Background
Methods
Study design
Inclusion criteria
Additional inclusion criteria for DED patients
Additional inclusion criteria for control subjects
Exclusion criteria
DED patients
Exclusion criteria for control subjects
Outcome measures
Efficacy measures | |
---|---|
Primary: | The percentage of patients with signs of DED progression based on at least 1 level increase in severity level as measured by ITF guidelines. Evidence of disease progression by ITF guidelines will require at least one of the following: • 1-unit increase in total corneal staining • New development of central corneal staining (≥ grade level 1) • Increase in OSDI score by ≥6 points • Increase in blurred vision ≥1 grade (using a 5-point scale) |
Secondary: | • % of patients who are discontinued from the study because they need a therapeutic intervention (i.e., the use of cyclosporine, punctal plugs, oral tetracyclines, topical steroids, topical antibiotic ointments, or oral nutritional supplements) due to dry eye disease progression • % of patients with a ≥ 6 point OSDI increase • % of patients with a 1 unit increase in blurred vision • % of patients with a 2 mm decrease in Schirmer’s test over 5 min • % of patients with at least a 1 grade increase in central or total corneal staining • Reduction in reading speed |
Other: | • Change from baseline in goblet cell density (by impression cytology) • Tear Break-up Time • Tear Cytokines • Dry Eye Patient Survey |
Safety Measures | • Adverse Events, Biomicroscopy, BCVA |
• Inclusion criteria and authorization | |
• Medical and ophthalmic history | |
• Concomitant medications review | |
• Adverse event review | |
• OSDI questionnaire | |
• Dry Eye Patient Survey | |
• Blurred/Fluctuating Vision Assessment | |
• Work Productivity and Activity Impairment Questionnaire | |
• Best-corrected visual acuity | |
• Reading Speed Assessment | |
• Tear collection | |
• Biomicroscopy | |
• Tear break-up time | |
• Corneal staining (with fluorescein) | |
• Conjunctival staining (with lissamine green) | |
• Schirmer’s test (with anesthesia) | |
• Goblet cell density (by impression cytology) | |
• Dispense patient diary |
Statistical methods
Results
Demographics of enrolled patients and control subjects
All cases (n = 217) | All controls (n = 67) |
P-value | |
---|---|---|---|
Gender | |||
Male | 40 (18.4%) | 16 (23.9%) | 0.3797 |
Female | 177 (81.6%) | 51 (76.1%) | |
Race | |||
Caucasian | 186 (85.7%) | 59 (88.1%) | 0.4000 |
Black | 12 (5.5%) | 3 (4.5%) | |
Asian | 0 (0.0) | 1 (1.5%) | |
Hispanic | 18 (8.3%) | 4 (6.0%) | |
Other | 1 (0.5%) | 0 (0.0%) | |
Age (yrs) | |||
Mean (SD) | 63.2 (10.5) | 61.1 (11.2) | 0.1607 |
Min–Max | 37–89 | 41–88 |
All cases (n = 217) | All controls (n = 67) |
P-value | |
---|---|---|---|
