Clinical trial NCT06154200
Conditions: Aqueous Tear Deficiency Meibomian Gland Dysfunction of Bilateral Eyes (Disorder)
Keywords: testosterone fluorescein breakup time androgen dry eye
Sponsor: Southern California College of Optometry at Marshall B. Ketchum University
Start date: 2023-04-02; Completion date: 2024-05-30
Enrollment: 24 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this research study is to evaluate the effectiveness and safety of applying androgen sex hormone (i.e., testosterone) gel on the eyelids in the treatment of dry eye patients. Several studies have demonstrated positive treatment effects in dry eye, but few have applied testosterone gels to the eyelids.

Detailed description:
The purpose of this study is to examine the safety and efficacy of transdermal eyelid application of testosterone gel along with the length of any beneficial effect following cessation of treatment.

Moderate to severe dry eye subjects will be enrolled into a randomized controlled trial with assignment to either an \~ 4.5% FDA-approved androgen gel (Natesto®, Acerus Pharmaceuticals, Mississagua, Canada) or a placebo formulated similar to Natesto® without testosterone. The gel will be applied to both eyelids in the morning and 12 hours later on both eyelids for a 30 day treatment period

Subjects will fulfil DEWS II criteria for eligibility and further be classified as moderate or severe based on DEWS II recommendations. A standardized examination involving signs and symptoms of dry eye and monitoring function of the meibomian and lacrimal glands, as well as clinical tear and ocular surface measures, IOP, and serum testosterone levels, at baseline, following 30 days of testosterone application, and at one and two months post-treatment.

Arms: arm 1: Vehicle gel applied to eyelids twice per day arm 2: Testosterone gel 4.5% applied to eyelids twice per day
Interventions: intervention 1: Testosterone gel 4.5% intervention 2: Vehicle gel
Intervention descriptions: intervention 1: Testosterone gel applied to eyelids twice per day intervention 2: Vehicle gel applied to eyelids twice per day

Protocol documents:
Prot_SAP_002.pdf: 
 
Eyelid Androgen Treatment in Dry Eye 
__________ 
 
June 7 2022 
 
PROTOCOL 21-18 
 
ClinicalTrials.gov ID:  NCT06154200 
 
Southern California College of Optometry at  
Marshall B. Ketchum University 
 
__________ 
 
Investigators: 
 
Jerry R. Paugh, OD, PhD, Principal Investigator 
Jay Ruzhan Jiang, MD, Co-Investigator 
Rima Khankan, PhD, Co-Investigator 
Willima Ridder III, OD, PhD, Co-Investigator__________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
1
Introduction 
Dry eye disease (DED), also known as dry eye syndrome, is one of the most common 
ocular conditions prompting patients to seek eye care. It is prevalent in 5%-50% of the 
population, depending on the diagnostic criteria and regions of the world investigated.1 
DED has a substantial negative impact on physical, potentially psychological, function 
and health-related quality of life on those patients.2  It is also associated with a 
considerable economic burden and caused an estimated loss of $3.3 billion USD in 2008 
in the USA alone.3  
The management of DED is complicated due to its multifactorial etiology, i.e., 
whether it is aqueous deficient or evaporative in nature, or a mixture of these two major 
subtypes.4 Treatment varies depending on severity, for example, with artificial tears, 
environmental alteration, and holistic approaches such as omega 3 intake in the early 
stages,  and  progressing to drug therapy both topically and systemically as the condition 
worsens.5,6 
DED becomes more frequent with age in both women and men, but women are at a 
higher risk of dry eye than men, which suggests that sex hormones may play a role in this 
condition.1 Sex hormones, particularly androgens, have been shown to impact the 
structure and function of tear apparatus and ocular surface tissues, leading to altered tear, 
lipid, and mucin production.7  
Previous studies support the efficacy of androgen treatment in relieving dry eye 
symptoms and signs related to both aqueous deficient dry eye (ADDE) and evaporative 
dry eye (EDE). Worda et al.8 treated one male patient with severe dry eye, probably of 
the aqueous deficient subtype, although this was not specified, and low serum 


 
2
testosterone levels, with 3% testosterone cream. The cream was applied topically to the 
eyelids three times per day (TID) for 3 months which brought tear stability and lipid layer 
thickness to normal levels.8 Further, they found no increase in serum testosterone levels 
from the eyelid application.  
Transdermal systemic androgen administration has demonstrated improved signs and 
symptoms in dry eye patients.9-11 Two retrospective case series show improvement of dry 
eye symptoms while receiving systemic androgen replacement in women with low 
testosterone; one with combined esterified estrogen and methyltestosterone 12 and the 
other with androgen alone. 9 
Supalaset et al.10 in a prospective study used conventional systemic transdermal 
testosterone treatment in postmenopausal women and andropausal men. Following four 
weeks of treatment, significant improvements in OSDI, tear break-up time, corneal 
fluorescein staining, and Schirmer test in the testosterone group were found compared to 
placebo. Further, they demonstrated a systemic increase in testosterone levels in the 
females (to normal levels) but little change in the andropausal males.  
Golebiowski et al.11 used 1.0% transdermal testosterone cream and 1mg/g estradiol 
gel applying to the inner thigh daily (QD) to investigate the impact of testosterone and 
estrogen on dry eye symptoms and signs in postmenopausal women. This randomized, 
placebo-controlled study recruited 10 subjects in each treatment arm (1.0% testosterone 
cream, 1mg/g estradiol gel, 1.0% testosterone cream combined with 1mg/g estradiol, and 
placebo). The results demonstrated increased tear secretion in the testosterone/estradiol 
combination group for 8 weeks and a strong association between increased serum 
androgen and improved tear stability in the testosterone group when running the within 


 
3
group analysis. However, there were no significant changes in total Ocular Comfort 
Index (OCI) or OSDI symptom scores nor tear function, meibomian gland function, lid 
morphology, corneal or conjunctival sensitivity in any of the three test arms when 
compared with the change in the placebo groups after 8 weeks. The results of this study 
suggested that 1% testosterone may be below the optimal therapeutic concentration, or 
local application is more effective than systemic transdermal delivery.  
Low levels of serum dehydroepiandrosterone (DHEA) have been noted in patients 
with primary Sjogren syndrome due to the impaired Hypothalamic Pituitary Adrenal 
(HPA) axis.13 In a pilot clinical trial of oral DHEA for Sjogren’s syndrome, Pillemer et 
al. found that 200 mg per day DHEA showed no evidence of improvement in dry eye 
symptoms and objective measures of ocular dryness.14 Though the examination of serum 
testosterone level was not conducted in this study, it is possible that the role of systemic 
serum androgen level is not as important as local sex hormone concentration in the 
management of dry eye disease. Table 1 summarizes clinical trials of systemic or topical 
application of androgen treatment in dry eyes. Taken together, these studies show that 
androgen is a potential treatment for dry eye disease, especially for those with primary 
androgen deficiency. The question is whether topical androgen treatment either on or in 
the eye may be effective in both deficient, and non-androgen-deficient individuals.   


 
4
Table 1  
Summary of Clinical Trials of Androgen Treatment in Dry Eye  
Author 
Subject 
N 
(comple
ted) 
Subject 
Type 
Route 
of 
Administ
ration 
Treatment  
Duration  Placebo  
Effect 
on 
Serum 
Level 
Effect on  
Tear Film 
Systemic Administration 
Pillemer 
2004 
RCT15 
F=28 
Sjogren 
syndrome 
systemic  
oral DHEA 
200mg (purified 
DHEA, Diosynth 
Inc, Chicago) 
qd for 24 
weeks  
placebo 
caps  
n/a 
no improvement 
in Schirmer I test 
and dry eye 
staining 
Nanavaty 
2014 9 
F = 14 
androgen 
deficiency 
systemic 
by thigh  
transdermal 
androgen patch 
(Intrinsa, P&G 
UK) 
Avg Tx = 
13 
months 
none 
144 % 
increase 
Sx improved, 
TBUT, Schirmer 
increased 
Golebiows
ki 2017 
RCT11 
F= 40; n = 
10 per arm 
Menopaus
al female 
systemic 
by thigh  
1% transdermal 
gel 0.5ml(5mg) 
8 weeks 
cream or 
gel; same 
componen
ts sans 
actives 
no 
change 
in testo 
group 
Testo group (n = 
10):  no change in 
tear rmeasures 
Supalaset 
2018  RCT 
10 
F=34 
M=12 
androgen 
deficiency 
systemic  
by 
adominal 
skin 
50mg 
Transdermal 
testosterone 
(Androgel, 
Besins 
Healthcare, 
Belgium) 
4 weeks  
100 mg 
urea 
cream 
Females 
= 828% 
increase; 
Males = 
17% 
increase 
vs. placebo: sig. 
increases in: 1) 
Sx, 2) TBUT, 3) 
staining, 4) 
Schirmer  
Ocular Administration 
Worda C 
20018 
M = 1 
KCS 
topical 
cream on 
eyelid 
3% testo cream  
three 
times 
daily for 
3 months 
none 
24% 
increase 
TBUT, lipid layer 
improved 
Connor et 
al 200116  
F=1 M=9 
dry eye 
topical  
eyedrops  
1% DHEA drops  
4 times 
daily for 
2 weeks  
artificial 
tears  
n/a 
improved TBUT 
and Schirmer I 
Connor C 
200217  
F=9 M=11 
complains 
of dry eye 
topical 
eyedrops  
1% testo drops 
VS 1% DHEA 
drops 
4 times 
daily for 
2 weeks  
artificial 
tears  
n/a 
improved TBUT 
and schirmer I, 
DHEA drops work 
better than 
artifical tears and 
testosterone 
Connor C 
2002 18 
F=15 M=5 
dry eye 
topical 
cream on 
eyelid 
2.5% testos 
cream 
twice 
daily for 
3 weeks  
transderm
al cream 
alone 
n/a 
improved TBUT, 
Schirmer test, 
increased contact 
lens wearing time 
Connor C 
200319   
F=25 M=3 
complains 
of dry eye 
topical 
cream on 
eyelid 
3% testo cream  
twice 
daily for 
2 weeks 
null 
transderm
al cream 
n/a 
improved 
Schirmer test and 
dry eye 
symptoms, post 
menopausal 
female perceived 
the greatest relief 
of symptoms 
 Connor, 
C.G. 
200420  
F=37 M=3 
retro 
symptoms 
based  
topical 
cream on 
eyelid 
3% testosterone 
cream 
bid for 
two 
weeks  
None  
n/a 
TBUT poor 
predictor, 
Successful group 
younger, schirmer 
test from 7 to 
12.72 in 
successful 
group( age and lid 
disease less 
sensitive)  
C.G.,Conn
or 200521  
F=17 M=3 
TBUT+Sx 
topical 
cream on 
eyelid 
5% testos cream 
twice 
daily for 
3 weeks  
None  
n/a 
increased 
TBUT(not 
significant), 


 
5
 
Several studies using topical application of androgen formulation have shown the 
efficacy of local androgen application to the eyelids on dry eye. Connor et al.30-32 
conducted 3 studies to explore the efficacy of testosterone cream in dry eye patients with 
or without androgen deficiency. The results showed that the 3% or 5% testosterone cream 
applied for 2-3 weeks significantly improved the Schirmer’s test results and/or the 
TBUT. The greatest improvement was found in the age group of 40-60 year old women 
but not in the group over age 60 who are reported to have lower systemic serum androgen 
levels.26 The underlying etiology is unknown, but a possible explanation is that 
androgenic receptor sensitivity in the ocular tissue is increased due to the reduced 
decreased OSDI 
scores  
C.G.,Conn
or 2006 22 
F=23 
 
topical 
cream on 
eyelid 
n/a 
twice 
daily for 
3 years 
None 
n/a 
increased TBUT, 
Schirmer 
test,increased 
contact lens 
wearing time,  but 
IOP not different,  
Schiffman 
R 2006 
RCT 23  
179 
MGD 
topical 
eyedrops  
0.01%, 0.03%, 
0.1%  drops  
6 months  
vehicle 
drop  
n/a 
0.03% most 
effective, 
improved MG 
secretion quality, 
no incidence of 
adverse effect  
C.G.,Conn
or 200724  
F=26 M=6 
dry eye  
topical 
cream on 
eyelid 
15% 
progesterone 
cream 
twice 
daily for 
3 weeks  
None 
n/a 
increased TBUT, 
Schirmer test(not 
significant), 
decrease OSDI, 
but IOP not 
different 
Connor C 
2008 25 
F=21 
EDE 
topical 
cream on 
eyelid 
5% testos cream 
twice 
daily for 
3 weeks  
None 
n/a 
increased TBUT, 
Schirmer test(not 
significant), 
decrease OSDI 
Connor C 
200926  
F=62 
dry 
eye/age 
topical 
cream on 
eyelid 
5% testos cream 
twice 
daily for 
3 weeks  
None 
n/a 
TBUT, Schirmer 
test, OSDI only 
significant chagne 
with 40-60 yo 
C.G.,Conn
or 201027  
F=22 
reduced 
CTL time  
topical 
cream on 
eyelid 
5% testos cream 
three 
weeks  
None 
n/a 
increased TBUT, 
Schirmer 
test,increased 
contact lens 
wearing time 
C.G.,Connor 
201128  
F=24  
HRT vs no 
HRT  
topical 
cream on 
eyelid 
5% testos cream 
n/a 
None 
n/a 
Presence of HRT 
positively influence 
response 
Connor C 
201229  
F=30 
dry eye 
topical 
cream on 
eyelid 
 5% testos 
cream 
twice 
daily for 
1 month 
none 
n/a 
increased TBUT 
from 3.53 to 7.11, 
no increase in BP 


