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    Summary
    EudraCT Number:2022-000757-93
    Sponsor's Protocol Code Number:ISIS721744-CS7
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2022-06-23
    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 ConcernedItaly - Italian Medicines Agency
    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)
    Studio in aperto sulla sicurezza e l’efficacia a lungo termine di donidalorsen nel trattamento profilattico dell’angioedema ereditario (AEE)
    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)
    Studio in aperto sulla sicurezza e l’efficacia a lungo termine di donidalorsen nel trattamento profilattico dell’angioedema ereditario (AEE)
    A.3.2Name or abbreviated title of the trial where available
    NA
    NA
    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 No
    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/infusion
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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 Ereditario (AAE)
    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
    Malattia genetica caratterizzata dal verificarsi edemi sottocutanei e/o sottomucosi transitori e ricorrenti con conseguente gonfiore e/o dolore addominale
    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
    L'obiettivo primario dello studio è valutare la sicurezza della somministrazione a lungo termine di donidalorsen in pazienti affetti da AEE
    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.
    Valutare l’efficacia e gli effetti a lungo termine di donidalorsen sul numero di attacchi di AEE e il loro impatto sulla qualità della vita (QoL) dei pazienti affetti da AEE
    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 placebocontrolled 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. I pazienti, se applicabile, i rappresentanti legalmente autorizzati (ad es. genitore(i)/tutore legale), devono fornire un modulo di consenso informato (ICF) scritto e firmato.
    2. I pazienti devono avere accesso a, e la capacità di, utilizzare =1 farmaco acuto (ad es. concentrato di C1-INH plasmaderivato o ricombinante o un antagonista del recettore 2 del recettore della bradichinina (BK)) per il trattamento degli attacchi di angioedema
    SOLO pazienti dell’estensione in aperto:
    3. Completamento soddisfacente di ISIS 721744-CS5 (studio indice randomizzato controllato con placebo) fino alla Settimana 25 o pazienti che possano uscire dallo studio ISIS 721744-CS5 come da protocollo con un profilo di sicurezza e tollerabilità accettabile
    SOLO nuovi partecipanti (non precedentemente su donidalorsen):
    4. I pazienti devono avere un’età =12 anni al momento del consenso informato e, se pertinente, dell’assenso
    5. I pazienti devono presentare una diagnosi documentata di AEE-1/AEE-2
    6. I pazienti devono essere in trattamento profilattico con lanadelumab o berotralstat a dose stabile (=12 settimane) o con inibitore della C1 esterasi per via sottocutanea prima del Periodo di screening
    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 12months of Screening if multiple doses received. This exclusion does not apply to vaccines
    1. Presenza di qualsiasi nuova condizione o peggioramento di una condizione esistente o cambiamento o cambiamento anticipato inerente nel farmaco
    Partecipanti De-novo:
    2. Diagnosi concomitante di qualsiasi altro tipo di angioedema ricorrente, tra cui angioedema acquisito idiopatico o AEE con C1-INH normale (noto anche come AEE di tipo III)
    3. Variazione prevista nell’uso della profilassi concomitante androgenica o con acido tranexamico utilizzata per prevenire gli attacchi di angioedema.
    Qualsiasi anomalia clinicamente significativa nello screening dei valori di laboratorio
    4. Neoplasie maligne entro 5 anni dallo screening, ad eccezione dei tumori cutanei non melanoma, carcinoma cervicale in situ, carcinoma duttale mammario in situ o carcinoma prostatico in stadio 1 che è stato trattato con successo.
    5. Ipersensibilità al principio attivo (donidalorsen) o ad uno qualsiasi degli eccipienti
    6. Trattamento con un altro farmaco sperimentale (non oligonucleotide) o agente biologico entro 1 mese dallo screening o 5 emivite dell'agente sperimentale, a seconda di quale sia il periodo più lungo
    7. Storia recente o attuale di abuso di droghe o alcol
    8. Ha partecipato a uno studio precedente su donidalorsen
    9. Esposizione a uno qualsiasi dei seguenti farmaci:
    - Inibitori dell'enzima di conversione dell'angiotensina (ACE) o qualsiasi farmaco contenente estrogeni con assorbimento sistemico
    - Oligonucleotidi (compreso il piccolo acido ribonucleico d'interferenza [siRNA]) entro 4 mesi dallo screening se è stata ricevuta una singola dose, o entro 12 mesi dallo screening se sono state ricevute più dosi. Questa esclusione non si applica ai vaccini
    E.5 End points
    E.5.1Primary end point(s)
    Incidence and severity of treatment-emergent adverse events (TEAEs).
    Incidenza e gravità degli eventi avversi emergenti dal trattamento (TEAEs)
    E.5.1.1Timepoint(s) of evaluation of this end point
    From week 1 to week 53
    Dalla settimana 1 alla settimana 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 Investigatorconfirmed 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
    • Numero normalizzato nel tempo di attacchi di AEE confermati dallo sperimentatore (al mese) dalla Settimana 1 alla Settimana 53
    • Numero normalizzato nel tempo di attacchi di AEE confermati dallo sperimentatore (al mese) dalla Settimana 5 alla Settimana 53
    • Percentuale di pazienti senza attacchi di AEE confermati dallo sperimentatore dalla Settimana 5 alla Settimana 53
    • Numero normalizzato nel tempo di attacchi di AEE moderati o gravi confermati dallo sperimentatore (al mese) dalla Settimana 5 alla Settimana 53
    • Numero di attacchi di AEE confermati dallo sperimentatore che necessitano di terapia acuta dalla Settimana 5 alla Settimana 53
    • Punteggio totale del questionario sulla qualità della vita con angioedema (AE-QoL) nel corso di 53 settimane
    E.5.2.1Timepoint(s) of evaluation of this end point
    From week 1 to week 53
    Dalla settimana 1 alla settimana 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 No
    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 Yes
    E.8.1.7.1Other trial design description
    open
    open
    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 concerned6
    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 Information not present in EudraCT
    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.
    La fine dello studio è definita come la data dell'ultima visita dell'ultimo paziente nello studio. Per i singoli pazienti, la fine dello studio è definita come il completamento dell'ultima visita dello studio.
    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.1.1.1In 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
    I minori al di sotto dell'età del consenso sono considerati incapaci di fornire il consenso personalmente
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state15
    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
    Nessuno
    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 Decision2022-09-02
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-09-14
    P. End of Trial
    P.End of Trial StatusOngoing
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