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: May 6, 2023
• Sponsor: EspeRare Foundation
• Collaborators: Pierre Fabre Medicament; Iqvia Pty Ltd
• Information provided by (Responsible Party): EspeRare Foundation

Study Description

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.

Condition or disease	Intervention/treatment	Phase
X-Linked Hypohidrotic Ectodermal Dysplasia (XLHED)	Biological: ER004	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 20 participants
• 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
• 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
• Actual Study Start Date: April 26, 2022
• Estimated Primary Completion Date: July 2024
• Estimated Study Completion Date: January 2029

Arms and Interventions

Arm	Intervention/treatment
Experimental: ER004; Human immunoglobulin G1 constant region - human ectodysplasin-A1 receptor binding domain fusion protein.	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

Outcome Measures

Primary Outcome Measures :

1. 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)

Secondary Outcome Measures :

1. 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 of age (secondary) ]
   Mean sweat pore density (number/cm2) determined by direct visualization with a VivaScope® at 2 different sites on the sole/soles of the foot/feet (up to 12 months) or at 2 different sites on the sole/soles of the foot/feet and/or palm/palms of the hand/hands (>12 months)
2. Dental development [ Time Frame: at 6 months of age (key secondary) and other timepoints : 12, 18, 24, 36, 48 and 60 months of age (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
3. Mean sweat volume [ Time Frame: At 3, 12, 18, 24, 36, 48, 60 months of age ]
   For treated subject, mean sweat volume is collected on both forearms after local stimulation with pilocarpine (pilocarpine-induced sweating)
4. Number of Meibomian glands [ Time Frame: At 6 and 60 months of age ]
   Number of Meibomian glands in the lower eyelids determined by Meibography
5. Ocular surface assessment [ Time Frame: At 24, 48 and 60 months of age ]
   Ocular surface assessment (normal, keratitis superficialis punctate) by eye using fluorescein
6. Tear film break-up time [ Time Frame: At 24, 48 and 60 months of age ]
   Tear film break-up time (seconds) determined using fluorescein
7. Ocular Surface Disease Index (OSDI) score [ Time Frame: At 60 months of age ]
   Score assessed on a scale of 0 to 100 through the OSDI questionnaire. Higher scores mean a worse outcome
8. Salivation [ Time Frame: At 60 months of age ]
   Saliva (volume and flow rate) assessed with Quantisal oral fluid collection device
9. XLHED-related hospitalizations [ Time Frame: Up to 60 months of age ]
   XLHED-related hospitalisation because of hyperthermia or because of unexplained fever, respiratory, skin, eye or ear infections
10. Assessment of eczema [ Time Frame: At different timepoints from 6 to 60 months of age ]
    Eczema will be assessed using the EASI score
11. Incidence of TEAEs (treatment-emergent adverse events) [ Time Frame: Up to 60 months of age ]
    Number of subjets with TEAEs
12. Incidence of TESAEs (treatment-emergent serious adverse events) [ Time Frame: Up to 60 months of age ]
    Number of subjects with TESAEs
13. Incidence of TEAEs (treatment-emergent adverse events) leading to treatment discontinuation [ Time Frame: Up to 60 months of age ]
    Number of subjects with TEAEs leading to treatment discontinuation

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: Female
• Gender Based Eligibility: Yes
• Gender Eligibility Description: Pregnant female
• Accepts Healthy Volunteers: No

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 aged between 6 months and 75 years 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.

Contacts and Locations

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

Locations

United States, Missouri

Washington University; Recruiting

Saint Louis, Missouri, United States, 63110

Contact: Dorothy Grange grangedk@wustl.edu

France

Hôpital Necker - Enfants Malades; Recruiting

Paris Cedex 15, Paris, France, 75743

Contact: Christine Bodemer christine.bodemer@aphp.fr

Germany

Universitaetsklinikum Erlangen; Recruiting

Erlangen, Bayern, Germany, 91054

Contact: Holm Schneider holm.schneider@uk-erlangen.de

Universitaetsklinikum Leipzig AoeR; Recruiting

Leipzig, Sachsen, Germany, 04103

Contact: Holger Stepan holger.stepan@uniklinik-leipzig.de

Italy

IRCCS Ca' Granda Ospedale Policlinico; Recruiting

Milan, Italy, 20122

Contact: Riccardo Cavalli riccardo.cavalli@policlinico.mi.it

Spain

Hospital Universitario Virgen de la Arrixaca; Recruiting

El Palmar, Murcia, Spain, 30120

Contact: Encarnacion Guillen Navarro guillen.encarna@gmail.com

United Kingdom

University Hospital of Wales Cardiff and Vale University Local Health; Recruiting

Cardiff, United Kingdom, CF14 4XW

Contact: Angus Clarke ClarkeAJ@cardiff.ac.uk

Sponsors and Collaborators

EspeRare Foundation

Pierre Fabre Medicament

Iqvia Pty Ltd

Investigators

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

More Information

Additional Information:

EDELIFE Study website (Germany) 

EDELIFE Study website (France) 

EDELIFE Study website (Spain) 

EDELIFE Study website (UK) 

EDELIFE Study website (Italy) 

EDELIFE Study website (USA) 

Publications of Results:

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.

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.

Other 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.

• Responsible Party: EspeRare Foundation
• ClinicalTrials.gov Identifier: NCT04980638
• Other Study ID Numbers: ER004-CLIN01/F60082AI201
• First Posted: July 28, 2021
• Last Update Posted: May 6, 2023
• Last Verified: January 2023

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

Additional relevant MeSH terms:

Ectodermal Dysplasia; Ectodermal Dysplasia 1, Anhidrotic; Abnormalities, Multiple; Congenital Abnormalities; Skin Abnormalities; Skin Diseases, Genetic; Genetic Diseases, Inborn; Skin Diseases; Genetic Diseases, X-Linked