Clinical trial NCT04201574
Conditions: Dry Eye Disease
Sponsor: Allysta Pharmaceutical
Start date: 2019-12-16; Completion date: 2020-09-15
Enrollment: 138 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Clinical Trial Evaluating the Safety and Tolerability of ALY688 in Subjects with Dry Eye Disease

Detailed description:
This is a multi-center, randomized, double-masked Phase 1/2a trial designed to evaluate the safety and tolerability of ALY688 Ophthalmic Solution in subjects with moderate to mildly severe dry eye for 8 weeks with 6 scheduled clinic visits.

Arms: arm 1: Vehicle Ophthalmic Solution arm 2: ALY688 0.1% Ophthalmic Solution arm 3: ALY688 0.4%Ophthalmic Solution
Interventions: intervention 1: ALY688 0.1% intervention 2: ALY688 0.4% intervention 3: Vehicle
Intervention descriptions: intervention 1: ALY688 0.1% Ophthalmic Solution intervention 2: ALY688 0.4% Ophthalmic Solution intervention 3: Vehicle Ophthalmic Solution

Protocol documents:
Prot_SAP_001.pdf: 
CLINICAL STUDY PROTOCOL
A Phase 1/2a, Randomized, Double-Masked, Vehicle-Controlled Study 
Evaluating the Safety and Exploratory Activity of Two Concentrations (0.1% 
and 0.4%) of ALY688 Ophthalmic Solution in Subjects with Dry Eye Disease
Study Phase: 1/2a
Product Name:
ALY688 Ophthalmic Solution
IND Number:
134,869
Formulation:
ALY688 Ophthalmic Solution, 0.1% and 0.4%
Study Number:
ALY688-201
NCT #:
NCT04201574
Date:
June 08, 2020


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1.
SYNOPSIS
Investigational Drug Product: 
ALY688 Ophthalmic Solution 
Active Ingredient: 
ALY688 
Study Title: 
A Phase 1/2a, Randomized, Double-Masked, Vehicle-Controlled Study 
Evaluating the Safety and Exploratory Activity of Two Concentrations (0.1% 
and 0.4%) of ALY688 Ophthalmic Solution in Subjects with Dry Eye Disease 
Study Number: 
ALY688-201 
Study Phase: 
1/2a 
Study Objectives: 
Primary objective: Evaluate the safety and tolerability of 2 concentrations of 
ALY688 in subjects with dry eye disease (DED) treated topically twice daily 
(BID) for 8 weeks. 
Additional objective: Evaluate the efficacy of 2 concentrations of ALY688 in 
subjects with DED treated BID for 8 weeks. 
Study Design: 
After meeting eligibility criteria during screening, qualified subjects will 
undergo a 14-day run-in period during which they will use Vehicle BID 
bilaterally. If they meet eligibility criteria at baseline, they will be randomized 
1:1:1 to receive ALY688 0.1% (n=40), ALY688 0.4% (n=40), or Vehicle 
(n=40). Dosing will be BID bilaterally. If there are no clinically significant 
drug-related adverse tolerability changes on Day 3, subjects will continue 
dosing BID bilaterally for the remaining dosing period for a total of 8 weeks.  
The study eye will be designated at randomization. If both eyes have an 
inferior corneal fluorescein staining score (ICSS) ≥2, the study eye will be the 
one with the greater ICSS. If both eyes have the same ICSS grade, the eye 
with the higher overall total corneal staining score will be selected. If both 
eyes show the same total corneal staining score, the eye with the lower tear 
volume by Schirmer’s test will be selected; if both eyes still score equally, the 
right eye will be selected. 
Ocular assessments should be conducted by the same assessor throughout a 
subject’s participation period to reduce observer variability. All efficacy 
assessments will be carried out consistently either in the morning or the 
afternoon (preferred time window is ±2 hours) throughout all study visits to 
minimize intra-subject diurnal variability.  
During the Baseline visit, all assessments will be carried out before dosing 
with the study medication in order to serve as pre-study baseline. For on-
treatment visits at Weeks 2, 4, and 8, all ocular assessments will take place at 
least 1 hour after receiving study medication. At Weeks 2, 4, and 8, subjects 
who arrive in clinic before 1 pm should receive their morning dose 
administered by clinic staff. Subjects who arrive in clinic after 1 pm should 
self-administer their morning dose and receive their afternoon/evening dose by 
clinic staff. 
A subset of subjects (up to 36) at selected sites will undergo blood collection 
for pharmacokinetic evaluation of the test article at 3 timepoints (15 and 45 
minutes and 3 hours) after final dose of study medication at Week 8. 
Investigational Product, Dose 
and Mode of Administration: 
Topical, sterile, non-preserved single-use vials of 0.25 mL ocular eye drop: 
•
ALY688 Ophthalmic Solution 0.1%
•
ALY688 Ophthalmic Solution 0.4%
•
Vehicle Ophthalmic Solution (same as ALY688 without active drug)


