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

Primary Purpose

X-Linked Hypohidrotic Ectodermal Dysplasia (XLHED)

Status

Recruiting

Phase

Phase 2

Locations

International

Study Type

Interventional

Intervention

ER004

About this trial

This is an interventional treatment trial for X-Linked Hypohidrotic Ectodermal Dysplasia (XLHED)

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)FemaleDoes not accept healthy volunteers

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.

Sites / Locations

Washington UniversityRecruiting
Hôpital Necker - Enfants MaladesRecruiting
Universitaetsklinikum ErlangenRecruiting
Universitaetsklinikum Leipzig AoeRRecruiting
IRCCS Ca' Granda Ospedale PoliclinicoRecruiting
Hospital Universitario Virgen de la ArrixacaRecruiting
University Hospital of Wales Cardiff and Vale University Local HealthRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

ER004

Arm Description

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

Outcomes

Primary Outcome Measures

Mean sweat volume

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

Secondary Outcome Measures

Mean sweat pore density (number/cm2)

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)

Dental development

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

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

Number of Meibomian glands

Number of Meibomian glands in the lower eyelids determined by Meibography

Ocular surface assessment

Ocular surface assessment (normal, keratitis superficialis punctate) by eye using fluorescein

Tear film break-up time

Tear film break-up time (seconds) determined using fluorescein

Ocular Surface Disease Index (OSDI) score

Score assessed on a scale of 0 to 100 through the OSDI questionnaire. Higher scores mean a worse outcome

Salivation

Saliva (volume and flow rate) assessed with Quantisal oral fluid collection device

XLHED-related hospitalizations

XLHED-related hospitalisation because of hyperthermia or because of unexplained fever, respiratory, skin, eye or ear infections

Assessment of eczema

Eczema will be assessed using the EASI score

Incidence of TEAEs (treatment-emergent adverse events)

Number of subjets with TEAEs

Incidence of TESAEs (treatment-emergent serious adverse events)

Number of subjects with TESAEs

Incidence of TEAEs (treatment-emergent adverse events) leading to treatment discontinuation

Number of subjects with TEAEs leading to treatment discontinuation

Full Information

NCT ID

NCT04980638

First Posted

July 20, 2021

Last Updated

May 3, 2023

Sponsor

EspeRare Foundation

Collaborators

Pierre Fabre Medicament, Iqvia Pty Ltd

1. Study Identification

Unique Protocol Identification Number

NCT04980638

Brief Title

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

Acronym

EDELIFE

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

Study Type

Interventional

2. Study Status

Record Verification Date

January 2023

Overall Recruitment Status

Recruiting

Study Start Date

April 26, 2022 (Actual)

Primary Completion Date

July 2024 (Anticipated)

Study Completion Date

January 2029 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

EspeRare Foundation

Collaborators

Pierre Fabre Medicament, Iqvia Pty Ltd

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. 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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

X-Linked Hypohidrotic Ectodermal Dysplasia (XLHED)

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

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)

Allocation

N/A

Enrollment

20 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

ER004

Arm Type

Experimental

Arm Description

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

Intervention Type

Biological

Intervention Name(s)

ER004

Intervention Description

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

Primary Outcome Measure Information:

Title

Mean sweat volume

Description

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

Time Frame

at 6 months of age (corrected age for subjects born at < 37 weeks)

Secondary Outcome Measure Information:

Title

Mean sweat pore density (number/cm2)

Description

Time Frame

at 6 months of age (key secondary) and other timepoints : 3, 12, 18, 24, 36, 48 and 60 months of age (secondary)

Title

Dental development

Description

Dental development evaluated by the number of erupted teeth and tooth germs (palpable alveolar structures in the alveolar ridge) as determined by dental examination

Time Frame

at 6 months of age (key secondary) and other timepoints : 12, 18, 24, 36, 48 and 60 months of age (secondary)

Title

Mean sweat volume

Description

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

Time Frame

At 3, 12, 18, 24, 36, 48, 60 months of age

Title

Number of Meibomian glands

Description

Number of Meibomian glands in the lower eyelids determined by Meibography

Time Frame

At 6 and 60 months of age

Title

Ocular surface assessment

Description

Ocular surface assessment (normal, keratitis superficialis punctate) by eye using fluorescein

