Conditions: Stargardt Disease
Keywords: Stargardt Disease STGD ABCA4
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 194
Healthy volunteers: no

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.

Arms:
arm 1: 10 mg arm 2: Includes identical tablets with only inactive ingredients (0 mg).

Interventions: intervention 1: Emixustat intervention 2: Placebo
Intervention descriptions: intervention 1: Once daily oral tablet taken for 24 months intervention 2: Once daily oral tablet taken for 24 months

Protocol document:
Prot_SAP_000.pdf: 
Acucela Inc. 
Clinical Study Protocol 
Protocol 4429-301, Amendment 3 
21 May 2020 
PROTOCOL TITLE: 
PROTOCOL NUMBER: 
NAME OF TEST ARTICLE: 
IND NUMBER: 
EUDRACT NUMBER: 
INDICATION: 
DEVELOPMENT PHASE: 
STUDY DESIGN: 
SPONSOR: 
DATE OF PROTOCOL: 
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  
4429-301 (NCT03772665)
Emixustat hydrochloride 
IND 101,084 
2018-003498-82 
Stargardt Disease  
Phase 3 
Multicenter, randomized, double-masked, placebo-
controlled, parallel-group  
Acucela Inc. 
818 Stewart St, Suite 1110 
Seattle, WA 98101 
Original:  12 September 2018 
Amendment 1:  7 November 2018 
Amendment 2:  10 June 2019 
Amendment 3:   21 May 2020 


Acucela Inc. 
Clinical Study Protocol 
Protocol 4429-301, Amendment 3 
21 May 2020 
3 
Protocol Summary 
Protocol Number: 
4429-301 
Protocol 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 
Phase: 
Phase 3 
Study Objectives 
Primary: 
To determine if emixustat hydrochloride (emixustat) reduces the rate 
of progression of macular atrophy (MA) compared to placebo in 
subjects with Stargardt disease (STGD) 
 
 
Study Population: 
Subjects who have MA secondary to STGD 


Acucela Inc. 
Clinical Study Protocol 
Protocol 4429-301, Amendment 3 
21 May 2020 
Study Design: 
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 MA secondary to STGD.  Subjects will 
be randomly assigned to one of two treatment arms in a 2:1 ratio.  
Treatment arms include: 
•
Emixustat 10 mg
•
Placebo
Subjects will take study drug once daily (QD) in the evening for 
24 continuous months. 
Subjects randomly assigned to the emixustat arm will start taking a 
dose of 5 mg on Day 1 and step-up to 10 mg at the Month 1 visit, 
then maintain that dose for the remainder of the dosing period, unless 
a dose reduction is taken.   
 
 
 
 
 
 
 
 
 
 
 
Number of Subjects: 
Approximately 189 subjects across multiple clinical sites will be 
enrolled in order to obtain approximately 159 evaluable subjects (106 
emixustat and 53 placebo). 
Inclusion Criteria: 
Subjects who meet all of the following criteria at Screening and 
Baseline (unless otherwise indicated) may be eligible for inclusion in 
the study: 
1. Males or females, age ≥ 16 years.
2. Clinical diagnosis of MA secondary to STGD in one or both eyes
as determined by the Investigator.
3. The subject must have 1 or more pathogenic mutation(s) of the
ABCA4 (ATP binding cassette subfamily A member 4) gene.  If
only one ABCA4 pathogenic mutation is identified or if two
ABCA4 pathogenic mutations that typically occur on the same
allele (ie, “in cis”) are identified, the subject must have a typical
STGD phenotype (at least one eye has flecks at the level of the
retinal pigmented epithelium [RPE] typically seen in STGD) and


