Clinical trial NCT04163328
Conditions: Dry Eye Contact Lens Complication
Keywords: HydroEye® Contact Lens Discomfort Dry Eye Supplement
Sponsor: University of Alabama at Birmingham
Start date: 2022-09-16; Completion date: 2024-08-21
Enrollment: 31 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
HydroEye® is a dietary omega 3 fatty acid supplement that contains both EPA and DHA, as well as GLA and ALA in the form of black currant seed oil. It also has vitamins A, E, C, B6, and magnesium, many of which are involved in fatty acid metabolism. In 2013, Sheppard et al. tested HydroEye® in dry eye patients who were not contact lens wearers and found that symptoms and corneal smoothness improved in response to HydroEye® supplementation. To date, HydroEye® has not been assessed in patients with contact lens discomfort; therefore, the purpose of this clinical trial is to determine the efficacy of HydroEye® as a treatment for contact lens discomfort.

Detailed description:

Arms: arm 1: Subjects will take a total of four capsules daily, with meals (two capsules taken orally, twice a day). arm 2: Subjects will take a total of four capsules daily, with meals (two capsules taken orally, twice a day).
Interventions: intervention 1: HydroEye®
Intervention descriptions: intervention 1: This is an omega-3 fatty acids supplement.

Protocol documents:
Prot_SAP_000.pdf: 
Protocol version Sept. 18, 2022, personnel June 16, 2023 
 
 
Supplementation with HydroEye® as a Treatment for Contact 
Lens Discomfort 
 
Study Protocol & Statistical Analysis Plan 
 
NCT04163328 
 
Date of Last Protocol Approval: September 18, 2022 
(personnel June 16, 2023) 
 
 
Kelly K. Nichols, OD, MPH, PhD; Dean and Professor 
School of Optometry 
University of Alabama at Birmingham 
Birmingham, AL 35294 
 
 
 


Protocol version Sept. 18, 2022, personnel June 16, 2023 
I. BACKGROUND 
 
An estimated 40.9 million people in the United States aged 18 or older wear contact 
lenses.1 While newer and healthier contact lens materials are constantly being developed, 
discomfort remains the top reason for contact lens discontinuation, and dropout rates 
are estimated to be as high as 15.9% in the United States.2 The Report of the International 
Workshop on Contact Lens Discomfort stated in 2013 that dryness is a primary reason for 
contact lens intolerance.3 Indeed, when a contact lens is placed on the eye, the tear film 
structure becomes altered resulting in a pre-lens thinned lipid layer and a post-lens 
thinned aqueous layer.4 As a result of this disruption from the contact lens, the tear film 
tends to have an increased rate of evaporation leading to poor wetting on the surface of 
the contact lens and inadequate lubrication on the surface of the eye. Because of these 
ocular surface dynamics, contact lens wear has been cited as one of several initiating 
factors that can induce dry eye disease.5 
 
According to the 2007 Report of the Dry Eye Workshop,5 dry eye disease is a multifactorial 
disease of the tears and ocular surface. Inflammation is a core component of its 
pathophysiology, and the presence of inflammatory biomarkers in the tear film has been 
reported extensively in the literature.6-8 To combat this inflammation, many therapeutic 
options intervene in the inflammatory cascade. One such anti-inflammatory option is the 
use of omega fatty acids. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) 
are polyunsaturated omega-3 fatty acids that have been linked to reduction of many 
inflammatory cytokines, including prostaglandin E2.9-11 Gamma-linolenic acid (GLA), an 
omega-6 fatty acid, has also demonstrated anti-inflammatory activity and improvement 
in the signs and symptoms of dry eye disease, alone or when combined with EPA and DHA 
in fish oil.12 A comprehensive review of the use of omegas in dry eye has recently been 
published.13  
 
HydroEye® is a dietary supplement that contains the fatty acid, GLA from black currant 
seed oil, as well as the fatty acids EPA and DHA from fish oil. It also includes vitamins A, 
E, C, B6, and magnesium and other nutrients, many of which are involved in fatty acid 
metabolism. In 2013, Sheppard et al. tested HydroEye® in dry eye patients who were not 
contact lens wearers and found symptom improvement, lower levels of inflammatory 
biomarkers and a smoother corneal surface compared with placebo..14 To date, 
HydroEye® has not been assessed in patients with contact lens discomfort; therefore, the 
purpose of this clinical trial is to determine the efficacy of a revised HydroEye® 
formulation (see Appendix) as a treatment for contact lens discomfort.  
 