OSDI Score | |||
Mean (SD) | 31.7 (19.6) | 4.1 (7.4) | <0.0001 |
Min-Max | 0.0–91.7 | 0.0–39.6 | |
Schirmer’s score (mm) | |||
Mean (SD) | 5.7 (4.2) | 15.3 (7.7) | <0.0001 |
Min-Max | 0.0–30.0 | 1.0–35.0 | |
Corneal staining score | |||
Mean (SD) | 1.4 (0.9) | 0.2 (0.5) | <0.0001 |
Min-Max | 0.0–4.0 | 0.0–2.0 | |
Conjunctival staining score | |||
Mean (SD) | 1.4 (1.0) | 0.3 (0.6) | <0.0001 |
Min-Max | 0.0–5.0 | 0.0–2.5 | |
Tear break-up time(s) | |||
Mean (SD) | 5.7 (4.0) | 8.5 (5.0) | <0.0001 |
Min-Max | 1.0–28.3 | 1.3–25.0 |
All cases (n = 217) | All controls (n = 67) |
P-value | ||
---|---|---|---|---|
Location | ||||
Inferior bulbar | N | 168 | 50 | 0.4271a
|
Mean (SD) | 86.16 (98.594) | 73.85 (86.680) | ||
Min–Max | 1.20–840.16 | 3.91–467.64 | ||
Temporal bulbar | N | 168 | 55 | 0.3643a
|
Mean (SD) | 61.79 (60.778) | 75.96 (172.540) | ||
Min–Max | 1.49–344.40 | 1.43–1258.31 | ||
Location comparisona
| 0.0067 | 0.9380 |
Time Period | Category | Statistic | All cases (n = 217) | All controls (n = 67) |
P-value |
---|---|---|---|---|---|
Past Week | |||||
Stinging/Burning | |||||
Experienced, n (%) | None of the time | 50 (23.04) | 58 (86.57) | <0.0001 | |
Some of the time | 103 (47.47) | 8 (11.94) | |||
Half of the time | 31 (14.29) | 0 (0.00) | |||
Most of the time | 21 (9.68) | 1 (1.49) | |||
All of the time | 8 (3.69) | 0 (0.00) | |||
Missing | 4 (1.84) | 0 (0.00) | |||
Bothered | N | 209 | 63 | <0.0001 | |
Mean (SD) | 1.49 (1.097) | 0.19 (0.503) | |||
Dryness | |||||
Experienced, n (%) | None of the time | 12 (5.53) | 53 (79.10) | <0.0001 | |
Some of the time | 73 (33.64) | 10 (14.93) | |||
Half of the time | 43 (19.82) | 3 (4.48) | |||
Most of the time | 58 (26.73) | 0 (0.00) | |||
All of the time | 28 (12.90) | 0 (0.00) | |||
Missing | 3 (1.38) | 1 (1.49) | |||
Bothered | N | 210 | 63 | <0.0001 | |
Mean (SD) | 2.17 (1.143) | 0.24 (0.560) | |||
Foreign Body Sensation | |||||
Experienced, n (%) | None of the time | 31 (14.29) | 55 (82.09) | <0.0001 | |
Some of the time | 117 (53.92) | 11 (16.42) | |||
Half of the time | 33 (15.21) | 0 (0.00) | |||
Most of the time | 20 (9.22) | 1 (1.49) | |||
All of the time | 13 (5.99) | 0 (0.00) | |||
Missing | 3 (1.38) | 0 (0.00) | |||
Bothered | N | 209 | 63 | <0.0001 | |
Mean (SD) | 1.66 (1.170) | 0.25 (0.671) | |||
Itching | |||||
Experienced, n (%) | None of the time | 50 (23.04) | 47 (70.15) | <0.0001 | |
Some of the time | 88 (40.55) | 18 (26.87) | |||
Half of the time | 36 (16.59) | 1 (1.49) | |||
Most of the time | 32 (14.75) | 1 (1.49) | |||
All of the time | 8 (3.69) | 0 (0.00) | |||
Missing | 3 (1.38) | 0 (0.00) | |||
Bothered | N | 205 | 63 | <0.0001 | |
Mean (SD) | 1.43 (1.168) | 0.37 (0.679) | |||
Light Sensitivity | |||||
Experienced, n (%) | None of the time | 39 (17.97) | 56 (83.58) | <0.0001 | |
Some of the time | 86 (39.63) | 11 (16.42) | |||
Half of the time | 35 (16.13) | 0 (0.00) | |||
Most of the time | 33 (15.21) | 0 (0.00) | |||
All of the time | 21 (9.68) | 0 (0.00) | |||
Missing | 3 (1.38) | 0 (0.00) | |||
Bothered | N | 207 | 63 | <0.0001 | |
Mean (SD) | 1.74 (1.265) | 0.21 (0.513) | |||
Painful/Sore | |||||
Experienced, n (%) | None of the time | 98 (45.16) | 61 (91.04) | <0.0001 | |
Some of the time | 77 (35.48) | 6 (8.96) | |||
Half of the time | 22 (10.14) | 0 (0.00) | |||
Most of the time | 14 (6.45) | 0 (0.00) | |||
All of the time | 2 (0.92) | 0 (0.00) | |||
Missing | 4 (1.84) | 0 (0.00) | |||
Bothered | N | 207 | 62 | <0.0001 | |
Mean (SD) | 1.01 (1.106) | 0.11 (0.409) | |||
Intermittent Blurred Vision | |||||
Experienced, n (%) | None of the time | 37 (17.05) | 57 (85.07) | <0.0001 | |
Some of the time | 104 (47.93) | 8 (11.94) | |||
Half of the time | 44 (20.28) | 2 (2.99) | |||
Most of the time | 18 (8.29) | 0 (0.00) | |||
All of the time | 10 (4.61) | 0 (0.00) | |||
Missing | 4 (1.84) | 0 (0.00) | |||
Bothered | N | 206 | 61 | <0.0001 | |
Mean (SD) | 1.67 (1.175) | 0.16 (0.522) | |||
Tired/Fatigued Eyes | |||||
Experienced, n (%) | None of the time | 23 (10.60) | 43 (64.18) | <0.0001 | |
Some of the time | 108 (49.77) | 21 (31.34) | |||
Half of the time | 32 (14.75) | 2 (2.99) | |||
Most of the time | 39 (17.97) | 0 (0.00) | |||
All of the time | 11 (5.07) | 1 (1.49) | |||
Missing | 4 (1.84) | 0 (0.00) | |||
Bothered | N | 208 | 62 | <0.0001 | |
Mean (SD) | 1.75 (1.109) | 0.37 (0.752) | |||
Frequent Blinking | |||||
Experienced, n (%) | None of the time | 52 (23.96) | 60 (89.55) | <0.0001 | |
Some of the time | 72 (33.18) | 6 (8.96) | |||
Half of the time | 40 (18.43) | 1 (1.49) | |||
Most of the time | 31 (14.29) | 0 (0.00) | |||
All of the time | 18 (8.29) | 0 (0.00) | |||
Missing | 4 (1.84) | 0 (0.00) | |||
Bothered | N | 207 | 61 | <0.0001 | |
Mean (SD) | 1.34 (1.188) | 0.10 (0.300) | |||
Other | |||||
Experienced, n (%) | None of the time | 55 (25.35) | 40 (59.70) | <0.0001 | |
Some of the time | 2 (0.92) | 0 (0.00) | |||
Half of the time | 6 (2.76) | 0 (0.00) | |||
Most of the time | 6 (2.76) | 0 (0.00) | |||
All of the time | 2 (0.92) | 0 (0.00) | |||
Missing | 146 (67.28) | 27(40.30) | |||
Bothered | N | 70 | 39 | 0.0015 | |
Mean (SD) | 0.69 (1.314) | 0.00 (0.000) |
All cases (n = 217) | All controls (n = 67) |
P-value | |
---|---|---|---|
Best-corrected visual acuity (study eye) | |||
Mean (SD) | 20/24.2 (7.6) | 20/22.5 (5.6) | 0.0817 |
Median | 20/20 | 20/20 | |
Symptom of blurred or fluctuating vision, n (%) | |||
None | 33 (15.2) | 49 (73.1) | |
Mild | 52 (24.0) | 10 (15.0) | |
Moderate | 94 (43.3) | 7 (10.5) | |
Severe | 25 (11.5) | 0 (0) | |
Very severe | 6 (2.8) | 0 (0) | |
Missing | 7 (3.2) | 1 (1.5) | |
Mean (SD) | 1.6 (1.0) | 0.4 (0.7) | <0.0001 |
Median | 2.0 | 0 |
Time Period | Category | Statistic | All cases (n = 217) | All controls (n = 67) |
P-value |
---|---|---|---|---|---|
Past month | Used artificial tears | N | 160 | 49 | |
Mean (SD) | 16.02 (12.722) | 2.27 (6.623) | <0.0001 | ||
Min–Max | 0.0–62.0 | 0.0–30.0 | |||
Used eye ointments | N | 139 | 45 | ||
Mean (SD) | 2.13 (7.087) | 0 (0) | 0.0457 | ||
Min–Max | 0.0–30.0 | 0.0–0.0 | |||
Past 3 months | Own money (dollars) spent on treatments for DE (dollars) | N | 162 | 47 | |
Mean (SD) | 33.56 (57.832) | 2.87 (7.854) | 0.0004 | ||
Med | 15 | 0 | |||
Min - Max | 0–400 | 0–30 | |||
DED symptoms main cause to use medication? n (%) | Eye Drops | ||||
Antibiotic drops | 3 (1.38) | 1 (1.49) | 0.5044 | ||
Non-prescription | 46 (21.20) | 6 (8.96) | |||
Prescription | 5 (2.30) | 0 (0.00) | |||
Steroids | 0(0.00) | 0 (0.00) | |||
Pills | |||||
Analgesic/anti-inflammatory (OTC) | 4 (1.84) | 0 (0.00) | <0.0001 | ||
Analgesics/anti-inflammatory (Rx) | 9 (4.15) | 0 (0.00) | |||
Antidepressants | 0 (0.00) | 1 (1.49) | |||
Antibiotics | 0 (0.00) | 0 (0.00) | |||
Anti-allergy (OTC) | 12 (5.53) | 3 (4.48) | |||
Anti-allergy (Rx) | 0 (0.00) | 0 (0.00) | |||
Other | 4 (1.84) | 0 (0.00) | |||
Special procedures, n (%) | |||||
Punctal occlusion or plugs, n (%) | Have not had | 134 (61.75) | 42 (62.69) | 0.2319 | |
Less than 1 yr. ago | 3 (1.38) | 0 (0.00) | |||
1–2 years ago | 3 (1.38) | 0 (0.00) | |||
3 or more yrs. ago | 8 (3.69) | 0 (0.00) | |||
Eye lid surgery, n (%) | Have not had | 138 (63.59) | 41 (61.19) | 0.6136 | |
Less than 1 yr. ago | 0 (0.00) | 0 (0.00) | |||
1–2 yrs. ago | 1 (0.46) | 0 (0.00) | |||
3 or more yrs. ago | 8 (3.69) | 1 (1.49) | |||
Overall satisfaction with treatment, n (%) | Currently not using treatments | 37 (17.05) | 37 (55.22) | <0.0001 | |
Overall dissatisfied | 0 (0.00) | 0 (0.00) | |||
Very dissatisfied | 11 (5.07) | 0 (0.00) | |||
Somewhat dissatisfied | 28 (12.90) | 1 (1.49) | |||
Neutral | 32 (14.75) | 5 (7.46) | |||
Somewhat satisfied | 36 (16.59) | 1 (1.49) | |||
Very satisfied | 19 (8.76) | 4 (5.97) | |||
Missing result | 54 (24.88) | 19 (28.36) |
Time Period | Category | Statistic | All cases (n = 217) | All controls (n = 67) |
P-value |
---|---|---|---|---|---|
Past Year | Doctor visits related to dry eye | ||||
Mean (SD) | 0.10 (0.439) | 0.00 (0.000) | |||
Min–Max | 0.0–4.0 | 0.0–0.0 | |||
1 Visit, n (%) | 7 (3.23%) | 0 (0.00) | |||
>1 Visit, n (%) | 3 (1.38%) | 0 (0.00) | |||
Ophthalmologist | N | 159 | 47 | <0.0001 | |
Mean (SD) | 0.64 (1.002) | 0.00 (0.000) | |||
Min–Max | 0.0–6.0 | 0.0–0.0 | |||
1 Visit, n (%) | 35 (16.13%) | 0 (0.00) | |||
