Study to Evaluate Safety and Efficacy of Cenegermin (Oxervate®) vs Vehicle in Severe Sjogren's Dry Eye Disease

The Schirmer test was used in ophthalmic examination to measure tear production for the diagnosis of conditions such as keratoconjunctivitis sicca and dry eye.

Without previously instilling anesthetic drops, the Schirmer strip was inserted into the lower conjunctival sac at the junction of the lateral and middle thirds, avoiding touching the cornea, and the length of wetting strips in millimeters was recorded after 5 minutes.

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).

Cutoff values:

<5 mm - pathologic dry eye 5-10 mm - marginal dry eye >10 and <30 mm - normal secretion The longer, the wetted length, the healthier the status of the eye. No units other than participants were assigned.

SANDE was a short questionnaire to evaluate both dry eye intensity and frequency. It uses a 100 mm horizontal line (Visual Analogue Scale - VAS), for each of the 2 questions, to assess ocular discomfort and/or dryness.

Frequency of symptoms ranged from "rarely" (best outcome) to "all of the time" (worst outcome), while the severity of symptoms ranged from "very mild" (best outcome) to "very severe" (worst outcome). Patients had to place a mark on the two given lines based on the extent of their symptoms.

The locations of the marks was measured in mm from left to right and recorded as frequency and severity scores, respectively.

The SANDE lines for intensity and for severity ranged from 0, being the minimal amount of dry eye symptoms (best outcome) to 100, being the maximal amount of dry eye symptoms (worst outcome).

The total SANDE score was calculated by multiplying the frequency score by the severity score and obtaining the square root (0-100; the lower, the better).

The Schirmer test was used in ophthalmic examination to measure tear production for the diagnosis of conditions such as keratoconjunctivitis sicca and dry eye.

Without previously instilling anesthetic drops, the Schirmer strip was inserted into the lower conjunctival sac at the junction of the lateral and middle thirds, avoiding touching the cornea, and the length of wetting strips in millimeters was recorded after 5 minutes.

After 5 minutes had elapsed, the Schirmer test strip was removed and the length of the tear absorption on the strip was measured (millimeters/5 minutes).

Cutoff values:

<5 mm - pathologic dry eye 5-10 mm - marginal dry eye >10 and <30 mm - normal secretion The longer, the wetted length, the healthier the status of the eye. No units other than participants were assigned.

The Symptom Assessment in Dry Eye (SANDE) questionnaire was a short questionnaire to evaluate both dry eye intensity/severity and frequency. This questionnaire used a 100 mm horizontal line (Visual Analogue Scale - VAS) for each of the 2 questions to assess ocular discomfort and/or dryness experienced by the patients. In the SANDE questionnaire, frequency of symptoms ranges from "rarely" to "all of the time" and the severity of symptoms ranged from "very mild" to "very severe". Patients were asked to place a mark on the two given lines based on the extent of their symptoms.

The locations of the marks was measured in mm from left to right and recorded as frequency and severity scores, respectively.

The SANDE scale ranged from 0, being the minimal amount of dry eye symptoms (best outcome) to 100, being the maximal amount of dry eye symptoms (worst outcome). In this outcome severity score at week 12 was assessed.

SANDE was a short questionnaire to evaluate both dry eye intensity and frequency. It uses a 100 mm horizontal line (Visual Analogue Scale, VAS), for each of the 2 questions, to assess ocular discomfort and/or dryness.

Frequency of symptoms ranged from "rarely" (best outcome) to "all of the time" (worst outcome), while the severity of symptoms ranged from "very mild" (best outcome) to "very severe" (worst outcome). Patients had to place a mark on the two given lines based on the extent of their symptoms.

The locations of the marks was measured in mm from left to right and recorded as frequency and severity scores, respectively.

The SANDE lines for intensity and for severity ranged from 0, being the minimal amount of dry eye symptoms (best outcome) to 100, being the maximal amount of dry eye symptoms (worst outcome).

The total SANDE score was calculated by multiplying the frequency score by the severity score and obtaining the square root (0-100; the lower, the better).

IDEEL was a 57-item questionnaire that assessed the impact of dry eye symptoms on everyday life. It consisted of 3 modules:

• Dry eye Quality of Life (27 items) composed by 3 dimensions:

• Impact on Daily Activities
• Emotional Impact
• Impact on Work Scores for each dimension of this module ranged from 0 to 100, where higher scores indicated less impact on daily activities, on work and emotions.
• Treatment Satisfaction & Bother (8 items) composed by 2 dimensions:

• Satisfaction with Treatment Effectiveness
• Treatment-Related Bother / Inconvenience Scores for each dimension of this module range from 0 to 100, where higher scores indicate greater satisfaction with treatment effectiveness and less treatment-related bother.
• Symptom Bother (20 items) composed by 1 dimension:

• Dry Eye Symptom-Bother Scores for the dimension of this module ranged from 0 to 100, where higher scores indicated a greater symptom bother.