Acucela Inc. 
Clinical Study Protocol 
Protocol 4429-301, Amendment 3 
21 May 2020 
be approved by the Sponsor.  If 2 or more pathogenic mutations 
that do not typically occur on the same allele are identified, a 
typical STGD phenotype and separate Sponsor approval are not 
required.  Segregation analysis is not required.  The pathogenicity 
of all mutations will be determined by the Sponsor working with 
experts in ophthalmic genetics.    
4. The study eye must meet the following criteria as determined by
the central reading center’s assessment of FAF imaging at
Screening:
a.
Total area of DDAF
i. If the lesion is unifocal:  ≥ 3.0 – 22.0 mm2 (~1.2 –
8.7 disc areas) in size.
ii. If the lesion is multifocal:  ≥ 1.0 – 22.0 mm2 (~0.4
– 8.7 disc areas) in size.
b. The entire lesion must be completely visualized on the
macula-centered image (Field 2 – Macula Image).  The
DDAF lesion must be able to be imaged in its entirety, and
all lesion borders must be ≥ 300 microns from all image
edges.
5. Early Treatment Diabetic Retinopathy Study (ETDRS) BCVA
letter score of ≥ 25 letters (approximately ≥ 20/320 Snellen) in the
study eye at Screening.
6. Adequate clarity of ocular media and adequate pupillary dilation
to permit good quality imaging of macular atrophy in the study
eye as determined by the Investigator.
7. Able to reliably administer oral medication by self or with
available assistance.
8. Able and willing to provide written informed consent/assent
a.
For subjects ≥ 18 years of age: able and willing to provide
written informed consent before undergoing any study-
related procedures.
b. For subjects ≥ 16 and < 18 years of age: able and willing
to provide written informed assent, and has a parent or
legal guardian able and willing to provide written
informed consent for the minor before the subject
undergoes any study-related procedures.  Where required
by local regulations, both parents must consent to the
subject’s participation in the study, if both have legal
custody.


Acucela Inc. 
Clinical Study Protocol 
Protocol 4429-301, Amendment 3 
21 May 2020 
Exclusion Criteria: 
Subjects will be excluded from participation in the study if they meet 
any of the following criteria at Screening or Baseline (unless 
otherwise indicated): 
1. Macular atrophy associated with a condition other than STGD in
either eye.
2. DDAF with contiguous area of peripapillary atrophy in the study
eye, as determined by the reading center.
3. Mutation(s) in any of the following genes – elongation of very
long chain fatty acids-like 4 (ELOVL4), prominin 1 (PROM1), or
peripherin 2 (PRPH2)/retinal degeneration slow (RDS) –
determined by the Sponsor working with experts in ophthalmic
genetics to likely be disease-causing.
4. If tested, any mutation(s):
a.
In a gene(s) encoding a visual cycle protein [e.g., retinal
pigment epithelium 65 (RPE65), lecithin:retinol
acyltransferase (LRAT), retinol dehydrogenase 12
(RDH12), RDH5, and retinaldehyde binding protein 1
(RLBP1)], confirmed by the Sponsor working with
experts in ophthalmic genetics to likely be disease-
causing.  Testing for these mutations is not required.
b. Associated with a non-STGD retinal
dystrophy/degeneration, confirmed by the Sponsor
working with experts in ophthalmic genetics to likely be
disease-causing.  Testing is not required.
5. Presence in either eye of an active ocular disease that in the
opinion of the Investigator compromises or confounds visual
function, including, but not limited to, choroidal
neovascularization, diabetic retinopathy, uveitis, other macular
diseases, or uncontrolled glaucoma/ocular hypertension.
6. History of any intraocular or ocular surface surgery in either eye
≤ 3 months prior to Screening.
7. Current or previous participation in an interventional study to
treat STGD using gene therapy or stem cell therapy.
8. Current or previous participation in a study to treat STGD using a
vitamin A derivative ≤ 6 months prior to Screening.
9. Current or previous participation in a study to treat STGD using a
complement inhibitor ≤ 6 months prior to Screening.


