IVIG-eye Drops Treatment for Dry Eye Disease

• Sponsor: Sandeep Jain, MD (Other)
• Overall Status: Completed
• CT.gov ID: NCT03992482
• Collaborator: (none)
• Enrollment: 27
• Location: 1
• Arms: 2
• Actual Duration (Months): 3.1
• Patients Per Site Per Month: 8.8

Study Details

Study Description

Brief Summary

The main objective of this study is to establish whether patients with Dry Eye Disease are able to safely tolerate receiving Intravenous Immunoglobulin (IVIG) eye drops two times a day for eight weeks (primary 'safety and tolerability' objective). The exploratory objective is to investigate the preliminary efficacy of the use of IVIG eye drops in treating Dry Eye Disease (exploratory efficacy objective) to estimate the effectiveness of the trial intervention and collecting data to inform the design of a future definitive trial.

This will be a Randomized controlled trial, in which a total of 28 subjects will be enrolled at 1 clinical site. Subjects will be randomly assigned to one of two groups (#1, #2), with 14 subjects per group. One group will be given placebo (Normal saline eye drops) and the other group will be given eye drops containing the study drug (IVIG).

Condition or Disease	Intervention/Treatment	Phase
Dry Eye	Drug: Intravenous Immune Globulin (IVIG); Drug: Placebo	Phase 1/Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 27 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase I/II Randomized, Placebo-controlled, Double-Blind, Single-Center, Tolerability and Preliminary Efficacy Clinical Trial of Intravenous Immunoglobulin (IVIG) Eye Drops in Patients With Dry Eye Disease
• Actual Study Start Date: May 1, 2019
• Actual Primary Completion Date: Aug 2, 2019
• Actual Study Completion Date: Aug 2, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: IVIG-Eye Drop Intravenous Immunoglobulin (IVIG), 4 mg/ml (0.4%) eye drops two times a day for eight weeks	Drug: Intravenous Immune Globulin (IVIG); Intravenous Immunoglobulin (IVIG), 4 mg/ml (0.4%) eye drops two times a day for eight weeks
Placebo Comparator: Placebo-Eye Drop Normal Saline Eye Drops (0.9% NaCl)	Drug: Placebo; Normal Saline Eye Drops (0.9% NaCl) two times a day for eight weeks

Outcome Measures

Primary Outcome Measures

1. Tolerability: The Primary Tolerability Endpoint is the Test Substance Tolerance (Visual Analog Scale) at 8 Weeks (56 Days) [8 Weeks]

   Subjects will assess their tolerance to the administration of the test medication (placebo/ study drug), utilizing a Visual Analog Scale (VAS). The VAS is a 100 mm horizontal line with verbal descriptors at either end. Subjects will place a single slash mark across the horizontal line between the end labeled "completely intolerable" (0 mm) and "easily tolerable" (100mm). The VAS ratings will be completed after administration of the test medication on Day 1 (post-dose), week 4 and week 8.

Other Outcome Measures

1. The Change in the Ocular Surface Disease Index (OSDI) Which is a Patient's Subjective Rating Scale [Between baseline and at 8 weeks of treatment]

   Ocular Surface Disease Index (OSDI), a 12-item questionnaire, assesses symptom of ocular irritation in dry eye disease (DED) and how it affects functioning related to vision in the past week. It has 3 subscales: ocular symptoms, vision-related function, and environmental triggers. Patients rate their responses on 0 to 4 scale with 0 being "none of the time" and 4 being "all of the time." OSDI score range from 0-100 with score 0-12 being normal, 13-22 being mild DED, 23-32 being moderate DED, and >33 being severe DED. OSDI=[(sum of scores for questions answered)×100]/[(total questions answered)×4]

2. Change in Corneal Staining Score as Measured by Lissamine Dye Staining [Between baseline and at 8 weeks of treatment]

   Corneal staining score as measured by Lissamine Green dye staining using National Eye Institute (NEI) grading scale. Dye was applied to each eye and a slit lamp was used to observe corneal staining. NEI scale relies on a chart that divides the cornea into 5 sections and assigns a value from 0 (absent) to 3 (severe) to each section, based on the density of punctate staining, final staining score being the sum of individual section scores with a range of 0 (minimum) -15 (maximum) points. Complete corneal staining clearance with Lissamine dye defined as a score of 0 indicating the best outcome.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Sign and date the informed consent form approved by the Institutional Review Board (IRB)

