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    Summary
    EudraCT Number:2015-000493-35
    Sponsor's Protocol Code Number:ISIS-304801-CS17
    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:2015-10-15
    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 number2015-000493-35
    A.3Full title of the trial
    A Randomized, Double-Blind, Placebo-Controlled, Phase 2/3 Study of ISIS 304801 Administered Subcutaneously to Patients with Partial Lipodystrophy
    Estudio de fase II/III, randomizado, doble ciego y controlado con placebo de ISIS 304801 administrado por vía subcutánea a pacientes con lipodistrofia parcial
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study of ISIS 304801 versus placebo Administered Subcutaneously to Patients with Partial Lipodystrophy
    Estudio de ISIS 304801 versus placebo administrado por vía subcutánea a pacientes con lipodistrofia parcial
    A.3.2Name or abbreviated title of the trial where available
    The BROADEN Study
    El estudio BROADEN
    A.4.1Sponsor's protocol code numberISIS-304801-CS17
    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 organisationMedpace Spain S.L
    B.5.2Functional name of contact pointMónica Bermejo
    B.5.3 Address:
    B.5.3.1Street AddressJorge Juan 54, 2 izquierda
    B.5.3.2Town/ cityMadrid
    B.5.3.3Post code28001
    B.5.3.4CountrySpain
    B.5.4Telephone number3491853 4105
    B.5.5Fax number34900981 853
    B.5.6E-mailm.bermejo@medpace.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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameVOLANESORSEN SODIUM, ApoC-III Antisense Oligonucleotide
    D.3.2Product code ISIS 304801
    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 304801
    D.3.9.1CAS number 915430-78-3
    D.3.9.2Current sponsor codeISIS 304801
    D.3.9.3Other descriptive nameISIS 304801
    D.3.9.4EV Substance CodeSUB130595
    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 type2'-MOE Chimeric Antisense Oligonucleotide
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for injection
    D.8.4Route of administration of the placeboSubcutaneous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Partial lipodystrophy
    Lipodistrofia parcial
    E.1.1.1Medical condition in easily understood language
    Patients with partial lipodystrophy
    Pacientes con lipodistrofia parcial
    E.1.1.2Therapeutic area Diseases [C] - Nutritional and Metabolic Diseases [C18]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.1
    E.1.2Level PT
    E.1.2Classification code 10053857
    E.1.2Term Partial lipodystrophy
    E.1.2System Organ Class 10040785 - Skin and subcutaneous tissue disorders
    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 efficacy of ISIS 304801 (300 mg once weekly) as compared to placebo on the percent change in fasting TG from baseline to Month 3.
    Evaluar la eficacia de ISIS 304801 (300 mg una vez a la semana) en comparación con el placebo respecto al cambio porcentual de los niveles de triglicéridos (TG) en ayunas desde al periodo basal al mes 3.
    E.2.2Secondary objectives of the trial
    To evaluate the efficacy of ISIS 304801 as compared to placebo on:
    ? Absolute change from Baseline in fasting TG at 3, 6 and 12 months
    ? Percent of patients who achieve a ? 40% reduction in fasting TG at 3, 6 and 12 months
    ? Change from Baseline in hemoglobin A1c (HbA1c) at 6, 9 and 12 months
    ? Change from Baseline in fasting plasma glucose (FPG) at 6, 9 and 12 months
    ? Change from Baseline in liver volume and hepatic steatosis (as assessed by magnetic resonance imaging [MRI]) at 6 and 12 months
    To evaluate the effects of ISIS 304801 as compared to placebo on:
    ? Safety and tolerability
    ? Prospectively adjudicated acute pancreatitis events (Atlanta classification) and Major Adverse Cardiovascular Events (MACE)
    Evaluar la eficacia de ISIS 304801 en comparación con el placebo sobre:
    - El cambio absoluto respecto al valor basal de las concentraciones de TG en ayunas a los 3, 6 y 12 meses.
    - El porcentaje de pacientes que consigue una reducción ? 40 % de las concentraciones de TG en ayunas a los 3, 6 y 12 meses.
    - El cambio respecto al valor basal de las concentraciones de hemoglobina A1c (HbA1c) a los 6, 9 y 12 meses.
    - El cambio respecto al valor basal de las concentraciones de glucemia plasmática (GPA) en ayunas a los 6, 9 y 12 meses.
    - El cambio respecto al valor basal del volumen hepático y de la esteatosis hepatica (conforme se evalúe mediante resonancia magnética [RM]) a los 6 y 12 meses.