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Study Population: 
Subjects with symptomatic DED confirmed by clinical examination 
Inclusion Criteria: 
1.
Males or females who are at least 18 years of age at the Screening visit
2.
Subject-reported history of dry eye in both eyes for at least 3 months prior
to screening
3.
Confirmed use, by either medical records or subject self-reporting, of
artificial tear substitute for symptoms of DED ≥3 times per week on
average for the 4 weeks prior to screening (including regular or as needed
use of prescription or over-the-counter products)
4.
Willing to suspend use of artificial tear substitutes for the duration of
study participation
5.
Eye dryness score (EDS) using 0- to 100-point visual analog scale (VAS)
in both eyes between 40 and 90 (inclusive) at screening and between 30
and 90 (inclusive) at baseline
6.
One eye (same eye) must meet all of the following criteria at both
screening and baseline:
a.
Total corneal fluorescein staining score between 6 and 17
(inclusive) using the Expanded National Eye Institute (NEI)
scoring system (0-20 scale)
b.
Inferior corneal fluorescein staining score (ICSS) ≥2 (0-4 scale)
c.
Schirmer’s test (without anesthesia) score between 1 and
9 mm/5 min (inclusive)
7.
Best-corrected visual acuity (BCVA) of +0.6 logarithm of the minimum
angle of resolution (logMAR) or better (using Early Treatment Diabetic
Retinopathy Study [ETDRS]); Snellen equivalent score of 20/80 or better)
and reading Snellen visual acuity of 20/40 (J3) or better in each eye at
screening and baseline
8.
An understanding, ability, and willingness to fully comply with study
procedures and restrictions
9.
Ability to voluntarily provide written, signed, and dated (personally or via
a legally authorized representative) informed consent to participate in the
study
10. For females of childbearing potential, confirmation of a negative urine
pregnancy test at screening and baseline and willing to comply with
applicable contraceptive requirements detailed in the protocol
Exclusion Criteria: 
Ocular history – medical 


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1.
Confluent (grade 4) fluorescein corneal staining in the superior zone in
either eye at screening or baseline
2.
Confluent (grade 4) fluorescein corneal staining in 3 or more zones in
either eye at screening or baseline
3.
Improvement in EDS by more than 25% between screening and baseline
(run-in period)
4.
Allergic conjunctivitis if active within 4 weeks prior to screening or
anticipated to be active during the study
5.
Severe meibomian gland dysfunction (MGD) using the Simplified
Scheme for Grading MGD (based on central 10 gland orifices of each
eyelid) with a score of Grade 3 or greater in the study eye evaluating both
the upper and lower eyelids. The subject will be excluded if any of the
following are present in either of the evaluated eyelids of the study eye:
a.
Plugging of meibomian gland: more than 2/3 of glands plugged
or >6 glands plugged in either eyelid of the study eye
b.
Character of secretion: paste or no observable expressate in
either eyelid of the study eye
c.
Expressibility: fewer than 2 glands expressible in either eyelid of
the study eye
NOTE: Mild or moderate (Grade 1 or 2) posterior lid margin disease 
(MGD) is allowed if the subject has not received topical or systemic 
treatment (eg, tetracycline, doxycycline, or azithromycin) or mechanical 
therapy such as lid scrubs, for at least 4 weeks prior to screening and will 
not receive any such therapy during the study 
6.
Glaucoma or ocular hypertension requiring treatment within 6 months of
screening
7.
Use of an intranasal tear stimulant (device or medication) within 4 weeks
prior to screening or planned use during the study
8.
Unwillingness to avoid wearing contact lenses starting at least 2 weeks
prior to screening and during the study
9.
DED secondary to scarring (eg, associated with irradiation, alkali burns,
Stevens-Johnson syndrome, cicatricial pemphigoid) or destruction of
conjunctival goblet cells (as with vitamin A deficiency)
10. Any other clinically significant ocular condition in the study eye that, in
the investigator’s judgment, is of a severity that adversely affects vision
and/or could affect the results of study assessments, including but not
limited to: eyelid margin abnormalities (eg, anterior blepharitis, excessive
lid laxity, floppy eyelid syndrome, ectropion, entropion), retinal disease
(eg, proliferative diabetic retinal disease [minimal early non-proliferative
diabetic retinopathy is permitted], age-related macular degeneration
[AMD; mild AMD untreated by intravitreal injection is permitted], or
retinal vein occlusion), lagophthalmos, exposure keratitis, limbic
keratoconjunctivitis, or active ocular or eyelid inflammation, including
uveitis
11. Corneal stromal and/or epithelial defects or anatomic abnormalities that,
in the investigator’s judgment, adversely affect vision and/or could affect
the results of study assessment not due to DED (eg, neurotrophic keratitis
recurrent corneal erosions, and filaments)
12. Currently active, or history of, ocular herpes or any other ocular infection
within 4 weeks prior to screening (with the exception of mild or moderate


