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

• ClinicalTrials.gov Identifier: NCT04980638
• Recruitment Status: Recruiting
• First Posted: July 28, 2021
• Last Update Posted: January 25, 2023
• Sponsor: EspeRare Foundation
• Collaborators: Pierre Fabre Medicament; Iqvia Pty Ltd
• Information provided by (Responsible Party): EspeRare Foundation

Tracking Information

• First Submitted Date: July 20, 2021
• First Posted Date: July 28, 2021
• Last Update Posted Date: January 25, 2023
• Actual Study Start Date: April 26, 2022
• Estimated Primary Completion Date: July 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 22, 2021)

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

For treated subject, mean sweat volume is collected on both forearms after local stimulation with pilocarpine (pilocarpine-induced sweating)

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: October 27, 2022)

• Mean sweat pore density (number/cm2) [ Time Frame: at 6 months of age (key secondary) and other timepoints : 3, 12, 18, 24, 36, 48 and 60 months(secondary) ]
  Mean sweat pore density (number/cm2) determined by direct visualization with a VivaScope® at 2 different sites on the soles of the feet (up to 12 months) or at 2 different sites on the soles of the feet and/or palms (>12 months)
• Dental development [ Time Frame: at 6 months of age (key secondary) and other timepoints : 12, 18, 24, 36, 48 and 60 months (secondary) ]
  Dental development evaluated by the number of erupted teeth and tooth germs (palpable alveolar structures in the alveolar ridge) as determined by dental examination
• Mean sweat volume [ Time Frame: At 3, 12, 18, 24, 36, 48, 60 months ]
  For treated subject, mean sweat volume is collected on both forearms after local stimulation with pilocarpine (pilocarpine-induced sweating)
• Dry eye issues [ Time Frame: At different timepoints from 6 to 60 months ]
  Number of Meibomian glands, Ocular surface assessment, Tear film break-up time, Ocular Surface Disease Index (OSDI) score (DEU, ESP, FRA, IT, UK; will be implemented also in US through an upcoming protocol amendment)
• Salivation [ Time Frame: At 60 months ]
  Saliva assessed with Quantisal oral fluid collection device
• XLHED-related hospitalizations [ Time Frame: Up to 60 months ]
  XLHED-related hospitalisation because of hyperthermia or because of unexplained fever, respiratory, skin, eye or ear infections
• Assessment of eczema [ Time Frame: At different timepoints from 6 to 60 months ]
  Eczema will be assessed using the EASI score
• Incidence of TEAEs (treatment-emergent adverse events) [ Time Frame: Up to 60 months ]
• Incidence of TESAEs (treatment-emergent serious adverse events) [ Time Frame: Up to 60 months ]
• Incidence of TEAEs (treatment-emergent adverse events) leading to treatment discontinuation. [ Time Frame: Up to 60 months ]

Original Secondary Outcome Measures (submitted: July 22, 2021)

• Mean sweat pore density (number/cm2) [ Time Frame: at 6 months of age (key secondary) and other timepoints : 3, 12, 18, 24, 36, 48 and 60 months(secondary) ]
  Mean sweat pore density (number/cm2) determined by direct visualization with a VivaScope® at 2 different sites on the soles of the feet (up to 12 months) or at 2 different sites on the soles of the feet and/or palms (>12 months)
• Dental development [ Time Frame: at 6 months of age (key secondary) and other timepoints : 12, 18, 24, 36, 48 and 60 months (secondary) ]
  Dental development evaluated by the number of erupted teeth and tooth germs (palpable alveolar structures in the alveolar ridge) as determined by dental examination
• Mean sweat volume [ Time Frame: At 3, 12, 18, 24, 36, 48, 60 months ]
  For treated subject, mean sweat volume is collected on both forearms after local stimulation with pilocarpine (pilocarpine-induced sweating)
• Dry eye issues [ Time Frame: At different timepoints from 6 to 60 months ]
  Number of Meibomian glands, Ocular surface assessment, Tear film break-up time
• Salivation [ Time Frame: At 60 months ]
  Saliva assessed with Quantisal oral fluid collection device
• XLHED-related hospitalizations [ Time Frame: Up to 60 months ]
  XLHED-related hospitalisation because of hyperthermia or because of unexplained fever, respiratory, skin, eye or ear infections
• Assessment of eczema [ Time Frame: At different timepoints from 6 to 60 months ]
  Eczema will be assessed using the EASI score
• Incidence of TEAEs (treatment-emergent adverse events) [ Time Frame: Up to 60 months ]
• Incidence of TESAEs (treatment-emergent serious adverse events) [ Time Frame: Up to 60 months ]
• Incidence of TEAEs (treatment-emergent adverse events) leading to treatment discontinuation. [ Time Frame: Up to 60 months ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Intraamniotic Administrations of ER004 to Male Subjects With X-linked Hypohidrotic Ectodermal Dysplasia
• Official Title: 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
• Brief Summary: 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.
• Detailed Description: 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.
• Study Type: Interventional
• Study Phase: Phase 2

Study Design

Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description:

This is an open-label, single-arm, genotype-match controlled for primary estimand, non randomized study. The primary efficacy outcome will be compared to genotype matched untreated male relatives with XLHED or to genotype-matched controls from an external XLHED database (clinical and natural history studies from which untreated genotype-matched controls will be identified).

Masking: None (Open Label)
Primary Purpose: Treatment

• Condition: X-Linked Hypohidrotic Ectodermal Dysplasia (XLHED)

Intervention

Biological: ER004

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

Study Arms

Experimental: ER004

Human immunoglobulin G1 constant region - human ectodysplasin-A1 receptor binding domain fusion protein.

Intervention: Biological: ER004

Publications *

• 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: 10.3390/genes14010153.
• 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.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: July 22, 2021): 20
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: January 2029
• Estimated Primary Completion Date: July 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

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 ages between 6 months and 60 years (US; age will be changed to 75 years through an upcoming protocol amendment) / 75 years (DEU, ESP, FRA, IT, UK) with the same EDA mutation as the treated subject

Exclusion Criteria:

• 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.

Sex/Gender

• Sexes Eligible for Study: Female
• Gender Based Eligibility: Yes
• Gender Eligibility Description: Pregnant female

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Florence Porte-Thormé, PharmD; +41 22 794 4004; Info.er004@esperare.org

Contact: Athmane Bouroubi, MD; +33 5 34 50 60 00; contact.edelife@pierre-fabre.com

• Listed Location Countries: France, Germany, Italy, Spain, United Kingdom, United States

Administrative Information

• NCT Number: NCT04980638
• Other Study ID Numbers: ER004-CLIN01/F60082AI201
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: EspeRare Foundation
• Original Responsible Party: Same as current
• Current Study Sponsor: EspeRare Foundation
• Original Study Sponsor: Same as current

Collaborators

• Pierre Fabre Medicament
• Iqvia Pty Ltd

Investigators

• Principal Investigator: Holm Schneider, MD; University Erlangen-Nürnberg Erlangen, Germany

• PRS Account: EspeRare Foundation
• Verification Date: January 2023