Tear Osmolarity Changes After Instilling Isotonic Hyaluronate Artificial Tears

• Sponsor: Thomas O Salmon, OD, PhD (Other)
• Overall Status: Completed
• CT.gov ID: NCT01614847
• Collaborator: (none)
• Enrollment: 8
• Location: 1
• Arms: 2
• Duration (Months): 2
• Patients Per Site Per Month: 4

Study Details

Study Description

Brief Summary

Background:

Osmolarity is defined as the concentration of particles dissolved in a solution. Normal tears contain various dissolved particles including proteins, salts and other electrolytes. The investigators plan to investigate how osmolarity of the tear film changes over time after instillation of artificial tears containing hyaluronate. This is one kind of artificial tear that is used to treat dry eye.

Dry eye and tear osmolarity:

Dry eye is a significant health problem, but diagnosis and treatment are often ambiguous and ineffective. There has been a resurgence of interest and research in dry eye in the past 5 years, and tear osmolarity has emerged as perhaps, one of the most effective ways to evaluate tear quality and dry eye status. Dry eye is usually treated with artificial tears, and many formulations are available. The investigators will test an isotonic solution that contains hyaluronate. Hyaluronate binds water and should help to maintain water on the eye.

Objective:

We plan to study the time course of possible changes in tear film osmolarity following instillation of an isotonic artificial tear containing hyaluronate. The investigators will use the TearLab, a new clinical instrument that has been developed to quickly and easily measure tear film osmolarity. Understanding how artificial tears affect tear film osmolarity over time can help doctors determine efficacy and dosing schedules. The investigators will test the isotonic hyaluronate (Blink Contacts) artificial tears relative to normal saline solution.

Hypothesis:

The investigators should be able to measure a decrease in tear osmolarity over time following instillation due to the water-binding effect of hyaluronate artificial tears relative to a control (normal saline solution).

Condition or Disease	Intervention/Treatment	Phase
Dry Eye	Drug: Artificial tears	Phase 4

Detailed Description

ABSTRACT:

Introduction: Tear hyper-osmolarity may be a fundamental cause of dry eye in many cases. Hyaluronate is an agent used in some artificial tears, which binds water and can protect against evaporation. It may therefore be an effective treatment for tear hyper-osmolarity.

Purpose: Our purpose was to measure changes in tear osmolarity over time following instillation of Blink Contacts, an isotonic ocular lubricant containing hyaluronate. We hypothesized that even in isotonic solution, the water-binding properties of hyaluronate would reduce tear osmolarity. This will help us better understand efficacy of this treatment and develop a rational basis for dosing schedules.

Methods: After baseline osmolarity measurements, eight subjects received either Blink Contacts or normal saline drops in both eyes. We re-measured osmolarity five minutes later, and then at 15-minute intervals up to 95 minutes. Subjects also rated comfort at each time. The next day, the experiment was repeated with the alternate drops for each subject.

Study Design

• Study Type: Interventional
• Actual Enrollment: 8 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Tear Osmolarity Changes After Instilling Isotonic Hyaluronate Artificial Tears
• Study Start Date: Jun 1, 2012
• Actual Primary Completion Date: Aug 1, 2012
• Actual Study Completion Date: Aug 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Isotonic hyaluronate artificial tear At random, subjects will receive isotonic hyaluronate artificial tear or a control (normal saline).	Drug: Artificial tears; At random, subjects will receive isotonic artificial tear or a control (normal saline).
Placebo Comparator: Normal saline	Drug: Artificial tears; At random, subjects will receive isotonic artificial tear or a control (normal saline).

Outcome Measures

Primary Outcome Measures

1. Osmolarity Change From Baseline (mOsms/L) as a Function of Time (Minutes) [Baseline, followed by 7 measurements made after instillation (5, 20, 35, 50, 65, 80, 95 minutes post-instillation).]