2. ≥ 18 years of age

3. Demonstrate at least any 2 of the following signs in the same eye or a sign and symptom.

4. Conjunctival staining present ≥ 1 (out of possible score of 6 per eye)

5. Corneal staining present ≥ 2 (out of a possible score of 15 per eye)

6. Tear film break up time (TFBUT) ≤ 7 seconds

7. Schirmer's test ≥ 0 to ≤ 9 mm/5min

8. Superior Limbic Keratoconjunctivitis (SLK) pattern staining ≥ 1

9. Meiboscale grade ≥ 2

10. Validated Bulbar Redness ≥ 40

11. Demonstrate symptoms of dry eye disease Ocular Surface Disease Index (OSDI) score of at least ≥ 13.

12. Demonstrate Symptom Intensity Assessment of ≥ 3.

13. Patient reported dry eye-related ocular symptoms for at least 6 months before the Screening Visit and use or desire to use artificial tears on average 2 times per day in the 2 weeks preceding the screening visit

14. Intraocular pressure (IOP) ≥ 5 mmHg and ≤ 22 mmHg in each eye

15. Women of child-bearing potential must agree to use a reliable method of contraception during study participation and must demonstrate a negative pregnancy test at the Screening Visit

16. Be willing/able to return for all study visits and to follow instructions from the study investigator and his/her staff

17. Ocular Surface Wash Anti-Citrullinated Protein Antibody (ACPA) value of > 4.4 units in either eye at any time in the past.

Exclusion Criteria:

1. Allergic to IVIG or any similar products, or excipients of IVIG eye drops 4 mg/ml.

2. Use of contact lenses within the last 2-weeks prior to the baseline Visit.

3. Use of Allogenic serum or plasma eye drops within the last 2-weeks prior to the baseline Visit.

4. Unwilling to commit to no use of contact lenses for the duration of the study.

5. Pregnant or nursing/lactating

6. Participation in a study of an investigational drug or device within the 30 days preceding the Screening Visit

7. Current diagnosis of any of the following ocular conditions:

1. Acute allergic conjunctivitis ii) Active infection (e.g. bacterial, viral, protozoan or fungal infection of the cornea, conjunctiva, lacrimal gland, lacrimal sac or eyelids) iii) Active intraocular inflammation (e.g., retinitis, choroiditis, uveitis)

1. A cognitive or psychiatric deficit that precludes informed consent or ability to perform

2. Vulnerable populations, such as neonates, pregnant women, children, prisoners, institutionalized individuals, or others who may be considered vulnerable populations.

3. Have active drug/alcohol dependence or abuse.

4. The corneal epithelial defect is larger than 1 mm2 in either eye.

5. Active ocular infection or ocular allergies.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Illinois Eye and Ear Infirmary	Chicago	Illinois	United States	60612

Sponsors and Collaborators

• Sandeep Jain, MD

Investigators

• Principal Investigator: Sandeep Jain, MD, University of Illinois at Chicago

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Apr 9, 2019

More Information

Additional Information:

• Related Info

Publications

• An S, Raju I, Surenkhuu B, Kwon JE, Gulati S, Karaman M, Pradeep A, Sinha S, Mun C, Jain S. Neutrophil extracellular traps (NETs) contribute to pathological changes of ocular graft-vs.-host disease (oGVHD) dry eye: Implications for novel biomarkers and therapeutic strategies. Ocul Surf. 2019 Jul;17(3):589-614. doi: 10.1016/j.jtos.2019.03.010. Epub 2019 Apr 6.
• Dourmishev LA, Guleva DV, Miteva LG. Intravenous Immunoglobulins: Mode of Action and Indications in Autoimmune and Inflammatory Dermatoses. Int J Inflam. 2016;2016:3523057. doi: 10.1155/2016/3523057. Epub 2016 Jan 18. Review.
• Martín-Nares E, Hernández-Molina G. Novel autoantibodies in Sjögren's syndrome: A comprehensive review. Autoimmun Rev. 2019 Feb;18(2):192-198. doi: 10.1016/j.autrev.2018.09.003. Epub 2018 Dec 18. Review.
• Mun C, Gulati S, Tibrewal S, Chen YF, An S, Surenkhuu B, Raju I, Buwick M, Ahn A, Kwon JE, Atassi N, Pradeep A, Rondelli D, Jain S. A Phase I/II Placebo-Controlled Randomized Pilot Clinical Trial of Recombinant Deoxyribonuclease (DNase) Eye Drops Use in Patients With Dry Eye Disease. Transl Vis Sci Technol. 2019 May 2;8(3):10. doi: 10.1167/tvst.8.3.10. eCollection 2019 May.