II. STUDY DESIGN 
 
A. Overview and analysis plan 
 


Protocol version Sept. 18, 2022, personnel June 16, 2023 
The proposed research study is a randomized, double-masked, controlled clinical trial to 
test the efficacy of HydroEye® nutraceutical in subjects with contact lens discomfort.  
Forty-two subjects will be recruited and randomized in a 1:1 ratio of HydroEye® to 
placebo. The trial will span 26 weeks, consisting of four clinical visits, two phone 
encounters to reinforce study drug compliance (investigator will ask about supplement 
usage and will ask subject contact lens survey question), and three two-week intervals of 
subject-entered, electronic data collection in the form of a daily diary (Figure 1). Visit 1 
(V1) is the Screening Visit to ensure that patients meet all inclusion and exclusion criteria. 
For two weeks following V1, subjects will complete daily diary entries using Qualtrics 
Research Suite to assess their daily symptoms and comfortable contact lens wear time. 
V2 is the Baseline Visit and will occur two weeks after V1. If a subject meets all inclusion 
and exclusion criteria through V2, then randomization will occur, and study product will 
be dispensed. Six weeks after V2, staff will call and email the subject to reinforce the 
importance of study product compliance. V3 will occur at 3 months from V2. All clinical 
testing will be identical except that previous study product will be collected and new 
product will be dispensed. Again, phone and email reinforcement will occur 6 weeks after 
V3, and V4 will occur 3 months after V3. At the conclusion of the clinical trial, significant 
knowledge will be gained regarding the clinical utility of HydroEye® in patients with 
contact lens discomfort. 
 
 
Testing to be performed at each clinical visit: 
 
Visit 1 
Screening Visit 
Visit 2 
Baseline Visit 
Visit 3 
3 months 
Visit 4 
6 months 
Informed consent 
X 
 
 
 
Ocular and medical 
history, including 
contact lens wear 
history 
X 
X 
X 
X 
CLDEQ-8 Questionnaire 
X 
X 
X 
X 
SPEED Questionnaire 
X 
X 
X 
X 
NPSI Questionnaire  
X 
X 
X 
X 
Visual acuity 
X 
X 
X 
X 
Slit lamp examination 
X 
X 
X 
X 
Capillary tear 
collection  
X 
X 
X 
X 
Tear break-up time  
 
X 
X 
X 
Corneal staining 
 
X 
X 
X 
Conjunctival and lid 
wiper staining 
 
X 
X 
X 
-2
0
2
4
6
8
10
12
14
16
18
20
22
24
Weeks
Electronic Diary Completion
Clinical Examination
Phone/Email Reinforcement
 
 
 


Protocol version Sept. 18, 2022, personnel June 16, 2023 
Schirmer’s I Test 
X 
X 
X 
X 
Meibography with 
Oculus Keratograph 
X 
 
 
 
Study drug or placebo 
dispense 
X 
X 
X 
 
Study drug collection 
 
X 
X 
X 
Expected Duration 
45 mins 
60 mins 
60 mins 
60 mins 
 
B. Sample Size and Analysis 
 
LTB4 values will serve as a primary biological outcome for judging if HydroEye® is able to 
improve ocular surface health. Work from Masoudi et al. suggests that LTB4 is significantly 
different between symptomatic (0.32 ± 0.06 ng/mL) and asymptomatic (0.17 ± 0.04 
ng/mL) contact lens wearers. A 0.06 ng/mL difference (equivalent to one standard 
deviation) in in LTB4 concentration will be considered a meaningful improvement in LTB4 
concentration. Thus, 16 subjects per group will be needed to determine if there is no 
difference in LTB4 concentration between groups at the final outcome visit (power = 80%; 
alpha = 0.05). After adjusting for 10% dropout, a total sample size of 36 subjects will be 
needed to determine if there is a statistical difference between subject groups.  
 