    Evaluar la eficacia de ISIS 304801 en comparación con el placebo respecto a:
    - La seguridad y la tolerabilidad.
    - Los acontecimientos de pancreatitis aguda (clasificación de Atlanta) y los acontecimientos adversos cardiovasculares graves (AACVG) validados prospectivamente.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Clinical diagnosis of partial lipodystrophy based on deficiency of subcutaneous body fat in a partial fashion assessed by physical examination, and at least one (1) MAJOR criterion and one (1) MINOR criterion (below):
    MAJOR Criteria
    a. Low skinfold thickness in anterior thigh by caliper measurement: men (? 10 mm) and women (? 22 mm) OR
    b. Genetic diagnosis of familial PL (e.g., mutations in LMNA, PPAR-?, AKT2, PLIN1 genes)
    MINOR Criteria
    a. Insulin resistance defined as fasting insulin ? 20 mcU/mL
    b. Diabetes mellitus
    c. Acanthosis nigricans
    d. Polycystic ovary syndrome (PCOS) or PCOS-like symptoms (hirsutism, oligomenorrhea, and/or polycystic ovaries)
    e. History of pancreatitis associated with hypertriglyceridemia
    f. History of hepatic steatosis or steatohepatitis
    g. Similar fat distribution and/or history of fat loss in a first degree relative
    h. Prominent muscularity and phlebomegaly (enlarged veins) in the extremities
    i. Disproportionate hyperphagia

    2. Fasting TG ? 500 mg/dL (? 5.7 mmol/L) at Screening.
    1. Diagnóstico clínico de lipodistrofia basada en la deficiencia de tejido adiposo corporal subcutáneo parcial evaluada mediante exploración física, y al menos, un (1) criterio PRINCIPAL y un (1) criterio SECUNDARIO (véase más abajo):
    Criterios principales:
    a. Grosor del pliegue cutáneo del muslo anterior bajo mediante medición con plicómetro: varones (? 10 mm) y mujeres (? 22 mm) O
    b. Diagnóstico genético de LP familiar (por ej., mutaciones de los genes LMNA, PPAR-?, AKT2 y PLIN1).
    Criterios SECUNDARIOS:
    a. Resistencia insulínica definida como insulina en ayunas ? 20 mcU/ml.
    b. Diabetes mellitus.
    c. Acantosis nigricans.
    d. Síndrome del ovario poliquístico o síntomas similares al síndrome del ovario poliquístico (hirsutismo, oligomenorrea u ovarios poliquísticos).
    e. Antecedentes de pancreatitis asociada con hipertrigliceridemia.
    f. Antecedentes de esteatosis hepática o esteatohepatitis.
    g. Distribución similar del tejido adiposo o antecedentes de pérdida de tejido adiposo en un familiar de primer grado.
    h. Musculatura prominente y flebomegalia (agrandamiento de las venas) en las extremidades.
    i. Hiperfagia desproporcionada

    2. Concentraciones de TG en ayunas ? 500 mg/dl (?5,7 mmol/l) en el screening y la
    visita de idoneidad.
    E.4Principal exclusion criteria
    1. A diagnosis of generalized lipodystrophy

    2. Current or history of autoimmune diseases (even with a diagnosis of PL) unless approved by the Investigator and Sponsor Medical Monitor

    3. Acute pancreatitis within 4 weeks of Screening

    4. History within 6 months of Screening of acute or unstable cardiac ischemia (myocardial infarction, acute coronary syndrome, new onset angina), stroke, transient ischemic attack or unstable congestive heart failure requiring a change in medication

