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

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.

Time frame: 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)

Population: The Full Analysis Set (FAS) population included all randomised patients, who received and used at least once the investigational device (Lubricin or Vismed®). This analysis set was used for the efficacy analysis. Please note that for participants, study eye and non-study eye values were assessed and reported.

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.

Time frame: From baseline (Day 1 - pre-dose) to day 22±2

Population: The Safety population (SAF) included all patients who received and used at least once the IMDs (Lubricin or Vismed ®).

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.

Time frame: Day 15±2 (Visit 2); Day 22±2 (Visit 3)

Population: The Full Analysis Set (FAS) population included all randomised patients, who received and used at least once the investigational device (Lubricin or Vismed®). Please note that for participants, study eye and non-study eye values were assessed and reported.

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.

Time frame: From baseline (Day 1 pre-dose) to Day 15±2 and Day 22±2

Population: The Full Analysis Set (FAS) population included all randomised patients, who received and used at least once the investigational device (Lubricin or Vismed®).

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.

Time frame: Day 15±2 (Visit 2); Day 22±2 (Visit 3)

Population: The Full Analysis Set (FAS) population included all randomised patients, who received and used at least once the investigational device (Lubricin or Vismed®). Please note that for participants, study eye and non-study eye values were assessed and reported.

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.

Time frame: Day 15±2 (Visit 2); Day 22±2 (Visit 3)

Population: The Full Analysis Set (FAS) population included all randomised patients, who received and used at least once the investigational device (Lubricin or Vismed®). Please note that for participants, study eye and non-study eye values were assessed and reported.

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.

Time frame: Day 15±2 (Visit 2); Day 22±2 (Visit 3)

Population: The Full Analysis Set (FAS) population included all randomised patients, who received and used at least once the investigational device (Lubricin or Vismed®). Please note that for participants, study eye and non-study eye values were assessed and reported.

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.

Time frame: Day 15±2 (Visit 2); Day 22±2 (Visit 3)

Population: The Full Analysis Set (FAS) population included all randomised patients, who received and used at least once the investigational device (Lubricin or Vismed®).

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.

Time frame: Day 15±2 (Visit 2); Day 22±2 (Visit 3)

Population: The Full Analysis Set (FAS) population included all randomised patients, who received and used at least once the investigational device (Lubricin or Vismed®). Please note that for participants, study eye and non-study eye values were assessed and reported.

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.

Time frame: Day 15±2 (Visit 2); Day 22±2 (Visit 3)

Population: The Full Analysis Set (FAS) population included all randomised patients, who received and used at least once the investigational device (Lubricin or Vismed®). Please note that for participants, study eye and non-study eye values were assessed and reported.