E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Congenital auditory neuropathy secondary to biallelic mutations of the otoferlin gene (hOTOF) |
Neuropatía auditiva congénita secundaria a mutaciones bialélicas del gen otoferlin (hOTOF) |
|
E.1.1.1 | Medical condition in easily understood language |
Infants and children who have hearing loss due to changes in the otoferlin gene. Patients with this diagnosis may be born with profound hearing loss and are not expected to improve without treatment. |
Lactantes y niños con pérdida de audición debido a cambios en el gen otoferlin.Los pacientes con este diagnóstico pueden nacer con pérdida auditiva profunda y no se espera que mejoren sin tratamiento. |
|
E.1.1.2 | Therapeutic area | Body processes [G] - Genetic Phenomena [G05] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10011874 |
E.1.2 | Term | Deaf |
E.1.2 | System Organ Class | 100000004854 |
|
E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
•To evaluate the safety and tolerability of DB-OTO in young children and infants diagnosed with biallelic otoferlin gene (hOTOF) mutations |
•Evaluar la seguridad y tolerabilidad de DB-OTO en niños pequeños y lactantes diagnosticados con mutaciones bialélicas del gen de la otoferlina (hOTOF) |
|
E.2.2 | Secondary objectives of the trial |
•To evaluate preliminary efficacy of DB-OTO in young children and infants diagnosed with biallelic hOTOF mutations |
•Evaluar la eficacia preliminar de la DB-OTO en niños pequeños y lactantes diagnosticados con mutaciones bialélicas de hOTOF |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1.Willingness of at least 1 parent/legal guardian to provide written informed consent and willingness to comply with trial protocol 2.Willingness of at least 1 parent/legal guardian to consent to genetic testing for the infant or child in order to evaluate a panel of hearing loss-related genes 3.Willingness of at least 1 parent/legal guardian to consent to vaccinations for the infant or child in accordance with the country-specific pediatric immunization schedule 4.Child/infant is 24 months of age or younger at the time of the parent/legal guardian signing the informed consent form 5.The Investigator determines the patient is eligible for cochlear implantation 6.Presence of biallelic, likely pathogenic or pathogenic hOTOF mutation 7.No clinically significant laboratory findings on clinical laboratory tests at time of Screening 8.Absence of an ABR neural signal in response to a click stimulus at or below 85 decibels normalized Hearing Level (dB nHL) in the ear(s) to be injected with DB-OTO 9.DPOAE present with ≥ 6 dB signal-to-noise ratio at ≥ 3 frequencies in a distortion product (DP) Gram measured from 1 to 8 kHz in the ear(s) to be injected with DB-OTO 10.No evidence from measures of hearing loss that show a dependence on body temperature 11.Willingness of at least 1 parent/legal guardian to complete questionnaires at protocol-specific timepoints |
1. Disposición de al menos 1 progenitor/tutor legal para proporcionar el consentimiento informado por escrito y disposición para cumplir con el protocolo del ensayo 2. Disposición de al menos 1 progenitor/tutor legal a dar su consentimiento para las pruebas genéticas para el bebé o niño/a con el fin de evaluar un panel de genes relacionados con la pérdida de audición 3. Disposición de al menos 1 progenitor/tutor legal a dar su consentimiento para las vacunas del bebé o niño/a de acuerdo con el calendario de vacunación pediátrica específico del país 4. El niño/a o lactante tiene 24 meses de edad o menos en el momento de la firma del formulario de consentimiento informado por parte del progenitor/tutor legal 5. El investigador determina que el paciente es apto para la implantación coclear 6. Presencia de mutación bialélica, probablemente patógena o patógena de hOTOF 7. Sin hallazgos de laboratorio clínicamente significativos en las pruebas de laboratorio clínico en el momento de la selección 8. Ausencia de una señal neuronal de ABR en respuesta a un estímulo de clic en el nivel de audición normalizado (dB nHL) de 85 decibelios o menos en el oído u oídos a inyectar con DB-OTO 9. EOAPD presentes con una relación señal/ruido ≥6 dB a ≥3 frecuencias en un producto de distorsión (DP) Gram medido de 1 a 8 kHz en el/los oído(s) a inyectar con DB-OTO 10. No hay evidencia de medidas de pérdida de audición que muestren dependencia de la temperatura corporal 11. Disposición de al menos 1 progenitor/tutor legal para cumplimentar cuestionarios en puntos temporales específicos del protocolo |
|
E.4 | Principal exclusion criteria |
1.Presence of any disease or disorder that, in the opinion of the Investigator, would interfere with conducting the trial 2.History of prior treatment with gene therapy 3.Surgical anatomy that would preclude the planned surgical approach as indicated by medical imaging (eg, computed tomography [CT] or MRI) in the ear(s) to be injected with DB-OTO 4.History or presence of any other permanent/untreatable hearing loss conditions 5.History or presence of malignancies 6.History or presence of meningitis 7.History or presence of treatment with ototoxic drugs that, in the opinion of the Investigator, would interfere with conducting the trial 8.History or presence of cochlear implants in the ear(s) to be injected with DB-OTO 9.History of risk factor(s) for auditory neuropathy not caused by hOTOF mutations including, but not limited to, prematurity, low birth weight, hyperbilirubinemia, neonatal intensive care unit (NICU) admission, and/or low Apgar scores that, in the opinion of the Investigator, would interfere with conducting the trial 10.Any condition that, in the opinion of the Investigator, would interfere with conducting the trial including, but not limited to, undergoing anesthesia\surgery, complying with the trial criteria, undergoing audiological assessment, and participating for the entire duration of the trial 11.Concurrent participation in another investigational trial |