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MGD—see above) or if on medication to suppress herpes simplex virus 
(HSV) 
13. Ocular trauma within 6 months prior to screening that, in the
investigator’s judgment, is of a severity that could affect results of study
assessments
Ocular history – surgical 
14. Have undergone laser in situ keratomileusis (LASIK) or other types of
refractive surgery within 12 months prior to screening, or have persistent
symptoms associated with LASIK surgery (neurotrophic etiology)
15. Have undergone penetrating keratoplasty, Descemet’s stripping with
endothelial keratoplasty, Descemet's membrane endothelial keratoplasty,
or deep anterior lamellar keratoplasty in the study eye
16. Have a dissolvable punctal plug placed in the study eye within 3 months
prior to screening
17. Have a non-dissolvable punctal plug placed in the study eye within 2
months prior to screening that is, in the investigator’s judgment,
considered to be unstable, irritating, likely to fall out (based on prior
history of a lost plug), or cannot be replaced immediately if it falls out
during the study
18. Have any planned ocular and/or lid surgeries during the study, including
placement of new punctal plugs (replacement of non-dissolvable plugs
that have fallen out is required)
19. Punctal cauterization within 12 weeks prior to screening
20. Prior ocular surgery or laser treatment within 6 months prior to screening
NOTE: Glaucoma laser procedures are permitted up to 3 months prior to
screening; yttrium aluminum garnet (YAG) capsulotomy is permitted up
to 4 weeks prior to screening
21. Eyelid surgery within 12 months prior to screening
Prior medications
22. Any use within 4 weeks prior to screening of any ocular topical
medications (excluding artificial tear substitutes)
23. Planned use of any ocular topical medications during the study (including
artificial tear substitutes)
24. Any use within 4 weeks prior to screening or planned use during the study
of any oral antibiotics (including tetracycline, doxycycline, or
azithromycin) for the treatment of blepharitis or MGD
25. Use of the following therapies prior to or during the study:
a.
Topical brimonidine within 4 weeks prior to screening
b.
Topical cyclosporine within 6 weeks prior to screening
c.
Topical lifitegrast within 4 weeks prior to screening
d.
Any other topical ocular dry eye treatments 4 weeks prior to
screening, with the exception of artificial tear substitutes
e.
The following treatments for MGD within 4 weeks prior to screening:
thermal pulsation (Lipiflow), debridement of lid margin (BlephEx),
or thermal application (MeiBoFlo, Tear Care)
f.
Any systemic (including oral) antibiotic 2 weeks prior to screening