   Raw data: Baseline (pre-instillation) tear osmolarity was measured for right and left eyes for each subject. Then measurements were repeated at 7 times (5, 20, 35, 50, 65 890 and 95 minutes) after instillation. Data processing: 1) Baseline osmolarity was subtracted from each post-baseline measurement to give a change-from-baseline values. 2) Right and left eye change values averaged to give a mean osmolarity change for each subject at each of the seven times. 3) Mean osmolarity changes values were averaged across 8 subjects for each of the 7 times and entered in the table below. Row 1 is for Drop A (hyaluronate); Row 2 for Drop B (saline). Column are for the 7 times.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 35 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• At least 18 years of age Normal vision in both eyes (20/30 best corrected) Preference for patient with dry eye symptoms

Exclusion Criteria:

• No ocular disease other than dry eye Currently taking no ocular or systemic medications that might affect results

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Northeastern State University	Tahlequah	Oklahoma	United States	74464

Sponsors and Collaborators

• Thomas O Salmon, OD, PhD

Investigators

• Study Director: Thomas O Salmon, OD, PhD, Northeastern State University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Thomas O Salmon, OD, PhD, Professor, Northeastern State University
• ClinicalTrials.gov Identifier: NCT01614847
• Other Study ID Numbers: NSUOCO-2012-11
• First Posted: Jun 8, 2012
• Last Update Posted: Apr 3, 2020
• Last Verified: Apr 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Thomas O Salmon, OD, PhD, Professor, Northeastern State University: dry eye; artificial tears; tear osmolarity; residence time
• Additional relevant MeSH terms: Dry Eye Syndromes; Lubricant Eye Drops

Study Results

Participant Flow

Recruitment Details	A convenience sample of 8 subjects was recuitted from among the student population at the NSU Oklahoma College of Optometry during May-June 2012.
Pre-assignment Detail	Subjects were assigned random ID numbers in preparation for assignment into the two groups. Half (4 subjects) chosen at random, would be assigned to Group 1, and receive Drop A on Day 1, then return 24 hours (Day 2) later to received Drop B. The other 4 subjects would be assigned to Group 1, and receive Drop B on Day 1 and Drop A on Day 2.

Arm/Group Title	Group 1: Four Subjects Who Received Drop A on Day 1	Group 2: Four Subjects Who Received Drop B on Day 1
Arm/Group Description	All eight subject received Drop A (hyaluronate) on one day and Drop B (saline) on the other day. Subjects #1, 2, 3, 4 received Drop A on Day 1 and Drop B on Day 2.	All eight subject received Drop A (hyaluronate) on one day and Drop B (saline) on the other day. Subjects #5, 6, 7, 8 received Drop B on Day 1 and Drop A on Day 2.
Period Title: Day 1
STARTED	4	4
COMPLETED	4	4
NOT COMPLETED	0	0
Period Title: Day 1
STARTED	4	4
COMPLETED	4	4
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Arm 1. Isotonic Hyaluronate Artificial Tear FIRST	Arm 2. Normal Saline FIRST	Total
Arm/Group Description	Per sequence. Four subject, chosen at random, will receive isotonic hyaluronate artificial tear in Session 1. After a 24-hour washout period, they will return for Session 2, when they will receive saline eye drops.	Per sequence. The four remaining subject (see comments to left), will receive saline eye drops in Session 1. After a 24-hour washout period, they will return for Session 2, when they will receive isotonic hyaluronate artificial tears.	Total of all reporting groups
Overall Participants	4	4	8
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	4 100%	4 100%	8 100%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	25.8 (1.5)	28.0 (4.8)	26.9 (3.5)
Sex: Female, Male (Count of Participants)
Female	2 50%	0 0%	2 25%
Male	2 50%	4 100%	6 75%
Region of Enrollment (participants) [Number]
United States	4 100%	4 100%	8 100%

Outcome Measures

1. Primary Outcome

Title	Osmolarity Change From Baseline (mOsms/L) as a Function of Time (Minutes)
Description	Raw data: Baseline (pre-instillation) tear osmolarity was measured for right and left eyes for each subject. Then measurements were repeated at 7 times (5, 20, 35, 50, 65 890 and 95 minutes) after instillation. Data processing: 1) Baseline osmolarity was subtracted from each post-baseline measurement to give a change-from-baseline values. 2) Right and left eye change values averaged to give a mean osmolarity change for each subject at each of the seven times. 3) Mean osmolarity changes values were averaged across 8 subjects for each of the 7 times and entered in the table below. Row 1 is for Drop A (hyaluronate); Row 2 for Drop B (saline). Column are for the 7 times.
Time Frame	Baseline, followed by 7 measurements made after instillation (5, 20, 35, 50, 65, 80, 95 minutes post-instillation).

