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    Summary
    EudraCT Number:2022-000757-93
    Sponsor's Protocol Code Number:ISIS721744-CS7
    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:2022-06-14
    Trial 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 number2022-000757-93
    A.3Full title of the trial
    An Open-Label, Long Term Safety and Efficacy Study of Donidalorsen in the Prophylactic Treatment of Hereditary Angioedema (HAE)
    Estudio sin enmascaramiento a largo plazo para evaluar la seguridad y la eficacia de donidalorsén como tratamiento profiláctico del angioedema hereditario (AEH)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    An Open-Label, Long Term Safety and Efficacy Study of Donidalorsen in the Prophylactic Treatment of Hereditary Angioedema (HAE)
    Estudio sin enmascaramiento a largo plazo para evaluar la seguridad y la eficacia de donidalorsén como tratamiento profiláctico del angioedema hereditario (AEH)
    A.4.1Sponsor's protocol code numberISIS721744-CS7
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT05392114
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorIONIS 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 supportIonis Pharmaceuticals, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationIonis Pharmaceuticals, Inc.
    B.5.2Functional name of contact pointIonis Clinical Trial Information
    B.5.3 Address:
    B.5.3.1Street Address2855 Gazelle Court
    B.5.3.2Town/ cityCarlsbad
    B.5.3.3Post codeCA 92010
    B.5.3.4CountryUnited States
    B.5.4Telephone number17609319200
    B.5.5Fax number17606032504
    B.5.6E-mailClinicalTrials@ionisph.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 nameDonidalorsen
    D.3.2Product code ISIS 721744
    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 INNDonidalorsen
    D.3.9.1CAS number 2304701-45-7
    D.3.9.2Current sponsor codeISIS 721744
    D.3.9.4EV Substance CodeSUB199751
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    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 antisense 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
    Hereditary Angioedema (HAE)
    angioedema hereditario (AEH)
    E.1.1.1Medical condition in easily understood language
    Genetic disease characterized by the occurrence of transitory and recurrent subcutaneous and/or submucosal edemas resulting in swelling and/or abdominal pain
    Enfermedad genética caracterizada por la aparición de edemas subcutáneos y/o submucosos transitorios y recurrentes que resultan en hinchazón y/o dolor abdominal
    E.1.1.2Therapeutic area Body processes [G] - Genetic Phenomena [G05]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 23.1
    E.1.2Level PT
    E.1.2Classification code 10019860
    E.1.2Term Hereditary angioedema
    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
    The primary objective of the study is to evaluate the safety of long-term dosing with donidalorsen in patients with HAE
    El objetivo principal del estudio es evaluar la seguridad de la dosificación a largo plazo con donidalorsen en pacientes con AEH
    E.2.2Secondary objectives of the trial
    To evaluate the long-term efficacy and the effects of donidalorsen on the number of HAE attacks and their impact on the quality of life (QoL) of patients with HAE.
    Evaluar la eficacia a largo plazo y los efectos de donidalorsen sobre el número de ataques de AEH y su impacto en la calidad de vida (CdV) de los pacientes con AEH.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Participants and, as applicable, legally authorized representatives (i.e., parent(s)/legal guardian), must provide written and signed informed consent form (ICF).
    2. Participants must have access to, and the ability to use, ≥ 1 acute medication(s) (e.g., plasma-derived or recombinant C1-INH concentrate or a bradykinin receptor (BK) 2-receptor antagonist) to treat angioedema attacks
    Open-Label Extension Participants ONLY:
    3. Satisfactory completion of ISIS 721744-CS5 (randomized placebo-controlled index study) through Week 25 or participants who are allowed to exit ISIS 721744-CS5 study per protocol with an acceptable safety and tolerability profile
    New (not previously on donidalorsen) Participants ONLY
    4. Participants must be aged ≥ 12 years at the time of informed consent and, as applicable, assent
    5. Participants must have a documented diagnosis of HAE-1/HAE-2
    6. Participants must be on a stable dose (≥ 12 weeks) of prophylaxis treatment with lanadelumab or berotralstat or SC C1-esterase inhibitor prior to the Screening Period
    1. Los participantes y, según corresponda, los representantes legalmente autorizados (es decir, padre(s)/tutor legal), deben proporcionar un formulario de consentimiento informado (ICF) por escrito y firmado.
    2. Los participantes deben tener acceso a, y la capacidad de usar, ≥ 1 medicamento(s) agudo(s) (p. ej., concentrado de C1-INH recombinante o derivado de plasma o un antagonista del receptor de bradicinina (BK) 2) para tratar los ataques de angioedema
    SÓLO participantes de extensión de etiqueta abierta:
    3. Finalización satisfactoria de ISIS 721744-CS5 (estudio de índice aleatorizado controlado con placebo) hasta la semana 25 o participantes a los que se les permite salir del estudio ISIS 721744-CS5 por protocolo con un perfil de seguridad y tolerabilidad aceptable
    Participantes nuevos (no previamente en donidalorsen) SOLAMENTE
    4. Los participantes deben tener ≥ 12 años en el momento del consentimiento informado y, según corresponda, el asentimiento.
    5. Los participantes deben tener un diagnóstico documentado de HAE-1/HAE-2
    6. Los participantes deben estar en una dosis estable (≥ 12 semanas) de tratamiento profiláctico con lanadelumab o berotralstat o inhibidor de la esterasa SC C1 antes del período de selección.