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g.
Initiation of oral omega fatty acid supplements within 3 months prior
to screening or anticipated changes during the study
h.
Any use within 2 months prior to screening or planned use during the
study of topical retinoids, such as retinol, tretinoin, adapalene,
tazarotene, alitretinoin, and bexarotene
i.
Initiation within 4 weeks prior to screening of any medication (oral or
topical) known to cause ocular drying or any anticipated change in
dosing of such medication during the study
j.
Oral aspirin or aspirin-containing products or nonsteroidal anti-
inflammatory drugs (NSAIDs) unless the subject is on a stable dose
for 4 weeks prior to screening with no dose change anticipated during
the study
NOTE: Use of aspirin or NSAIDs on an as needed basis is allowed if
it is no more than 3 doses per week; acetaminophen is allowed
k.
Systemic, inhalation, intranasal, or topical ocular corticosteroids
within 4 weeks prior to screening and during the study. Dermatologic
formulations are allowed
l.
Antihistamines (oral or ocular) within 4 weeks prior to screening or
planned use during study participation
m. Systemic immunosuppressive medications within 4 weeks prior to
screening and during the study
Product related 
26. Known hypersensitivity to investigational product or its components
Systemically related 
27. Any known history of alcohol or drug abuse within 12 months prior to
screening that, in the investigator’s judgment, may interfere with the
subject’s participation in the study
28. Positive urine pregnancy test or nursing an infant (female subjects only) at
screening or baseline
29. Any blood donation or significant loss of blood within 4 weeks prior to
screening or planned donation during the study
30. History of immunodeficiency disorder, human immunodeficiency virus,
hepatitis B or C, or evidence of acute active hepatitis A or organ or bone
marrow transplant
31. History or presence of Sjogren’s syndrome treated with systemic
immunosuppressants
NOTE: mild to moderate Sjogren’s is permitted if untreated with
medications within 3 months prior to screening and no planned treatment
during the trial
32. Any other significant physical or mental illness or condition that, in the
investigator’s judgment, could interfere with study parameters, including
but not limited to: poorly controlled diabetes or hypertension, active
inflammatory or infectious condition, unstable cardiac disease, or active
malignancy
33. Planned surgical procedure(s) during the study that, in the investigator’s
judgment, may interfere with the subject’s participation in the study
34. Clinically significant abnormalities in laboratory tests at screening based
upon the investigator’s judgment


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Administrative 
35. Are employees, or immediate family members of employees, at the
investigational site
36. Are members of the same household
37. Are unable or unwilling to follow instructions and participate in all study
assessments and visits
38. Less than 80% compliance with BID bilateral Vehicle dosing during the
14-day run-in period (as determined by counting returned single-use vials
at baseline)
39. Have used any investigational product or device within 4 weeks prior to
screening or planned use during the study
Description of Study Sites: 
Up to 150 subjects are planned to be enrolled across up to 12 sites throughout 
the United States. 
Individual Subject 
Participation: 
Vehicle run-in period:   2 weeks 
Treatment period: 
 8 weeks 
Total: 
 10 weeks 
Duration of Study: 
Up to 4 months for recruiting plus 2 months for subject treatment, for a total of 
6 months 
Study Assessments: 
The following study assessments and procedures will be performed: 
•
Informed consent
•
Medical/Ophthalmic history
•
Concomitant medications
•
Vital signs (blood pressure [BP] and heart rate [HR])
•
EDS and ocular discomfort score (ODS) assessments by VAS
•
Symptom Assessment in Dry Eye (SAnDE) score assessment
•
Additional dry eye symptom assessment by VAS
•
BCVA assessment
•
Reading speed assessment
•
Slit lamp biomicroscopy
•
Conjunctival hyperemia grading
•
Tear film break-up time (TFBUT)
•
Corneal fluorescein staining
•
Conjunctival lissamine green staining
•
Schirmer’s test (without anesthesia); strips to be retained for
inflammatory marker analysis
•
Intraocular pressure (IOP)
•
Impression cytology
•
Multidimensional Psychological Questionnaire
•
Blood collection for laboratory testing, and pharmacokinetic
evaluation in a subset of subjects
•
Urine pregnancy test (if applicable)
•
Urinalysis
•
Dilated fundus exam
•
Collect study drug and diary card