Outcome Measure Data

Analysis Population Description

Eight subjects recruited from among students at the NSU Oklahoma College of Optometry, including 6 males and 2 females who were at least 18 years of age and who had no known ocular or systemic disease other than dry eye. Six subjects did not have dry eye and 2 were diagnosed with dry eye based on Ocular Surface Disease Index (OSDI) survey scores.

Arm/Group Title	5 Minutes	20 Minutes	35 Minutes	50 Minutes	65 Minutes	80 Minutes	95 Minutes
Arm/Group Description	Mean* change in tear osmolarity (mOsmol/L) from baseline 5 minutes after instillation of Drop A (Blink Contacts; hyaluronate) for each subject. (*Mean of change values measured for right and left eyes.)	Mean* change in tear osmolarity (mOsmol/L) from baseline 20 minutes after instillation of Drop A (Blink Contacts; hyaluronate) for each subject. (*Mean of change values measured for right and left eyes.)	Mean* change in tear osmolarity (mOsmol/L) from baseline 35 minutes after instillation of Drop A (Blink Contacts; hyaluronate) for each subject. (*Mean of change values measured for right and left eyes.)	Mean* change in tear osmolarity (mOsmol/L) from baseline 50 minutes after instillation of Drop A (Blink Contacts; hyaluronate) for each subject. (*Mean of change values measured for right and left eyes.)	Mean* change in tear osmolarity (mOsmol/L) from baseline 65 minutes after instillation of Drop A (Blink Contacts; hyaluronate) for each subject. (*Mean of change values measured for right and left eyes.)	Mean* change in tear osmolarity (mOsmol/L) from baseline 80 minutes after instillation of Drop A (Blink Contacts; hyaluronate) for each subject. (*Mean of change values measured for right and left eyes.)	Mean* change in tear osmolarity (mOsmol/L) from baseline 95 minutes after instillation of Drop A (Blink Contacts; hyaluronate) for each subject. (*Mean of change values measured for right and left eyes.)
Measure Participants	8	8	8	8	8	8	8
Measure Eyes	16	16	16	16	16	16	16
Drop A	-0.94 (0.62)	7.25 (1.49)	5.31 (2.19)	-4.25 (1.26)	7.5 (1.61)	2.31 (1.54)	9.25 (1.39)
Drop B	-0.8 (0.97)	-2.1 (1.43)	2.5 (2.09)	4.4 (1.35)	4.9 (1.31)	1.9 (1.32)	8.6 (1.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	5 Minutes
	Comments	Drop A: Mean change in osmolarity from baseline H0: No osmolarity change from baseline (e.g. mean change = 0) H1: Significant osmolarity change from baseline (mean change ≠ 0)
	Type of Statistical Test	Equivalence
	Comments	Two tailed, alpha = 0.05
Statistical Test of Hypothesis	p-Value	0.4
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments	df=7

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	20 Minutes
	Comments	Drop A: Mean change in osmolarity from baseline H0: No osmolarity change from baseline (e.g. mean change = 0) H1: Significant osmolarity change from baseline (mean change ≠ 0)
	Type of Statistical Test	Equivalence
	Comments	two-tailed, alpha = 0.05
Statistical Test of Hypothesis	p-Value	0.109
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments	df=7

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	35 Minutes
	Comments	Drop A: Mean change in osmolarity from baseline H0: No osmolarity change from baseline (e.g. mean change = 0) H1: Significant osmolarity change from baseline (mean change ≠ 0)
	Type of Statistical Test	Equivalence
	Comments	Two tailed, alpha = 0.05
Statistical Test of Hypothesis	p-Value	0.779
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments	df=7

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	50 Minutes
	Comments	Drop A: Mean change in osmolarity from baseline H0: No osmolarity change from baseline (e.g. mean change = 0) H1: Significant osmolarity change from baseline (mean change ≠ 0)
	Type of Statistical Test	Equivalence
	Comments	Two tailed, alpha = 0.05
Statistical Test of Hypothesis	p-Value	0.262
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments	df=7

