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    Summary
    EudraCT Number:2021-003603-18
    Sponsor's Protocol Code Number:331-201
    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:2022-07-05
    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 number2021-003603-18
    A.3Full title of the trial
    A Phase 1/2, Open-Label, Dose-Escalation Study to Determine the Safety, Tolerability, and Efficacy of BMN 331, an Adeno-Associated Virus (AAV) Vector-Mediated Gene Transfer of Human SERPING1, in Subjects with Hereditary Angioedema (HAE) due to Human C1 Esterase Inhibitor (C1-INH) Deficiency
    Estudio de fase 1/2, abierto y de aumento escalonado de la dosis para determinar la seguridad, tolerabilidad y la eficacia de BMN 331, un gen de transferencia de SERPING1 humano mediada por el vector del virus adenoasociado (AAV), en pacientes con angioedema hereditario (AEH) debido a carencia del inhibidor de la esterasa C1 (INH-C1) humano
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase 1/2 Study to evaluate the Safety, Tolerability and Efficacy of BMN 331 Gene Therapy in Subjects with Hereditary Angioedema (HAE)
    Un estudio de fase 1/2 para evaluar la seguridad, tolerabilidad y eficacia de la terapia génica BMN 331 en sujetos con angioedema hereditario (AEH)
    A.3.2Name or abbreviated title of the trial where available
    HAErmony-1
    A.4.1Sponsor's protocol code number331-201
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT05121376
    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 SponsorBioMarin Pharmaceutical 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 supportBioMarin Pharmaceutical Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationBioMarin Pharmaceutical Inc.
    B.5.2Functional name of contact pointClinical Trials Information
    B.5.3 Address:
    B.5.3.1Street Address105 Digital Drive
    B.5.3.2Town/ cityNovato
    B.5.3.3Post code94949
    B.5.3.4CountryUnited States
    B.5.6E-mailclinicaltrials@bmrn.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 BMN 331
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNNot available
    D.3.9.2Current sponsor codeBMN 331
    D.3.9.4EV Substance CodeSUB259292
    D.3.10 Strength
    D.3.10.1Concentration unit vector genomes (vg)/mL
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number60000000000000
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    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) Yes
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product Yes
    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 Yes
    D.3.11.10Medicinal product containing genetically modified organisms Yes
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    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
    Hereditary Angioedema (HAE)
    Angioedema hereditario (AEH)
    E.1.1.2Therapeutic area Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]
    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.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level LLT
    E.1.2Classification code 10080957
    E.1.2Term Hereditary angioedema C1 inhibitor deficiency
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    - Evaluate the safety of a single IV administration of BMN 331 for all dose levels administered during Part A
    - Evaluate the safety of a single IV administration of BMN 331 for the dose(s) determined in Part A
    - Evaluar la seguridad de una única administración intravenosa de BMN 331 para todos los niveles de dosis administrados durante la Parte A
    - Evaluar la seguridad de una única administración intravenosa de BMN 331 para la(s) dosis determinada(s) en la Parte A
    E.2.2Secondary objectives of the trial
    - Determine BMN 331 doses required to achieve and sustain clinically meaningful long-term expression of C1-INH
    - Determine the impact of BMN 331 on number of investigator confirmed HAE attack
    - Determine the impact of BMN 331 on use of HAE medication
    - Determinar las dosis de BMN 331 necesarias para lograr y mantener una expresión clínicamente significativa a largo plazo de C1-INH
    - Determinar el impacto de BMN 331 en el número de ataques de AEH confirmados por el investigador
    - Determinar el impacto de BMN 331 en el uso de medicamentos para el AEH
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Female or male adults ( ≥ 18 years old)
    Confirmed diagnosis of HAE due to C1-INH deficiency (Type I or II) confirmed by genotyping of SERPING1 gene
    Currently using an HAE medication regimen that consists of a routine long-term prophylactic treatment or an on-demand therapy for the last 6 months prior to enrollment for a documented attack frequency of at least 1 attack per month on average
    Trained in self-administering acute attack treatment and is able to adequately manage acute attacks in a home setting
    Willingness to abstain from consumption of alcohol for at least 52 weeks post BMN 331 infusion and to use highly effective contraception
    Mujeres o hombres adultos (≥ 18 años)
    Diagnóstico confirmado de AEH por deficiencia de C1-INH (Tipo I o II) confirmado por genotipificación del gen SERPING1
    Actualmente usa un régimen de medicación para AEH que consiste en un tratamiento profiláctico de rutina a largo plazo o una terapia a demanda durante los últimos 6 meses antes de la inscripción para una frecuencia de ataque documentada de al menos 1 ataque por mes en promedio
    Capacitado en la autoadministración de tratamiento para ataques agudos y es capaz de manejar adecuadamente los ataques agudos en un entorno domiciliario
    Voluntad de abstenerse de consumir alcohol durante al menos 52 semanas después de la infusión de BMN 331 y de usar métodos anticonceptivos altamente efectivos
    E.4Principal exclusion criteria
