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    Summary
    EudraCT Number:2021-002571-19
    Sponsor's Protocol Code Number:ISIS721744-CS5
    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:2022-01-27
    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 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)
    Studio di fase 3, in doppio cieco, controllato con placebo per valutare l’efficacia e la sicurezza di ISIS 721744 in pazienti con angioedema ereditario (AEE)
    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)
    Studio di fase 3, in doppio cieco, controllato con placebo per valutare l’efficacia e la sicurezza di ISIS 721744 in pazienti con angioedema ereditario (AEE)
    A.3.2Name or abbreviated title of the trial where available
    -
    -
    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 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
    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 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 nameISIS 721744
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for injection/infusion
    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 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 di transitori e edemi sottocutanei e/o sottomucosi 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 clinical efficacy of ISIS 721744 in patients with HAE.
    L'obiettivo primario dello studio è valutare l'efficacia clinica di ISIS 721744 in pazienti con HAE.
    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.
    Valutare gli effetti di ISIS 721744 sulla qualità e il modello degli attacchi di HAE e il loro impatto sulla qualità della vita.
    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
    I pazienti devono avere un'età >= 12 anni al momento del consenso informato e, se applicabile, dell'assenso
    I pazienti devono avere una diagnosi documentata di HAE-1/HAE-2 basata su TUTTI i seguenti:
    a. Anamnesi clinica documentata coerente con HAE (episodi di gonfiore sottocutaneo [SC] o delle mucose, non pruriginosi senza accompagnamento di orticaria)
    b. Risultati dei test diagnostici che confermano HAE-1/HAE-2: livello funzionale C1-INH < 40% livello normale. I pazienti con un livello funzionale dal 40% al 50% del normale possono essere arruolati se il loro livello di fattore C4 del complemento è inferiore al limite inferiore della norma (LLN) o se è stata dimostrata una mutazione patogena nota nel gene SERPING1
    c. Almeno 1 dei seguenti: età all'esordio dell'HAE segnalato = 30 anni; una storia familiare coerente con HAE-1/HAE-2; o complemento componente 1q entro il range di normalità
    I pazienti devono:
    a. Avere avuto un minimo di 2 attacchi di HAE (confermati dallo Sperimentatore) durante il Periodo di Screening
    b. Essere disposti a completare le valutazioni PRO durante lo studio
    I pazienti devono avere accesso e la capacità di utilizzare = 1 farmaco/i acuti (ad es. concentrato di C1-INH derivato dal plasma o ricombinante o un antagonista del recettore BK2) per trattare gli attacchi di 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 estrogencontaining 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 previsto della profilassi a breve termine per gli attacchi di angioedema per una procedura pre-programmata durante i periodi di screening, trattamento o post-trattamento
    • Diagnosi concomitante di qualsiasi altro tipo di angioedema ricorrente, incluso angioedema acquisito, idiopatico o HAE con C1-INH normale (noto anche come HAE di tipo III)
    • Cambiamento previsto nell'uso concomitante della profilassi androgena utilizzata per il trattamento degli attacchi di angioedema
    • Partecipazione a un precedente studio ISIS 721744
    • Esposizione a uno dei seguenti farmaci:
    a. Inibitori dell'enzima di conversione dell'angiotensina (ACE) o qualsiasi farmaco contenente estrogeni ad assorbimento sistemico (come contraccettivi orali o terapia ormonale sostitutiva) nelle 4 settimane precedenti lo screening
    b. Profilassi cronica con Takhzyro, Haegarda, Cinryze o Orladeyo entro 5 emivite prima dello screening (cioè, Takhzyro entro 10 settimane prima dello screening, Haegarda/Cinryze entro 2 settimane prima dello screening, Orladeyo entro 3 settimane prima dello screening)
    c. Oligonucleotidi (incluso acido ribonucleico di piccola interferenza) entro 4 mesi dallo screening se ricevuto una dose singola, o entro 12 mesi dallo screening se ricevuto più dosi. Questa esclusione non si applica ai vaccini.
    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.
    L'endpoint primario è il numero normalizzato nel tempo di attacchi di HAE confermati dallo sperimentatore (al mese) dalla settimana 1 alla settimana 25 rispetto al placebo.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The time-normalized number of Investigator-confirmed HAE attacks (per month) from W5 to W25 compared to placebo
    • The percentage of Investigator-confirmed HAE attack-free patients from W5 to W25 compared to placebo
    • The time-normalized number of moderate or severe Investigatorconfirmed HAE attacks (per month) from W5 to W25 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 W5 to W25 compared to placebo
    • Percent of patients who are well-controlled based on the AECT at W25
    • Change in AE-QoL questionnaire total score at W25
    • The number of Investigator-confirmed HAE attacks requiring acute therapy from W5 to W25 compared to placebo.
    Il num normalizzato nel tempo di attacchi di HAE confermati dallo sper (al mese) da W5 a W25 rispetto al placebo
    • La perc di pa senza attacchi di HAE confermati dallo sperimentatore da W5 a W25 rispetto al placebo
    • Il num normalizzato nel tempo di attacchi di HAE moderati o gravi confermati dallo sper (al mese) dalla W5 alla W25 rispetto al placebo
    • Il num di paz con una risposta clinica definita come una rid = 50%, = 70% o = 90% rispetto al basale (ovvero, tasso di screening) nel tasso di attacchi di HAE confermato dallo speri tra W5 e W25 rispetto al placebo
    • Perc di paz ben controllati in base all'AECT a W25
    • Modifica del punteggio tot del questionario AE-QoL a W25
    • Il num di attacchi di HAE confermati dallo spere che richiedono una terapia acuta da W5 a W25 rispetto al placebo.
    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 concerned6
    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 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
    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.
    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 della loro ultima visita di studio.
    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.1.1.1In 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.
    I minori di età inferiore al consenso sono considerati incapaci di prestare il consenso personalmente.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state12
    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.
    Ciascun paziente sarà seguito per le valutazioni di sicurezza fino a 13 settt dopo il completamento o l'ET dal Periodo di trattamento. Durante il Periodo Post-Trattamento i pazienti rientreranno presso il Centro (o usufruiranno dell'Assistenza Domiciliare, se disponibile), come disposto dal personale del Centro.
    A tutti i pazienti sarà data la possibilità di iscriversi all'OLE; i pazienti che ricevono il beneficio potranno continuare a ricevere il farmaco dopo la fine dello studio.
    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 Decision2022-04-05
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-03-09
    P. End of Trial
    P.End of Trial StatusOngoing
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