    E.4Principal exclusion criteria
    1. Have any new condition or worsening of an existing condition or change or anticipated change in medication
    De-novo Participants:
    2. Concurrent diagnosis of any other type of recurrent angioedema, including acquired, idiopathic angioedema or HAE with normal C1-INH (also known as HAE Type III)
    3. Anticipated change in the use of concurrent androgen or tranexamic acid prophylaxis used to prevent angioedema attacks
    Any clinically-significant abnormalities in screening laboratory values
    4. Malignancy within 5 years of Screening, except for non-melanoma skin cancers, cervical in situ carcinoma, breast ductal carcinoma in situ, or stage 1 prostate carcinoma that has been successfully treated.
    5. Hypersensitivity to the active substance (donidalorsen) or to any of the excipients
    6. Treatment with another investigational drug (non-oligonucleotide) or biological agent within 1 month of Screening or 5 half-lives of investigational agent, whichever is longer
    7. Recent history of, or current drug or alcohol abuse
    8. Participated in a prior donidalorsen study
    9. Exposure to any of the following medications:
    Angiotensin-converting enzyme (ACE) inhibitors or any estrogen containing medications with systemic absorption
    Oligonucleotides (including small interfering ribonucleic acid [siRNA]) within 4 months of Screening if single dose received, or within 12 months of Screening if multiple doses received. This exclusion does not apply to vaccines
    1. Tiene alguna condición nueva o empeoramiento de una condición existente o cambio o cambio anticipado en la medicación
    Participantes nuevos:
    2. Diagnóstico concurrente de cualquier otro tipo de angioedema recurrente, incluido el angioedema idiopático adquirido o AEH con C1-INH normal (también conocido como AEH tipo III)
    3. Cambio anticipado en el uso de andrógenos concomitantes o profilaxis con ácido tranexámico para prevenir ataques de angioedema
    Cualquier anormalidad clínicamente significativa en los valores de laboratorio de detección
    4. Neoplasia maligna dentro de los 5 años posteriores a la detección, a excepción de los cánceres de piel no melanoma, el carcinoma in situ de cuello uterino, el carcinoma ductal de mama in situ o el carcinoma de próstata en estadio 1 que se haya tratado con éxito.
    5. Hipersensibilidad al principio activo (donidalorsen) o a alguno de los excipientes
    6. Tratamiento con otro fármaco en investigación (no oligonucleótido) o agente biológico en el plazo de 1 mes desde la selección o 5 semividas del agente en investigación, lo que sea más largo
    7. Historial reciente o abuso actual de drogas o alcohol
    8. Participó en un estudio anterior de donidalorsen
    9. Exposición a cualquiera de los siguientes medicamentos:
    Inhibidores de la enzima convertidora de angiotensina (ECA) o cualquier medicamento que contenga estrógeno con absorción sistémica
    Oligonucleótidos (incluido el ácido ribonucleico de interferencia pequeño [siRNA]) dentro de los 4 meses posteriores a la selección si se recibió una dosis única, o dentro de los 12 meses posteriores a la selección si se recibieron dosis múltiples. Esta exclusión no se aplica a las vacunas.
    E.5 End points
    E.5.1Primary end point(s)
    Incidence and severity of treatment-emergent adverse events (TEAEs).
    Incidencia y gravedad de los eventos adversos emergentes del tratamiento (TEAE).
    E.5.1.1Timepoint(s) of evaluation of this end point
    From week 1 to week 53
    De la semana 1 a la semana 53
    E.5.2Secondary end point(s)
    • The time-normalized number of Investigator-confirmed HAE attacks (per month) from Week 1 to Week 53
    • The time-normalized number of Investigator-confirmed HAE attacks (per month) from Week 5 to Week 53
    • The percentage of Investigator-confirmed HAE attack-free patients from Week 5 to Week 53
    • The time-normalized number of moderate or severe Investigator-confirmed HAE attacks (per month) from Week 5 to Week 53
    • The number of Investigator-confirmed HAE attacks requiring acute therapy from Week 5 to Week 53
    • Angioedema Quality of Life (AE-QoL) questionnaire total score over 53 weeks
    • El número normalizado en el tiempo de ataques de AEH confirmados por el investigador (por mes) desde la semana 1 hasta la semana 53
    • El número normalizado en el tiempo de ataques de AEH confirmados por el investigador (por mes) desde la semana 5 hasta la semana 53
    • El porcentaje de pacientes sin ataque de AEH confirmado por el investigador desde la semana 5 hasta la semana 53
    • El número normalizado en el tiempo de ataques de AEH moderados o graves confirmados por el investigador (por mes) desde la semana 5 hasta la semana 53
    • El número de ataques de AEH confirmados por el investigador que requirieron tratamiento agudo desde la semana 5 hasta la semana 53
    • Puntuación total del cuestionario Angioedema Quality of Life (AE-QoL) durante 53 semanas
    E.5.2.1Timepoint(s) of evaluation of this end point
    From week 1 to week 53
    De la semana 1 a la semana 53
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis Yes
    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.8.2.4Number 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 concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA26
    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
    Canada
    Israel
    United States
    France
    Poland
    Bulgaria
    Netherlands
    Spain
    Germany
    Italy
    Belgium
    Denmark
    Turkey
    United Kingdom
    E.8.7Trial 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
    The End-of-Study is defined as the date of the last visit of the last patient in the study. For individual patients, End-of-Study is defined as completion of their last study visit.
    El final del estudio se define como la fecha de la última visita del último paciente del estudio. Para pacientes individuales, el final del estudio se define como la finalización de su última visita del estudio.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months9
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months9
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 10
    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) Yes
    F.1.1.6.1Number of subjects for this age range: 10
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 99
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 5
    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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Children under the age of consent are considered incapable of giving consent personally.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 59
    F.4.2.2In the whole clinical trial 114
    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)
    None
    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 Decision2022-10-06
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-09-26
    P. End of Trial
    P.End of Trial StatusOngoing
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