Intraamniotic Administrations of ER004 to Male Subjects With X-linked Hypohidrotic Ectodermal Dysplasia

Официальное название

A Prospective, Open-label, Genotype-match Controlled, Multicenter Clinical Trial to Investigate the Efficacy and Safety of Intra-amniotic ER004 as a Prenatal Treatment for Male Subjects With XLHED

Обзор

This is an open-label, prospective, genotype-match controlled for primary estimand, non randomized, multicenter, international Phase 2 clinical trial designed to investigate the efficacy and safety of ER004 administered intraamniotically as a treatment for unborn XLHED male subjects.

Подробное описание

X-linked hypohidrotic ectodermal dysplasia (XLHED) is a rare developmental disease affecting body parts derived from the embryonal ectoderm. It is caused by a broad spectrum of mutations in the ectodysplasin A gene (EDA). The main symptoms of XLHED are hypo- or anhidrosis, oligo- or anodontia, and hypotrichosis. Current treatment options are limited to the management of disease symptoms and prevention of complications. Effective corrective treatment for XLHED remains a high unmet medical need. ER004 represents a first-in-class signaling protein replacement molecule designed for specific, high affinity binding to the endogenous EDA1 receptor (EDAR). The proposed mechanism of action of ER004 is the replacement of the missing EDA1 protein in patients with XLHED. The aim of this prospective, open-label, genotype-match controlled, multicenter Phase 2 trial is to confirm the efficacy and safety results for ER004 administered intra-amniotically in a larger cohort of subjects. The target population will consist of male XLHED fetuses/subjects with EDA mutation confirmed by genetic diagnosis of a mutation in one of the maternal EDA alleles and ultrasonographic diagnosis of a significantly reduced number of fetal tooth germs, or by documented direct genetic diagnosis of a hemizygous EDA mutation. In the main study phase, efficacy and safety of the treated subjects will be assessed up to 6 months of age and safety of the mothers will be assessed up to 1 month after delivery of the child. In long-term follow-up phase, efficacy and safety of the treated subjects will be assessed up to 5 years of age. Treated subjects sweating ability will be compared to an untreated relative from his family, when available, or from a matched controlled subject from a previous natural history.

Вмешательства

• Биопрепарат ER004
  Intra-amniotic route 100 mg/kg of estimated fetal weight per injection. 3 injections, approximately 3 weeks apart starting from gestational week 26

Первичные конечные точки

• Mean sweat volume [Срок оценки: at 6 months of age (corrected age for subjects born at < 37 weeks)]

Вторичные конечные точки (12)

• Mean sweat pore density (number/cm2) [Срок оценки: at 6 months of age (key secondary) and other timepoints : 3, 12, 18, 24, 36, 48 and 60 months of age (secondary)]
• Dental development [Срок оценки: at 6 months of age (key secondary) and other timepoints : 12, 18, 24, 36, 48 and 60 months of age (secondary)]
• Mean sweat volume [Срок оценки: At 3, 12, 18, 24, 36, 48, 60 months of age]
• Number of Meibomian glands [Срок оценки: At 6 and 60 months of age]
• Ocular surface assessment [Срок оценки: At 24, 48 and 60 months of age]
• Tear film break-up time [Срок оценки: At 24, 48 and 60 months of age]
• Ocular Surface Disease Index (OSDI) score [Срок оценки: At 60 months of age]
• Salivation [Срок оценки: At 60 months of age]
• XLHED-related hospitalizations [Срок оценки: Up to 60 months of age]
• Assessment of eczema [Срок оценки: At different timepoints from 6 to 60 months of age]
• Incidence of TEAEs (treatment-emergent adverse events) [Срок оценки: Up to 60 months of age]
• Incidence of TESAEs (treatment-emergent serious adverse events) [Срок оценки: Up to 60 months of age]

Критерии участия

Критерии включения

For mother: adult mother with confirmed pregnancy no later than week 23+6 and genetically confirmed as carrier of an EDA mutation

• For fetal subject : male fetal subject with confirmed diagnosis of XLHED
• For untreated relative: untreated male relative subject aged between 6 months and 75 years with the same EDA mutation as the treated subject

Критерии исключения

• For mother: any evidence of active maternal infection associated with a risk of preterm birth and/or congenital anomalies of prenatal and postnatal risk to the child. Documented maternal HIV infection. Any pre-existing maternal medical condition that increases the risk of preterm birth or increases the risk of a serious untoward event occurring to the mother during pregnancy. Any pregnancy disorder associated with an increased risk of preterm birth, and/or maternal, fetal or neonatal morbidity/mortality.
• For fetal subject : second major anatomic anomaly (not related to the underlying XLHED) that contributes to a significant morbidity or mortality risk, or echocardiogram or ultrasonography or other findings that indicate a high risk of fetal demise or risk of preterm birth. Any condition other than XLHED that is likely to have an impact on the number of tooth germs. Any other medical condition which in the opinion of the investigator would not allow for safe conduct of the study for the subject, or that would interfere with efficacy assessments.
• For untreated relative: carrier of an hypomorphic EDA mutation. Known hypersensitivity to pilocarpine or pilocarpine-like muscarinic agonists. Presence of an implanted device (e.g., defibrillator, neurostimulator, pacemaker). Previous treatment with the study intervention by any route of administration prior to study start.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

США · 2 центра

• Cedars-Sinai Medical Center — Los Angeles
• Washington University — St Louis

Германия · 2 центра

• Universitaetsklinikum Erlangen — Erlangen
• Universitaetsklinikum Leipzig AoeR — Leipzig

Франция · 1 центр

• Hôpital Necker - Enfants Malades — Paris

Италия · 1 центр

• IRCCS Ca' Granda Ospedale Policlinico — Milan

Испания · 1 центр

• Hospital Universitario Virgen de la Arrixaca — El Palmar

Великобритания · 1 центр

• University Hospital of Wales Cardiff and Vale University Local Health — Cardiff

Публикации

• Schneider H, Faschingbauer F, Schuepbach-Mallepell S, Korber I, Wohlfart S, Dick A, Wahlbuhl M, Kowalczyk-Quintas C, Vigolo M, Kirby N, Tannert C, Rompel O, Rascher W, Beckmann MW, Schneider P. Prenatal Correction of X-Linked Hypohidrotic Ectodermal Dysplasia. N Engl J Med. 2018 Apr 26;378(17):1604-1610. doi: 10.1056/NEJMoa1714322. PMID 29694819
• Schneider H, Hadj-Rabia S, Faschingbauer F, Bodemer C, Grange DK, Norton ME, Cavalli R, Tadini G, Stepan H, Clarke A, Guillen-Navarro E, Maier-Wohlfart S, Bouroubi A, Porte F. Protocol for the Phase 2 EDELIFE Trial Investigating the Efficacy and Safety of Intra-Amniotic ER004 Administration to Male Subjects with X-Linked Hypohidrotic Ectodermal Dysplasia. Genes (Basel). 2023 Jan 6;14(1):153. doi: PMID 36672894
• Schneider H, Schweikl C, Faschingbauer F, Hadj-Rabia S, Schneider P. A Causal Treatment for X-Linked Hypohidrotic Ectodermal Dysplasia: Long-Term Results of Short-Term Perinatal Ectodysplasin A1 Replacement. Int J Mol Sci. 2023 Apr 12;24(8):7155. doi: 10.3390/ijms24087155. PMID 37108325

Идентификаторы

NCT: NCT04980638 · ER004-CLIN01/F60082AI201

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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