CLDEQ-4 scores (Rasch validated version; max score of 18) will serve as the primary 
outcome for judging if HydroEye® is able significantly improve contact lens comfort.27 
Data from Pucker et al. suggests that the average contact lens wearer has a mean CLDEQ-
4 score of 7.6 ± 3.8.27 A 4-point difference in CLDEQ-4 scores will be considered a 
meaningful improvement in CL comfort. Therefore, 19 subjects per group will be needed 
to determine if there is no difference in contact lens comfort between the two groups at 
the final outcome visit (power = 90%; alpha = 0.05). After adjusting for 10% dropout and 
subject withdrawals, a total sample size of 42 subjects will be needed to determine if 
there is a statistical difference in contact lens comfort scores between subject groups. 
Since the sample size based upon CLDEQ-4 is larger, 42 subjects will be recruited.  
 
An additional 10 subjects are being requested to account screen fails, and 8 more subjects 
are being requested for assay protocol development. Therefore, this study is requesting 
a maximum of 60 subjects. If additional subjects are not needed to account for screen 
fails, recruitment will be stopped accordingly.  
 
Baseline data of the active and placebo groups will be analyzed at study completion. 
Primary and all secondary outcomes will be compared to baseline and between groups. 
SPSS will be used for all analysis. 
 


Protocol version Sept. 18, 2022, personnel June 16, 2023 
C. Objectives 
 
CO-PRIMARY OBJECTIVE 
To assess changes in comfortable contact lens wear time and subjective symptom severity 
(CLDEQ-4) in response to HydroEye® supplementation in those who experience contact 
lens discomfort 
 
SECONDARY OBJECTIVE 
To assess changes in LTB4 levels in response to HydroEye® supplementation in those who 
experience contact lens discomfort 
 
D. Endpoints 
 
CO-PRIMARY ENDPOINTS 
Mean change in the difference between overall wear time and comfortable wear time at 
6 months 
Mean change in CLDEQ-4 scores at 6 months 
 
SECONDARY ENDPOINTS 
Mean change in LTB4 levels at 6 months 
Mean change in SPEED scores at 6 months 
Mean change in NPSI scores at 6 months  
Mean change in TBUT at 6 months 
Mean change in Schirmer I at 6 months 
Mean change in corneal staining at 6 months 
Mean change in conjunctival staining at 6 months 
Mean change in lid wiper epitheliopathy at 6 months 
Mean change in tear cytokine levels (RayBiotech Human Inflammation Array Q3) at 6 
months 
 
E. Inclusion Criteria 
 
1. Age ≥18 years 
2. Provide informed consent and authorization to disclose protected health information 
3. Willing to follow study protocol  
4. Habitual, contact lens-corrected visual acuity of at least 20/30 in each eye 
5. Wear soft contact lenses as daily wear for at least 6 hours per day and at least 5 days 
per week for the past 30 days 
6. Have at least a 2-hour difference between overall wear time and comfortable wear 
time of contact lenses 
7. Have symptoms consistent with Contact Lens Dry Eye based on CLDEQ-8 (score ≥ 12) 
8. Increased severity of dry eye symptoms with contact lens wear by at least 25% as 
determined by patient self-report 


Protocol version Sept. 18, 2022, personnel June 16, 2023 
9. Clinical assessment that contact lens material, fit, prescription, and care system are 
not reasons for contact lens discomfort 
10. Demonstrate at least 80% compliance in completion of daily electronic diary 
(submitted through Qualtrics Research Suite) between V1 and V2  
11. Willing to discontinue use of any current dry eye treatment (including use of 
commercial hygiene masks, and except for artificial tears) for 4 weeks before 
randomization and during the course of the 6-month study. 
 