Time Frame

At 24, 48 and 60 months of age

Title

Tear film break-up time

Description

Tear film break-up time (seconds) determined using fluorescein

Time Frame

At 24, 48 and 60 months of age

Title

Ocular Surface Disease Index (OSDI) score

Description

Score assessed on a scale of 0 to 100 through the OSDI questionnaire. Higher scores mean a worse outcome

Time Frame

At 60 months of age

Title

Salivation

Description

Saliva (volume and flow rate) assessed with Quantisal oral fluid collection device

Time Frame

At 60 months of age

Title

XLHED-related hospitalizations

Description

XLHED-related hospitalisation because of hyperthermia or because of unexplained fever, respiratory, skin, eye or ear infections

Time Frame

Up to 60 months of age

Title

Assessment of eczema

Description

Eczema will be assessed using the EASI score

Time Frame

At different timepoints from 6 to 60 months of age

Title

Incidence of TEAEs (treatment-emergent adverse events)

Description

Number of subjets with TEAEs

Time Frame

Up to 60 months of age

Title

Incidence of TESAEs (treatment-emergent serious adverse events)

Description

Number of subjects with TESAEs

Time Frame

Up to 60 months of age

Title

Incidence of TEAEs (treatment-emergent adverse events) leading to treatment discontinuation

Description

Number of subjects with TEAEs leading to treatment discontinuation

Time Frame

Up to 60 months of age

10. Eligibility

Sex

Female

Gender Based

Yes

Gender Eligibility Description

Pregnant female

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

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 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.

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Florence Porte-Thormé, PharmD

Phone

+41 22 794 4004

Info.er004@esperare.org

First Name & Middle Initial & Last Name or Official Title & Degree

Athmane Bouroubi, MD

Phone

+33 5 34 50 60 00

contact.edelife@pierre-fabre.com

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Holm Schneider, MD

Organizational Affiliation

University Erlangen-Nürnberg Erlangen, Germany

Official's Role

Principal Investigator

Facility Information:

Facility Name

Washington University

City

Saint Louis

State/Province

Missouri

ZIP/Postal Code

63110

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Dorothy Grange

grangedk@wustl.edu

Facility Name

Hôpital Necker - Enfants Malades

City

Paris Cedex 15

State/Province

Paris

ZIP/Postal Code

75743

Country

France

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Christine Bodemer

christine.bodemer@aphp.fr

Facility Name

Universitaetsklinikum Erlangen

City

Erlangen

State/Province

Bayern

ZIP/Postal Code

91054

Country

Germany

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Holm Schneider

holm.schneider@uk-erlangen.de

Facility Name

Universitaetsklinikum Leipzig AoeR

City

Leipzig

State/Province

Sachsen

ZIP/Postal Code

04103

Country

Germany

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Holger Stepan

holger.stepan@uniklinik-leipzig.de

Facility Name

IRCCS Ca' Granda Ospedale Policlinico

City

Milan

ZIP/Postal Code

20122

Country

Italy

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Riccardo Cavalli

riccardo.cavalli@policlinico.mi.it

Facility Name

Hospital Universitario Virgen de la Arrixaca

City

El Palmar

State/Province

Murcia

ZIP/Postal Code

30120

Country

Spain

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Encarnacion Guillen Navarro

guillen.encarna@gmail.com

Facility Name

University Hospital of Wales Cardiff and Vale University Local Health

City

Cardiff

ZIP/Postal Code

CF14 4XW

Country

United Kingdom

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Angus Clarke

ClarkeAJ@cardiff.ac.uk

12. IPD Sharing Statement

Citations:

PubMed Identifier

36672894

Citation

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.

Results Reference

background

PubMed Identifier

29694819

Citation

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.

Results Reference

result

PubMed Identifier

37108325

Citation

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.

Results Reference

result

Links:

URL

http://www.EDELIFEklinischestudie.com/

Description

EDELIFE Study website (Germany)

URL

http://www.essaicliniqueEDELIFE.com/

Description

EDELIFE Study website (France)

URL

http://www.ensayoclinicoEDELIFE.com/

Description

EDELIFE Study website (Spain)

URL

http://www.EDELIFEclinicaltrial.com/

Description

EDELIFE Study website (UK)

URL

http://www.studioclinicoEDELIFE.com

Description

EDELIFE Study website (Italy)

URL

http://www.EDELIFEclinicaltrial.com/

Description

EDELIFE Study website (USA)

Learn more about this trial

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

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