 
6
androgen level in the 40 to 60 year age group, although serum levels were not measured 
in this investigation.26 
In contrast to the systemic endocrine system, human beings have a unique intracrine 
system to regulate sex hormone production and metabolism locally. Intracrinology 
describes the local synthesis of androgens and estrogens made locally in each cell of each 
peripheral tissue from the adrenal precursors dehydroepiandrosterone (DHEA) and 
dehydroepiandrosterone sulfate (DHEA-S).33 These androgens and estrogens exert their 
action on the same cells where their synthesis takes place and are released from these 
target cells only after being inactivated.34 In humans, DHEA levels in circulation reach 
maximum levels between age 20 and 30 years, decreasing by 80% by the age of 70 in 
males and females.35 The great reduction in adrenal secretion of DHEA and DHEA-S 
results in a large fall in the formation of androgens and estrogens in peripheral tissue with 
age.36 Since the prevalence of DED increases with age, this drop in DHEA, and DHEA-S 
could be a contributing factor.7 Thus, intracrinology allows circulation levels of androgen 
to remain subthreshold while potentially allowing topical application of androgen to play 
an important role in the management of dry eye disease.  
 
The risk of adverse effects from androgen supplementation is low in individuals with 
depressed serum androgen levels except for at risk groups such as when breast carcinoma 
or prostate cancer are suspected. Current commercially available FDA approved 
transdermal testosterone formulations are indicated for testosterone replacement therapy 
in males and females with androgen deficiency. Therefore, monitoring serum testosterone 
concentrations is critical.  


 
7
The common side effects of excess androgen intake include cardiovascular, 
musculoskeletal, and psychiatric effects, as well as acne and hair growth.37 Increases in 
LDL-cholesterol and reduction in total cholesterol, HDL-cholesterol, and triglycerides 
have been demonstrated in oral testosterone intake whereas non-oral treatment (via 
transdermal patch or cream) has no such adverse effects.37 The meta-analysis reported by 
Islam et al. 37 indicates testosterone treatment administrated at doses intended to 
approximate physiological replacement levels is not associated with an increase in 
serious adverse events in women. Prostate safety is a major concern in men receiving 
androgen replacement therapy. The current evidence does not support the view that 
appropriate treatment of hypogonadal elderly men with androgen has a causal 
relationship with prostate cancer.38 
Several studies have examined the serum levels of testosterone in relation to studies 
of dry eye treatment efficacy.9,11  
Nanavaty et al.9 applied a transdermal androgen patch in androgen deficient females 
and found that after three weeks of patch therapy the serum level of testosterone 
increased approximately 144%, but this brought the serum level into the normal range.39 
Supalaset et al.10 administered a dose of 50 mg testosterone every other day for four 
weeks in men and women with decreased serum testosterone levels. They found that 
serum levels increased approximately 17% in men and 828% in women, but both higher 
levels were within the normal testosterone range for males and females.39 Further, 20 
percent of androgen-treated subjects reported having oily skin and 4% reported acne.10  
Golebiowski et al11 also examined transdermal delivery of testosterone alone, and a 
testosterone/estradiol combination in postmenopausal women. It is unclear whether the 


 
8
dose was appropriate for treating low testosterone, but there was no change in serum 
testosterone level (DHEA-S) in either testosterone-containing arm.11 
One aspect of local, transdermal application of testosterone to the eyelids is the 
affected surface area. The upper and lower eyelid surface area is around 8% of one adult 
handprint (the average surface area of both sides upper and lower eyelid is 14.2 cm2 (* 
1.5cm*1.5cm*2: the area of upper and lower eyelid is close to a circle with diameter of 
the length of horizontal eyelid fissure around 3.0 cm. 40) compared to one handprint 
180cm2 (1% of body surface area BSA 1.8m2)). The total dosage needed to cover both 
upper and lower eyelid surfaces is much lower than the systemic application of androgen 
in the study of Supalaset10 (98 cm2; 7cm*14cm: the area the author used to apply 
androgen cream).  The eyelid application is thus a small, and likely safe dosage relative 
to systemic safety. 
There is very little reported data concerning serum testosterone levels following 
eyelid application. Worda et al.,8  in one subject who was testosterone deficient, applied 
3.0% testosterone cream three times daily and had no change in serum testosterone levels 
following 2.5 months of drug application. Dr. Charles Connor has conducted several 
studies16-21,24,26,31,41 of eyelid testosterone cream application but has not surveyed the 
serum testosterone changes that might result.  
In collaboration with Zhijun Wang, PhD, of the College of Pharmacy at MBKU, we 
have examined the likely systemic absorption of androgen applied to the upper and lower 
eyelids BID in the dosage form currently FDA approved for androgen insufficiency 
(Natesto gel, 11 mg each single application for two eyelids or 22 mg per day total for two 


 
9
applications to the eyelids per day). This simulation and report is attached as Appendix I 
(Simulation report, v3, Z Wang, 12-6-21).  
The assumption for the simulation was that the amount of gel necessary for one eyelid 
application was the size of a pea (Dr. Charles Connor, personal communication; email of 
11-1-21) which Dr. Zhijun Wang measured to be approximately 0.122 grams. This 
represents one pump of the Natesto dispenser or 5.5 mg of testosterone delivered.42 
Applied to both eyelids at one application, this represents 11 mg total for a single 
application.  
Beginning on Page 5, the simulation demonstrates for Natesto applied once per day to 
right and left eyelids, both upper and lower eyelids (11 mg total) that the mean increase 
in serum levels above baseline of total testosterone is about 0.15 to 0.18 ng/ml, whether 
for a single application or repeated applications over a 30-day period (Figure 3. A – D). 
Clark et al.39 have published the weighted average range values for total testosterone (TT, 
the parameter that is measured during routine clinical laboratory assay) as 2.54 – 8.90 
ng/ml for males and 0.12 – 0.58 ng/ml for females. From the simulation, this indicates 
that male serum TT increase will be minimal and potentially double the minimum normal 
level for females, yet still possibly within the normal range for females. It is unlikely that 
any virilization effects (e.g., facial hair growth, scalp hair loss etc.) will be observed in 
males and it is unknown whether these same effects will occur in females. 
 
Dr. Connor has monitored patients who were using testosterone cream applied to the 
eyelids twice a day for at least 3 years and found no elevation in IOP.41 In another study, 
Connor observed that short term treatment with 5% transdermal testosterone cream for 


 
10 
dry eye enhances female patient TBUT but doesn’t significantly impact the patient’s 
blood pressure.43 
In our proposed study, we will monitor total serum testosterone levels in all subjects 
at baseline, and within two hours of the morning eyelid dose at the four-week visit (end 
of dosing). Until this blood work is accomplished, the effects of 4.5% eyelid testosterone 
gel applied BID will remain unknown. 
Research Rationale  
Androgen, especially when topically applied to the eyelids, appears to be effective in 
management of dry eye disease due to its impact on function of tear apparatus.7 The 
results of systemic dermatological application of androgen in the treatment of DED are 
mixed due to the varying testosterone concentrations and dosage time frames. These 
studies9-11 of non-ocular dermatological application of androgen have shown desirable 
effects and a good safety profile.  
In contradistinction, the studies by Worda et al8 and Connor et al.16-21,26,31 have 
examined topical eyelid androgen application with generally favorable effects on tear 
film parameters and also a good safety profile. However, the eyelid application studies 
were not consistent in the subject type (e.g., both males and females were not uniformly 
enrolled), the androgen status and serum levels were not assessed prior to, or following 
androgen application and the studies were only published as peer-reviewed abstracts and 
mostly were done in one laboratory. This prospective randomized, controlled double 
masked study aims to evaluate the efficacy and safety of topical transdermal application 
to the eyelids of low dosage androgen in a population of patients with evaporative dry 
eye associated with meibomian gland dystrophy and aqueous tear deficient dry eye.  


 
11 
 
Methods  
Study objective 
To evaluate the safety and efficacy of an FDA-approved androgen nasal supplement 
(Natesto, Acerus Pharmaceuticals Corporation, 4.5% gel concentration) in males and 
females with dry eye of either aqueous tear deficiency or evaporative subtype. 
Clinical hypothesis 
• Natesto applied to upper and lower eyelid skin is more effective than placebo 
as measured by fluorescein tear breakup time (TBUT) and mean scores for 
meibomian secretion quality at 4 weeks and overall ocular comfort at 8 weeks.  
• Natesto has an acceptable safety profile in ocular structures and general 
systemic system.  
Statistical Hypotheses: 
 
Ho:  There is no difference in change from baseline to week four for either fluorescein 
breakup time (TBUT) or meibomian secretion score (0 – 24 scale) between the test and 
placebo-treated sample.   
 
HA:  There is a difference in the change from baseline to week four for either fluorescein 
breakup time (TBUT) or meibomian secretion score (0 – 24 scale) between the test and 
placebo-treated sample 
 
Overall study design  
Structure 
 
We propose a randomized controlled trial (RCT) of one month duration dosing BID with 
an FDA-approved androgen nasal supplement (Natesto, Acerus Pharmaceuticals 


 
12 
Corporation, 4.5% gel concentration) in males and females with dry eye of either aqueous 
tear deficiency or evaporative subtype.  
The test formulation will be marketed Natesto gel, containing 5.5 mg testosterone per 
pump (17β-Hydroxyandrost-4-en-3-one; inactive ingredients are castor oil, oleoyl 
polyoxylglycerides and colloidal silicone dioxide; Natesto package insert). The placebo is 
the exact same formulation without 17β-Hydroxyandrost-4-en-3-one. The drug and 
placebo will be delivered to and dispensed by Caduceus Medical group in Yorba Linda 
for MBKU’s study use.  
Dosage regimen 
 
One dose per eyelid of masked gel, which is one pump from the dispenser, represents 5.5 
mg for each eyelid, will be applied on the surface of upper and lower eyelid skin each eye 
twice per day (separated by 8 hours) for a total daily dose of 22mg.  
Duration 
 
2-week screening period; 4-week masked treatment phase, 8-week washout phase. 
Overall study duration 14 weeks  
Visit schedule (see Table 4 and 5) 
• Visit 1: Screening visit (Day -14) 
• Visit 2: Baseline (Day 0) : the drug (placebo) is prescribed and dispensed. 
Instructions are given on how to properly apply the drug. Subjects are instructed 
to keep the container even if the drug is finished. All containers need to be 
checked in the following two visits (visit 3 & 4) 
• Visit 2a:  serum blood draw for baseline total testosterone level, hematocrit, lipid 
panel, PSA for men only at clinical laboratory  


 
13 
• Visit 3:  Two-week visit: check the drug (placebo) to see if supplement needed.  
Empty containers need to be collected.  
• Visit 4: Week 4:  the drug (placebo) is discontinued. All dispensed containers 
need to be collected.  
• Visit 4a:  serum blood draw for treatment period total testosterone level at clinical 
laboratory (must be in AM, and must be within two hours of application) 
• Visit 5: Week 8:  4-weeks washout phase follow up 
• Visit 6:  Week 12:  8-week washout phase follow up 
Evaluation criteria 
 