F. Exclusion Criteria 
 
1. Meibomian gland dropout ≥75% in either eyelid  
2. Any changes to the contact lens material, fit, prescription, or care system in the 30 
days preceding enrollment or anticipates needing to make changes during the course 
of the study 
3. Any systemic disease known to be associated with dry eye 
4. Any significant ocular surface abnormality that could be associated with ocular 
surface discomfort, such as ectropion, entropion, trichiasis, infection, severe allergic 
conjunctivitis, severe eyelid inflammation, etc. 
5. Any overnight wear of contact lenses  
6. Any previous corneal surgery, including all types of corneorefractive surgery 
7. Have temporary and/or permanent punctal plugs inserted 
8. Use of supplemental fish oil, or seed oils from borage, evening primrose, sea 
buckthorn, flaxseed, or black currant within the last 60 days  
9. Routine, usual dietary intake of more than 8 oz. of cold-water fatty fish (tuna, salmon, 
mackerel, sea bass, sardines or herring) per week).  
10. Use of anticoagulant therapy or regular, daily use of aspirin, NSAIDs, or steroid 
medications within the past 30 days, or a history of easy bruising 
11. Allergy or intolerance to fish or any ingredients contained in the active or placebo 
formulas [See appendix or ingredient list] 
12. Participation in a clinical trial in the past 30 days  
13. Current pregnancy or breast feeding as indicated by self-report  
 


Protocol version Sept. 18, 2022, personnel June 16, 2023 
III. TIMELINE AND REPORTING 
 
 
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Protocol Development and IRB Review
Subject Recruitment
Data Collection
Data Analysis
Manuscript Preparation
Projected Monthly Timeline


Protocol version Sept. 18, 2022, personnel June 16, 2023 
IV. BUDGET 
 
The following budget outlines the estimated costs associated with the proposed clinical trial.  
  
Item  
Unit Cost  
Total  
Clinical Assessment  
   
   
Consumables (fluorescein, lissamine 
green, alcohol pads, charts, Schirmer 
strips, etc.)  
--------  
$550.00  
Salaries  
   
   
Clinician (3.75 h/subject * 55 subjects 
= 112.5 clinician hours)  
$150.00/hour  
$30,937.5  
Study coordinator (0.5 hours/visit * 
120 visits = 60 coordinator hours)  
$50.00/hour  
$3,000.00  
Subject Compensation   
   
   
Subject Visit ($20 for V1; $40 for each 
V2-V4)  
$140.00/subject  
$4,200.00  
Laboratory Assessment  
   
   
RayBiotech Human Dry Eye Disease 
Array Q1 (32-50 sample kit, Qty 3)  
$4,694.00  
$14,082  
  
Enzolife Sciences LTB4 ELISA Kit (50 
sample kit, Qty 3)  
$559  
$3,501  
Other  
   
  
Protocol development and IRB 
review  
$2,500.00  
$2,500.00  
Report and publication in peer-
reviewed journal   
$4,000.00  
$4,000.00  
UAB Study Management Fee   
---------  
$5650  
TOTAL DIRECT COSTS  
   
$68,709.78  
TOTAL INDIRECT COSTS (30%)  
   
$20,612.93  
   
TOTAL  
$89,322.71  
*Both HydroEye® and placebo will be supplied by sponsor.  
  
 
 