• Responsible Party: Sandeep Jain, MD, Professor, University of Illinois at Chicago
• ClinicalTrials.gov Identifier: NCT03992482
• Other Study ID Numbers: 2019-0263
• First Posted: Jun 20, 2019
• Last Update Posted: Apr 10, 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 Sandeep Jain, MD, Professor, University of Illinois at Chicago: Dry Eye; Intravenous Immunoglobulin (IVIG) Eye Drops; Treatment; ocular Graft-vs-Host Disease (oGVHD)
• Additional relevant MeSH terms: Dry Eye Syndromes; Keratoconjunctivitis Sicca; Eye Diseases; Immunoglobulins; Antibodies; gamma-Globulins; Immunoglobulins, Intravenous; Rho(D) Immune Globulin

Study Results

Participant Flow

Recruitment Details	Subjects were recruited from the clinical practice of the investigator at the time of their routine eye examination visit. The clinical practice is located in the Illinois Eye and Ear Infirmary (EEI), the University of Illinois at Chicago (UIC). The first participant was enrolled on 6 May 2019, and the last participant was enrolled on 7 June 2019.

Arm/Group Title	IVIG-Eye Drop	Placebo-Eye Drop
Arm/Group Description	Intravenous Immunoglobulin (IVIG), 4 mg/ml (0.4%) eye drops two times a day for eight weeks Intravenous Immune Globulin (IVIG): Intravenous Immunoglobulin (IVIG), 4 mg/ml (0.4%) eye drops two times a day for eight weeks	Normal Saline Eye Drops (0.9% NaCl) Placebo: Normal Saline Eye Drops (0.9% NaCl) two times a day for eight weeks
Period Title: Overall Study
STARTED	13	14
COMPLETED	13	14
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	IVIG-Eye Drop	Placebo-Eye Drop	Total
Arm/Group Description	Intravenous Immunoglobulin (IVIG), 4 mg/ml (0.4%) eye drops two times a day for eight weeks Intravenous Immune Globulin (IVIG): Intravenous Immunoglobulin (IVIG), 4 mg/ml (0.4%) eye drops two times a day for eight weeks	Normal Saline Eye Drops (0.9% NaCl) Placebo: Normal Saline Eye Drops (0.9% NaCl) two times a day for eight weeks	Total of all reporting groups
Overall Participants	13	14	27
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	57	65	62
Sex: Female, Male (Count of Participants)
Female	9 69.2%	10 71.4%	19 70.4%
Male	4 30.8%	4 28.6%	8 29.6%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	5 38.5%	3 21.4%	8 29.6%
Not Hispanic or Latino	8 61.5%	11 78.6%	19 70.4%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	2 15.4%	2 14.3%	4 14.8%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	2 15.4%	2 14.3%	4 14.8%
White	9 69.2%	10 71.4%	19 70.4%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	13 100%	14 100%	27 100%
Diagnosis (Count of Participants)
Auto-immune tear deficient DED	7 53.8%	6 42.9%	13 48.1%
ocular GVHD	6 46.2%	1 7.1%	7 25.9%
Non-autoimmune tear deficient DED	0 0%	5 35.7%	5 18.5%
Meibomian Gland Dysfunction (MGD)	0 0%	2 14.3%	2 7.4%
OSDI (units on a scale) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [units on a scale]	52.3	40.9	43.18
Corneal Staining (units on a scale) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [units on a scale]	5	2	3

Outcome Measures

1. Primary Outcome

Title	Tolerability: The Primary Tolerability Endpoint is the Test Substance Tolerance (Visual Analog Scale) at 8 Weeks (56 Days)
Description	Subjects will assess their tolerance to the administration of the test medication (placebo/ study drug), utilizing a Visual Analog Scale (VAS). The VAS is a 100 mm horizontal line with verbal descriptors at either end. Subjects will place a single slash mark across the horizontal line between the end labeled "completely intolerable" (0 mm) and "easily tolerable" (100mm). The VAS ratings will be completed after administration of the test medication on Day 1 (post-dose), week 4 and week 8.
Time Frame	8 Weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	IVIG-Eye Drop	Placebo-Eye Drop
Arm/Group Description	Intravenous Immunoglobulin (IVIG), 4 mg/ml (0.4%) eye drops two times a day for eight weeks Intravenous Immune Globulin (IVIG): Intravenous Immunoglobulin (IVIG), 4 mg/ml (0.4%) eye drops two times a day for eight weeks	Normal Saline Eye Drops (0.9% NaCl) Placebo: Normal Saline Eye Drops (0.9% NaCl) two times a day for eight weeks
Measure Participants	13	14
Median (Inter-Quartile Range) [score on a scale]	100	100

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	IVIG-Eye Drop, Placebo-Eye Drop
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	1.000
	Comments
	Method	Kruskal-Wallis
	Comments

2. Other Pre-specified Outcome

Title	The Change in the Ocular Surface Disease Index (OSDI) Which is a Patient's Subjective Rating Scale
Description	Ocular Surface Disease Index (OSDI), a 12-item questionnaire, assesses symptom of ocular irritation in dry eye disease (DED) and how it affects functioning related to vision in the past week. It has 3 subscales: ocular symptoms, vision-related function, and environmental triggers. Patients rate their responses on 0 to 4 scale with 0 being "none of the time" and 4 being "all of the time." OSDI score range from 0-100 with score 0-12 being normal, 13-22 being mild DED, 23-32 being moderate DED, and >33 being severe DED. OSDI=[(sum of scores for questions answered)×100]/[(total questions answered)×4]
Time Frame	Between baseline and at 8 weeks of treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	IVIG-Eye Drop	Placebo-Eye Drop
Arm/Group Description	Intravenous Immunoglobulin (IVIG), 4 mg/ml (0.4%) eye drops two times a day for eight weeks Intravenous Immune Globulin (IVIG): Intravenous Immunoglobulin (IVIG), 4 mg/ml (0.4%) eye drops two times a day for eight weeks	Normal Saline Eye Drops (0.9% NaCl) Placebo: Normal Saline Eye Drops (0.9% NaCl) two times a day for eight weeks
Measure Participants	13	14
Median (Inter-Quartile Range) [score on a scale]	-20.9	0.00

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	IVIG-Eye Drop, Placebo-Eye Drop
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0044
	Comments
	Method	Mixed Models Analysis
	Comments

3. Other Pre-specified Outcome

Title	Change in Corneal Staining Score as Measured by Lissamine Dye Staining
Description	Corneal staining score as measured by Lissamine Green dye staining using National Eye Institute (NEI) grading scale. Dye was applied to each eye and a slit lamp was used to observe corneal staining. NEI scale relies on a chart that divides the cornea into 5 sections and assigns a value from 0 (absent) to 3 (severe) to each section, based on the density of punctate staining, final staining score being the sum of individual section scores with a range of 0 (minimum) -15 (maximum) points. Complete corneal staining clearance with Lissamine dye defined as a score of 0 indicating the best outcome.
Time Frame	Between baseline and at 8 weeks of treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	IVIG-Eye Drop	Placebo-Eye Drop
Arm/Group Description	Intravenous Immunoglobulin (IVIG), 4 mg/ml (0.4%) eye drops two times a day for eight weeks Intravenous Immune Globulin (IVIG): Intravenous Immunoglobulin (IVIG), 4 mg/ml (0.4%) eye drops two times a day for eight weeks	Normal Saline Eye Drops (0.9% NaCl) Placebo: Normal Saline Eye Drops (0.9% NaCl) two times a day for eight weeks
Measure Participants	13	14
Measure Eye	26	28
Median (Inter-Quartile Range) [score on a scale]	-1.50	0.00

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	IVIG-Eye Drop, Placebo-Eye Drop
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0002
	Comments
	Method	Mixed Models Analysis
	Comments

Adverse Events

Time Frame	Between baseline and 8-weeks of treatment
Arm/Group Title	IVIG-Eye Drop		Placebo-Eye Drop
Arm/Group Description	Intravenous Immunoglobulin (IVIG), 4 mg/ml (0.4%) eye drops two times a day for eight weeks Intravenous Immune Globulin (IVIG): Intravenous Immunoglobulin (IVIG), 4 mg/ml (0.4%) eye drops two times a day for eight weeks		Normal Saline Eye Drops (0.9% NaCl) Placebo: Normal Saline Eye Drops (0.9% NaCl) two times a day for eight weeks
All Cause Mortality
	IVIG-Eye Drop		Placebo-Eye Drop
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/13 (0%)		0/14 (0%)
Serious Adverse Events
	IVIG-Eye Drop		Placebo-Eye Drop
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/13 (0%)		0/14 (0%)
Other (Not Including Serious) Adverse Events
	IVIG-Eye Drop		Placebo-Eye Drop
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/13 (38.5%)		8/14 (57.1%)
Eye disorders
Ocular discomfort	2/13 (15.4%)		5/14 (35.7%)
Pain	0/13 (0%)		1/14 (7.1%)
Tearing	0/13 (0%)		2/14 (14.3%)
Blurring of vision	2/13 (15.4%)		4/14 (28.6%)
Light sensitivity	1/13 (7.7%)		5/14 (35.7%)
Dryness	2/13 (15.4%)		4/14 (28.6%)
Redness	0/13 (0%)		2/14 (14.3%)

Limitations/Caveats

Outcomes of this clinical trial shouldn't be over-interpreted for benefit. Accurate assessment of therapeutic implications of IVIG eye drops will only be possible after adequately powered definitive pivotal trials. Small sample size is a limitation.

More Information

Certain Agreements

All Principal Investigators ARE 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.