    Evidence of active or chronic infection, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), or any immunosuppressive disorder
    Contraindication to using glucocorticosteroids GCS, including a diagnosis of glaucoma or untreated osteoporosis
    Active malignancy (except non-melanoma skin cancer) autoimmune, metabolic (i.e., diabetes), hematologic, cardiac, or renal disease that is of clinical significance defined as requiring regular medical attention and treatment
    Prior gene therapy treatment
    Prior use of attenuated androgens in the last 1 year prior the study
    History or current clinically relevant liver disease (eg, nonalcoholic steatohepatitis [NASH], or chronic viral hepatitis B or C [HBV or HCV] or autoimmune hepatitis)
    Have a history or are at risk for clinically significant thromboembolic events (TEE) , or known underlying risk factor for thrombosis including thrombotic microangiopathy (TMA
    Evidencia de infección activa o crónica, incluido el síndrome respiratorio agudo severo coronavirus 2 (SARS-CoV-2), o cualquier trastorno inmunosupresor
    Contraindicación para el uso de glucocorticosteroides GCS, incluido un diagnóstico de glaucoma u osteoporosis no tratada
    Enfermedad maligna activa (excepto cáncer de piel no melanoma) enfermedad autoinmune, metabólica (por ej., diabetes), hematológica, cardíaca o renal de importancia clínica definida como que requiere atención y tratamiento médico regular
    Tratamiento previo de terapia génica
    Uso previo de andrógenos atenuados en el último año antes del estudio
    Antecedentes o enfermedad hepática actual clínicamente relevante (por ej., esteatohepatitis no alcohólica [EHNA], o hepatitis viral crónica B o C [VHB o VHC] o hepatitis autoinmune)
    Tiene antecedentes o está en riesgo de eventos tromboembólicos clínicamente significativos (ETE), o factor de riesgo subyacente conocido para la trombosis, incluida la microangiopatía trombótica (MAT).
    E.5 End points
    E.5.1Primary end point(s)
    - Incidence of AEs, SAEs, AESI
    - Clinical laboratory test results (serum chemistry, hematology, coagulation)
    - Vital signs
    - Physical examination findings
    - Vector shedding (blood, urine, semen, stool, saliva)
    - Liver test results (including ALT, AST, GGT, LDH, total bilirubin, and alkaline phosphatase)
    - Incidencia de AEs, SAEs, AESI
    - Resultados de pruebas de laboratorio clínico (química sérica, hematología, coagulación)
    - Signos vitales
    - Resultados del examen físico
    - Excreción de vector (sangre, orina, semen, heces, saliva)
    - Resultados de pruebas hepáticas (incluyendo ALT, AST, GGT, LDH, bilirrubina total y fosfatasa alcalina)
    E.5.1.1Timepoint(s) of evaluation of this end point
    Time Frame: Through 5 years.
    Marco de tiempo: A través de 5 años.
    E.5.2Secondary end point(s)
    Number and severity of investigator-confirmed HAE attacks
    Annualized use of HAE medication
    Plasma levels of functional C1-INH following BMN-331 infusion
    Plasma levels of C1-INH antigen following BMN 331 infusion
    Levels of total antibodies against AAV5 capsid following BMN 331 infusion
    Levels of total antibodies against C1-INH following BMN 331 infusion
    Levels of neutralizing antibodies against C1-INH following BMN 331 infusion
    Número y gravedad de los ataques de AEH confirmados por el investigador
    Uso anualizado de medicamentos para el AEH
    Niveles plasmáticos de C1-INH funcional después de la infusión de BMN-331
    Niveles plasmáticos de antígeno C1-INH después de la infusión de BMN 331
    Niveles de anticuerpos totales contra la cápside AAV5 después de la infusión de BMN 331
    Niveles de anticuerpos totales contra C1-INH después de la infusión de BMN 331
    Niveles de anticuerpos neutralizantes contra C1-INH tras la infusión de BMN 331
    E.5.2.1Timepoint(s) of evaluation of this end point
    Time Frame: Through 5 years.
    Marco de tiempo: A través de 5 años.
    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 No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    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) Yes
    E.7.1.1First administration to humans Yes
    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) No
    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.8.3 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 EEA4
    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
    United States
    France
    Spain
    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
    Last Visit Last Subject (LVLS)
    Última visita Último Sujeto (UVUS)
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years7
    E.8.9.2In all countries concerned by the trial months0
    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 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: 34
    F.1.3Elderly (>=65 years) No
    F.1.3.1Number of subjects for this age range: 0
    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 No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    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 state4
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 8
    F.4.2.2In the whole clinical trial 34
    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)
    This protocol includes assessment of safety and efficacy for approximately 5 years. No additional treatment will be given following the end of the study.
    Este protocolo incluye la evaluación de la seguridad y eficacia durante aproximadamente 5 años. No se administrará ningún tratamiento adicional después del final del estudio.
    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 Opinion2022-10-05
    P. End of Trial
    P.End of Trial StatusOngoing
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