    5. Major surgery within 3 months of Screening

    6. Previous treatment with ISIS-APOCIII Rx

    7. Have any other conditions in the opinion of the investigator which could interfere with the patient participating in our completing the study
    1. Diagnóstico de lipodistrofia generalizada.
    2. Antecedentes o enfermedad autoinmunitaria actual (incluso con diagnóstico de LP) a no ser que haya sido autorizado por el Investigador o el Monitor Médico del Promotor.
    3. Pancreatitis aguda en las 4 semanas previas al screening.
    4. Antecedentes en los 6 meses previos al screening de isquemia cardíaca aguda o inestable (infarto de miocardio, síndrome coronario agudo, angina de pecho de nueva aparición), ictus, accidente isquémico transitorio o insuficiencia cardíaca congestiva inestable que exija un cambio de medicación.
    5. Cirugía mayor en los 3 meses previos al screening.
    6. Antecedentes de insuficiencia cardíaca con una clasificación superior a II conforme a la clasificación funcional de la New York Heart Association (NYHA) o insuficiencia cardiaca congestiva inestable que exija un cambio de medicación.
    7. Hipertensión no controlada (presión arterial [PA] > 160/100 mm Hg).
    E.5 End points
    E.5.1Primary end point(s)
    The primary efficacy analysis will be the comparison of percent changes from Baseline to the primary analysis time point in fasting TG between ISIS 304801 300 mg once weekly group and placebo group
    Las evaluaciones de la eficacia incluyen el cambio porcentual con respecto al valor basal y el cambio absoluto con respecto al valor basal de los TG en ayunas,
    E.5.1.1Timepoint(s) of evaluation of this end point
    The primary analysis time point is at the end of Month 3 where the value is defined as the average of Week 12 and Week 13 fasting assessments
    El momento del análisis principal es al final del tercer mes, de forma que el valor en el momento del análisis principal se define como el promedio de los valores en ayunas de las semanas 12 y 13.
    E.5.2Secondary end point(s)
    The secondary endpoints include:
    ? Absolute change from Baseline in fasting TG at 3, 6 and 12 months
    ? Proportion of patients who achieve a ? 40% reduction in fasting TG at 3, 6 and 12 months
    ? Change from Baseline in HbA1c at 6, 9 and 12 months
    ? Change from Baseline in fasting plasma glucose at 6, 9 and 12 months
    ? Change from Baseline in liver volume and hepatic steatosis (as assessed by MRI) at 6 and 12 months
    Las valoraciones secundarias incluyen:
    - el cambio absoluto con respecto al valor basal de los TG en ayunas a los 3, 6 y 12 meses
    - proporción de pacientes que alcanzan un areducción del ? 40% en el valor de los TG en ayunas a los 3, 6 y 12 meses
    - cambio respecto al valor basal de HbA1c a los 6, 9 y 12 meses
    - cambio respecto al valor basal de la glucose en plasma en ayunas a los 6, 9 y 12 meses
    - cambio respecto al valor basal en el volume hepático y de la esteatosis hepática (evaluada mediante RM) a los 6 y 12 meses
    E.5.2.1Timepoint(s) of evaluation of this end point
    At the end of Month 3 where the value is defined as the average of Week 12 (Day 78) and Week 13 (Day 85) fasting assessments. The value at Month 6 is defined as the average of Week 25 and Week 26 and the value at Month 12 is defined
    as the average of Week 51 and Week 52 fasting assessments.
    Al final del tercer mes, el valor en el momento del análisis principal se define como el promedio de los valores en ayunas de las semanas 12 y 13, el valor del mes 6 se define como el promedio de las semanas 25 y 26 y el valor del mes 12 se define como el promedio de los valores en ayunas de las semanas 51 y 52
    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 No
    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) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    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 Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    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 EEA23
    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
    Australia
    Belgium
    Brazil
    Canada
    France
    Germany
    Italy
    Netherlands
    Poland
    Portugal
    Russian Federation
    Spain
    Turkey
    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
    LVLS
    Última visita del çultimo 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 months32
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial months32
    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: 47
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 3
    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 65
    F.4.2.2In the whole clinical trial 125
    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 or patients may choose to participate in the proposed Open Label Extension trial
    los pacientes podrán optar por participar en un estudio de extension abierto o según con su tratamiento habitual
    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 Decision2015-12-04
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-11-17
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2019-11-13
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