Efficacy Secondary Outcome Measures in Period 1: CFS score at each visit in Period 1
Period 1 is Baseline to Month 12 included. CFS is Corneal Fluorescein Score. Staining using fluorescein (provided by the Sponsor) will be graded using the modified Oxford scale (7-point ordinal scale, score 0, 0.5, and 1 to 5 per area [cornea + nasal and temporal conjunctiva]) for cornea and conjunctiva separately. On this modified scale, the score 0 corresponds to no staining dots and the score 0.5 corresponds to one staining dot per area.
A CFS grade of 0 represents complete corneal clearing.
Efficacy Secondary Outcome Measures in Period 1: Change from baseline in CFS score at each visit in Period 1
Period 1 is Baseline to Month 12 included. CFS is Corneal Fluorescein Score. Staining using fluorescein (provided by the Sponsor) will be graded using the modified Oxford scale (7-point ordinal scale, score 0, 0.5, and 1 to 5 per area [cornea + nasal and temporal conjunctiva]) for cornea and conjunctiva separately. On this modified scale, the score 0 corresponds to no staining dots and the score 0.5 corresponds to one staining dot per area.
A CFS grade of 0 represents complete corneal clearing.
Efficacy Secondary Outcome Measures in Period 1: Conjunctival fluorescein staining score at each visit in Period 1
Period 1 is Baseline to Month 12 included. Staining using fluorescein (provided by the Sponsor) will be graded using the modified Oxford scale (7-point ordinal scale, score 0, 0.5, and 1 to 5 per area [cornea + nasal and temporal conjunctiva]) for cornea and conjunctiva separately. On this modified scale, the score 0 corresponds to no staining dots and the score 0.5 corresponds to one staining dot per area.
A CFS grade of 0 represents complete corneal clearing.
Efficacy Secondary Outcome Measures in Period 1: Change from Baseline in Conjunctival fluorescein staining score at each visit in Period 1
Period 1 is Baseline to Month 12 included. Staining using fluorescein (provided by the Sponsor) will be graded using the modified Oxford scale (7-point ordinal scale, score 0, 0.5, and 1 to 5 per area [cornea + nasal and temporal conjunctiva]) for cornea and conjunctiva separately. On this modified scale, the score 0 corresponds to no staining dots and the score 0.5 corresponds to one staining dot per area.
A CFS grade of 0 represents complete corneal clearing.
Efficacy Secondary Outcome Measures in Period 1: SANDE symptoms score at each visit in Period 1
Period 1 is Baseline to Month 12 included. SANDE is Symptom Assessment iN Dry Eye. The self-administered Symptom Assessment iN Dry Eye (SANDE) questionnaire must be completed by the patient him/herself.
SANDE questionnaire will be used to score both severity and frequency of dry eye symptoms. This 2-item frequency- and severity-based visual analogue scales (0-100mm ranging respectively from" rarely" to "all the time", and from "very mild" to "very severe") is short and quick, and provides reliable measure for Dry Eye Disease symptoms assessment. Symptoms will be evaluated for both eyes together.
A negative change from baseline (Period 1) or from Month 12 (Period 2) will indicate an improvement in dry eye disease symptoms.
Efficacy Secondary Outcome Measures in Period 1: Change from Baseline in SANDE symptoms score at each visit in Period 1
Period 1 is Baseline to Month 12 included. SANDE is Symptom Assessment iN Dry Eye. The self-administered Symptom Assessment iN Dry Eye (SANDE) questionnaire must be completed by the patient him/herself.
SANDE questionnaire will be used to score both severity and frequency of dry eye symptoms. This 2-item frequency- and severity-based visual analogue scales (0-100mm ranging respectively from" rarely" to "all the time", and from "very mild" to "very severe") is short and quick, and provides reliable measure for Dry Eye Disease symptoms assessment. Symptoms will be evaluated for both eyes together.
A negative change from baseline (Period 1) or from Month 12 (Period 2) will indicate an improvement in dry eye disease symptoms.
Efficacy Secondary Outcome Measures in Period 1: Symptoms score (5-point scale) at each visit, for each of the five symptoms assessed in Period 1
Period 1 is Baseline to Month 12 included.The 5-point Likert scales are a self-administered questionnaire and must be completed by the patient him/herself.
Burning/stinging, foreign body sensation, eye dryness, photophobia, pain and blurred/poor vision, will be assessed by the study patients using a 5-point Likert scale from none to very severe (0 to 4). Symptoms will be evaluated for both eyes together.