Efficacy measures 
Primary 
• Fluorescein tear breakup time (FTBUT) 
• MGD secretion grade (0-24 scale) 
Secondary:  
1. Schein Questionnaire and Ocular Surface Disease Index (OSDI) 
2. Corneal and conjunctival staining as per the Oxford and National Eye Institute 
(NEI) schemes 
3. Tear Meniscus Height (TMH) utilizing Keratography 5M (K5M Oculus, Inc 
Arlington,WA) 
4. Eyelid signs grading of orifice metaplasia, vascularity, plugged orifice, lid margin 
irregularity, ridging between orifices, and antero-posterior orifice displacement 
5. Meiboscore utilizing K5M 
6. Schirmer I test without anesthetic 


 
14 
Exploratory:   
 
1. Comparison of National eye Institute (NEI) to Ocular Staining Score (OSS) 
(DEWS II recommendation) staining scheme for efficiency 
2. Repeatability of the above two staining schemes and meibomian gland secretion 
scores 
Pharmacokinetic measures 
 
• The patients will have blood samples (20 ml) drawn for the determination of total 
serum testosterone. Blood will be drawn at baseline and within two hours of dose 
application at Week 4 visit.   
Safety measures 
 
• Adverse events (treatment related and treatment unrelated)  
• Visual acuity (BCVA ETDRS) 
• Biomicroscopy  
• Ophthalmoscopy exam  
• IOP 
• Male scalp hair evaluation  
• Female hair evaluation (upper lip, chin, cheeks, scalp)  
 
Subjects  
Subjects will consist of a convenience sample of patients over 18 years old with signs and 
symptoms of dry eye disease (DED). Moderate to severe dry eye subjects who have 
either aqueous tear deficiency or evaporative dry eye related to meibomian gland 


 
15 
dysfunction will be recruited. The diagnosis of DED is made according to the DEWS II 
diagnostic criteria based on:   
1. DE symptomatology:  OSDI score ≥ 13 and Modified Schein score ≥ 7.5  
2. Plus one of the following:   
a. NIBUT < 10 seconds or fluorescein breakup time ≤ 6.0 seconds or  
b. Osmolarity ≥ 308 mosm/L in either eye or intraocular difference > 8 
mosm/L or  
c. Ocular surface staining (SICCA scale) > 5 corneal spots, > 9 conjunctival 
spots 
d. Conjunctival-corneal epithelial damage (fluorescein, rose bengal, or 
lissamine green staining score >3 points).  
3. Subtype Tests:  severity according to the DEWS II Dx report;4 page 556 
a. Aqueous tear deficiency:  non-invasive meniscus height (TMH) ≤ 0.2 mm 
b. Evaporative:  only moderate to severe included: 
1. Moderate:  1) orifice plugging, 2) lid margin vascularity, 3) 
gland secretion grade 8 – 12 (central 8 glands, 0 – 3 scale each), 
4) expressibility grade 2  
2. Severe:  1) lid margin dropout or displacement, 2) gland 
secretion score ≥ 13, 3) expressibility grade of 3 
The subjects will be recruited from among students, staff, faculty and patients 
from Ketchum Health, the clinical facility at Marshall B. Ketchum University. 
Additionally, the study will be advertised on social media to maximize the 
recruitment pool, such as Facebook, Instagram, and Twitter. Subjects will be sex-, 


 
16 
and age-matched as they are enrolled since these parameters affect dry eye 
parameters such as marginal changes and meibomian gland secretion. 44 
  
Sample size estimation  
1. In this present investigation the principal outcome measures, fluorescein TBUT 
(using 2.0 microliters of 1.0% sodium fluorescein) and the system for meibomian 
gland secretion (0-24 scale) are recommended by the MGD workshop and DEWS 
II diagnostic committees.4  Table 2 shows the sample size estimation with two arm 
parallel design, comparing the change from baseline in FTBUT in each arm with a 
two sample t-test continuous data, clinically meaningful change of 2.5 seconds with 
Standard Deviation (SD) following treatment of 2.5 seconds. The results are as 
follow:  
• 2-Sample t Test 
• Testing mean 1 = mean 2 (versus ≠) 
• Calculating power for mean 1 = mean 2 + difference 
• α = 0.05   
• Assumed standard deviation = 2.5 
Table 2: Sample size estimation  
Difference 
Sample Size 
Target Power 
Actual Power 
2.0 
26 
0.8 
0.807487 
2.5 
17 
0.8 
0.807037 
3.0 
12 
0.8 
0.802079 
3.5 
10 
0.8 
0.841306 


 
17 
4.0 
8 
0.8 
0.844793 
2.  
3. With the actual power of 0.807, total of 34 subjects with seventeen (17) subjects 
per arm will be recruited for this study. 
 
Randomization method 
Due to the relatively small sample size (n < 200) and the need to control and 
balance the influence of covariates, such as age and sex, we adopted the method of 
covariate adaptive randomization.45 With two covariates of sex (2 levels: male, 
female) and age (2 levels: <50, >50) between study arms (treatment and control), a 
total of 4 block combinations is produced. After a participant has passed the screening 
and day 0 examinations, the first 10 participants will be assigned to one of the 
treatment groups within each block by simple randomization, according to a 
randomization scheme (Dr. Andrew Loc Nguyen will generate this). The next new 
participant is then sequentially assigned to a particular treatment group by 
considering the specific covariates and previous assignments of participants. For 
example, the first 10 participants assignment are broken down by covariates as in 
Table 3. Then the 11th participant, who is male and >50 years old, needs to be 
assigned to a group (control vs. treatment). Based on the characteristics of the 11th 
participant, the method adds marginal totals of the corresponding covariate categories 
for each group and compares the totals. The participant is assigned to the group with 
the lower covariate total to minimize imbalance. In this example, the appropriate 
categories are male and > 50 years old, which results in a total of 6 (3 for male and 3 
for >50) for the control group and a total of 5 (3 for male and 2 for >50) for the 


 
18 
treatment group. Because the sum of marginal totals is lower in treatment group 
(5<6), the 11th participant is assigned to the treatment group.  
 
 
Table 3.  Procedure of randomization  
Control group  
Sex 
Marginal total 
Male  
Female  
Age  
<50 
2 
0 
2 
>50 
1 
2 
3 
Marginal total  
3 
2 
5 
 
 
Treatment group  
Sex 
Marginal total 
Male  
Female  
Age  
<50 
1 
2 
3 
>50 
2 
0 
2 
Marginal total  
3 
2 
5 
 
Every participant is assigned a number from 001 to 100 and recorded with the 
specific number during the whole study until de-identified at the end of the study.  
 
Masking  
1. The participants will be masked from the assignment of the treatment group. 
2. An unmasked research assistant will recruit and schedule subjects and administer 
the questionnaires and exclude subjects based on the above-mentioned inclusion 
and exclusion criteria.  
3. Another unmasked research assistant will implement the randomization based on 
the above covariate adaptive randomization method.  


 
19 
4. The principal investigator is masked from tests and placebo formulation during 
the follow up dry eye evaluations on subjects. 
5. All masked information will only be opened at the end of the study or unless an 
adverse event (AE) requires unmasking to determine whether the AE was due to 
the treatment medication.  
Study Sites  
1. Southern California College of Optometry at Main Campus (2575 Yorba Linda 
Blvd. Fullerton, CA 92831). Main site for dry eye examination  
Inclusion & Exclusion Criteria  
Inclusion criteria 
 
There are no restrictions for subject inclusion based on ethnicity, race, or occupation. All 
subjects meet the following criteria:  
1. Male or female age over 18   
2. Able and willing to follow study instructions.  
3. Are able to provide written informed consent  
4. Written authorization for use or release of health and research study information 
will be obtained  
5. Are willing to discontinue use of artificial tears and makeup on the study visit 
days 
6. Able and willing to attend the clinical laboratory for morning blood draws to 
assay serum testosterone in addition PSA levels for men.  
7. Patient must have a best corrected visual acuity of 20/40 or better in each eye  
8. Patients must have normal lid position and closure  


 
20 
9. Patients’ willingness and ability to cooperate with the investigator and follow all 
instructions  
10. A negative urine pregnancy test result for women of childbearing potential 
11. Women of childbearing potential (from 18 to 50 years old) must have a history of 
bilateral tubal ligation or use contraceptives, implants, injectables, transdermal 
patch or IUD for birth control during the study. Patients taking oral contraceptives 
must not miss 2 or more doses in a one-month period. If these methods of birth 
control do not apply, women of childbearing potential must have a monogamous 
partner who has had a vasectomy at least 3 months before the screening visit. The 
date of the vasectomy and physician contact information must be documented in 
the source documents.  
12. Subjects must have a meibomian gland secretion score of 8 or greater (0 – 24 
scale). 
13. Subject s must have at least 50% meibomian glands present in the upper eyelids. 
Exclusion criteria 
 
1. Uncontrolled systemic disease or the presence of any significant illness or 
condition that could, in the judgement of the investigator, jeopardize patient 
safety or interfere with interpretation of the study results (Sjogren’s syndrome and 
related autoimmune disease are allowed). 
2. Known or suspected prostate cancer or male patients with a PSA level > 4ng/mL. 
If PSA level is > 4 ng/mL, the patient can participate only if the patient receives 
written approval by a urologist. If a man has had a recent prostate exam, at least 4 
weeks should separate the prostate exam and our study screen test. If a man has 


 
21 
benign prostatic hyperplasia (BPH), the participants should be notified the risk of 
worsening BPH if he wants to participate.  
3. Current or recent venous thromboembolism (VTE), including deep vein 
thrombosis (DVT) and pulmonary embolism (PE). Evaluate subjects who report 
symptoms of pain, edema, warmth and erythema in the lower extremity or acute 
shortness of breath and seek medical care. 
4. Recent cardiovascular events (e.g., MI, stroke). Subjects who report signs or 
symptoms of heart attack or stroke should seek medical care. 
5. Hepatic disorders (hepatitis, jaundice, hepatic cancer et al.). Subjects should 
monitor for signs or symptoms of hepatic dysfunction (e.g. jaundice) 
6. Subjects with cancer and at risk for hypercalcemia (e.g., lung cancer, kidney 
cancer, multiple myeloma, lymphoma, leukemia, ovarian cancer. et al.) 
7. Subjects taking insulin, warfarin or systemic corticosteroids.  
8. Contact lens wear during the six months prior to study start and at any time during 
the study. 
9. Punctal occlusion done within 3 months of the screening visit or during the study  
10. Active ocular infection, non-KCS ocular surface inflammation (e.g., episcleritis) 
or intraocular inflammation (e.g., uveitis)  
11. Female patient who is pregnant or nursing or planning a pregnancy during the 
study.  
12. Males or females with a personal history of breast cancer.  


 
22 
13. Patients who are currently on any androgen or anti-androgen treatment or who 
have discontinued such treatment less than three months prior to the screening 
visit. Anti-androgen therapy includes medications or supplements that may 
interfere with testosterone metabolism, such as 5-alpha reductase inhibitors (e.g., 
finasteride, dutasteride). 
14. Patients use of any topical ophthalmic formulations (including over the counter 
ointments and gels), except the study supplied non-preserved artificial tears (low 
viscosity Refresh Tears) used as escape medication after the screening visit. Oil 
and gel-based products are prohibited. 
15. Known sensitivity to any components of the study or procedural treatments, 
including sodium fluorescein  
16. History or evidence of herpes keratitis  
17. Corneal disorder or abnormalities other than those caused by meibomian gland 
dysfunction, including those that may affect corneal sensitivity or normal 
spreading of the tear film (e.g., corneal dystrophy)  
18. History of anterior segment surgery or trauma which could affect corneal 
sensitivities (e.g., cataract surgery, or any surgery involving a limbal or corneal 
incision within the last 12 months) or patients who have had refractive surgery  
19. Patients with CAIS (complete androgen insensitivity syndrome)  
20. Ocular surface disease secondary to the destruction of conjunctival goblet cells as 
with vitamin A deficiency or scarring such as that with cicatricial pemphigoid, 
limbal stem cell deficiency, graft vs. host disease, alkali burns, Stevens-Johnson 
syndrome, trachoma, or irradiation 


 
23 
21. Current enrollment in any other clinical trial involving an investigational 
drug/device or participation in a clinical trial within the last 30 days preceding the 
screening examination.  
22. Patient has a condition or is in a situation which in the investigator’s opinion may 
put the patient at significant risk, may confound the study results, or may interfere 
significantly with the patient’s participation in this study.  
 
 
Study Procedures 
General Procedures 
4. All procedures will be conducted on both eyes of the subject. After the completion 
of data collection and the determination that the data collected on both eyes on all 
subjects are of equal quality and reliability, the worst eye with the staining score is 
selected for analysis. If the staining scores for the two eyes are the same, the 
secretion grade is used as the tie breaker. If both the staining scores and secretion 
grades are the same, a random eye is selected by flipping a coin.  Table 4 is the 
summary of all related procedures in our study.  
Guidelines for Visit Preparation 
5. Subjects are required to refrain from using any eye drops or artificial tears for a 
minimum of 12 hours prior to their visit and dilation drops within 1 week prior to 
their visit. Subjects will be asked to refrain from any eye rubbing, eye makeup, or 
facial products (e.g., creams, lotions) near the eyes on the day of the study. Table 5 
shows the schedule for all the visits and procedures 
 
 


 
24 
 
Table 4:  Procedure summary  
 
Procedure 
Notes 
 
 
Informed Consent / HIPAA  
 
Medical/CL History 
 
Visual Acuity 
 
Questionnaires:  OSDI, Schein  
Survey results masked from examining 
clinician 
Biomicroscopy – lid signs (0 – 5 scale) 
Plugging, notching, ridging, teleangiectasia, 
metaplasia 
Tear osmolarity 
Tearlab; take higher of R, L values 
NIBUT (Oculus Keratograph) 
3 blinks, hold, average 3 values each eye 
[5 minute rest period to stabilize tear film]  
 
Tear meniscus height (Oculus 
Keratograph) 
< 0.2 mm; not specified by DEWS II 
TBUTa, seconds (fluorescein; nearest 
1/10th)\ 
Mean, median of 3 measurements; alternate 
eyes; 30 sec. rest periods 
Corneal Staininga:  Both OSS (0 – 12 
system) and NEI (1995) scale (0 – 33) for 
cornea, conjunctiva 
OSS (SICCA group):  0 – 6 for cornea, 0 – 3 
for nasal, temporal conjunctiva) 
NEI:  0 – 3 score for each of 5 zones on 
cornea (0 – 15), 6 zones for conj. (0 – 18); 
Total Scale 0 – 33. 
Conjunctival Stainingb,  
OSS (SICCA group):  0 – 3 for nasal, 
temporal conjunctiva (0 – 6 total)) 
NEI:  six-zone system. 0 – 3 per zone; 0 – 18 
per eye 
Total Staining, for Severity Purposes:   
1. OSS:  0 – 12; if cornea > 5 spots, 
and conjunctiva > 9 spots = dry eye 
2. NEI:  0 – 15 + 0 – 18 = 0 – 33 
maximum 
 
Meibomian Gland Excreta Grading 
(DEWS II/MGD workshop):  lower eyelid 
(central 8 glands); 0 – 3 scalec 
Q-tip or MGE 
Gland Imaging:   
LipiView II or Keratograph 5M; 
meiboscore in 0.5 scale increments; % 
gland area present 
Schirmer I sans anesthetic; 5 mins 
Move strip at 2 mins if no wetting46 
a 2.0 µL of 1% NaFl (micropipette); measure TBUT, then both OSS and NEI within 4 minutes 
b Lissamine green (strips; wet once, shake off excess; measue within 2 minutes due to elution of 
dye) 
c Bron et al., 1991 and Bron and Foulks, 2003, scale:  0 = clear; 1 = cloudy; 2 -= cloudy with 
particles, 3 = inspissated/toothpaste 
 
 
 
 


 
25 
Table 5:  Schedule of visits and procedures  
 
Procedure 
Screening 
0 Week 
Baseline 
(Day 0) 
2 Weeks 
 
4 Weeks 
 
8 Weeks 
(4 Weeks 
washout) 
12 Weeks 
(8 Weeks 
washout) 
Informed 
Consent / 
HIPAA  
X 
 
 
 
 
 
Medical/C
L History 
X 
x 
 
 
 
 
Ophthalm
oscopy 
exam  
 
x 
 
x 
 
x 
Visual 
Acuity 
X 
x 
x 
x 
x 
x 
Hair 
evaluation 
 
x 
 
x 
 
x 
Blood 
Pressure  
 
x 
 
x 
 
x 
Blood 
draw for 
sex 
hormone 
 
x 
 
x 
 
 
Questionn
aires:  
OSDI, 
Schein, 
MGD-
Specific 
X 
X 
X 
x 
x 
X 
Biomicros
copy:  
general, 
and lid 
signs (0 – 
5 scale) 
X 
X 
X 
x 
x 
X 
Tear 
osmolarity 
X 
X 
X 
 
 
X 
NIBUT 
(Keratogr
aph) 
X 
X 
X 
x 
x 
X 
Tear 
meniscus 
height 
(Keratogr
aph) 
X 
X 
X 
x 
x 
X 
TBUT, 
seconds 
(fluorescei
n; nearest 
1/10th) 
X 
X 
X 
x 
x 
X 


 
26 
Corneal 
Staininga:  
Both OSS 
(0 – 12) 
and NEI 
(1995) 
scale (0 – 
33)  
OSS and 
NEI 
OSS and 
NEI 
NEI 
X 
NEI 
x 
NEI 
x 
NEI 
X 
Conjuncti
val 
Staining,  
X 
X 
X 
x 
x 
X 
Total 
Staining, 
for 
Severity 
Purposes:   
X 
X 
X 
x 
x 
X 
Meibomia
n Gland 
Excreta 
Grading 
(0-24) 
X 
x 
X 
x 
x 
X 
Gland 
Imaging:   
X 
 
 
x 
 
X 
Schirmer 
I sans 
anesthetic; 
5 mins 
X 
x 
x 
x 
x 
X 
IOP 
 
x 
 
x 
 
x 
Drug or 
Placebo 
Applicatio
n 
 
Initiate 
Drug or 
Placebo 
Applicatio
n 
 
Halt Drug 
or Placebo 
Applicatio
n 
 
 
 
Procedure I:  Enrollment  
• Informed consent and HIPAA documentation and California Research 
Subject’s Bill of Rights. We will discuss the study with subjects and check 
verbally that they have understood important points, particularly potential 
risks.  
• Comprehensive Ocular and Medical History  


 
27 
• The history questionnaire, which includes questions on contact lens use as 
well as complete medical and ocular history, will be administered by the 
examiner and used to further determine whether the subject met the inclusion 
and exclusion criteria.  
• Verify compliance with guidelines for visit preparation 
• Best Corrected Visual Acuity (BCVA) (OD/OS) 
• BCVA must be 20/25 (0.1 log MAR) or better OD and OS 
• LogMAR chart, calibrated at a testing distance of ten feet, and Snellen 
Equivalent will be recorded. 
• If the subject was deemed eligible to participate in the study, they will be 
asked to participate in Procedure II. 
Procedure II:  Dry Eye Work-up  
• Symptomatology questionnaires (Appendix II Symptoms questionnaires):  
• Schein questionnaire;47a score of ≥ 7.5 out of 24 indicates dry eye.48 
• Ocular Surface Disease Index (OSDI);49,50 a score of ≥13 out of 100 indicates 
dry eye  
o Subjects will be asked to fill out the questionnaires prior to reporting for 
the study. The questionnaires will not be scored until after data capture 
was completed on the subject. 
• Tear meniscus height (OD/OS):  Measured using Oculus Keratograph 5M:  
cursor measurement of three lower meniscus heights at approximately 7:00, 
6:00 and 5:00  
• Tear osmolarity using the Tear Lab method  


 
28 
• Slit Lamp Examination of the health of anterior structures (OD/OS):   
o Upper and lower lids and lashes assessed utilizing white light, diffuse 
beam (14 mm round), low illumination and 10x magnification 
o Bulbar and palpebral conjunctiva were then assessed using the same 
settings as those used for lids 
o Corneal health will be assessed utilizing white light parallel parallelepiped 
beam (~2mm wide, 14 mm tall) at a medium illumination and 16x 
magnification.   
• Eyelid sign grading (OD/OS): Each of the following signs was given a grade 
of 0 (absent) or 1 (present). A grade of 1 was given if a feature had 2 or more 
appearances along the lid margin for that eye: 51-53 
o Orifice metaplasia.  
o Orifice metaplasia:  Clear-white filamentous shafts at the gland orifice, 
evident on direct illumination. 
o Vascularity/ brush marks.  
o Telangiectasia coming from palpebral conjunctiva.  
o Plugged or capped orifices (present if more than one caps on a given 
eyelid).  
o Ridging between orifices.  
o Eyelid margin irregularity.  
o Notching, ridging at the posterior lid margin border. [these two are 
equivalent]  
o Anterior or posterior orifice displacement.  


 
29 
• Tear Break Up Time (TBUT) with fluorescein staining (OD/OS):  Detailed 
procedure description below.  
• Corneal staining with sodium fluorescein (OD/OS)   
• Staining was assessed as per the NEI (Score of 0-15) and OSS (screening and 
baseline only) schemes for each eye;54-56 detailed procedure description 
below.  
• Conjunctival Staining with lissamine green (OD/OS):   
• Staining was assessed as per the NEI (Score of 0-18) and OSS(Score of 0-12) 
schemes for each eye; 54-56 detailed procedure description below.  
• Secretion Quality (OD/OS):   
• Meibomian gland secretion quality will be assessed according to the Bron 
scale6,57 utilizing a Meibomian Gland Evaluator (MGE)58 in order to 
standardize pressure applied and therefore values measured (gentle rather than 
a forceful expression);detailed procedure below. 
• Schirmer I test, without anesthetic (OD/OS); detailed procedure below.  
• Meibography using LipiView II (OD/OS) or K5M keratograpy); detailed 
procedure below.    
Dry eye classification 
 
Data from Procedure II will be analyzed, and each subject will be 
classified as moderate or severe ADDE or EDE-related to MGD; detailed 
classification scheme follows.  


 
30 
Detailed Description of Selected Tests 
Fluorescein Tear Break-Up Time (TBUT) 
6. Liquid sodium fluorescein (NaFl) will be used to visualize the breakup time. The 
dye will be sourced from Greenpark compounding pharmacy (Houston TX, USA) 
in 4 ml “droptainers” for study use. An amount of 2.0 µl of 1.0% wt./vol 
preservative-free NaFl was instilled using sterile pipette tips and a calibrated 
micropipette. The NaFl dye was stored at 4°C when not in use. Once opened, each 
bottle of dye was labeled with the date of opening and discarded after 28 days. The 
slit lamp biomicroscope was utilized to visualize the cornea with high illumination 
of cobalt blue light, wide beam (~14mm round), and 16x magnification. A yellow 
#12, 55mm Tiffen filter was held in front of the slit lamp optics to enhance 
observation of TBUT. A hand-held stopwatch was used to measure TBUT to the 
nearest 1/10th of a second. 
7. The examiner has the subjects tilt their head back and look inferiorly while the 
examiner lifted the right upper eyelid to instill 2.0 µl of 1.0% wt./vol. preservative-
free NaFl dye onto the superior bulbar conjunctiva of the right eye, and the process 
was repeated for the left eye.55 The subject was then asked to position their head on 
the patient side of the slit lamp, and close their eyes until the examiner was ready 
to take a measurement, which took between 45-60 seconds. If there appeared to be 
inadequate fluorescein in the eye due to rapid drainage or excessive tearing from 
the subject such that tear break up time could not be measured, the investigator 
instilled an additional 2.0 µl of 1.0% wt./vol. preservative-free NaFl via pipette and 
documented on the chart that re-instillation was necessary. The amount of 


 
31 
fluorescein even with re-instillation is so minimal compared to everyday regular 
clinical practice amounts of fluorescein dye used on the eye that it was unlikely to 
cause the adverse effects of sequential staining or confound the results. 
8. The subject is asked to undertake three natural blinks (i.e., not rapid or “squeeze” 
blinks) and then to hold the eyelids open while looking at one spot. The first sign 
of break up (dark spot or change) is recorded to the nearest tenth of a second. 
Following the first measurement a twenty to thirty second rest period of eye closure 
is allotted for the patient to re-establish tear stability before measuring the other 
eye. A minimum of three measurements are taken for each eye with the rest period 
between each measurement, alternating between eyes. If a measurement is deemed 
unreliable (i.e., if a subject did not follow instructions, observation is uncertain, or 
if the tear film contains too much debris) a fourth measurement is taken and the 
unreliable value is recorded. The mean of the three TBUT measurements, not 
including the unreliable measurement, is also recorded for each eye.  
Corneal Staining 
1. The slit lamp used to view the corneal staining is set at maximum illumination on 
cobalt blue filter, 14 mm round beam, and medium (16x) magnification. 
Additionally, a yellow #12, 55mm Tiffen filter is used to maximize visibility of the 
fluorescein staining.  
2. Corneal staining is evaluated immediately following TBUT without additional 
instillation of NaFl solution. Observations are made shortly after TBUT evaluation 
because the fluorescein diffuses rapidly into the tissue.55,59,60 If not enough dye is 
present to evaluate fluorescein staining due to quick lacrimal drainage, study 


 
32 
procedures allow for an additional amount of fluorescein to be instilled prior to 
grading.  
3. National Eye Institute (NEI) systems. The NEI scheme has an integer severity scale 
of 0 to 3 for each of five corneal sectors for a total corneal scale of 15.54-56 For NEI 
schemes, the scales are outlined with illustrated grading panels (Appendix III, Case 
report form). The scales assess the area, but not depth, of punctate staining, which 
increase on a log scale, with the highest number being the most staining and most 
severe. When the examiner graded the level of staining, the grading panels were 
readily visible and referenced during the evaluation.  
4. Corneal staining evaluation is quantified using the Ocular Staining Score (OSS) 
(only at screening and baseline).61 Punctate epithelial erosions (PEE) that stain with 
fluorescein are counted, and scored. If there are no PEE, the score is 0. If 1-5 PEE 
are seen, the corneal score is 1 (Appendix IV); 6-10 PEE are scored as 2; and >30 
PEE are scored as 3. An additional point is added if 1) PEE occurred in the central 
4mm diameter portion of the cornea; 2) one or more filaments are seen anywhere 
on the cornea; or 3) one or more patches of confluent staining, including linear 
stains, are found anywhere on the cornea. The total fluorescein score for the cornea 
(the PEE grade plus any extra points for modifiers) is noted in the central square of 
the SICCA ocular staining score form (Appendix IV). The maximum possible score 
for each cornea is 6.  
Conjunctival Staining 
9. A sterile lissamine green strip is wetted with a drop of sterile saline solution. The 
dye is applied on the superior bulbar conjunctiva on the right eye, followed by the 


 
33 
left eye. The subject is then moved back into the slit lamp headrest, and analysis is 
performed immediately after the dye was applied. The slit lamp biomicroscope is 
immediately utilized to visualize the bulbar conjunctiva with moderate high 
illumination of white light, wide beam (~14mm round), and 16x magnification. The 
subject is asked to look opposite to the side of the conjunctiva being visualized in 
order to reveal more of the conjunctiva clearly.  
10. Conjunctival staining evaluation is quantified using the OSS and NEI systems. In 
the OSS, grade 0 is defined as 0-9 dots of lissamine green staining of the 
interpalpebral bulbar conjunctiva (nasal and temporal conjunctivae graded 
separately); grade 1 is defined as the presence of 10 to 32 dots; grade 2 as 33 to 
100; and grade 3 >100 dots. Because of the difficulty of counting individual dots 
in a moving eye at the slit lamp, any area of confluent staining >=4 mm2 is 
considered to be >100 dots. Nasal and temporal areas of the conjunctiva are graded 
separately with a maximum score of three for each area or a total maximum score 
of 6 for each eye. The total OSS for each eye is the summation of the fluorescein 
score for the cornea and the lissamine green scores for the nasal and temporal bulbar 
conjunctiva.61  The NEI scheme has an integer severity scale of 0 to 3 for each of 
six conjunctival sections (three sections each nasal and temporal sides) for a total 
corneal scale of 0-18.54-56 For both schemes, the scales are outlined with illustrated 
grading panels(Appendix III Case Report form). The scales assess the area, but not 
depth, of punctate staining, which increase on a log scale, with the highest number 
being the most staining and most severe. When the examiner grades the level of 
staining, the grading panels are readily visible and referenced during the evaluation.  


 
34 
Meibum Gland Excreta Grading  
1. Procedure:  Gland expression is assessed using a slit-lamp biomicroscope at 
medium (16x) magnification, moderate white light and a wide, 14 mm diffuse 
beam. A constant pressure device, the Meibomian Gland Evaluator (MGE) 
developed by Blackie and Korb in 200858 is utilized, allowing for standardized and 
consistent pressure. Prior to gland expression, a Q-tip wetted with non-preserved 
saline will be used to gently wipe the lid margin to remove any debris.58 First, the 
subject is informed that they will feel a tickling sensation on the eyelid margin as 
it gets wiped with the Q-tip, and the pressure exerted by the MGE is demonstrated 
on the subject’s hand. The subject is instructed to look up and away from the Q-tip 
or the MGE for the duration of the procedure. To clean the eyelid margin, the 
investigator gently pulled the skin down by placing the index finger over the edge 
of the orbital margin in order to prevent any accidental expression of the meibomian 
glands. Once the eyelid margin is revealed, it is gently wiped with a moistened Q-
tip. The investigator held the MGE 1-2 inches from the tip and applied it to the 
subject’s lower eyelid at the base of the lash line to locally push the tarsal plate of 
the lower eyelid against the globe to express the meibomian glands. As the MGE is 
applied, it is angled down and the pressure was held for 10 – 15 seconds, watching 
for oil excretion from the glands to evaluate both the secretion quality and number 
of glands expressing oil. Expression proceeds targeting approximately 8 glands at 
the center of lower eyelid. Expression grade and secretion quality are graded 
individually. The procedure is repeated for each eye. 


 
35 
2. Grading Scales:  Grading is based on the average appearance of the center lower 
eyelid region of a single eye. The Bron scale, initially proposed in 1991,62 is utilized 
for Meibomian secretion quality, which uses the color and viscosity of the excreta 
observed graded on a scale of 0 to 3, as described in  Table 6.6,57  
11.  
Table 6:  "Bron Scale" Meibomian Gland Expression Grading6,57 
Grade 
Meibum 
Quality 
Meibum Quality Description 
Grade 0 Clear 
Normal 
Grade 1 Cloudy 
Diffusely turbid fluid secretions 
Grade 2 Granular 
Usually turbid fluid secretions, but contains 
particulate matter. The color of these secretions 
varies from whitish to yellow. 
Grade 3 Inspissated 
A semisolid plug or a substance of toothpaste-
like consistency; may be extruded as a plug or 
curled thread. Expression is usually delayed or 
requires extra pressure. The material contains 
keratinized epithelial cells. 
12.  
Schirmer 1 Test 
13. The Schirmer test without anesthetic is performed with the subject’s eyes gently 
closed. The subject is told to look upward and blink normally while the strip is 
placed in the right eye then the left. The Schirmer strips are placed at the junction 
of the middle and lateral one-third of the lower eyelid. After five minutes the strips 
are removed, and the amount of wetting is recorded in millimeters. While in the 
subject’s eye, the strip is monitored carefully; if after 2 minutes no wetting is 


 
36 
observed the strip is repositioned for the remainder of the five minutes, and the 
action is recorded. Due to the discomfort during the procedure, if a subject wets a 
minimum of 10mm of both strips in less than five minutes, the strips are removed. 
Care is taken to avoid contaminating the test strip with skin oil from the 
examiner.46,59 
Meibography with LipiView II ( TearScience, Morrisville, North Carolina, USA)  
1. The LipiView II (Tear Science, Morrisville, North Carolina, USA) instrument is 
used to assess the area of Meibomian gland loss. Images of the subject’s eyes are 
saved on a password protected LipiView instrument consistent with HIPAA. The 
images are transferred to a flash drive then to a secure research computer for 
analysis using Image J software for percent Meibomian glands remaining. 
2. The subject is seated in front of the instrument with their forehead against the bar. 
Ambient room lighting is on but slightly dimmed. The lower eyelid is everted using 
the curved instrument transillumination device to visualize the silhouette of the 
meibomian glands under the palpebral conjunctiva, and the subject is instructed to 
look up.  The subject’s head is turned slightly away from the examiner, until both 
canthi are equally focused in the frame and the puncta identifiable in the image. 
Images are then captured. This procedure is repeated for the upper eyelid, using a 
cotton swab to evert the upper eyelid while instructing the subject to look down. 
The upper image is taken with reflected IR only, rather than using transillumination 
lighting, since the instrument does not allow transillumination of the upper eyelids. 
Both the upper and lower eyelids are imaged since it has been demonstrated that 
contact lens wear may affect the meibomian glands of both the upper and lower 


 
37 
lids.63 Additionally, adding the scores of both upper and lower lids proved to have 
a high AUC sensitivity and specificity in diagnosing MGD.52  
3. Grading of the meibomian gland loss or dropout used fractions of glands remaining 
according to the method outlined by Arita et al.52,64 After imaging both the upper 
and lower eyelids as stated above, the number of partial and complete glands lost  
was graded according to Table 7  by investigators MA and Jerry Paugh The percent 
area occupied by the meibomian glands for each eyelid was compared to the percent 
area affected by partial and total loss of glands for the lower lid only.   
14.  
Table 7:  Meiboscore52,64 
Grade 
Affected Area 
Grade 0 
No loss of meibomian glands 
Grade 1 
Affected area < 1/3 of total area 
Grade 2 
Affected area 1/3≤ x ≤ 2/3 
Grade 3 
Affected area > 2/3 
 
15.  
16. Dry eye classification  
Subjects are classified as dry eye patients if they met 2 out of the 3 following 
criteria:  TBUT equal to or lower than 6 seconds, dry eye criteria on the NEI staining 
scale, and dry eye criteria on either meibomian gland expression grade or meibomian 
gland drop out (Meiboscore). Subjects in Evaporative/MGD group will be classified 
by severity levels from the international workshop of MGD report of diagnosis 
subcommittee. 6  Only subjects meeting the criteria of levels 3,4 and 5 will be enrolled. 
The criteria used to diagnose whether a subject will be enrolled is summarized in 


 
38 
Appendix III: Dry Eye Classification Criteria and Appendix V: Staging the Severity of 
MGD-Related Ocular Surface Disease 
 
17. General statistical methods and types of analyses  
• Comparisons, ANOVA, meibomian secretion scores, meibomian gland dropouts, 
OSDI 
• The primary visit is week 4 and primary efficacy variables are the FTBUT and 
quality of meibomian secretions  
• A two-sided test with p-value less than or equal to 0.05 will be considered as 
statistically significant.  
18. Comparisons between pairs of treatment groups will be done with Cochran-Mantel 
Haenszel (CMH) tests, stratified by the ocular discomfort strata. Within Strata 
comparisons will be done with Wilcoxon rank-sum tests for both ordinal and 
continuous variables. For nominal variables, within strata comparisons will be done 
with Pearson’s chi-square or Fisher’s exact tests.  
 
19. Exploratory pharmacokinetics data analysis  
• Summary statistics of testosterone, dihydrosterosterone, and 3-alpha-
androstanediol glucuronide serum concentrations will be calculated. The 
relationships between treatment time and gender will be examined.  
Confidentiality  
 
The identity of the subjects will be treated as confidential. The results of the study, 
including any other data, may be published for scientific purposes but will not reveal the 
name of the subject or include any identifiable references to the subject. Although 


 
39 
measures will be taken to ensure confidentiality, it cannot be guaranteed. Any records or 
data obtained as a result of subject participation in this study may be inspected by any 
relevant government agency (e.g., by the US Food and Drug Administration, FDA), by 
the Marshall B. Ketchum University Institutional Review Board, or by persons 
conducting this study (providing that such inspectors are legally obligated to protect any 
identifiable information from public disclosure, except where disclosure is otherwise 
required by law or a court of competent jurisdiction.) Subject records will be kept 
confidential in so far as permitted by law. All data from the study will be maintained 
confidentially on a separate record of the visits where each subject is identified by 
number identification only. Study records will be kept in a separate file within the locked 
research storage area at the Paugh laboratory on main campus, and not in the main 
records area. Any electronic files created that include any patient information or medical 
data obtained during the study will be kept in password and encryption secured 
computers of the research staff and Investigators (Drs. Jiang, Paugh, Khankan, Ridder) at 
the MBKU main campus. These files will not be accessible outside of their respective 
offices.  
 