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•
Compliance assessment
•
Inclusion/exclusion criteria assessment
•
Randomization
•
Study drug dispensing
•
Study drug administration (with post-instillation comfort VAS)
•
Adverse event assessment
Safety Endpoints: 
To evaluate the safety and tolerability of ALY688 administered BID over 8 
weeks compared with Vehicle, as assessed by ocular examinations (including 
any changes from baseline in slit lamp biomicroscopy, dilated fundus exam, 
visual acuity, IOP, and post-dosing comfort) and systemic evaluations (AEs, 
BP and HR, clinical laboratory test results, and pharmacokinetic results [in a 
subset of subjects]) in subjects with DED. 
Efficacy Endpoints: 
To evaluate the efficacy of ALY688 compared with Vehicle by the following 
measures: 
•
Mean change from baseline at Weeks 2, 4, and 8 in total corneal
fluorescein staining score using the NEI/Industry Workshop scale (0-
20 scale).
•
Mean change from baseline at Weeks 2, 4, and 8 in EDS using a VAS
(0-100 scale, both eyes) during the visit.
NOTE: This will also be assessed by a daily EDS score card for the
7-day period prior to baseline and the Weeks 2, 4, and 8 visits. The
mean of these scores for the 7 days prior to the Weeks 2, 4, and 8
visits will be compared with the mean of the scores for the 7 days
prior to baseline.
Additional exploratory endpoints: 
•
Mean change from baseline at Weeks 2, 4, and 8 in ICSS (0-4 scale)
using the Expanded NEI/Industry Workshop scale (5 zones with 0-4
scale/zone)
•
Mean change from baseline at Weeks 2, 4, and 8 in ODS using a
VAS (0-100 scale, both eyes)
o
NOTE: This will be assessed in the same manner and at the
same timepoints as the EDS score
•
Mean change from baseline at Weeks 2, 4, and 8 in SAnDE score
(frequency and severity) based upon subject recollection for the week
prior to visit
•
Mean change from baseline at Weeks 2, 4, and 8 in conjunctival
lissamine green staining score using the NEI/Industry Workshop
scale (6 zones with 0-4 scale/zone)
•
Mean change from baseline at Weeks 2, 4, and 8 in conjunctival
hyperemia by clinical scoring (0-4 clinical grading scale using
standardized grading photos)
•
Mean change from baseline at Weeks 2, 4, and 8 in TFBUT using
fluorescein
•
Mean change from baseline at Week 2, 4 and 8 in tear volume as
assessed by Schirmer’s test (without anesthesia)
•
Mean change from baseline at Week 8 in the following components
of the VAS dry eye symptom index: 1) burning/stinging, 2) itching,
3) foreign body sensation, 4) photophobia, and 5) pain. In addition,


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the symptom that each subject self-identifies at baseline as the most 
bothersome will be analyzed separately. 
•
Mean change from baseline at Week 8 in reading speed as assessed
by New International Reading Speed Texts (IReST) in subjects with
adequate near visual acuity (BCVA of 20/40 or better) and
appropriate language comprehension
•
Mean change from baseline at Week 8 in conjunctival goblet and
lymphocyte cell densities as assessed by impression cytology
•
Mean change from baseline at Week 8 in selected inflammatory
markers in tears from retained Schirmer’s tear strips (post hoc
analysis)
o
NOTE: Selected measures from those listed above will also
be undertaken as part of the Screening visit to determine
eligibility; refer to the Schedule of Events for specific
evaluations
Analysis Populations: 
Safety and mITT populations: All randomized subjects who receive at least 1 
dose of investigational product 
Per protocol population: All randomized subjects who meet enrollment criteria 
and complete efficacy evaluations at week 4 or 8 
Sample Size and Statistical 
Methods: 
This is an exploratory, hypothesis-generating study. However, with 40 
subjects per group (N=120), there is 80% power to detect an effect size of 0.63 
with a 2-sided, two-sample t-test at an alpha level of 0.05 (uncorrected for 
multiplicity). 
A repeated measures analysis will be performed using the Wei-Lachin 
approach. In addition to repeated measures, the Week 8 change from baseline 
will be tested as a single timepoint measure. An aggregated efficacy measure 
(specific endpoints TBD) will be analyzed as a means to look for consistent 
trends and to increase the overall power. For example, an aggregate of ICSS, 
TFBUT, and Schirmer’s test results may be analyzed. 
The test of the several endpoints involves a comparison of mean change from 
baseline across visits. A fixed effects longitudinal model will be utilized where 
the data of both eyes will be used for measures evaluated in both eyes with 
measures repeated across visits. Baseline score will be a covariate in the 
model. An unstructured correlation matrix will be utilized for correlation 
between eyes and across visits. Measures that do not involve both eyes will 
utilize an unstructured matrix to model the correlation across visits. 
The randomization will be stratified on study site to achieve a balance among 
treatment groups within a site. Each site will be preloaded with complete 
blocks. The site will dispense kits by Interactive Web Response System as 
subjects qualify for treatment assignment. To the extent possible, study drug 
resupply to sites will be done with complete block(s). 
Statistical details will be specified more fully in the Statistical Analysis Plan.