>1 Visit, n (%) | 27 (12.44%) | 0 (0.00) | |||
Optometrist | N | 158 | 47 | 0.0013 | |
Mean (SD) | 0.37 (0.919) | 0.00 (0.000) | |||
Min–Max | 0.0–6.0 | 0.0–0.0 | |||
1 Visit, n (%) | 17 (7.83%) | 0 (0.00) | |||
>1 Visit, n (%) | 14 (6.45%) | 0 (0.00) | |||
Rheumatologist | N | 154 | 46 | 0.4085 | |
Mean (SD) | 0.05 (0.425) | 0.00 (0.000) | |||
Min–Max | 0.0–5.0 | 0.0–0.0 | |||
1 Visit, n (%) | 3 (1.38%) | 0 (0.00) | |||
>1 Visit, n (%) | 1 (0.46%) | 0 (0.00) | |||
Mental health counselor | N | 154 | 46 | 0.5860 | |
Min–Max | 0.0–5.0 | 0.0–0.0 | |||
1 Visit, n (%) | 0 (0.00) | 0 (0.00) | |||
>1 Visit, n (%) | 1 (0.46%) | 0 (0.00) | |||
Other | N | 86 | 32 | 0.2323 | |
Mean (SD) | 0.08 (0.382) | 0.00 (0.000) | |||
Min–Max | 0.0–2.0 | 0.0–0.0 | |||
1 Visit, n (%) | 1 (0.46%) | 0 (0.00) | |||
>1 Visit, n (%) | 3 (1.38%) | 0 (0.00) |
Question | All cases (n = 217) | All controls (n = 67) |
P-value |
---|---|---|---|
Currently employed, n (%) | |||
Yes | 100 (46.76%) | 40 (59.70%) | 0.0699 |
No | 114 (53.27%) | 27 (40.30%) | |
Hours missed work due to health | |||
N | 106 | 42 | |
Mean (SD) | 0.48 (2.846) | 0.19 (1.234) | 0.5248 |
Min–Max | 0–25 | 0–8 | |
Hours missed work due to other reasons | |||
N | 106 | 42 | |
Mean (SD) | 2.02 (5.174) | 2.30 (6.098) | 0.7776 |
Min–Max | 0–40 | 0–30 | |
Hours actually worked | |||
N | 109 | 42 | |
Mean (SD) | 30.87 (16.202) | 31.04 (17.603) | 0.9554 |
Min–Max | 0–62 | 0–60 | |
Productivity affected by health problems | |||
N | 108 | 42 | |
Mean (SD) | 1.63 (2.538) | 0.17 (0.660) | 0.0003 |
Min–Max | 0–10 | 0–3 | |
Regular activities affected by health problems | |||
N | 200 | 66 | |
Mean (SD) | 1.83 (2.280) | 0.59 (1.617) | <0.0001 |
Min–Max | 0–10 | 0–9 |
Variable pg/mL/mm | All cases (n = 217) | All controls (n = 67) |
P-value | |
---|---|---|---|---|
EGF | N | 164 | 51 | |
Mean (SD) | 2074.88 (3739.842) | 1724.86 (2632.770) | 0.5348 | |
Min-Max | 0.0–21,938 | 0.0–12,827 | ||
IFN-γ | N | 164 | 51 | |
Mean (SD) | 23.16 (125.014) | 18.77 (57.550) | 0.8083 | |
Min-Max | 0.0–1168.4 | 0.0–322.5 | ||
IL-1α | N | 164 | 51 | |
Mean (SD) | 214.58 (404.996) | 159.45 (223.319) | 0.3543 | |
Min-Max | 0.0–3244.0 | 0.0–1241.3 | ||
IL-1β | N | 164 | 51 | |
Mean (SD) | 55.89 (155.754) | 25.02 (36.211) | 0.1626 | |
Min-Max | 0.0–1580.9 | 0.0–194.6 | ||
IL-2 | N | 164 | 51 | |
Mean (SD) | 7.79 (25.646) | 4.07 (7.751) | 0.3091 | |
Min-Max | 0.0–253.4 | 0.0–33.3 | ||
IL-4 | N | 164 | 51 | |
Mean (SD) | 124.53 (433.605) | 152.13 (331.354) | 0.6765 | |
Min-Max | 0.0–3229.7 | 0.0–1913.5 | ||
IL-6 | N | 164 | 51 | |
Mean (SD) | 147.45 (476.145) | 104.72 (290.994) | 0.5451 | |
Min-Max | 0.0–3996.7 | 0.0–1801.2 | ||
IL-8 | N | 164 | 51 | |
Mean (SD) | 722.86 (1617.582) | 563.38 (769.371) | 0.4974 | |
Min-Max | 0.0–15,528 | 0.0–3240.8 | ||