No combination of dimensions scores was done.

Tear film break-up time (TFBUT) was the time taken to appear first dry spot on cornea after a complete blinking. TFBUT measurement was an easy and fast method used to assess the stability of tear film. It was a standard diagnostic procedure in the dry eye clinics. TFBUT was measured by determining the time to tear break-up. The TFBUT was performed after instillation of 5 μL of 2% preservative-free sodium fluorescein solution into the inferior conjunctival sac of each eye. The patient was instructed to blink several times to thoroughly mix the fluorescein with the tear film.

A TFBUT greater than 15 seconds was considered normal, while a break time of less than 10 seconds was to be considered pathological. Hence, the shorter the time, the worse the outcome.

The Schirmer test was used in ophthalmic examination to measure tear production for the diagnosis of conditions such as keratoconjunctivitis sicca and dry eye.

Without previously instilling anesthetic drops, the Schirmer strip was inserted into the lower conjunctival sac at the junction of the lateral and middle thirds, avoiding touching the cornea, and the length of wetting strips in millimeters was recorded after 5 minutes.

After 5 minutes had elapsed, the Schirmer test strip was removed and the length of the tear absorption on the strip was measured (millimeters/5 minutes).

Cutoff values:

<5 mm - pathologic dry eye 5-10 mm - marginal dry eye >10 and <30 mm - normal secretion The longer, the wetted length, the healthier the status of the eye.

The NEI/Industry Workshop guidelines were used for grading the scale of corneal and conjunctival damage. The cornea was divided into five sectors (central, superior, inferior, nasal and temporal), each of which was scored on a scale of 0-3, with a maximal total corneal staining score of 15.

Both nasally and temporally, the conjunctiva was divided into a superior paralimbal area, an inferior paralimbal area, and a peripheral area with a grading scale of 0-3 and with a maximal total score of 9 for the nasal and temporal conjunctiva (overall the total score ranged from 0-18).

Briefly, grade 0 reflected normal/healthy situation, whereas grade 3 reflected a severe damage in the considered sector.

Tear film break-up time (TFBUT) was the time taken to appear first dry spot on cornea after a complete blinking. TFBUT measurement was an easy and fast method used to assess the stability of tear film. It was a standard diagnostic procedure in the dry eye clinics. TFBUT was measured by determining the time to tear break-up. The TFBUT was performed after instillation of 5 μL of 2% preservative-free sodium fluorescein solution into the inferior conjunctival sac of each eye. The patient was instructed to blink several times to thoroughly mix the fluorescein with the tear film.

A TFBUT greater than 15 seconds was considered normal, while a break time of less than 10 seconds was to be considered pathological. The shorter the time, the worse the outcome.

SANDE was a short questionnaire to evaluate both dry eye intensity and frequency. It uses a 100 mm horizontal line (Visual Analogue Scale - VAS), for each of the 2 questions, to assess ocular discomfort and/or dryness.

Frequency of symptoms ranged from "rarely" (best outcome) to "all of the time" (worst outcome), while the severity of symptoms ranged from "very mild" (best outcome) to "very severe" (worst outcome). Patients had to place a mark on the two given lines based on the extent of their symptoms.

The locations of the marks was measured in mm from left to right and recorded as frequency and severity scores, respectively.

The SANDE lines for intensity and for severity ranged from 0, being the minimal amount of dry eye symptoms (best outcome) to 100, being the maximal amount of dry eye symptoms (worst outcome).

The total SANDE score was calculated by multiplying the frequency score by the severity score and obtaining the square root (0-100; the lower, the better).

Symptoms Scores (SANDE) and/or NEI Score were punctually described in the previous outcome descriptions.

For Sande score, the scale ranges from 0 to 100 for both severity and frequency, where 0 was the best condition and 100 marked the worst condition. Hence the higher the score, the worse the outcome.

For NEI score, the maximum score (worst outcome) was 15, and the minimum (best outcome) was 0; hence the higher the score, the worse the outcome.

Please note that mean is an adjusted mean.

