Safety and Efficacy of Emixustat in Stargardt Disease (SeaSTAR)

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

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

Study Overview

• Status: Completed
• Conditions: Stargardt Disease
• Intervention / Treatment: Drug: Emixustat; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 194
• Phase: Phase 3

Contacts and Locations

Study Locations

• Brazil
  • São Paulo, Brazil, 04024-002
    • Hospital Sao Paulo
  • Minas Gerais
    • Belo Horizonte, Minas Gerais, Brazil, 30150-320
      • Santa Casa de Misericordia de Belo Horizonte
• Canada
  • Ontario
    • Toronto, Ontario, Canada, MSG 1X8
      • The Hospital for Sick Children
• Denmark
  • Hovedstaden
    • Glostrup, Hovedstaden, Denmark, DK-2600
      • Rigshospitalet-Glostrup
• France
  • Île-de-France
    • Créteil, Île-de-France, France, 94000
      • Service D'Ophtalmologie Chi Creteil
    • Paris, Île-de-France, France, 75012
      • CHNO Quinze-Vingts - CIC
• Germany
  • Bonn, Germany, 53127
    • Universitats-Augenklinik Bonn
  • Baden-Württemberg
    • Tübingen, Baden-Württemberg, Germany, 72076
      • Universitätsklinikum Tübingen, Department für Augenheilkunde
• Italy
  • Campania
    • Naples, Campania, Italy, 80131
      • AOU Università della Campania Luigi Vanvitelli
  • Lazio
    • Rome, Lazio, Italy, 00168
      • Università Cattolica del Sacro Cuore - Fondazione Policlinico Gemelli
  • Lombardy
    • Milan, Lombardy, Italy, 20132
      • IRCCS Ospedale San Raffaele
    • Milan, Lombardy, Italy, 20157
      • UOC Oculistica Asst Fatebene Pratelli Sacco Universita delgi Studi di Milano
  • Tuscany
    • Florence, Tuscany, Italy, 50134
      • SODC di Oculistica AOU Careggi
• Netherlands
  • Gelderland
    • Nijmegen, Gelderland, Netherlands, 6500
      • Radboud University Medical Center
• South Africa
  • Gauteng
    • Pretoria, Gauteng, South Africa, 0082
      • Pretoria Eye Institute
• Spain
  • Madrid, Spain, 28040
    • Fundacion Jimenez Diaz University Hospital
• United Kingdom
  • London, United Kingdom, EC1V 2PD
    • Moorfields Eye Hospital NHS Foundation Trust
  • Oxfordshire
    • Oxford, Oxfordshire, United Kingdom, OXD3 9DU
      • Oxford Eye Hospital,Oxford University Hospitals NHS Foundation Trust
• United States
  • California
    • Beverly Hills, California, United States, 90211
      • Retina-Vitreous Associates Medical Group
    • San Francisco, California, United States, 94143-0730
      • UCSF Dept. of Ophthalmology
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • The Wilmer Eye Institute Johns Hopkins University
  • Michigan
    • Ann Arbor, Michigan, United States, 48105
      • University of Michigan Kellogg Eye Center
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic Rochester
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke Eye Center
  • Oregon
    • Portland, Oregon, United States, 97239
      • Casey Eye Institute - OHSU
  • Texas
    • Dallas, Texas, United States, 75231
      • Retina Foundation of the Southwest
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah John Moran Eye Center
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College of Wisconsin-Eye Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Emixustat; 10 mg	Drug: Emixustat; Once daily oral tablet taken for 24 months; Other Names: emixustat hydrochloride
Placebo Comparator: Placebo; Includes identical tablets with only inactive ingredients (0 mg).	Drug: Placebo; Once daily oral tablet taken for 24 months

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Rate of Change in Total Area of Macular Atrophy, as Measured by Fundus Autofluorescence (FAF)	Mean rate of change in total area of macular atrophy, as measured by fundus autofluorescence (FAF)	24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants with treatment-related adverse events as assessed by common terminology for adverse events v5.0		24 months
Mean rate of change in retinal sensitivity as measured by microperimetry		24 months
Mean change in contrast sensitivity		24 months
Mean change in reading speed		24 months
Mean change in best-corrected Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity letter score	Scores range from 0 to 100, with 100 being the best visual acuity.	24 months
Mean rate of change in total area of decreased autofluorescence on FAF		24 months
Mean rate of change in area of ellipsoid zone loss on optical coherence tomography (OCT)		24 months
Mean change from baseline in mean outer nuclear layer thickness on OCT		24 months
Mean change in patient assessment of how vision affects their ability to perform everyday tasks, using the Visual Function Questionnaire 25-item (VFQ-25) composite score	Score ranges from 0 to 100, with 100 representing better ability	24 months
Mean change in patient assessment of the ability to perform reading activities independently, using the Functional Reading Independence Index (FRII) score	Score ranges from 0 to 4, with 4 representing higher independence	24 months
Mean change in patient assessment of general health, using the EQ-5D-5L (a 5-dimension, 5-level, generic measure of health) index value	Values range from 0 to 1, with 1 representing better health	24 months

Collaborators and Investigators

• Sponsor: Kubota Vision Inc.
• Collaborators: Food and Drug Administration (FDA)
• Investigators: Study Director: Jeff Gregory, MD, VP of Clinical Development, Acucela

Study record dates

Study Major Dates

• Study Start (Actual): November 7, 2018
• Primary Completion (Actual): June 13, 2022
• Study Completion (Actual): June 23, 2022

Study Registration Dates

• First Submitted: November 30, 2018
• First Submitted That Met QC Criteria: December 9, 2018
• First Posted (Actual): December 11, 2018

Study Record Updates

• Last Update Posted (Actual): August 3, 2023
• Last Update Submitted That Met QC Criteria: July 13, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Keywords: Stargardt Disease; STGD; ABCA4
• Additional Relevant MeSH Terms: Eye Diseases; Retinal Degeneration; Retinal Diseases; Genetic Diseases, Inborn; Eye Diseases, Hereditary; Macular Degeneration; Stargardt Disease
• Other Study ID Numbers: 4429-301; R01FD006849 (U.S. FDA Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No