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    Summary
    EudraCT Number:2021-002571-19
    Sponsor's Protocol Code Number:ISIS721744-CS5
    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:2022-02-08
    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 number2021-002571-19
    A.3Full title of the trial
    A Phase 3 Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of ISIS 721744 in Patients with Hereditary Angioedema (HAE)
    Estudio de fase 3, doble ciego, controlado con placebo para evaluar la eficacia y seguridad de ISIS 721744 en pacientes con angioedema hereditario (AEH)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase 3 Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of ISIS 721744 in Patients with Hereditary Angioedema (HAE)
    Estudio de fase 3, doble ciego, controlado con placebo para evaluar la eficacia y seguridad de ISIS 721744 en pacientes con angioedema hereditario (AEH)
    A.4.1Sponsor's protocol code numberISIS721744-CS5
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT05139810
    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
    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 code92010
    B.5.3.4CountryUnited States
    B.5.4Telephone number1760931 9200
    B.5.5Fax number1760603-2504
    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.3.2Product 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
    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
    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 clinical efficacy of ISIS 721744 in patients with HAE.
    El objetivo principal del estudio es evaluar la eficacia clínica de ISIS 721744 en pacientes con AEH.
    E.2.2Secondary objectives of the trial
    Evaluate the effects of ISIS 721744 on the quality and pattern of HAE attacks and their impact on Quality of Life.
    Evaluar los efectos de ISIS 721744 en la calidad y el patrón de los ataques de AEH y su impacto en la calidad de vida.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Patients must be aged ≥ 12 years at the time of informed consent, and, as applicable, assent
    Patients must have a documented diagnosis of HAE-1/HAE-2 based upon ALL of the following:
    a. Documented clinical history consistent with HAE (subcutaneous [SC] or mucosal, non-pruritic swelling episodes without accompanying urticaria)
    b. Diagnostic testing results that confirm HAE-1/HAE-2: C1-INH functional level < 40% normal level. Patients with a functional level of 40% to 50% of normal can be enrolled if their complement factor C4 level is below the lower limit of normal (LLN) or if a known pathogenic mutation in the SERPING1 gene has been demonstrated
    c. At least 1 of the following: age at reported HAE onset ≤ 30 years; a family history consistent with HAE-1/HAE-2; or complement component 1q within the normal range
    Patients must:
    a. Experience a minimum of 2 HAE attacks (confirmed by the Investigator) during the Screening Period
    b. Be willing to complete the PRO assessments throughout the study
    Patients must have access to, and the ability to use, ≥ 1 acute medication(s) (e.g., plasma-derived or recombinant C1-INH concentrate or a BK2-receptor antagonist) to treat angioedema attacks
    Los pacientes deben tener ≥ 12 años de edad en el momento del consentimiento informado y, en su caso, el asentimiento.
    Los pacientes deben tener un diagnóstico documentado de HAE-1/HAE-2 basado en TODO lo siguiente:
    A. Historia clínica documentada compatible con AEH (episodios de hinchazón subcutánea [SC] o mucosa, no pruriginosa sin urticaria acompañante)
    B. Resultados de las pruebas de diagnóstico que confirman HAE-1/HAE-2: nivel funcional de C1-INH <40 % del nivel normal. Los pacientes con un nivel funcional del 40 % al 50 % del normal pueden inscribirse si su nivel del factor C4 del complemento está por debajo del límite inferior normal (LLN) o si se ha demostrado una mutación patogénica conocida en el gen SERPING1.
    C. Al menos 1 de los siguientes: edad de inicio del AEH notificado ≤ 30 años; antecedentes familiares compatibles con HAE-1/HAE-2; o complemento componente 1q dentro del rango normal

    Los pacientes deben:
    A. Experimente un mínimo de 2 ataques de HAE (confirmados por el investigador) durante el período de selección
    B. Estar dispuesto a completar las evaluaciones PRO a lo largo del estudio
    Los pacientes deben tener acceso a, y la capacidad de usar, ≥ 1 medicamento(s) agudo(s) (p. ej., concentrado de C1-INH derivado de plasma o recombinante o un antagonista del receptor BK2) para tratar los ataques de angioedema
    E.4Principal exclusion criteria
    • Anticipated use of short-term prophylaxis for angioedema attacks for a pre-planned procedure during the Screening, Treatment or Post-Treatment Periods
    • 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)
    • Anticipated change in the use of concurrent androgen prophylaxis used to treat angioedema attacks
    • Participation in a prior ISIS 721744 study
    • Exposure to any of the following medications:
    a. Angiotensin-converting enzyme (ACE) inhibitors or any estrogen-containing medications with systemic absorption (such as oral contraceptive or hormonal replacement therapy) within 4 weeks prior to Screening
    b. Chronic prophylaxis with Takhzyro, Haegarda, Cinryze or Orladeyo within 5 half-lives prior to Screening (i.e., Takhzyro within 10 weeks prior to Screening, Haegarda/Cinryze within 2 weeks prior to screening, Orladeyo within 3 weeks prior to Screening)
    c. Oligonucleotides (including small interfering ribonucleic acid) 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
    • Uso anticipado de profilaxis a corto plazo para ataques de angioedema para un procedimiento planificado previamente durante los Períodos de selección, tratamiento o postratamiento
    • 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)
    • Cambio anticipado en el uso de la profilaxis androgénica concurrente para tratar los ataques de angioedema
    • Participación en un estudio anterior ISIS 721744
    • Exposición a cualquiera de los siguientes medicamentos:
    A. Inhibidores de la enzima convertidora de angiotensina (ACE) o cualquier medicamento que contenga estrógeno con absorción sistémica (como anticonceptivos orales o terapia de reemplazo hormonal) dentro de las 4 semanas anteriores a la selección
    B. Profilaxis crónica con Takhzyro, Haegarda, Cinryze u Orladeyo en las 5 semividas anteriores a la Selección (es decir, Takhzyro en las 10 semanas anteriores a la Selección, Haegarda/Cinryze en las 2 semanas anteriores a la Selección, Orladeyo en las 3 semanas anteriores a la Selección)
    C. Oligonucleótidos (incluido el ácido ribonucleico pequeño que interfiere) dentro de los 4 meses de
    Detección si se recibió una dosis única, o dentro de los 12 meses posteriores a la Detección si se recibieron dosis múltiples. Esta exclusión no se aplica a las vacunas.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is the time-normalized number of Investigator-confirmed HAE attacks (per month) from Week 1 to Week 25 compared to placebo.
    El criterio principal de valoración es el número normalizado en el tiempo de ataques de AEH confirmados por el investigador (por mes) desde la semana 1 hasta la semana 25 en comparación con el placebo.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Described in section E5.1
    Descrito en la sección E5.1
    E.5.2Secondary end point(s)
    The time-normalized number of Investigator-confirmed HAE attacks (per month) from Week 5 to Week 25 compared to placebo
    • The percentage of Investigator-confirmed HAE attack-free patients from Week 5 to Week 25 compared to placebo
    • The time-normalized number of moderate or severe Investigator-confirmed HAE attacks (per month) from Week 5 to Week 25 compared to placebo
    • The number of patients with a clinical response defined as a ≥ 50%, ≥ 70%, or ≥ 90% reduction from Baseline (i.e., screening rate) in Investigator-confirmed HAE attack rate between Week 5 to Week 25 compared to placebo
    • Percent of patients who are well-controlled based on the AECT at Week 25
    • Change in AE-QoL questionnaire total score at Week 25
    • The number of Investigator-confirmed HAE attacks requiring acute therapy from Week 5 to Week 25 compared to placebo.
    El número normalizado en el tiempo de ataques de AEH confirmados por el investigador (por mes) desde la semana 5 hasta la semana 25 en comparación con el placebo
    • El porcentaje de pacientes sin ataque de AEH confirmado por el investigador desde la semana 5 hasta la semana 25 en comparación con el placebo
    • 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 25 en comparación con el placebo
    • El número de pacientes con una respuesta clínica definida como una reducción de ≥ 50 %, ≥ 70 % o ≥ 90 % desde el valor inicial (es decir, tasa de detección) en la tasa de ataque de AEH confirmada por el investigador entre la semana 5 y la semana 25 en comparación con el placebo
    • Porcentaje de pacientes que están bien controlados según el AECT en la semana 25
    • Cambio en la puntuación total del cuestionario AE-QoL en la semana 25
    • El número de ataques de AEH confirmados por el investigador que requirieron tratamiento agudo desde la Semana 5 hasta la Semana 25 en comparación con el placebo.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Described in section E5.1
    Descrito en la sección E5.1
    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 Yes
    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 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 Yes
    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 concerned3
    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
    Belgium
    Bulgaria
    Canada
    France
    Germany
    Israel
    Italy
    Netherlands
    Poland
    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
    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 years1
    E.8.9.1In the Member State concerned months11
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months11
    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: 69
    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 state9
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 44
    F.4.2.2In the whole clinical trial 84
    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)
    Each patient will be followed for safety assessments for up to 13 weeks after completion of, or ET from, the Treatment Period. During the Post-Treatment Period, patients will return to the Study Center (or have Home Healthcare, if available), as arranged by the Study Center personnel.
    All patients will be given the opportunity to enroll in the OLE; patients who receive benefit will be allowed to continue receiving drug after the trial has ended.
    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 Decision2022-05-17
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-05-06
    P. End of Trial
    P.End of Trial StatusOngoing
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