Safety and Efficacy of 2 Concentrations of Lubricin vs Sodium Hyaluronate in Ocular Discomfort After Refractive Surgery.

Not Applicable

Completed

Conditions: Ocular Discomfort

Interventions: Device: Lubricin 50µg/ml eye drops
Device: Lubricin 20µg/ml eye drops
Device: Sodium hyaluronate (HA) 0.18% eye drops

Registration Number: NCT03031327

Lead Sponsor: Dompé Farmaceutici S.p.A

Brief Summary: The objective of this study was to evaluate tolerability, safety, permanence on the ocular surface and efficacy of Lubricin (20 and 50 μg/mL) eye drops vs Sodium Hyaluronate (Vismed®) 0.18% eye drops in patients with ocular discomfort following refractive surgery.

Primary objectives:

* Tolerability using a Visual analogue scale (VAS) for dryness, foreign body sensation, burning/stinging, itching, pain, stick feeling, blurred vision and photophobia;

* Treatment-emergent adverse events (TEAEs), assessed throughout the study.

Secondary objectives:

* Ocular surface vital staining with Fluorescein (Oxford scale)

* Schirmer-I test (without anaesthesia);

* Permanence of Lubricin on the Ocular Surface Tear film break-up time (TFBUT);

* Best corrected distance visual acuity (BCDVA);

* SANDE questionnaire scores - discomfort improvement entity;

* SANDE questionnaire scores - discomfort improvement speed;

* Signs evaluated by Slit lamp examination (SLE) (blepharitis, eyelid hyperemia/oedema, lashes, conjunctiva hyperemia);

* Intraocular pressure (IOP) ;

* Corneal sensitivity by Cochet-Bonnet aesthesiometry.

All parameters were evaluated at V1 (Day 1 - Baseline), V2 (Day 15±2) and V3 (Day 22±2/ETV).

Detailed Description: This study was a 2 week randomized (1:1:1), controlled, double-masked, parallel group, pre-market study to evaluate tolerability, safety, permanence on the ocular surface and efficacy of Lubricin (20 and 50 μg/mL) eye drops vs Sodium Hyaluronate (Vismed®) 0.18% eye drops in patients with ocular discomfort following refractive surgery.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 30

Inclusion Criteria

Patients 18 years of age or older;
Patients undergone ocular refractive surgery within 6 months from V1 - Day 1;
Patients with ocular discomfort defined as SANDE score ≥ 30 at baseline;
Average VAS score (dryness, foreign body sensation, burning/stinging, itching, pain, stick feeling, blurred vision and photophobia) ≥ 25 mm;
Best corrected distance visual acuity (BCDVA) score ≥ 0.1 decimal units in both eyes at the time of study enrolment;
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

Patients with a severe Dry Eye condition (severity level 4 according to the Report of the International Dry Eye Workshop -DEWS, 2007);
Best corrected distance visual acuity (BCDVA) score of < 0.1 decimal units in either eye at the time of study enrolment;
Evidence of an active ocular infection in either eye;
History or presence of ocular surface disorders other than ocular discomfort in either eye;
Use of any ocular topical medication other than the study medications for the treatment of ocular diseases including artificial tears during the study period;
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;
History of any ocular surgery (excluding laser or refractive surgical procedures) in either eye within 30 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;
Known hypersensitivity to one of the components of the study or procedural medications;
Participation in another clinical study at the same time as the present study or within 90 days of screening/baseline visit;
History of drug, medication or alcohol abuse or addiction;
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:
1. are currently pregnant or,
2. have a positive result on the urine pregnancy test at the Screening/Baseline Visit or,
3. intend to become pregnant during the study treatment period or,
4. are breast-feeding or,
5. 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 IUD (intrauterine device ) during the entire course of and 30 days after the study treatment periods.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Lubricin 50µg/ml eye drops	Lubricin 50µg/ml eye drops	Lubricin 50µg/ml eye drops 3 times per day
Lubricin 20µg/ml eye drops	Lubricin 20µg/ml eye drops	Lubricin 20µg/ml eye drops 3 times per day
Sodium hyaluronate (HA) 0.18% eye drops	Sodium hyaluronate (HA) 0.18% eye drops	Sodium hyaluronate (HA) 0.18% eye drops 3 times per day