Protocol version Sept. 18, 2022, personnel June 16, 2023 
V. REFERENCES 
 
1. Cope JR, Collier SA, Rao MM, R. C, G.L. M, K. R. Contact Lens Wearer Demographics and Risk 
Behaviors for Contact Lens-Related Eye Infections, United States, 2014. 2015; 
http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6432a2.htm. Accessed August 15, 2016. 
2. Rumpakis J. New Data on Contact Lens Dropouts: An International Perspective. 2010; 
http://www.reviewofoptometry.com/content/d/contact_lenses_and_solutions/c/18929/. 
Accessed August 15, 2016. 
3. Dumbleton K, Caffery B, Dogru M, et al. The TFOS International Workshop on Contact Lens 
Discomfort: report of the subcommittee on epidemiology. Invest Ophthalmol Vis Sci. 
2013;54(11):Tfos20-36. 
4. Craig JP, Willcox MD, Argueso P, et al. The TFOS International Workshop on Contact Lens 
Discomfort: report of the contact lens interactions with the tear film subcommittee. Invest 
Ophthalmol Vis Sci. 2013;54(11):Tfos123-156. 
5. No authors listed. The definition and classification of dry eye disease: report of the Definition 
and Classification Subcommittee of the International Dry Eye Workshop. Oc Surf. 2007;5(2):75-
92. 
6. Meadows JF, Dionne K, Nichols KK. Differential profiling of T-cell cytokines as measured by 
protein microarray across dry eye subgroups. Cornea. 2016;35(3):329-35. 
7. Lee SY, Han SJ, Nam SM, et al. Analysis of tear cytokines and clinical correlations in Sjogren 
syndrome dry eye patients and non-Sjogren syndrome dry eye patients. Am J Ophthalmol. 
2103;156;247-253. 
8. Lam H, Bleiden L, de Paiva CS, et al. Tear cytokine profiles in dysfunctional tear syndrome. Am J 
Ophthalmol. 2009;147:198-205. 
9. Rees D, Miles EA, Banerjee T, et al. Dose-related effects of eicosapentaenoic acid on innate 
immune function in healthy humans: a comparison of young and older men.  Am J Clin Nutr. 
2006;83:331-342. 
10. Trebble TM, Wootton SA, Miles EA, et al . Prostaglandin E2 production and T cell function after 
fish oil supplementation: response to antioxidant co supplementation. Am J Clin Nutr. 
2003;78:376-382. 
11. Lo CJ, Chiu KC, Fu M, et al. Fish oil decreases macrophage tumor necrosis factor gene 
transcription by altering the NF kappa B activity. J Surg Res. 1999;82:216-221. 
12. Wu D, Meydani M, Leka LS, et al. Effect of dietary supplementation with black currant seed oil 
on the immune response of healthy elderly subjects. Am J Clin Nutr. 1999;70:56-543. 
13. Hom MM, Asbell P, Barry B. Omegas and Dry Eye: More Knowledge, More Questions. Optom Vis 
Sci. 2015;92(9):948-956. 
14. Sheppard JD, Singh R, McClellan AJ, et al. Long-term supplementation with n-6 and n-3 PUFAs 
improves moderate to severe keratoconjunctivitis sicca: a randomized double-blind clinical trial. 
Cornea. 2013; 32:1297-1304.  
 
 
 
 
 
 
 
 


Protocol version Sept. 18, 2022, personnel June 16, 2023 
VI. APPENDIX  
 
Combined Ingredient List – Active and Placebo Formulas 
 
 
CONFIDENTIAL STUDY MATERIALS – FOR INVESTIGATOR REFERENCE 
ONLY 
 
 
Ingredients in the study formulations may variously include: 
 
• 
Sunflower seed oil 
• 
Black currant seed oil 
• 
Bovine gelatin 
• 
Calcium carbonate 
• 
Glycerine 
• 
Vitamin C (ascorbic acid) 
• 
N-acetyl-cysteine (NAC) (antioxidant) 
• 
Beeswax 
• 
Fish oil (USP-Verified) 
• 
Sunflower Lecithin 
• 
Magnesium sulfate 
• 
Lemon oil 
• 
Vitamin E (d-alpha tocopherol) 
• 
Vitamin B6 (pyridoxine-5-phosphate) 
• 
Caramel color (MEI-4 free, gluten free; from organic cane juice) 
• 
Titanium dioxide  
• 
Trans-pterostilbene (plant extract from pterocarpus marsupium) (antioxidant) 
• 
Vitamin A (retinyl palmitate) 
• 
Vitamin B12 (methylcobalamin) 
• 
Vitamin D3 (cholecalciferol)