IL-10 | N | 164 | 51 | |
Mean (SD) | 29.06 (112.567) | 34.11 (104.294) | 0.7765 | |
Min-Max | 0.0–1175.0 | 0.0–727.5 | ||
IL-13 | N | 164 | 51 | |
Mean (SD) | 48.48 (181.660) | 19.36 (44.051) | 0.2586 | |
Min-Max | 0.0–1662.7 | 0.0–277.6 | ||
IL-17 | N | 164 | 51 | |
Mean (SD) | 15.77 (91.369) | 16.17 (67.701) | 0.9768 | |
Min-Max | 0.0–911.4 | 0.0–394.7 | ||
IP-10 | N | 164 | 51 | |
Mean (SD) | 42,229.7 (61,361.73) | 33,137.9 (37,534.33) | 0.3182 | |
Min-Max | 0.0–449,861 | 0.0–144,295 | ||
TNF-α | N | 164 | 51 | |
Mean (SD) | 13.30 (66.885) | 5.95 (17.235) | 0.4387 | |
Min-Max | 0.0–642.1 | 0.0–86.1 |
EGF | IFN-γ | IL-1α | IL-1β | IL-2 | IL-6 | IL-8 | IL-17 | IP-10 | TNF-α | |
---|---|---|---|---|---|---|---|---|---|---|
IFN-γ | 0.30400 < 0.0001 | – | ||||||||
IL-1α | 0.23297 0.0027 | 0.32068 < 0.0001 | – | |||||||
IL-1β | 0.51640 < 0.0001 | 0.41754 < 0.0001 | 0.66743 < 0.0001 | – | ||||||
IL-2 | 0.25249 0.0011 | 0.49808 < 0.0001 | 0.16664 0.0329 | 0.42179 < 0.0001 | – | |||||
IL-6 | 0.76740 < 0.0001 | 0.35501 < 0.0001 | 0.33220 < 0.0001 | 0.57020 < 0.0001 | 0.23707 0.0022 | – | ||||
IL-8 | 0.75670 < 0.0001 | 0.28040 0.0003 | 0.24529 0.0015 | 0.40306 < 0.0001 | 0.27415 0.0004 | 0.80562 < 0.0001 | – | |||
IL-17 | 0.31044 < 0.0001 | 0.45138 < 0.0001 | 0.27422 0.0004 | 0.30745 < 0.0001 | 0.17318 0.0266 | 0.38157 < 0.0001 | 0.26181 0.0007 | – | ||
IP-10 | 0.58512 < 0.0001 | 0.15471 0.0479 | 0.33144 < 0.0001 | 0.38843 < 0.0001 | 0.06706 0.3936 | 0.64034 < 0.0001 | 0.69808 < 0.0001 | 0.21564 0.0056 | – | |
TNF-α | 0.37737 < 0.0001 | 0.58537 < 0.0001 | 0.27896 0.0003 | 0.44958 < 0.0001 | 0.56420 < 0.0001 | 0.49181 < 0.0001 | 0.40005 < 0.0001 | 0.36543 < 0.0001 | 0.26294 0.0007 | – |
EGF | IFN-γ | IL-1α | IL-1β | IL-2 | IL-6 | IL-8 | IL-17 | IP-10 | TNF-α | |
---|---|---|---|---|---|---|---|---|---|---|
IFN-γ | 0.28163 0.0431 | – | ||||||||
IL-1α | 0.04026 0.7769 | 0.16494 0.2426 | – | |||||||
IL-1β | 0.29569 0.0333 | 0.05001 0.7248 | 0.51570 < 0.0001 | – | ||||||
IL-2 | 0.20250 0.1500 | 0.19394 0.1683 | 0.27698 0.0468 | 0.47065 0.0004 | – | |||||
IL-6 | 0.40299 0.0031 | 0.08991 0.5262 | 0.42265 0.0018 | 0.51464 < 0.0001 | 0.38000 0.0055 | – | ||||
IL-8 | 0.57592 < 0.0001 | 0.09937 0.4834 | 0.25712 0.0657 | 0.32132 0.0202 | 0.25218 0.0713 | 0.70706 < 0.0001 | – | |||
IL-17 | 0.21875 0.1192 | 0.29428 0.0342 | 0.31177 0.0245 | 0.32902 0.0172 | 0.09588 0.4989 | 0.35271 0.0103 | 0.26003 0.0626 | – | ||
IP-10 | 0.59353 < 0.0001 | 0.09289 0.5125 | 0.28451 0.0409 | 0.25914 0.0636 | 0.18776 0.1826 | 0.42547 0.0017 | 0.55959 < 0.0001 | 0.20005 0.1551 | – | |
TNF-α | 0.18272 0.1948 | 0.29141 0.0361 | 0.13719 0.3321 | 0.32506 0.0187 | 0.55169 < 0.0001 | 0.57917 < 0.0001 | 0.34301 0.0128 | 0.36613 0.0076 | 0.15190 0.2824 | – |