Primary Outcome Measures

Name	Time	Method
Changes From Baseline (Day 1 Pre-dose) in Ocular Tolerability Using a Visual Analogue Scale (VAS)	Day 1 (baseline = Visit 1) at pre-dose, 15, 30 min post-dose; Day 15±2 (= Visit 2) at pre-dose, 15, 30 min post-dose; Day 22±2 (= Visit 3)	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 ophtalmic assessment at each scheduled visit. Specific ocular symptoms 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 extreme limits of the parameter.
Treatment-emergent Adverse Events (TEAEs) Assessed Throughout the Study	From baseline (Day 1 - pre-dose) to day 22±2	TEAEs included all AEs occurring or worsening after the first dose of IMD. These comprise AEs during the treatment and follow-up period. For TEAE, the number of events was provided. At each visit (Visit 1 which took place at Day 1; Visit 2 which took place at day 15 ± 2; Visit 3, i.e. final visi FU, at Day 22 ± 2/ETV), patients could spontaneously report any physical or medical occurrence and the investigator or designee inquired about the occurrence of TEAEs by asking specific questions. Any untoward (unfavorable \& unintended) change in subject's medical conditions was to be reported as an AE. Changes in any protocol-specific ocular or systemic parameter evaluated during the study were to be reviewed by the investigator. In addition, each patient's response to any questionnaire was to be reviewed by the investigator. Any untoward (unfavorable and unintended) change in a protocol-specific parameter or questionnaire response clinically relevant was to be reported as an AE.

Secondary Outcome Measures

Name	Time	Method
Change From Baseline in Ocular Surface Vital Staining With Fluorescein (Oxford Scale)	Day 15±2 (Visit 2); Day 22±2 (Visit 3)	The corneal fluorescein staining was graded by using the Oxford scheme to assess cornea and conjunctiva epithelium damage. It was performed after instillation of sodium fluoresce 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 Oxford scale grading divides corneal staining into six groups for each panel, based on the severity \[from 0 (absent) to 5 (severe)\]. The corneal staining is represented by punctate dots on a series of panels (panel A=grade 0 to panel \>E=grade 5). Staining ranges from 0-5 for each panel, and 0-15 for the total exposed inter-palpebral conjunctiva and cornea. The examiner selected the appropriate grade that best represented the state of corneal staining intuitional. The higher the grade, the worst is the overall outcome value.
Change From Baseline in Schirmer-I Test (Without Anaesthesia)	Day 15±2 (Visit 2); Day 22±2 (Visit 3)	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). The longer the wetted length, the healthier the status of the eye.
Change From Baseline in Permanence of Lubricin on the Ocular Surface - Tear Film Break-up Time (TFBUT)	Day 15±2 (Visit 2); Day 22±2 (Visit 3)	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. The higher the value, the better the outcome.
Change From Baseline in Best Corrected Distance Visual Acuity (BCDVA) - ETDRS Score	Day 15±2 (Visit 2); Day 22±2 (Visit 3)	Best corrected visual acuity (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 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 meters, the subject was tested at 1 meter. If 20 or more letters were read at 4 meters, the VAS for that eye was recorded as the number of letters correct at 4 meters plus 30. Otherwise, the VAS was the number of letters read correctly at 1 meter plus the number read at 4 meters. The higher the score the better the outcome.
Change From Baseline in SANDE (Symptom Assessment in Dry Eye) Questionnaire Scores	Day 15±2 (Visit 2); Day 22±2 (Visit 3)	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. The subject symptoms of ocular dryness and/or irritation were quantified on the scale based on two questions that assess both severity and frequency of symptoms. 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 millimeters 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.
Change From Baseline in Slit Lamp Examination (SLE) Values	Day 15±2 (Visit 2); Day 22±2 (Visit 3)	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 (to 0-no opacification to 3-severe 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 vascularization to 4- neovascularization between 270° and 360°). The higher the score the worse the outcome. There was not a total score.
Change From Baseline in IOP (Intraocular Pressure)	Day 15±2 (Visit 2); Day 22±2 (Visit 3)	The IOP (intraocular pressure) of the eye was determined by the balance between the amount of aqueous humor that the eye marked and 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 SLEs to avoid potential interference with the other evaluations. Both eyes were tested. Normal eye pressure was between 10 to 21 mmHg. High ocular pressure was greater than 21 mmHg.
Change From Baseline in Corneal Sensitivity by Cochet-Bonnet Aesthesiometry	From baseline (Day 1 pre-dose) to Day 15±2 and Day 22±2	The Cochet-Bonnet aesthesiometer contained a thin, retractable, nylon monofilament that extended up to 6 cm in length. Variable pressure could be applied to the cornea by adjusting the monofilament length. The monofilament length ranged from 6 to 0.5 cm. As the monofilament length was decreased the pressure increased from 11 mm/gm to 200 mm/gm. Corneal sensation was measured in the affected eye(s) in the central area of the cornea using a Cochet Bonnet aesthesiometer before the instillation of any dilating or anesthetic eye drops. The length of the filament in cm at which the patient corneal sensation was observed for the tested area of the cornea was reported. With decreasing length of monofilament, the corneal touch threshold increased and the corneal sensitivity decreased. Therefore, decreasing the length of monofilament was proportional to decreased corneal sensitivity.