Acucela Inc. 
Clinical Study Protocol 
Protocol 4429-301, Amendment 3 
21 May 2020 
10. Known hypersensitivity to emixustat or any of the excipients in
emixustat tablets (ie, silicified microcrystalline cellulose,
pregelatinized starch, colloidal silicon dioxide, and stearic acid).
11. Prohibited medications:
a.
Systemic use of a strong inducer of or a strong or
moderate inhibitor of cytochrome P450 2D6 (CYP2D6)
beginning 4 weeks prior to Screening or between
Screening and Baseline, or planned use during the study
period.
b. Systemic use of a Vitamin A or beta-carotene supplement
beginning 4 weeks prior to Screening or between
Screening and Baseline, or planned use during the study
period.
c.
As determined by the Investigator, use of medications
known to affect vision (eg, hydroxychloroquine,
isotretinoin) or that might interfere with the evaluation of
the efficacy or safety of emixustat, beginning 4 weeks
prior to Screening or between Screening and Baseline, or
planned use during the study period.
12. Any of the following laboratory abnormalities at Screening:
a.
Aspartate transaminase (AST) or alanine transaminase
(ALT) > 3.0 × upper limit of normal (ULN)
b. Total bilirubin > 1.5 × ULN
c.
Serum creatinine > 2.0 mg/dL
d. Estimated glomerular filtration rate (eGFR)
< 60 mL/min/1.73 m2
e.
Impaired hematologic function:  hemoglobin < 11 g/dL;
neutrophil count < 1.6 × 109/L; or platelet count < 100 ×
109/L.
Any laboratory screening test that meets the abnormality criteria 
stated above can be repeated once within the 45-day period from 
Screening to Baseline. 
13. Participation in any study using an investigational drug within 30
days or 5 half-lives (of the investigational drug) of Screening.
14. Participation in any study of an interventional, investigational
device within 60 days of Screening.


Acucela Inc. 
Clinical Study Protocol 
Protocol 4429-301, Amendment 3 
21 May 2020 
15. Anticipated participation during the study period in any study
using an investigational drug or an interventional, investigational
device.
16. Presence of other medical or ophthalmic disease, physical
examination finding, or clinical laboratory finding that in the
opinion of the Investigator contraindicates the use of an
investigational drug, places the subject at risk by participating in
the study, might interfere with the evaluation of the efficacy or
safety of emixustat, negatively impacts subject compliance with
the protocol, confounds the ability to interpret data from the
study, or jeopardizes the subject’s ability to complete the
protocol.
17. Current or history of cancer (except for adequately treated basal
cell or squamous cell carcinoma of the skin) within 1 year of
Screening.
18. History of myocardial infarction, stroke, unstable ischemic heart
disease, uncontrolled cardiac arrhythmia, or hospitalization for
congestive heart failure within 6 months of Screening.
19. Abnormal electrocardiogram (ECG) results that are considered by
the Investigator to be clinically significant at Screening.
20. Female subjects who are pregnant or lactating.
21. Female subjects of childbearing potential [ie, not postmenopausal
(without menses for 12 months without an alternative medical
cause) and not surgically sterile via hysterectomy, bilateral
salpingectomy, or bilateral oophorectomy] who are not willing to
practice a medically accepted method of birth control with their
non-surgically sterile male sexual partner from Screening through
30 days following the completion of the study.  Medically
accepted methods of birth control include true abstinence,
estrogen+progestogen hormonal contraceptives, progestogen-only
hormonal contraceptives, nonhormonal or hormonal intrauterine
contraceptive device, bilateral tubal occlusion, male or female
condom, contraceptive sponge with spermicide, diaphragm with
spermicide, or cervical cap with spermicide.  True abstinence is
when abstinence from heterosexual intercourse is in line with the
preferred and usual lifestyle of the subject and is not just limited
to the duration of this study.
22. Male subjects who are not surgically sterile and are not willing to
practice a medically accepted method of birth control with their