 
 
 
 
 
 


 
40 
Appendix I: see separate word document titled  
 
Appendix II: Symptom Questionnaires  
 
 
Demographic Data 
 
Subject Name _______________________  
Sex: □ Male  □ Female     Today’s Date: 
____ / ____ / ____ 
 
Subject’s Date of Birth:  __  __  / __  __  / __  __    
Visit #  __________
 
Time: __________ 
                                         mm        dd           yy                  
 
          
Age  ______  
Subject #     
____________  
 
 
Race □ White 
□ Black 
□ Asian 
□ Hispanic 
□ Other (specify) 
__________ 
 
 
 
Symptomatology Questionnaires 
 
I. Schein Questionnaire, modified by SCCO* 
 
DURING THE PAST WEEK:   
 
1.  Do your eyes ever feel dry? 
      
□  Never   □  Rarely   □  Sometimes   □  Often   □  All of the time 
2.  Do you ever feel a gritty or sandy sensation in your eye?       
      
□  Never   □  Rarely   □ Sometimes   □  Often  □  All of the time 
3.  Do your eyes ever have a burning sensation?       
     
□  Never   □  Rarely   □  Sometimes   □  Often   □  All of the time 
4.  Are your eyes ever red?      
  
□  Never   □  Rarely   □  Sometimes   □  Often   □  All of the time 
5.  Do you notice much crusting on your lashes?     
   
□  Never   □  Rarely   □  Sometimes   □  Often   □  All of the time 
6.  Do your eyes ever get stuck shut in the morning?       


 
41 
□  Never   □  Rarely   □  Sometimes   □  Often   □  All of the time 
Total:  _____________ (score of greater than 5 indicates dry eye) 
* a new category of “never” added for Grade 0, and 0-4 scoring added (4 = all the time) from the 
questions used by Schein OD, Tielsh JM, Munoz MS, Bandeen-Roche K, West S. Relation between the signs 
and symptoms of dry eye in the elderly.  Ophthalmol. 1997; 104: 1395-1401. 
 
II.  
Symptomatology:  Ocular Surface Disease Index (from Allergan) 
 
DURING THE PAST WEEK:  Have you ever experienced any of the following? 
 
1. Eyes that are sensitive to light? 
□  All of the time  □  Most of the time   □  Half of the time   □  Some of the time   □  
None of the time 
2. Eyes that feel gritty? 
□  All of the time  □  Most of the time   □  Half of the time   □  Some of the time   □  
None of the time    
3. Painful or sore eyes? 
□  All of the time  □  Most of the time   □  Half of the time   □  Some of the time   □  
None of the time    
4. Blurred vision? 
□  All of the time  □  Most of the time   □  Half of the time   □  Some of the time   □  
None of the time 
5. Poor vision? 
□  All of the time  □  Most of the time   □  Half of the time   □  Some of the time   □  
None of the time 
 
Have you had problems with your eyes that limited you in performing any of the 
following during the last week? 
6. Reading? 
□  All of the time  □  Most of the time   □  Half of the time   □  Some of the time   □  
None of the time   □  N/A 
7. Driving at night? 


 
42 
□  All of the time  □  Most of the time   □  Half of the time   □  Some of the time   □  
None of the time   □  N/A 
8. Working with a computer or bank machine (ATM)? 
□  All of the time  □  Most of the time   □  Half of the time   □  Some of the time   □  
None of the time   □  N/A 
9. Watching TV? 
□  All of the time  □  Most of the time   □  Half of the time   □  Some of the time   □  
None of the time   □  N/A 
 
Have your eyes felt uncomfortable in any of the following situations during the last 
week? 
10. Windy conditions? 
□  All of the time  □  Most of the time   □  Half of the time   □  Some of the time   □  
None of the time   □  N/A 
11. Places or areas with low humidity (very dry)? 
□  All of the time  □  Most of the time   □  Half of the time   □  Some of the time   □  
None of the time   □  N/A 
12. Areas that are air conditioned? 
□  All of the time  □  Most of the time   □  Half of the time   □  Some of the time   □  
None of the time   □  N/A 
Total: ________   Analysis of Score: ________ 
*0-4 scoring (0 = none of the time; 1 = some of the time; 2 = half of the time; 3 = most of the time; 4 = all 
of the time) 
 
(Sum of Scores for All Questions Answered  x  100)  (total # of Qs answered X 4.) 
Note:  any “N/A” questions are not counted in the total # of questions answered 
 
 
 
 
 
 
 


 
43 
 
Appendix III:  Case report form  
 
 
I. 
Demographic Data  
 
 
 
 
 
 
 
 
Patient Name _______________________  
Sex: □ Male  □ Female     Today’s Date: 
____ / ____ / ____ 
 
Patient’s Date of Birth:  __  __  / __  __  / __  __    
Age  __________
 
Time:  __________ 
                                         mm        dd           yy                  
 
 
Race □ White     □ Black     □ Asian…..□ Hispanic…..□ Other (specify) ________ 
 
II. 
Medical, Eye and Contact Lens History, and Medications    
Pertinent Ocular History 
Current Ophthalmic Medications  
(please list medications and reason for use, including artificial 
tears) 
 
 
 
 
 
 
 
Contact Lens History 
Ever Worn Lenses? □ Yes  □ No   
If lens wear, how long since 
stopped wearing? 
____________ (for protocol, must have been 12 
months of total lens deprivation) 
If Soft (SiHy or Hydrogel) 
Daily Wear?         □ Yes  □ No           How Long (years) 
__________ 
Overnight Wear? □ Yes  □ No           How Long (years) 
__________ 
If Rigid or Gas permeable 
Daily Wear?         □ Yes  □ No           How Long (years) 
__________ 
Overnight Wear? □ Yes  □ No           How Long (years) 
__________ 
 
Pertinent Medical History 
 


 
44 
Benign Prostatic Hyperplasia (BPH)? 
 □ Yes  □ No   
Prostate Cancer Diagnosis? exclusion criteria□ 
Yes  □ No   
Breast Cancer Diagnosis? □ Yes  □ No   Allergies? □ Yes  □ No  List:   
 
History or Symptoms of Venous 
Thromboembolism? Yes  □ No     
e.g., deep vein thrombosis:  pain, 
edema, redness in lower extremity 
e.g., pulmonary embolism:  shortness of 
breath 
 
History or Symptoms of 
Polycythemia/erythrocytosis:  □ Yes  □ No 
e.g., erythrocytosis:  HA, dizziness, shortness of 
breath, nosebleeds 
e.g., polycythemia:  fatigue, itching, HA, sweating 
Hepatic Changes? (mainly jaundice):  
□ Yes  □ No   
Edema: □ Yes  □ No   
Seborrheic dermatitis? □ Yes  □ No   
Acne Rosacea? □ Yes  □ No   
Blood thinners? e.g., wayfarin?  
□ Yes  □ No   
Recent MI or stroke:  exclusion criteria  
□ Yes  □ No   
Current Systemic Medications 
(please list medications and reason for 
use) 
 
 
 
 
 
 
 
 
III.  Visual Acuity  Snellen / LogMAR (spectacles / unaided; circle one) 
 
O.D.      20 /       ____  
  
O.S.       20 /      ____ 
 
IV. 
Tear Osmolarity:  Measured with TearLab; take greater of R, L value as osmolarity 
 
O.D. _______  
O.S. _______  
 
 
Visit Osmolarity:  _____  (msOms/L) 
 
 
 
 
V.  Interferometry/Blink Analysis (Lipiview, lights dim, warn of flashing lights) 
 


 
45 
 
OD  Avg LLT _______ nm 
 
 
 
OS  Avg LLT  _______ nm 
 
 
SD          _______ 
SD          _______ 
 
 
OD  Partial Blinks _______ (20 seconds) 
 
OS  Partial Blinks  _______ 
(20 seconds) 
 
 
VI. 
Tear Meniscus Height  (Oculus Keratograph or reticule eyepiece (at 25X, 1.0 
reticule unit = 0.20 mm height)) 
 
 
O.D.   __________mm  
 
 
O.S.   __________mm 
 
VII.  Biomicroscopy, General Examination 
 
OD 
 
 
 
 
 
 
OS 
 
Corneal findings:  
Corneal findings: 
 
 
 
 
 
 
 
 
Eyelid findings:  
 
 
 
Eyelid findings:  
Y   N 
 
 
 
 
 
 
Y   N 
 
 
 
□   □   orifice metaplasia 
  
 
 
□   □   orifice metaplasia 
 
□   □   vascularity / brush marks 
 
 
□   □   vascularity / brush 
marks 
 
□   □   plugged orifices 
  
 
 
□   □   plugged orifices 
 
□   □   ridging between orifices  
 
 
□   □   ridging between 
orifices 
 
 
□   □   anterior/posterior orifice displacement              □   □  anterior/posterior 
orifice displacement 
 
(circle one ) 
  
 
 
 
(circle one) 
 
Total:  OD:  _____ (0 – 6; score 1 if present)  
Total OS:  _____ (0 – 6; score 1 if present) 
 
 
VIII. Non-Invasive and Fluorescein Breakup Time   
Notes:  
1. alternate eyes, 30 seconds rest between measurements to restore tear homeostatic tear 
stability; ask patient to blink three natural blinks then hold open, use stopwatch  
2. if fluorescein, use Tiffen Yellow 12 filter, wide beam, minimal beam movement 
 
 
O.D. ______, ______, ______ Average _______ (secs) 
 


 
46 
 
 
 
 
 
 
 
 
 
 
T 
T 
 
O.S. ______, ______, ______ Average _______ (secs) 
IX. 
Ocular Surface Staining, NEI (0 – 3 for each of 5 zones for cornea, 0 -3 for six zones 
(each eye) for conjunctiva, refer to NEI scale) Integer Grading Only 
 
 
 
 
 
 
 
 
 
 
 
 
 
Corneal Staining:  0 – 15 for each eye 
O.D. ___________  
O.S. ___________  
 
Use lissamine green for conjunctiva (strip; wet with one drop, shake excess) 
 
 
    
 
 
 
Conjunctival Staining:  0 – 18 for each eye: 
O.D. ___________  
O.S. ___________  
 
Total NEI Staining:  cornea and conjunctiva:  0 – 33:   
 
O.D. _______  
 
 
 
 
 
O.S. _______ 
 
XI. 
Ocular Surface Staining:  sketch the stained areas 
Efron:  overall stain for cornea, conjunctiva, 0 – 4 scale with 0.5-unit increments  
Oxford Scheme:   (0 – 5 for each of 3 zones for cornea, nasal, temporal conjunctiva  
(each eye); refer to separate grading scheme Integer Grading Only 


 
47 
 
                                        
 
 
Corneal Staining:  Fluorescein; 0 - 5 
 
O.D. ___________ 
 
 
O.S. ___________  
 
Conjunctival Staining:  Lissamine green; 0 - 10 
 
O.D. ___________  
 
 
O.S. ___________  
 
Total Staining:  Efron, 0 – 4 X 3 = 0 – 12; Oxford, 0 – 5 X 3 = 0 - 15 
O.D. _______  
 
 
 
 
 
O.S. _______ 
 
 
X. 
Meibomian Gland Expression, Lower Eyelid:  Q-tip (gentle pressure) or MGE  
 
 
  
OD ____________ 
 
 
OS ____________  
 
 
Expression, Overall Grade:  Bron et al., 1991 scale:  0 = normal, clear; 1 = cloudy; 2 = cloudy with 
particles; 3 = inspissated, like toothpaste 
 
XI. 
Meibography Number of images taken: 
 
 
  
OD  
UL ______ 
 
 
 
OS 
UL ______ 
 
 
  
 
 LL ______ 
 
 
 
 
 LL ______ 
 
XII. Meiboscopy, clinical transilluminator (~8 glands assumed in each sector of 
eyelid):  
 
 
 
 
 
 
 
 
 
 
O.D. 
 