1. Presencia de cualquier enfermedad o trastorno que, en opinión del investigador, pudiera interferir con la realización del ensayo 2. Antecedentes de tratamiento previo con terapia génica 3. Anatomía quirúrgica que afectaría de forma significativa al enfoque quirúrgico previsto según lo indicado por las imágenes médicas (p. ej.,tomografía computarizada [TAC] o resonancia magnética [RM]) en el/los oído(s) a inyectar con DBOTO 4. Antecedentes o presencia de cualquier otra afección de pérdida de audición permanente/no tratable 5. Antecedentes o presencia de neoplasias malignas 6. Antecedentes o presencia de meningitis 7. Antecedentes o presencia de tratamiento con fármacos ototóxicos que, en opinión del investigador, interferirían en la realización del ensayo 8. Antecedentes o presencia de implantes cocleares en el/los oído(s) a inyectar con DB-OTO 9. Antecedentes de factor(es) de riesgo de neuropatía auditiva no causada por mutaciones en hOTOF, incluidos, entre otros, nacimiento prematuro, bajo peso al nacer, hiperbilirrubinemia, ingreso en la unidad de cuidados intensivos neonatales (UCIN) y/o puntuaciones de Apgar bajas que, en opinión del investigador, interferirían con la realización del ensayo 10. Cualquier afección que, en opinión del investigador, pudiera interferir con la realización del ensayo, incluidas, entre otras, someterse a anestesia/cirugía, cumplir con los criterios del ensayo, someterse a una evaluación audiológica y participar durante todo el ensayo 11. Participación simultánea en otro ensayo de investigación |
|
E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint of the trial is the incidence and severity of treatment-emergent systemic and local adverse events |
El criterio principal de valoración del ensayo es la incidencia y la gravedad de los acontecimientos adversos locales y sistémicos emergentes del tratamiento |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Adverse events (AEs) and SAEs will be monitored and recorded at the time of signing of the informed consent throughout the Baseline, Perioperative, Short-term follow-up and Long-term follow-up period. |
Los acontecimientos adversos (EA) y los SAEs se supervisarán y registrarán en el momento de la firma del consentimiento informado durante el periodo basal, perioperatorio, de seguimiento a corto plazo y de seguimiento a largo plazo. |
|
E.5.2 | Secondary end point(s) |
Auditory brainstem response (ABR) – change in intensity threshold (decibels Hearing Level [dB nHL]) across frequency domains Pure-tone audiometry – change in intensity thresholds (dB HL) in treated ear across frequency domains Speech awareness threshold (SAT) – change in threshold in treated ear |
Respuesta auditiva del tronco cerebral (ABR): Cambio en el umbral de intensidad (decibelios Nivel auditivo [dB NHL]) en todos los dominios de frecuencia Audiometría de tono puro: Cambio en los umbrales de intensidad (dB HL) en el oído tratado en todos los dominios de frecuencia Umbral de reconocimiento del habla (SAT): Cambio en el umbral del oído tratado |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Subjects will undergo ABR and Efficacy assessment at Week 4 ± 3 d, Week 6± 3 d, Week 12 ± 7 d, Week 24 ± 7 d, and Week 48 ± 7 d, during short term follow-up period and every 12 months from last visit (4 years) ± 2 weeks during long term follow-up period. |
Los sujetos se someterán a una tasa de reabsorción específica y a una evaluación de la eficacia en la semana 4 ± 3 d, semana 6± 3 d, semana 12 ± 7 d, semana 24 ± 7 d,y la semana 48 ± 7 d, durante el periodo de seguimiento a corto plazo y cada 12 meses desde la última visita (4 años) ± 2 semanas durante el periodo de seguimiento a largo plazo. |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
Tolerability |
Tolerabilidad |
|
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | Yes |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
Ensayo multicéntrico con una única cohorte de dosis ascendente seguida de una cohorte de expansión b |
Multicenter Trial With a Single Ascending Dose Cohort followed by a Bilateral Expansion Cohort |
|
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | 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.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 5 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
United States |
Spain |
United Kingdom |
|
E.8.7 | Trial 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
|
LVLS |
Última visita del último paciente |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 7 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | 22 |
E.8.9.2 | In all countries concerned by the trial years | 7 |
E.8.9.2 | In all countries concerned by the trial months | 5 |
E.8.9.2 | In all countries concerned by the trial days | 22 |