IDEEL was a 57-item questionnaire that assessed the impact of dry eye symptoms on everyday life. It consisted of 3 modules:

• Dry eye Quality of Life (27 items) composed by 3 dimensions:

• Impact on Daily Activities
• Emotional Impact
• Impact on Work Scores for each dimension of this module ranged from 0 to 100, where higher scores indicated less impact on daily activities, on work and emotions.
• Treatment Satisfaction & Bother (8 items) composed by 2 dimensions:

• Satisfaction with Treatment Effectiveness
• Treatment-Related Bother / Inconvenience Scores for each dimension of this module range from 0 to 100, where higher scores indicate greater satisfaction with treatment effectiveness and less treatment-related bother.
• Symptom Bother (20 items) composed by 1 dimension:

• Dry Eye Symptom-Bother. Scores for the dimension of this module ranged from 0 to 100, where higher scores indicated greater symptom bother.

No combination of dimensions scores was done.

Treatment emergent adverse events (TEAEs) were undesirable events not present prior to medical treatment, or an already present event that worsens either in intensity or frequency following the treatment.

Use of Preservative Free Artificial Tears by Study Period is calculated as: total number of drops of the preservative free artificial tears during the X period/ total number of days of the X period * 100.

The Schirmer test was used in ophthalmic examination to measure tear production for the diagnosis of conditions such as keratoconjunctivitis sicca and dry eye.

Without previously instilling anesthetic drops, the Schirmer strip was inserted into the lower conjunctival sac at the junction of the lateral and middle thirds, avoiding touching the cornea, and the length of wetting strips in millimeters was recorded after 5 minutes.

After 5 minutes had elapsed, the Schirmer test strip was removed and the length of the tear absorption on the strip was measured (millimeters/5 minutes).

Cutoff values:

<5 mm - pathologic dry eye 5-10 mm - marginal dry eye >10 and <30 mm - normal secretion The longer, the wetted length, the healthier the status of the eye.

The NEI/Industry Workshop guidelines were used for grading the scale of corneal and conjunctival damage. The cornea was divided into five sectors (central, superior, inferior, nasal and temporal), each of which was scored on a scale of 0-3, with a maximal total corneal staining score of 15.

Both nasally and temporally, the conjunctiva was divided into a superior paralimbal area, an inferior paralimbal area, and a peripheral area with a grading scale of 0-3 and with a maximal total score of 9 for the nasal and temporal conjunctiva (overall the total score ranged from 0-18).

Briefly, grade 0 reflected normal/healthy situation, whereas grade 3 reflected a severe damage in the considered sector.

Tear film break-up time (TFBUT) was the time taken to appear first dry spot on cornea after a complete blinking. TFBUT measurement was an easy and fast method used to assess the stability of tear film. It was a standard diagnostic procedure in the dry eye clinics. TFBUT was measured by determining the time to tear break-up. The TFBUT was performed after instillation of 5 μL of 2% preservative-free sodium fluorescein solution into the inferior conjunctival sac of each eye. The patient was instructed to blink several times to thoroughly mix the fluorescein with the tear film.

A TFBUT greater than 15 seconds was considered normal, while a break time of less than 10 seconds was to be considered pathological.

SANDE was a short questionnaire to evaluate both dry eye intensity and frequency. It uses a 100 mm horizontal line (Visual Analogue Scale - VAS), for each of the 2 questions, to assess ocular discomfort and/or dryness.

Frequency of symptoms ranged from "rarely" (best outcome) to "all of the time" (worst outcome), while the severity of symptoms ranged from "very mild" (best outcome) to "very severe" (worst outcome). Patients had to place a mark on the two given lines based on the extent of their symptoms.

The locations of the marks was measured in mm from left to right and recorded as frequency and severity scores, respectively.

The SANDE lines for intensity and for severity ranged from 0, being the minimal amount of dry eye symptoms (best outcome) to 100, being the maximal amount of dry eye symptoms (worst outcome).

The total SANDE score was calculated by multiplying the frequency score by the severity score and obtaining the square root (0-100; the lower, the better).

Symptoms Scores (SANDE) and/or NEI Score were punctually described in the previous outcome descriptions.

For Sande score, the scale ranges from 0 to 100 for both severity and frequency, where 0 was the best condition and 100 marked the worst condition. Hence the higher the score, the worse the outcome.

For NEI score, the maximum score (worst outcome) was 15, and the minimum (best outcome) was 0; hence the higher the score, the worse the outcome.

Schirmer Test II (with anaesthetic) measured baseline plus reflex secretion. The Schirmer strip was inserted into the lower conjunctival sac at the junction of the lateral and middle thirds, avoiding touching the cornea, and the length of wetting strips in millimeters was recorded after 5 minutes.

After 5 minutes had elapsed, the Schirmer test strip was removed and the length of the tear absorption on the strip was measured (millimeters/5 minutes).

Cutoff values:

<5 mm - pathologic dry eye 5-10 mm - marginal dry eye >10 and <30 mm - normal secretion The longer, the wetted length, the healthier the status of the eye.

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.