 
 
O.S. 
Dropout Grade:  nasal lower lid  
_____________ 
 
______________ 
Dropout Grade:  central lower lid 
_____________ 
 
______________ 
Dropout Grade:  temporal lower lid 
_____________ 
 
______________ 
Total Eyelid Dropout Score:   
_____________ 
 
______________ 
 
Dropout:  0 = No Dropout; 1  25%; 2  50%; 3  75%; 4  100%; 0.2 grade increments per 5% change 


 
48 
 
 
XV. Schirmer I without anesthetic (amount of wetting in 5 minutes; < 5 mm = ATD) 
O.D.  ________ (mm) 
 
O.S.  ________ (mm) 
 
 
 
 
 


 
49 
Appendix IV: OSS Staining Form 
 
 
 


 
50 
 
 
 
Appendix V Staging the severity of MGD-Related Ocular Surface 
Disease 6 4 
 
Severity 
 
Level 0 
Normal 
Level 1 
Subclinica
l  
Level 2 
Minimally 
Level 3 
Mildly 
Level 4 
Moderatel
y  
Level 5 
Severely  
 
 
No 
symptoms  
Asymptomat
ic or 
occasional  
Some of the 
time 
Half the 
time  
Most of the 
time  
All the time  
OSDI range 
0 
0-12 
0-12 
13-22 
23-32 
33-100 
TFBUT s 
>=10 
<10 to >=7 
<7 to >=5 
<5 to >=3 
<3 to >=1 
<1  
Tear 
osmolarity 
mOsM 
Normal 
<308 
Normal <308 
Normal 
<308 
<=313 to 
>308 
<= 317 to 
>314 
>317 
Grading of 
MGD 
Quality(0-
24) 
Expressibilit
y 
Quality 
0 
Expressiblit
y 
 0 
Quality  
0 
Expressibilit
y 
0 
Quality  
0-3 
Expressibilit
y 
0 
Quality  
4-7 
Expressibilt
y 
1 
Quality  
8-12 
Expressibilit
y  
2 
Quality 
 >13 
Expressibilit
y  
3 
Ocular 
surface 
staining 
NEI 
Industry 
scale (0-33) 
0 
0 
0-7 
8-14 
15-23 
24-33 
Schirmer 
Score mm 
>=10 
>=10 
<10 to>=7 
<7 to>=5 
<5 to >=3 
<3 
 
 
 
 


 
51 
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Schiffman RM, Christianson MD, Jacobsen G, Hirsch JD, Reis BL. Reliability and 
validity of the ocular surface disease index. Archives of ophthalmology. 
2000;118(5):615-621. 
50. 
Miller KL, Walt JG, Mink DR, et al. Minimal clinically important difference for the 
ocular surface disease index. Arch Ophthalmol. 2010;128(1):94-101. 


 
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51. 
Pflugfelder SC, Tseng SC, Sanabria O, et al. Evaluation of subjective assessments 
and objective diagnostic tests for diagnosing tear-film disorders known to cause 
ocular irritation. Cornea. 1998;17(1):38-56. 
52. 
Arita R, Itoh K, Maeda S, et al. Proposed Diagnostic Criteria for Obstructive 
Meibomian Gland Dysfunction. Ophthalmology. 2009;116(11):2058-2063.e2051. 
53. 
Arita R, Minoura I, Morishige N, et al. Development of Definitive and Reliable 
Grading Scales for Meibomian Gland Dysfunction. American journal of 
ophthalmology. 2016;169:125-137. 
54. 
Lemp MA CL, Bron AJ, Foulks GN, Sullivan BD. Distribution of Aqueous Tear 
Deficient and Evaporative Dry Eye in a Clinic-Based Patient Cohort: A 
Retrospective Study. Cornea. 2012;31(5):472-478. 
55. 
Bron AJ, Evans, V.E., Smith, J.A. Grading of corneal and conjunctival staining in 
the context of other dry eye tests. Cornea. 2003;22(7):640-650. 
56. 
Lemp M. Report of the National Eye Institute/Industry workshop on clinical trials 
in dry eyes. CLAO J. 1995;21:221-232. 
57. 
Bron AJ, Benjamin L, Snibson GR. Meibomian gland disease. Classification and 
grading of lid changes. Eye. 1991;5:395-411. 
58. 
Korb DR, Blackie CA. Meibomian gland diagnostic expressibility: correlation with 
dry eye symptoms and gland location. Cornea. 2008;27(10):1142-1147. 
59. 
Lemp MA. Report of the National Eye Institute/Industry workshop on Clinical 
Trials in Dry Eyes. The CLAO journal : official publication of the Contact Lens 
Association of Ophthalmologists, Inc. 1995;21(4):221-232. 
60. 
Schwallie JD MC, Long WD, McNeil A. Corneal staining patterns in normal non-
contact lens wearers. Optom Vis Sci. 1997;74:92-98. 
61. 
Whitcher JP, Shiboski CH, Shiboski SC, et al. A simplified quantitative method for 
assessing keratoconjunctivitis sicca from the Sjogren's Syndrome International 
Registry. Am J Ophthalmol. 2010;149(3):405-415. 
62. 
Bron AJ, Benjamin L, Snibson GR. Meibomian gland disease. Classification and 
grading of lid changes. Eye (London, England). 1991;5 ( Pt 4):395-411. 
63. 
Arita R, Itoh K, Inoue K, Kuchiba A, Yamaguchi T, Amano S. Contact lens wear is 
associated with decrease of meibomian glands. Ophthalmology. 
2009;116(3):379-384. 
64. 
Arita R, Itoh K, Inoue K, Amano S. Noncontact infrared meibography to 
document age-related changes of the meibomian glands in a normal population. 
Ophthalmology. 2008;115(5):911-915. 
 

ICF_004.pdf: 
Androgen Consent 6-28-22 
 
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Marshall B. Ketchum University 
2575 Yorba Linda Blvd Fullerton CA 92831 
Jerry R. Paugh, OD, 
PhD  
Principal Investigator 
Telephone(direct):   
714-449-7487 
jpaugh@ketchum.edu  
Jay Jiang, PhD  
Student Investigator 
jayjiang.ms24@ketchum.edu 
William Ridder III, OD, 
PhD 
Co-Investigator 
Telephone (direct):   
714-449-7494 
wridder@ketchum.edu  
Daniel May, MD 
Co-investigator 
Telephone(direct)  
714-872-5690 
dmay@ketchum.edu  
 
Rima Khankan, PhD 
Co-Investigator 
Telephone (direct):   
714-992-7831 
rkhankan@ketchum.edu  
 
Day Emergency 
Number 
(714) 870-0258 
Night Emergency Number 
(714) 870-0258 
 
 
Consent Document  
 
A Randomized Controlled Trial of Topical Androgen Treatment in 
Dry Eye  
 
Please take as much time as you need 
to read this information and to ask 
questions 
Key Points to Consider 
• Because you are suffering the discomfort of dry eyes we are inviting you to 
participate in a research study of a drug to treat dry eye. It is called androgen gel. 
• The investigators will choose to give you either the androgen gel or placebo gel.  
• You will put the gel on your eyelid two times a day for 4 weeks 
• You need to attend the clinic six times. We will do dry eye tests on you at each 
visit and two blood draws before and after 4 weeks of the treatment.  


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• We will not charge you for the gel or study visits. You will receive $65 per 
visit to participate for the six study visits to the research laboratory at 
MBKU.  
 
About This Study  
The purpose of this research study is to evaluate the effectiveness and safety of 
applying androgen sex hormone (i.e., testosterone) gel on the eyelids in the 
treatment of dry eye patients. Several studies have demonstrated positive treatment 
effects in dry eye, but few have applied testosterone gels to the eyelids. There is 
approximately a 50% chance that you will be assigned to receive the placebo. 
Neither you nor the investigators will know which medication you are given, but in 
the event of an emergency, access to that information can be obtained.  
 
Up to 40 subjects will be enrolled in this study. We will arbitrarily (randomly) 
assign one-half of the subjects to use a commercially marketed testosterone gel 
called Natesto, made by Acerus Pharmaceuticals, that is normally applied as a nasal 
spray three times a day. The placebo (sham treatment) will be a similar gel 
formulation, but without the testosterone drug.   
 
This study is sponsored by Marshall B. Ketchum University.  
  
First, we want you to know that taking part in this study is entirely voluntary.  
You may choose not to take part, or you may withdraw from the study at any time 
without fear of penalty or loss of eye care.  
 
AM I ELIGIBLE TO PARTICIPATE IN THIS STUDY? 
 
Your examining clinician will determine if you are eligible to participate in this study. Your 
participation is dependent upon you having signs and symptoms of dry eye disease and 
meeting the criteria below.  
 
Please note this is not a complete list of eligibility criteria. We have included a few examples 
of study criteria to help you better understand how your eligibility in the study will be 
determined; your study team will go through the study eligibility criteria with you to verify 
whether you qualify for participation in this study. 
 
INCLUSION CRITERIA 
You can participate in this study if you:   
• 
Are male or female 18 years and older 
• 
Have signs or symptoms of dry eye (ranging from moderate to severe) 
• 
Are willing to discontinue use of artificial tears on the day of the study visit 


 
 
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• Can provide a negative urine pregnancy test at study start (if female) 
 
EXCLUSION CRITERIA 
You cannot participate in this study if you:  
• 
Have known or suspected prostate cancer 
• 
Have known or suspected breast cancer 
• 
Females who are pregnant, nursing or planning a pregnancy during the study period 
• 
Use any topical eye medication other than artificial tears 
• 
Wear contact lenses of any type 
 
Conflicts of Interest 
The investigators and Marshall B. Ketchum University have no conflicts of interest in this 
study.  
Procedures:  What Will Happen 
Location of this study:    
This study is carried out at the main campus of Marshall B. Ketchum University in the 
laboratory of Dr. Jerry R. Paugh.  
Duration of patient participation:   
There will be total of six visits over a period of 14 weeks (three and half months). Blood 
samples will be taken at two visits in addition to the 6 testing visits at Dr. Paugh’s laboratory 
to monitor systemic blood levels of testosterone.   
• 
Visit 1:  screening visit  
• 
Visit 2:  baseline exam (pre-treatment phase) 
• 
Visit 3:  2 weeks after starting the treatment  
• 
Visit 4:  4 weeks after starting the treatment  
• 
Visit 5:  4 weeks after stopping the treatment  
• 
Visit 6:  8 weeks after stopping the treatment 
 
Study procedures  
 
Visit 1:  the screening visit, approximately 90 minutes; the procedures include: 
• 
Documentation of your medical and eye history  
• 
Evaluation of your meibomian gland condition (you may experience some mild 
discomfort during exam procedures) 
• 
A urine pregnancy test (if applicable)  
• 
An examination of the front of the eye for dry eye  
• 
Patient questionnaires  
 


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If you qualify at the screening visit, you will be able to continue to the next steps. If you 
are not qualified, you still can be reimbursed $65 for your participation.  
 
Visit 2:  the Baseline exam Visit (Day 0), approximately 90 minutes; the procedures will 
include: 
• 
Evaluation of your meibomian gland condition (you may experience some mild 
discomfort during exam procedures) 
• 
An examination of the front of the eye for dry eye  
• 
Patient questionnaire(s) 
• 
An evaluation of head and facial hair growth  
• 
Measurement of blood pressure and intraocular pressure 
• 
A blood draw (about 2 tablespoonfuls of blood will be taken from a vein in your 
arm for evaluation) at a nearby clinical laboratory. Your investigator will receive 
the results of the blood evaluation. If you would like to know the results of your 
test, ask the investigator to discuss them with you.  
• 
You will be dispensed study gel and shown how to apply the gel on the surface of 
upper and lower eyelid in each eye 
• 
You will be instructed to apply of the study medication in each eye twice daily (in 
the morning after washing your face and at least one-half hour before bedtime). 
On the days of your study visit, one of the two daily doses of study medication 
will be given at the doctor’s office.  
 
Visit 3 and 4:  at Weeks 2 and 4, all visits approximately 90 minutes; the procedures will 
include: 
• 
Evaluation of your meibomian gland condition (you may experience some mild 
discomfort during exam procedures) 
• 
An examination of the front of the eye for dry eye  
• 
Patient questionnaire(s) 
• 
Apply study gel  
• 
An evaluation of head and facial hair growth (week 4 only) 
• 
A blood draw of about 2 tablespoonsful of blood will be taken from a vein in your 
arm for evaluation. (Week 6 only)  
• 
You will be asked to stop using any study gel at week 4.  
• 
You will be instructed to return to the study doctor’s office at the fourth visit with all 
unused units of investigational medication. You should discard the used unit doses after 
applying gel to the surface of upper and lower eyelid of your eyes.   