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	65 Minutes
	Comments	Drop A: Mean change in osmolarity from baseline H0: No osmolarity change from baseline (e.g. mean change = 0) H1: Significant osmolarity change from baseline (mean change ≠ 0)
	Type of Statistical Test	Equivalence
	Comments	Two tailed, alpha = 0.05
Statistical Test of Hypothesis	p-Value	0.150
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments	df=7

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	80 Minutes
	Comments	Drop A: Mean change in osmolarity from baseline H0: No osmolarity change from baseline (e.g. mean change = 0) H1: Significant osmolarity change from baseline (mean change ≠ 0)
	Type of Statistical Test	Equivalence
	Comments	Two tailed, alpha = 0.05
Statistical Test of Hypothesis	p-Value	0.726
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments	df=7

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	95 Minutes
	Comments	Drop A: Mean change in osmolarity from baseline H0: No osmolarity change from baseline (e.g. mean change = 0) H1: Significant osmolarity change from baseline (mean change ≠ 0)
	Type of Statistical Test	Equivalence
	Comments	Two tailed, alpha = 0.05
Statistical Test of Hypothesis	p-Value	0.055
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments	df=7

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	5 Minutes
	Comments	Drop B: Mean change in osmolarity from baseline H0: No osmolarity change from baseline (e.g. mean change = 0) H1: Significant osmolarity change from baseline (mean change ≠ 0)
	Type of Statistical Test	Equivalence
	Comments	Two tailed, alpha = 0.05
Statistical Test of Hypothesis	p-Value	0.945
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments	df=7

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	20 Minutes
	Comments	Drop B: Mean change in osmolarity from baseline H0: No osmolarity change from baseline (e.g. mean change = 0) H1: Significant osmolarity change from baseline (mean change ≠ 0)
	Type of Statistical Test	Equivalence
	Comments	Alpha = 0.05
Statistical Test of Hypothesis	p-Value	0.844
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments	df=7

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	35 Minutes
	Comments	Drop B: Mean change in osmolarity from baseline H0: No osmolarity change from baseline (e.g. mean change = 0) H1: Significant osmolarity change from baseline (mean change ≠ 0)
	Type of Statistical Test	Equivalence
	Comments	Two tailed, alpha = 0.05
Statistical Test of Hypothesis	p-Value	0.945
	Comments	df=7
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	50 Minutes
	Comments	Drop B: Mean change in osmolarity from baseline H0: No osmolarity change from baseline (e.g. mean change = 0) H1: Significant osmolarity change from baseline (mean change ≠ 0)
	Type of Statistical Test	Equivalence
	Comments	Two tailed, alpha = 0.05
Statistical Test of Hypothesis	p-Value	0.383
	Comments	Alpha = 0.05
	Method	Wilcoxon (Mann-Whitney)
	Comments	df=7

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	65 Minutes
	Comments	Mean change in osmolarity from baseline. H0: No change (e.g. mean change = 0) H1: Significant change (mean change ≠ 0)
	Type of Statistical Test	Equivalence
	Comments	Two tailed, alpha = 0.05
Statistical Test of Hypothesis	p-Value	0.383
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments	df=7

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	80 Minutes
	Comments	Drop B: Mean change in osmolarity from baseline H0: No osmolarity change from baseline (e.g. mean change = 0) H1: Significant osmolarity change from baseline (mean change ≠ 0)
	Type of Statistical Test	Equivalence
	Comments	Two tailed, alpha = 0.05
Statistical Test of Hypothesis	p-Value	0.672
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments	df=7

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	95 Minutes
	Comments	Drop B: Mean change in osmolarity from baseline H0: No osmolarity change from baseline (e.g. mean change = 0) H1: Significant osmolarity change from baseline (mean change ≠ 0)
	Type of Statistical Test	Equivalence
	Comments	Two tailed, alpha = 0.05
Statistical Test of Hypothesis	p-Value	0.107
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments	df=7