Efficacy Secondary Outcome Measures in Period 1: Change from Baseline in Symptoms score (5-point scale) at each visit, for each of the five symptoms assessed in Period 1
Period 1 is Baseline to Month 12 included. The 5-point Likert scales are a self-administered questionnaire and must be completed by the patient him/herself.
Burning/stinging, foreign body sensation, eye dryness, photophobia, pain and blurred/poor vision, will be assessed by the study patients using a 5-point Likert scale from none to very severe (0 to 4). Symptoms will be evaluated for both eyes together.
Efficacy Secondary Outcome Measures in Period 1: Occurrence of markedly improved in Period 1
Period 1 is Baseline to Month 12 included. Markedly improved is defined as CFS score improvement of 2 grades or more on the modified Oxford scale at Month 12.
Efficacy Secondary Outcome Measures in Period 1: time to become markedly improved in Period 1
Period 1 is Baseline to Month 12 included. Markedly improved is defined as CFS score improvement of 2 grades or more on the modified Oxford scale at Month 12.
Efficacy Secondary Outcome Measures in Period 1: TBUT at each visit in Period 1
Period 1 is Baseline to Month 12 included. TBUT is Tear Breakup Time. Tear break-up time (TBUT) will be measured by determining the time to tear break-up. The examiner will monitor the integrity of the tear film, noting the time it takes to form lacunae (clear spaces in the tear film) from the time that the eye is opened after the last blink.
A higher value means longer time to tear break-up which is better. A positive change from baseline (Period 1) or from Month 12 (Period 2) will indicate improvement.
Efficacy Secondary Outcome Measures in Period 1: Change from Baseline in TBUT at each visit in Period 1
Period 1 is Baseline to Month 12 included. TBUT is Tear Breakup Time. Tear break-up time (TBUT) will be measured by determining the time to tear break-up. The examiner will monitor the integrity of the tear film, noting the time it takes to form lacunae (clear spaces in the tear film) from the time that the eye is opened after the last blink.
A higher value means longer time to tear break-up which is better. A positive change from baseline (Period 1) or from Month 12 (Period 2) will indicate improvement.
Efficacy Secondary Outcome Measures in Period 1: Schirmer test at Month 12 visit
The rounded bent end of a sterile strip will be inserted into the lower conjunctival sac over the temporal one-third of the lower eyelid margin. After 5 minutes have elapsed the Schirmer test strip will be removed and the length of the tear absorption on the strip will be measured.
A higher value means higher tear absorption which is better. A positive change from baseline (Period 1) or from Month 12 (Period 2) will indicate improvement.
Efficacy Secondary Outcome Measures in Period 1: Change from Baseline in Schirmer test at Month 12 visit
The rounded bent end of a sterile strip will be inserted into the lower conjunctival sac over the temporal one-third of the lower eyelid margin. After 5 minutes have elapsed the Schirmer test strip will be removed and the length of the tear absorption on the strip will be measured.
A higher value means higher tear absorption which is better. A positive change from baseline (Period 1) or from Month 12 (Period 2) will indicate improvement.
Efficacy Secondary Outcome Measures in Period 1: Use of Artificial Tears over the last week at each visit in Period 1
Period 1 is Baseline to Month 12 included. The use of artificial tears will be monitored over the course of the study for each patient. Patients will be asked about the average number of times per day artificial tears was used over the last week, and number of days they were not used during the week preceding the visits.
Efficacy Secondary Outcome Measures in Period 1: Change from Baseline in Use of Artificial Tears over the last week at each visit in Period 1
Period 1 is Baseline to Month 12 included. The use of artificial tears will be monitored over the course of the study for each patient. Patients will be asked about the average number of times per day artificial tears was used over the last week, and number of days they were not used during the week preceding the visits.
Efficacy Secondary Outcome Measures in Period 2: CFS score at each visit in Period 2
Period 2 is Month 12 excluded to Month 36 included. CFS is Corneal Fluorescein Score. Staining using fluorescein (provided by the Sponsor) will be graded using the modified Oxford scale (7-point ordinal scale, score 0, 0.5, and 1 to 5 per area [cornea + nasal and temporal conjunctiva]) for cornea and conjunctiva separately. On this modified scale, the score 0 corresponds to no staining dots and the score 0.5 corresponds to one staining dot per area.
A CFS grade of 0 represents complete corneal clearing.