Acucela Inc. 
Clinical Study Protocol 
Protocol 4429-301, Amendment 3 
21 May 2020 
female partner of childbearing potential (as listed above) from 
Screening through 30 days after completion of the study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Procedures: 
The scheduled visits include Screening (within 45 days prior to 
Baseline), Baseline (Day 1), and Months 1, 2, 3, 6, 9, 12, 15, 18, 21, 
and 24.  The visits conducted at Months 9, 15, and 21 will be 
performed on the telephone.  A study exit visit will be performed 
60 days after the last dose of study drug.  During the COVID-19 
crisis, visit windows are extended. 
Subjects who discontinue from the study early will undergo an Early 
Termination visit where safety and efficacy assessments will be 
performed when study drug is stopped, or as soon as possible after 
stopping study drug.  Subjects who discontinue from treatment will 
remain in the study, attending all clinical site visits through Month 
24. 
 
Criteria for Evaluation 
Variables: 


Acucela Inc. 
Clinical Study Protocol 
Protocol 4429-301, Amendment 3 
21 May 2020 
Efficacy 
Efficacy variables will include total areas of the definitely decreased 
and questionably decreased autofluorescence MA lesion(s), total area 
of EZ loss, mean ONL thickness, extent of abnormal near-infrared 
FAF, BCVA letter score, reading speed, contrast sensitivity, photopic 
microperimetry retinal sensitivity, and QOL instruments. 
Safety 
Safety variables will include the incidence of ocular and non-ocular 
AEs, and the changes from baseline in BCVA letter score, slit-lamp 
biomicroscopy and dilated ophthalmoscopy findings, IOP, spectral 
domain optical coherence tomography (SD-OCT) and scotopic 
microperimetry assessments, physical examination findings, vital 
signs, ECG parameters, and clinical laboratory tests. Pregnancy tests 
will be conducted in women of childbearing potential. 
An independent Data Monitoring Committee (DMC) will monitor the 
safety aspects of the study and periodically review safety summaries 
prepared by an external group.   
Study Endpoints: 
Primary Efficacy 
The primary efficacy endpoint will be the mean rate of change from 
baseline in the total area of the MA lesion(s) in the study eye (in mm2 
per year), defined as the area of definitely decreased autofluorescence 
as imaged by reduced-illuminance FAF. 


Acucela Inc. 
Clinical Study Protocol 
Protocol 4429-301, Amendment 3 
21 May 2020 
 
 
 
Statistical Analyses: 
The sample size is determined based on the primary efficacy 
endpoint, the mean rate of change from baseline in area of DDAF in 
the study eye.  Approximately 189 subjects will be enrolled in order 
to obtain approximately 159 evaluable subjects (106 emixustat and 53 
placebo).  This sample size will provide approximately 90% power to 
detect a difference in means between treatment arms of 0.50 mm2 per 
year (1.00 mm2/year for placebo vs. 0.50 mm2/year for emixustat), or 
a 50% improvement with emixustat over placebo.  These estimates 
are based on using a Student’s t-test and assuming a common 
standard deviation of 0.90 mm2 per year and a 0.049 two-sided 
significance level. 
The primary efficacy analysis will be performed on the data through 
Month 24 in order to determine the magnitude of effect of emixustat 
compared to placebo.  Efficacy analyses will be performed on the 
intent-to-treat (ITT) and efficacy evaluable (EE) sets of subjects. 
Safety and tolerability will be assessed on the basis of ocular and 
non-ocular AEs, serious adverse events, ophthalmic examination 
findings, vital signs, physical examination findings, ECG findings, 
and laboratory analyses.  Safety assessments will be summarized 
descriptively. 
Study Duration: 
The protocol calls for up to 45 days between initial Screening and 
Baseline (Day 1), a 24-month dosing duration, and follow-up 60 days 
after last the study drug dose; this yields a total duration of up to 
27 months.  During the COVID-19 crisis, the window for screening is 
extended to up to 59 days, the window for the Month 24 visit is 
extended by 42 days, and the window for follow-up (Study Exit visit) 


Acucela Inc. 
Clinical Study Protocol 
Protocol 4429-301, Amendment 3 
21 May 2020 
is extended by 42 days to 102 days; this yields a total duration of 
up to approximately 31 months.