Clinical trial NCT03772665: Safety and Efficacy of Emixustat in Stargardt Disease
Official title: A Phase 3 Multicenter, Randomized, Double-Masked Study Comparing the Efficacy and Safety of Emixustat Hydrochloride With Placebo for the Treatment of Macular Atrophy Secondary to Stargardt Disease
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Stargardt Disease
Keywords: Stargardt Disease
STGD
ABCA4
Lead sponsor: Kubota Vision Inc.
Sponsor class: INDUSTRY
Collaborators: name: Food and Drug Administration (FDA)
First posted: 2018-12-11
Enrollment: 194
Sex: ALL
Minimum age (years): 16
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This is a multicenter, randomized, double-masked, placebo-controlled study to evaluate the efficacy and safety of emixustat compared to placebo in subjects who have Macular Atrophy secondary to Stargardt disease.
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to determine if emixustat hydrochloride reduces the rate of progression of macular atrophy compared to placebo in subjects with Stargardt disease.

Funding Source -- FDA OOPD

Detailed description: Stargardt disease is a rare, inherited degenerative disease of the retina affecting approximately 1 in 8000 to 10 000 people and is the most common type of hereditary macular dystrophy. There are no approved treatments for STGD. This disease is characterized by an excessive accumulation of lipofuscin at the level of the retinal pigment epithelium (RPE). Lipofuscin is made of lipids, proteins, and toxic bis retinoids (such as N retinylidene N retinylethanolamine \[A2E\]). Accumulation of the toxic bis retinoids found in lipofuscin is thought to cause RPE cell dysfunction and eventual apoptosis, resulting in photoreceptor death and loss of vision.

Stargardt disease has several sub types, where autosomal recessive STGD (STGD1) accounts for the majority (\>95%) of all cases. STGD1 is typically diagnosed in the first 3 decades of life and is caused by mutations of the adenosine triphosphate binding cassette subfamily A member 4 (ABCA4) gene. The ABCA4 gene product transports N retinylidene phosphatidylethanolamine (a precursor of toxic bis retinoids) from the lumen side of photoreceptor disc membranes to the cytoplasmic side where the retinal is hydrolyzed from phosphatidylethanolamine. Mutations of the ABCA4 gene result in accumulation of this precursor in disc membranes that are eventually phagocytized by RPE cells, where the precursors are converted into toxic bis retinoids such as A2E. In addition to being a precursor to A2E, all trans retinal has also been implicated in the pathogenesis of STGD through its role in light-mediated toxicity.

Emixustat hydrochloride (emixustat) has been developed by Acucela Inc. for retinal diseases including Stargardt disease (STGD). Emixustat is a potent inhibitor of RPE65 isomerization activity and reduces visual chromophore (11 cis retinal) production in a dose-dependent and reversible manner. Because 11 cis-retinal and its photoproduct (all trans retinal) are substrates for biosynthesis of retinoid toxins (eg, A2E), chronic treatment with emixustat retards the rate at which these toxins accumulate.

Eligibility criteria: Inclusion Criteria:

* A clinical diagnosis of macular atrophy secondary to Stargardt disease (STGD)
* Macular atrophy measured to fall within a defined size range
* Two mutations of the ABCA4 gene. If only one mutation, a typical STGD appearance of the retina.
* Visual acuity in the study eye of at least 20/320

Exclusion Criteria:

* Macular atrophy secondary to a disease other than STGD
* Mutations of genes, other than ABCA4, that are associated with retinal degeneration
* Surgery in the study eye in the past 3 months
* Prior participation in a gene therapy or stem cell clinical trial for STGD
* Recent participation in a clinical trial for STGD evaluating a complement inhibitor or vitamin A derivative
* Use of certain medications in the past 4 weeks that might interfere with emixustat
* An abnormal electrocardiogram (ECG)
* Certain abnormalities on laboratory blood testing
* Female subjects who are pregnant or nursing

Primary outcomes:
measure: Mean Rate of Change in Total Area of Macular Atrophy, as Measured by Fundus Autofluorescence (FAF)
timeFrame: 24 months
Secondary outcomes:
Other outcomes:
Locations:
city: Beverly Hills
country: United States
facility: Retina-Vitreous Associates Medical Group
state: California
city: San Francisco
country: United States
facility: UCSF Dept. of Ophthalmology
state: California
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Baltimore
country: United States
facility: The Wilmer Eye Institute Johns Hopkins University
state: Maryland
city: Ann Arbor
country: United States
facility: University of Michigan Kellogg Eye Center
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic Rochester
state: Minnesota
city: Durham
country: United States
facility: Duke Eye Center
state: North Carolina
city: Portland
country: United States
facility: Casey Eye Institute - OHSU
state: Oregon
city: Dallas
country: United States
facility: Retina Foundation of the Southwest
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah John Moran Eye Center
state: Utah
city: Milwaukee
country: United States
facility: Medical College of Wisconsin-Eye Institute
state: Wisconsin
city: Belo Horizonte
country: Brazil
facility: Santa Casa de Misericórdia de Belo Horizonte
state: Minas Gerais
city: São Paulo
country: Brazil
facility: Hospital Sao Paulo
city: Toronto
country: Canada
facility: The Hospital for Sick Children
state: Ontario
city: Glostrup
country: Denmark
facility: Rigshospitalet-Glostrup
state: Hovedstaden
city: Créteil
country: France
facility: Service D'Ophtalmologie Chi Creteil
state: Île-de-France
city: Paris
country: France
facility: CHNO Quinze-Vingts - CIC
state: Île-de-France
city: Tübingen
country: Germany
facility: Universitätsklinikum Tübingen, Department für Augenheilkunde
state: Baden-Württemberg
city: Bonn
country: Germany
facility: Universitäts-Augenklinik Bonn
city: Naples
country: Italy
facility: AOU Università della Campania Luigi Vanvitelli
state: Campania
city: Rome
country: Italy
facility: Università Cattolica del Sacro Cuore - Fondazione Policlinico Gemelli
state: Lazio
city: Milan
country: Italy
facility: IRCCS Ospedale San Raffaele
state: Lombardy
city: Milan
country: Italy
facility: UOC Oculistica Asst Fatebene Pratelli Sacco Universita delgi Studi di Milano
state: Lombardy
city: Florence
country: Italy
facility: SODC di Oculistica AOU Careggi
state: Tuscany
city: Nijmegen
country: Netherlands
facility: Radboud University Medical Center
state: Gelderland
city: Pretoria
country: South Africa
facility: Pretoria Eye Institute
state: Gauteng
city: Madrid
country: Spain
facility: Fundacion Jimenez Diaz University Hospital
city: Oxford
country: United Kingdom
facility: Oxford Eye Hospital,Oxford University Hospitals NHS Foundation Trust
state: Oxfordshire
city: London
country: United Kingdom
facility: Moorfields Eye Hospital NHS Foundation Trust
Study officials:
affiliation: VP of Clinical Development, Acucela
name: Jeff Gregory, MD
role: STUDY_DIRECTOR
References: