Tolerability, Safety and Efficacy of Lubricin Versus Sodium Hyaluronate Eye Drops in Patients With Moderate Dry Eye

2 Week, Randomized, Double-masked, Controlled, Parallel Group+1 Week Follow-up Study to Evaluate Tolerability, Safety and Efficacy of Lubricin 150 µg/ml vs Sodium Hyaluronate (HA) 0.18% Eye Drops (Vismed®) in Patients With Moderate Dry Eye

The objective of this study is to evaluate tolerability, safety and efficacy of Lubricin 150 µg/ml eye drops when compared to a widely used commercial 0.18% sodium hyaluronate eye drop formulation in moderate dry eye patients.

Primary objectives:

• Tolerability using a Visual Analogue Scale (VAS) for foreign body sensation, burning/stinging, itching, pain, stick feeling, blurred vision, and photophobia;
• Treatment-emergent adverse events (TEAEs), assessed throughout the clinical investigation.

Secondary objectives:

• Corneal fluorescein staining (scored using the Oxford scale);
• Schirmer test type I (without anaesthesia);
• Symptom assessment in dry eye (SANDE);
• Ocular protection index (OPI);
• Tear film break-up time (TFBUT);
• Best corrected distance visual acuity (BCDVA);
• Slit lamp examination (SLE) (Eyelid - Meibomian glands, eyelid erythema, eyelid oedema, lashes, conjunctiva erythema, lens, iris, anterior chamber, corneal transparency, corneal neovascularisation);
• Intraocular pressure (IOP);
• Number of instillations of investigational medical device during the second week of the clinical investigation.

All parameters will be evaluated at Screening visit-V1 (Day -7 up to day -5), baseline visit-V2 (Day 1), V3 (Day 7±1), V4 (Day 14±1) and at Final Visit follow-up-V5 (Day 21±1).

Study Overview

• Status: Completed
• Conditions: Dry Eye Syndrome
• Intervention / Treatment: Device: Lubricin; Device: Sodium Hyaluronate

Detailed Description

This study is a 2 week, randomized, double-masked, controlled, parallel group and 1 week follow-up investigation to evaluate tolerability, safety and efficacy of Lubricin (150 µg/mL) eye drops versus sodium hyaluronate (HA) 0.18% eye drops (Vismed®) in patients with moderate dry eye (DE).

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Italy
  • Rome, Italy, 00161
    • Dipartimento "Organi di senso" Università La Sapienza- Policlinico Umberto I

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

To be checked at the screening visit (V1) within 7 days before study treatment and confirmed at baseline visit (V2):

1. Patients 18 years of age or older;
2. Patients with moderate dry eye characterized by at least one eye with signs and symptoms of moderate dry eye (grade 2 or 3 of the 2007 DEWS report);
3. Patients diagnosed with dry eye from at least 3 months (current use or recommended use of artificial tears for the treatment of Dry Eye);
4. Average VAS score for typical symptoms of Dry Eye (foreign body sensation, burning/stinging, itching, pain, stick feeling, blurred vision and photophobia) ≥ 25 mm;
5. Corneal staining score with fluorescein > 3 using the Oxford corneal grading system in the worst performing eye;
6. Schirmer test without anaesthesia ≤ 10 mm/5 minutes in the worst performing eye;
7. Tear film break-up time (TBUT) ≤ 10 seconds in the worst performing eye;
8. Best corrected distance visual acuity (BCDVA) score ≥ 0.1 decimal units in both eyes at the time of study enrollment;
9. Only patients who satisfy all Informed Consent requirements may be included in the study. The patient and/or his/her legal representative must read, sign and date the Informed Consent document before any study-related procedures are performed. The Informed Consent form signed by patients and/or legal representative must have been approved by the Ethics Committee for the current study.

Exclusion Criteria:

1. Patients with a mild Dry Eye condition (severity level 1 according to the Report of the International Dry Eye Workshop -DEWS, 2007);
2. Patients with a severe Dry Eye condition (severity level 4 according to the Report of the International Dry Eye Workshop -DEWS, 2007);
3. Best corrected distance visual acuity (BCDVA) score of < 0.1 decimal units in either eye at the time of study enrolment;
4. Evidence of an active ocular infection in either eye;
5. History or presence of ocular surface disorders not related to dry eye in either eye;
6. Use of any ocular topical medication other than the study medications for the treatment of ocular diseases including artificial tears during the study period;
7. Use of topical cyclosporine, topical corticosteroids or any other topical medication for the treatment of dry eye in either eye within 30 days of study enrolment;
8. History of any ocular surgery (including laser or refractive surgical procedures) in either eye within the 90 days before study enrolment. Ocular surgery will not be allowed during the study treatment period and elective ocular surgery procedures should not be planned during the duration of the follow-up period;
9. Presence or history of any ocular or systemic disorder or condition that might significantly hinder the efficacy of the study treatment or its evaluation, could possibly interfere with the interpretation of study results, or could be judged by the investigator to be incompatible with the study visit schedule or conduct of trail procedures (e.g. ocular trauma, progressive or degenerative corneal conditions, uveitis, systemic infection.);
10. Known hypersensitivity to one of the components of the study or procedural medications;
11. Participation in another clinical study at the same time as the present study or within 90 days of screening/baseline visit;
12. History of drug, medication or alcohol abuse or addiction;

13. Females of childbearing potential (those who are not surgically sterilized or post-menopausal for at least 1 year) are excluded from participation in the study if they meet any one of the following conditions:

    • are currently pregnant or,
    • have a positive result on the urine pregnancy test at the Screening/Baseline Visit or,
    • intend to become pregnant during the study treatment period or,
    • are breast-feeding or,
    • not willing to use highly effective birth control measures, such as: Hormonal contraceptives - oral, implanted, transdermal, or injected and/or mechanical barrier methods - spermicide in conjunction with a barrier such as a condom or diaphragm or an Intra Uterine Device during the entire course of and 30 days after the study treatment periods.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Lubricin; Lubricin 150 μg/ml eye drops solution Test investigational device was instilled b.i.d. (two times a day), one drop into each eye, from day 1 to day 7±1 and, then, from 2 to 6 times a day as needed (i.e. prn), one drop into each eye, from day 7±1 to day 14±1. After the end of the treatment period, all the subjects used Vismed® 0.18% b.i.d. every 8±1 h, one drop into each eye, from day 14±1 to day 21±1. Before the start of the treatment (from day -6/-4 to day -1), the subjects were allowed to use only Nebul®, NaCl 0.9% ocular solution q.i.d. every 4±1 h, one drop into each eye.	Device: Lubricin; Lubricin 150 µg/ml eye drops
Active Comparator: Sodium Hyaluronate; Vismed®, 0.18% sodium hyaluronate eye drops Comparator was instilled b.i.d. (two times a day), one drop into each eye, from day 1 to day 7±1 and, then, from 2 to 6 times a day as needed (i.e. prn), one drop into each eye, from day 7±1 to day 14±1. After the end of the treatment period, all the subjects used Vismed® 0.18% b.i.d. every 8±1 h, one drop into each eye, from day 14±1 to day 21±1. Before the start of the treatment (from day -6/-4 to day -1), the subjects were allowed to use only Nebul®, NaCl 0.9% ocular solution q.i.d. every 4±1 h, one drop into each eye.	Device: Sodium Hyaluronate; Sodium hyaluronate 0.18% eye drops; Other Names: Vismed®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Foreign Body Sensation, Burning/Stinging, Itching, Pain, Stick Feeling, Blurred Vision, Photophobia and Total Ocular Tolerability Score (VAS)	A global ocular tolerability score was determined using a 100 mm Visual Analogue Scale (VAS) on which 0 meant no symptoms and 100 meant the worst possible discomfort. This evaluation was to be performed before any ophthalmic assessment at each scheduled visit. Specific ocular symptoms were measured with the VAS included: foreign body sensation, burning/stinging, itching, pain, sticky feeling, blurred vision, photophobia. The patients evaluated their symptoms using the VAS giving the value they were feeling from none to an extreme value. The VAS scale was a straight horizontal line of fixed length (100 mm). The ends were defined as the extreme limits of the parameter. Please note that Ophthalmological evaluations were performed for both eyes. Hence both the eyes - right and left - were "study-eyes".	Visit 3 - Day 7±1, Visit 4 - Day 14±1 and Visit 5/Final visit/Follow up - Day 21±1
Treatment-emergent Adverse Events (TEAEs), Assessed Throughout the Study.	TEAEs included all AEs occurring or worsening after the first dose of the IMD. These comprise AEs during the treatment and follow-up period. For TEAE the number of events was provided.	Visit 5/Final visit/Follow up - Day 21±1

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Corneal Fluorescein Surface Staining (Oxford Score)	The corneal fluorescein staining was graded by using the Oxford scheme to assess cornea and conjunctiva epithelium damage. The Oxford grading scale divides corneal staining into six groups according to severity from 0 (absent) to 5 (severe). The examiner compared the overall appearance of the patient's corneal staining with a reference figure, simulating the pattern of staining encountered in dry eye disease. No attempt was made to count the dots or to assess the position or confluence of the dots. The examiner selected the appropriate grade that best represented the state of corneal staining. The grading system recommended by NEI divides the cornea into five zones (central, superior, temporal, nasal, and inferior) and for each zone, the severity of corneal fluorescein staining is graded on a scale from 0 to 3 based on reference figures. Therefore, the maximum score (worst outcome) was 15, the minimum (best outcome) was 0. Please note: both the eyes, right & left, were "study-eyes".	Visit 3 - Day 7±1, Visit 4 - Day 14±1 and Visit 5/Final visit/Follow up - Day 21±1
Change From Baseline in Schirmer Test I (Without Anaesthesia)	The Schirmer test type I (without anaesthesia) was performed to measure aqueous tear secretion prior to the instillation of any dilating or anaesthetic eye drops.The rounded bent end of a sterile strip was inserted into the lower conjunctival sac over the temporal one-third of the lower eyelid margin. After 5 minutes had elapsed, the Schirmer"s test strip was removed and the length of the tear absorption on the strip was measured (millimeters/5 minutes). Changes from baseline in values of Schirmer's test type I were summarised by eye and evaluation visit, and stratified by severity level. The longer the wetted length, the healthier the status of the eye. Please note that Ophthalmological evaluations were performed for both eyes. Hence both the eyes - right and left - were "study-eyes".	Visit 3 - Day 7±1, Visit 4 - Day 14±1 and Visit 5/Final visit/Follow up - Day 21±1
Change From Baseline in SANDE (Symptom Assessment in Dry Eye) - Frequency of Symptoms	The SANDE (Symptom Assessment in Dry Eye) questionnaire was a short questionnaire to evaluate both dry eye frequency and severity by using a 100 mm VAS. For the assessment, the subjects marked on the 100 mm VAS line the point that they felt represented their perception of their current state. The VAS score was determined by measuring in millimetres from the left hand end of the line to the point that the subject marked. The SANDE scores was then evaluated for the 2 questions severity (0-100) and frequency (0-100), where 0 was the best condition and 100 marked the worst condition. Please note that ophthalmological evaluations were performed for both eyes. Hence both the eyes - right and left - were "study-eyes".	Visit 3 - Day 7±1, Visit 4 - Day 14±1 and Visit 5/Final visit/Follow up - Day 21±1
Change From Baseline in SANDE (Symptom Assessment in Dry Eye) - Severity of Symptoms	The SANDE (Symptom Assessment in Dry Eye) questionnaire was a short questionnaire to evaluate both dry eye severity and frequency by using a 100 mm VAS. For the assessment, the subjects marked on the 100 mm VAS line the point that they felt represented their perception of their current state. The VAS score was determined by measuring in millimetres from the left hand end of the line to the point that the subject marked. The SANDE scores were evaluated for the 2 questions severity (0-100) and frequency (0-100), where 0 was the best condition and 100 marked the worst condition. Please note that ophthalmological evaluations were performed for both eyes. Hence both the eyes - right and left - were "study-eyes".	Visit 3 - Day 7±1, Visit 4 - Day 14±1 and Visit 5/Final visit/Follow up - Day 21±1
Change From Baseline in OPI (Ocular Protection Index)	OPI was used to quantify the interaction between tear film break-up time and blink intervals of a subject. It was based on the idea that, even when the TBUT was normal, if the blink interval was too slow it may cause breakage of tear film due to increased evaporation. The OPI was calculated by dividing TFBUT by inter blink interval (IBI). A visual count of the number of blinks per minute was performed while the subject read the ETDRS chart. ETDRS charts had five Sloan letters on each line; the lines were of equal difficulty, and there was a geometric progression in letter size from line to line. If the IBI and TBUT was same, dividing both give a value of 1.0. If TFBUT was more than IBI, dividing both, gave a value more than 1.0, so dryness would not occur. If TFBUT was less than IBI, dividing both gave a value less than 1.0. A subject was at risk of developing dry eye if the OPI was < 1.0; so the higher the score the better the outcome. Both eyes - right and left - were "study-eyes".	Visit 3 - Day 7±1, Visit 4 - Day 14±1 and Visit 5/Final visit/Follow up - Day 21±1
Change From Baseline in TFBUT (Tear Film Break Up Time)	TFBUT was measured by determining the time to tear break-up. The TFBUT test was performed after instillation of 5 µl of 2% preservative-free sodium fluorescein solution into the inferior conjunctival cul-de-sac of each eye. With the aid of a slit lamp at 10X magnification using cobalt blue illumination, the examiner monitored the integrity of the tear film, noting the time it took to form lacunae (clear spaces in the tear film) from the time that the eye was opened after the last blink. This measurement was performed within 10 seconds maximum. The TFBUT was measured twice during the first minute after the instillation of the fluorescein. If the 2 readings differed by more than 2 seconds, a third reading was taken. The TFBUT value was the average of the 2 or 3 measurements. Generally, a TFBUT value of 10-35 seconds was considered normal. A value of less than 10 seconds was usually suspicious and may indicate tear film instability. Both the eyes - right and left - were "study-eyes".	Visit 3 - Day 7±1, Visit 4 - Day 14±1 and Visit 5/Final visit/Follow up - Day 21±1
Change From Baseline in BCDVA (Best-corrected Distance Visual Acuity) - ETDRS Score	BCDVA was determined by careful refraction according to the standard protocol for refraction. Chart 1 was used for testing the VA of the right eye; Chart 2 for the left eye; and Chart R for refraction only. Retroilluminated standard Early Treatment of Diabetic Retinopathy Study (ETDRS) charts were used. They had 5 Sloan letters on each line of equal difficulty, and there was a geometric progression in letter size from line to line.VAS awarded one point for every letter correctly guessed. A distance of 4 meters (m) was required between the subject's eyes and the VA chart. When a subject cannot read at least 20 letters on the chart at 4 m, the subject was tested at 1 m. If 20 or more letters were read at 4 m, the VAS for that eye was recorded as the no of letters correct at 4 m plus 30. Otherwise, the VAS was the no of letters read correctly at 1 m plus the no read at 4 m. The higher the score the better the outcome. Both eyes - right and left - were "study-eyes".	Visit 3 - Day 7±1, Visit 4 - Day 14±1 and Visit 5/Final visit/Follow up - Day 21±1
Change From Baseline in Slit Lamp Examination (SLE)	The Slit Lamp Examination was used to examine the structures of the eye (eyelids, lashes, conjunctiva, cornea, lens, iris and anterior chamber) according to different scales: Eyelid - Meibomian glands (from 0-none to 3-severe), Eyelid - Erythema (from 0-none to 4-very severe), Eyelid - Oedema (from 0-none to 4-very severe), Lashes (0-normal 1-abnormal), Conjunctiva - Erythema (from 0-none to 3-severe), Conjunctiva - Oedema (from 0-none to 4-very severe), Lens (from 0-no opacification to 3-severe lens opacification), Iris (0-normal 1-abnormal), Anterior chamber inflammation (from 0-none to 3-severe), Cornea transparency (from 0-completely transparent to 4-complete cornea opacity), Cornea neovascularization (0-absence of neovascularization to 4-neovascularization between 270° and 360°). The higher the score the worse the outcome. There was not a total score. Please note: ophthalmological evaluations were performed for both eyes. Hence both eyes - right and left - were "study-eyes".	Visit 3 - Day 7±1, Visit 4 - Day 14±1 and Visit 5/Final visit/Follow up - Day 21±1
Change From Baseline in IOP (Intraocular Pressure)	The intraocular pressure (IOP) of the eye was determined by the balance between the amount of aqueous humor that the eye marked and the ease with which it leaved the eye. IOP was performed using Goldmann applanation tonometry after the instillation of a topical anaesthetic. The Goldmann applanation tonometer measured the force necessary to flatten a corneal area of 3.06 mm diameter. At this diameter, the resistance of the cornea to flattening was counterbalanced by the capillary attraction of the tear film meniscus for the tonometer head. The IOP (in mm Hg) equals the flattening force (in grams) multiplied by 10. IOP was measured in both eyes after completion of all other SLEs to avoid potential interference with the other evaluations. Both eyes were tested. Normal eye pressure was between 10 to 21 mm Hg. High intraocular pressure was greater than 21 mm Hg. Please note: ophthalmological evaluations were performed for both eyes. Hence both eyes - right and left - were "study-eyes".	Visit 3 - Day 7±1, Visit 4 - Day 14±1 and Visit 5/Final visit/Follow up - Day 21±1
Number of Instillations of IMD During the Second Week of the Clinical Investigation	The number of daily instillations of test and comparator IMD from from Visit 3 - Day 7±1 to Visit 4 - Day 14±1	from Visit 3 - Day 7±1 to Visit 4 - Day 14±1

Collaborators and Investigators

• Sponsor: Dompé Farmaceutici S.p.A
• Investigators: Study Director: Flavio Mantelli, MD-PhD, Dompé Farmaceutici SpA

Publications and helpful links

General Publications

• Lambiase A, Sullivan BD, Schmidt TA, Sullivan DA, Jay GD, Truitt ER 3rd, Bruscolini A, Sacchetti M, Mantelli F. A Two-Week, Randomized, Double-masked Study to Evaluate Safety and Efficacy of Lubricin (150 mug/mL) Eye Drops Versus Sodium Hyaluronate (HA) 0.18% Eye Drops (Vismed(R)) in Patients with Moderate Dry Eye Disease. Ocul Surf. 2017 Jan;15(1):77-87. doi: 10.1016/j.jtos.2016.08.004. Epub 2016 Sep 8.

Study record dates

Study Major Dates

• Study Start (Actual): June 26, 2015
• Primary Completion (Actual): October 5, 2015
• Study Completion (Actual): October 6, 2015

Study Registration Dates

• First Submitted: July 23, 2015
• First Submitted That Met QC Criteria: July 23, 2015
• First Posted (Estimated): July 24, 2015

Study Record Updates

• Last Update Posted (Actual): October 15, 2024
• Last Update Submitted That Met QC Criteria: July 9, 2024
• Last Verified: July 1, 2024

More Information

Terms related to this study

• Keywords: Dry Eye
• Additional Relevant MeSH Terms: Eye Diseases; Lacrimal Apparatus Diseases; Keratoconjunctivitis; Conjunctivitis; Conjunctival Diseases; Keratitis; Corneal Diseases; Dry Eye Syndromes; Keratoconjunctivitis Sicca; Physiological Effects of Drugs; Immunologic Factors; Protective Agents; Adjuvants, Immunologic; Viscosupplements; Hyaluronic Acid
• Other Study ID Numbers: LUB0115MD; CIV-15-05-013553 (Other Identifier: EudaMed)