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	5 Minutes
	Comments	Comparison of Drop A versus Drop B change in osmolarity at this point in time. H0: No difference in osmolarity change between Drop A and B (Drop A = Drop B) H1: Significant difference in osmolarity change between Drop A and Drop B
	Type of Statistical Test	Equivalence
	Comments	Two tailed, alpha = 0.05
Statistical Test of Hypothesis	p-Value	0.64
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments	df=12

Statistical Analysis 16

Statistical Analysis Overview	Comparison Group Selection	20 Minutes
	Comments	Comparison of Drop A versus Drop B change in osmolarity at this point in time. H0: No difference in osmolarity change between Drop A and B (Drop A = Drop B) H1: Significant difference in osmolarity change between Drop A and Drop B
	Type of Statistical Test	Equivalence
	Comments	Two tailed, alpha = 0.05
Statistical Test of Hypothesis	p-Value	0.040
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments	df=14

Statistical Analysis 17

Statistical Analysis Overview	Comparison Group Selection	35 Minutes
	Comments	Comparison of Drop A versus Drop B change in osmolarity at this point in time. H0: No difference in osmolarity change between Drop A and B (Drop A = Drop B) H1: Significant difference in osmolarity change between Drop A and Drop B
	Type of Statistical Test	Equivalence
	Comments	Two tailed, alpha = 0.05
Statistical Test of Hypothesis	p-Value	0.20
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments	df=12

Statistical Analysis 18

Statistical Analysis Overview	Comparison Group Selection	50 Minutes
	Comments	Comparison of Drop A versus Drop B change in osmolarity at this point in time. H0: No difference in osmolarity change between Drop A and B (Drop A = Drop B) H1: Significant difference in osmolarity change between Drop A and Drop B
	Type of Statistical Test	Equivalence
	Comments	Two tailed, alpha = 0.05
Statistical Test of Hypothesis	p-Value	0.150
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments	df-=12

Statistical Analysis 19

Statistical Analysis Overview	Comparison Group Selection	65 Minutes
	Comments	Comparison of Drop A versus Drop B change in osmolarity at this point in time. H0: No difference in osmolarity change between Drop A and B (Drop A = Drop B) H1: Significant difference in osmolarity change between Drop A and Drop B
	Type of Statistical Test	Equivalence
	Comments	Two tailed, alpha = 0.05
Statistical Test of Hypothesis	p-Value	0.730
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments	df=12

Statistical Analysis 20

Statistical Analysis Overview	Comparison Group Selection	80 Minutes
	Comments	Comparison of Drop A versus Drop B change in osmolarity at this point in time. H0: No difference in osmolarity change between Drop A and B (Drop A = Drop B) H1: Significant difference in osmolarity change between Drop A and Drop B
	Type of Statistical Test	Equivalence
	Comments	Two tailed, alpha = 0.05
Statistical Test of Hypothesis	p-Value	0.89
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments	df=12

Statistical Analysis 21

Statistical Analysis Overview	Comparison Group Selection	95 Minutes
	Comments	Comparison of Drop A versus Drop B change in osmolarity at this point in time. H0: No difference in osmolarity change between Drop A and B (Drop A = Drop B) H1: Significant difference in osmolarity change between Drop A and Drop B
	Type of Statistical Test	Equivalence
	Comments	Two tailed, alpha = 0.05
Statistical Test of Hypothesis	p-Value	0.89
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments	df=12

Adverse Events

Arm/Group Title	Isotonic Hyaluronate Artificial Tear		Normal Saline
Arm/Group Description	At random, subjects will receive isotonic hyaluraonate artificial tear or a control (normal saline).		Subject not assigned to Arm1 (experimental group) were assigned to this group during Session 1. Twenty-four hours later subjects were assigned to the alternate groups (cross-over).
All Cause Mortality
	Isotonic Hyaluronate Artificial Tear		Normal Saline
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/8 (0%)		0/8 (0%)
Serious Adverse Events
	Isotonic Hyaluronate Artificial Tear		Normal Saline
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/8 (0%)		0/8 (0%)
Other (Not Including Serious) Adverse Events
	Isotonic Hyaluronate Artificial Tear		Normal Saline
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/8 (0%)		0/8 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.