 
 
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Visit 5 and 6:  at weeks 8 and 12, approximately 90 minutes; the procedures will include:   
• 
Evaluation of your meibomian gland condition (you may experience some mild 
discomfort during exam procedures) 
• 
An examination of the front of the eye for dry eye  
• 
Patient questionnaire(s) 
• 
An evaluation of head and facial hair growth (week 12 only) 
• 
Measurement of blood pressure and intraocular pressure (week 12 only) 
 
You should return promptly for all study visits. If you cannot make your scheduled 
appointments, please notify the investigators as soon as possible to reschedule your visit.   
Please report any of the following to the investigator:   
• 
changes in your medications (over the counter and prescription) 
• 
missed doses of the study medication. Please use twice per day, once in the morning and 
once in the evening. 
• 
changes in how you feel 
• 
if you suspect you may be pregnant 
 
Safety, Risks, and Discomforts 
Side effects and discomfort associated with study treatment which you may experience 
include hirsutism (excessive hair growth), scalp hair loss, acne, change in sexual 
functioning and voice deepening. If these side effects occur, they should go away after 
the study medication is stopped. Very high doses of testosterone (much higher than used 
in this study) given by mouth or applied to the skin for a long period of time have been 
shown to result in changes in liver function, cholesterol, or mood.  
Although the risk is low after topical administration of testosterone, subjects with the 
following conditions will be excluded from the study: 
• Current or recent vein blockages (venous thromboembolism (VTE), including deep 
vein thrombosis (DVT) and pulmonary embolism (PE). Subjects who have symptoms 
of pain, edema, warmth and erythema in the lower extremity or acute shortness of 
breath during the study should report these to the investigators and seek medical care. 
• Recent cardiovascular events (e.g., myocardial infarction (heart attack), stroke). 
Subjects who report signs or symptoms of heart attack or stroke should seek medical 
care. 
• Liver (hepatic) disorders (hepatitis, jaundice, hepatic cancer et al.). Subjects should 
monitor for signs or symptoms of hepatic dysfunction (e.g., jaundice) 


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• Subjects who are taking insulin, warfarin, or corticosteroids 
 
Although the risk is low after topical administration of testosterone, subjects who 
experience the following conditions will be monitored and possibly exited from 
the study: 
 
• Swelling due to sodium and water retention  
• Enlargement of breast tissue 
• Sleep apnea or worsening of sleep apnea 
• Serum lipid changes 
 
Blood samples will be taken similar to a routine blood panel ordered by your 
physician at baseline and after four weeks of topical gel application. At baseline 
we will use the red blood cell count (called “hematocrit”) to exclude those with 
elevated levels. Other monitoring measurements will be for blood lipid levels, 
blood testosterone levels, and to monitor prostate specific antigen for males. You 
might feel pain or light-headedness from this. You might get a bruise at the 
injection site, and there is a small chance you might get an infection.  
There may be risks associated with stopping the ophthalmic medication you are 
currently taking, such as changes in your symptoms of dry eye. These may include 
stinging/burning, tearing, discharge, itching, sandiness/grittiness, blurred vision, 
dryness of the eye, light sensitivity, or pain. 
The investigational gel must be used only by the person for whom it has been 
prescribed, and must be kept out of the reach of children and persons of limited 
capacity to read or understand. In order to avoid inadvertent administration of the 
testosterone, subjects should be warned to keep their eyelids away from children, 
adults, and pets (hugging or kissing) for several hours after administration of the 
treatment gel. It is highly recommended to use disposable towels and cleaning 
hands after administration rather than regular bathroom linens.  
If you experience any illness or discomfort during the study, you should notify 
any of the study doctors. One of the study doctors will then evaluate you to 
determine if you should continue in the study. If necessary, your study medication 
may be stopped, and appropriate therapy may be started. 
There may be side effects or discomforts from the study treatment, which are not 
yet known. You could have an allergic reaction to the study medication. A severe 
allergic reaction could be life-threatening. In addition, if you are pregnant or become 
pregnant, there may be a risk to the fetus. 
Risks for women who could become pregnant 
The risks to an unborn baby or a nursing child from the study drug are not known. There 
may be possible masculinization of a female fetus. If you are pregnant or become 


 
 
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pregnant, the study drug may cause problems to your unborn baby. Birth defects and 
other problems including premature birth are known risks of some drugs. Women who 
are pregnant or nursing a child may not participate in this study. You must confirm that, 
to the best of your knowledge, you are not pregnant now, and you do not plan to become 
pregnant during the study. You may be required to have more pregnancy tests than are 
currently scheduled during the study. A pregnancy test does not stop you from becoming 
pregnant. If you are of childbearing potential, the study doctor will discuss appropriate 
birth control options with you. If you think that you have become pregnant during the 
study, you must tell any of the study doctors immediately.  
Childbearing female subjects would be safe to pursue a pregnancy after the testosterone 
level has returned to pre-study levels. It can be confirmed at weeks 8 after 
discontinuation of treatment and can be rechecked 4 weeks later if the testosterone level 
is still above pre-study level.  
Benefits 
You may not receive any direct medical benefit from participating in this study. 
However, the possible benefits to other people with this condition include more 
information about dry eye and the development of future treatments. If the 
treatment is found to be effective, it will not be offered to those subjects who were 
in the placebo group as this is a proof of principle study only.  
Costs and Payments 
You will not be charged to take part in this study. You will be reimbursed upon 
completion of the study for your time and inconvenience for each of the visits that 
you complete according to the following visit schedule: 
 
Screening visit  
$65 
Week 0(Day 0)   
$65 
Week 2   
 
$65 
Week 4.  
 
$65  
Week 8               
$65 
Week 12             
$65 
                          $390 total for completing all visits 
In the event that you do not complete the full visit at screening, you will receive a 
prorated amount based on the procedures performed to determine your eligibility. If you 
withdraw for unforeseen personal reasons or circumstances preventing further 
participation, you will receive a prorated amount for each scheduled visit you completed. 
Other Health Care Options  
Alternative treatments that are available to treat your dry eye and meibomian gland 
dysfunction include artificial tears (eye drops, ointments, or gels), lids scrubs, lid massages, 
warm compresses and medications prescribed by your investigator. The investigator will 
discuss with you the advantages and disadvantages of alternative treatments. Please consider 
asking your doctor about these options before you decide whether to take part in this study.  


8 of 11 
There may be risks associated with stopping the ophthalmic medication you are currently 
taking, such as changes in your symptoms of dry eye. These may include stinging/burning, 
tearing, discharge, itching, sandiness/grittiness, blurred vision, dryness of the eye, light 
sensitivity, or pain. 
Care if You are Injured 
The risk of injury in this study is minimal. If you experience an adverse reaction as a 
direct result of the drug(s) being administered in this study, you should consult your 
own doctor for emergency care if you are injured in this study. You or your insurance 
company will need to pay for any healthcare you require. The Marshall B. Ketchum 
University is not required to pay your medical costs if you become sick or are injured.  
 
Confidentiality 
A report of the results of this study may be published or sent to the appropriate health 
authorities in any country, where testosterone cream may ultimately be marketed, but 
your name will not be disclosed in these documents. Your name may be disclosed to 
the governing health authorities, the FDA (The U.S. Food and Drug Administration), 
or the MBKU Institutional Review Board (IRB) if they inspect your medical records.   
Appropriate precautions will be taken to maintain confidentiality of medical records 
and personal information. All data from the study will be maintained confidentially in 
a separate record of your visits where each patient is identified by number 
identification only. Any electronic files created that include any patient information 
or medical data obtained during the study will be kept in password and encryption 
secured computers of the research staff and Investigators (Drs. Jiang, Paugh, 
Khankan, Ridder) at the MBKU main campus. These files will not be accessible 
outside of their respective offices.  
However, complete confidentiality cannot be assured, as research records are not 
exempt from subpoena. Only Center for Vision Research (CVR) personnel (principal 
investigators, study coordinator, and MBKU IRB) will have access to your study 
records. Study records will be kept in a secured, separate file within the offices of the 
Paugh Laboratory at MBKU, and not in the main records area.   
A description of this clinical trial will be available on http://www.clinicaltrials.gov as 
required by U.S. law. This website will not include information that can identify you. 
At most the web site will include a summary of the results. You can search this web 
site at any time. 
 
Possible Future Research on Your Data  
We may remove all personal identifiers from your data, and then store them for 
possible future research studies. This research may include other sites outside 
Marshall B. Ketchum University. The biospecimens (blood draw) will destroyed 
after the lab tests.  


 
 
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Future Contacts 
We will send you a disposition of your dry eye when the study is complete., but not 
summaries of the study findings.  
 
Termination of Participation 
Your participation in this study is entirely voluntary. You may choose to stop taking part 
at any time. There are no penalties. You will not lose benefits or services that the 
University owes you. 
 
If you decide to stop taking part in this study, we will respect your decision. However, we 
request your permission to contact you and follow up on your health status, if necessary. 
 
Studies show that the effects of the drug wear off after 90 days of discontinuation when 
applied systemically. Topical application on the eyelids will last for even shorter time. 
Where to Find More Information 
If you have questions about the study procedures, please contact the Principal 
Investigator. Dr. Jerry R. Paugh. Dr. Paugh’s contact details are listed on the front page. 
 
If you have questions about your rights as a research subject, or you were injured in this 
study, or wish to complain about this study, please contact: 
 
Lawrence R. Stark, Chairperson 
Institutional Review Board 
Marshall B. Ketchum University 
2575 Yorba Linda Blvd Fullerton CA 92831 
e-mail: irb@mbku.edu 
In addition, we will inform you of anything we learn that could influence your willingness 
to continue in this study. 
 
Experimental Subject’s Bill of Rights 
Under the California Protection of Human Subjects in Medical Experimentation Act, a 
subject or subject’s conservator or guardian, or other representative, has the right 
to: 
(a) 
Be informed of the nature and purpose of the experiment; 
(b) 
Be given an explanation of the procedures to be followed in the medical 
experiment, and any drug or device to be utilized; 


10 of 11 
(c) 
Be given a description of any attendant discomforts and risks reasonably to be 
expected from the experiment; 
(d) 
Be given an explanation of any benefits to the subject reasonably to be 
expected from the experiment, if applicable; 
(e) 
Be given a disclosure of any appropriate alternative procedures, drugs or 
devices that might be advantageous to the subject, and their relative risks and 
benefits; 
(f) 
Be informed of the avenues of medical treatment, if any, available to the 
subject after the experiment if complications should arise; 
(g) 
Be given an opportunity to ask any questions concerning the experiment or 
the procedures involved; 
(h) 
Be instructed that consent to participate in the medical experiment may be 
withdrawn at any time and the subject may discontinue participation in the 
medical experiment without prejudice; 
(i) 
Be given a copy of the signed and dated written consent form; 
(j) 
Be given the opportunity to decide to consent or not to consent to a medical 
experiment without the intervention of any element of force, fraud, deceit, 
duress, coercion, or undue influence on the subject’s decision. 
 
Subject Statement 
• I have read this consent form 
• I have been given a copy of this Experimental Subject’s Bill of Rights 
• I have been told that I will be given a copy of this form 
• I have been given the opportunity to ask questions concerning this study and my 
participation in this study 
• I feel that I am sufficiently informed about this study 
• I choose voluntarily to take part in this study 
• I have been told that refusal to participate will involve no penalties 
• I have been told that I may choose to stop taking part at any time without penalty 
• I continue to hold my legal rights should someone in this study be negligent or act 
illegally 
• I understand that this document does not replace any Federal, state, or local law 
 
 
 
 
 
Subject’s name 
 
 
 
 
 
 
 
 
 
Subject’s signature 
 
Date 
 
Time 


 
 
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Investigator Statement 
(The subject must not sign in this gray area) 
I verify that I have discussed this research study, its objectives, methods, associated 
risks, and benefits with the subject and have fully answered all questions to their 
satisfaction. I have assessed the subject’s comprehension of this information. 
 
 
 
 
 
Investigator’s name 
 
 
 
 
 
 
 
 
 
Investigator’s signature 
 
Date 
 
Time 
 
 
 
 
 
 
RECEIVED 28 JUNE 2022 
1 July 2022 
LRStark 
21-18