en el IMC y el IMCm desde la línea basal hasta las semanas 78 y 156
    ?Cambio en la puntuación PND desde la línea basal hasta las semanas 78 y 156
    ?Cambio en GLS mediante ECO desde la línea basal hasta las semanas 78 y 156 en el subgrupo ECO del estudio ISIS 420915-CS2 y en el conjunto de CM-ECO
    E.5.2.1Timepoint(s) of evaluation of this end point
    Week 78 and Week 156
    Semana 78 y Semana 156
    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 Yes
    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) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    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 No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA13
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Argentina
    Brazil
    Bulgaria
    France
    Germany
    Italy
    New Zealand
    Portugal
    Spain
    United Kingdom
    United States
    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
    LSLV
    último paciente, última visita
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months3
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months3
    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: 120
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 75
    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 state8
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 121
    F.4.2.2In the whole clinical trial 195
    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)
    Standard of care
    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 Decision2015-12-28
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-12-04
    P. End of Trial
    P.End of Trial StatusOngoing
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