Efficacy Secondary Outcome Measures in Period 2: Change from Month 12 visit in CFS score at each visit in Period 2
Period 2 is Month 12 excluded to Month 36 included. CFS is Corneal Fluorescein Score. Staining using fluorescein (provided by the Sponsor) will be graded using the modified Oxford scale (7-point ordinal scale, score 0, 0.5, and 1 to 5 per area [cornea + nasal and temporal conjunctiva]) for cornea and conjunctiva separately. On this modified scale, the score 0 corresponds to no staining dots and the score 0.5 corresponds to one staining dot per area.
A CFS grade of 0 represents complete corneal clearing.
Efficacy Secondary Outcome Measures in Period 2: Conjunctival fluorescein staining score at each visit in Period 2
Period 2 is Month 12 excluded to Month 36 included. Staining using fluorescein (provided by the Sponsor) will be graded using the modified Oxford scale (7-point ordinal scale, score 0, 0.5, and 1 to 5 per area [cornea + nasal and temporal conjunctiva]) for cornea and conjunctiva separately. On this modified scale, the score 0 corresponds to no staining dots and the score 0.5 corresponds to one staining dot per area.
A CFS grade of 0 represents complete corneal clearing.
Efficacy Secondary Outcome Measures in Period 2: Change from Month 12 visit in Conjunctival fluorescein staining score at each visit in Period 2
Period 2 is Month 12 excluded to Month 36 included. Staining using fluorescein (provided by the Sponsor) will be graded using the modified Oxford scale (7-point ordinal scale, score 0, 0.5, and 1 to 5 per area [cornea + nasal and temporal conjunctiva]) for cornea and conjunctiva separately. On this modified scale, the score 0 corresponds to no staining dots and the score 0.5 corresponds to one staining dot per area.
A CFS grade of 0 represents complete corneal clearing.
Efficacy Secondary Outcome Measures in Period 2: SANDE symptoms score at each visit in Period 2
Period 2 is Month 12 excluded to Month 36 included. SANDE is Symptom Assessment iN Dry Eye. The self-administered Symptom Assessment iN Dry Eye (SANDE) questionnaire must be completed by the patient him/herself.
SANDE questionnaire will be used to score both severity and frequency of dry eye symptoms. This 2-item frequency- and severity-based visual analogue scales (0-100mm ranging respectively from" rarely" to "all the time", and from "very mild" to "very severe") is short and quick, and provides reliable measure for Dry Eye Disease symptoms assessment. Symptoms will be evaluated for both eyes together.
A negative change from baseline (Period 1) or from Month 12 (Period 2) will indicate an improvement in dry eye disease symptoms.
Efficacy Secondary Outcome Measures in Period 2: Change from Month 12 visit in SANDE symptoms score at each visit in Period 2
Period 2 is Month 12 excluded to Month 36 included. SANDE is Symptom Assessment iN Dry Eye. The self-administered Symptom Assessment iN Dry Eye (SANDE) questionnaire must be completed by the patient him/herself.
SANDE questionnaire will be used to score both severity and frequency of dry eye symptoms. This 2-item frequency- and severity-based visual analogue scales (0-100mm ranging respectively from" rarely" to "all the time", and from "very mild" to "very severe") is short and quick, and provides reliable measure for Dry Eye Disease symptoms assessment. Symptoms will be evaluated for both eyes together.
A negative change from baseline (Period 1) or from Month 12 (Period 2) will indicate an improvement in dry eye disease symptoms.
Efficacy Secondary Outcome Measures in Period 2: Symptoms score (5-point scale) at each visit, for each of the five symptoms assessed in Period 2
Period 2 is Month 12 excluded to Month 36 included. The 5-point Likert scales are a self-administered questionnaire and must be completed by the patient him/herself.
Burning/stinging, foreign body sensation, eye dryness, photophobia, pain and blurred/poor vision, will be assessed by the study patients using a 5-point Likert scale from none to very severe (0 to 4). Symptoms will be evaluated for both eyes together.
Efficacy Secondary Outcome Measures in Period 2: Change from Month 12 visit in Symptoms score (5-point scale) at each visit, for each of the five symptoms assessed in Period 2
Period 2 is Month 12 excluded to Month 36 included. The 5-point Likert scales are a self-administered questionnaire and must be completed by the patient him/herself.
Burning/stinging, foreign body sensation, eye dryness, photophobia, pain and blurred/poor vision, will be assessed by the study patients using a 5-point Likert scale from none to very severe (0 to 4). Symptoms will be evaluated for both eyes together.
Efficacy Secondary Outcome Measures in Period 2: TBUT at each visit in Period 2
Period 2 is Month 12 excluded to Month 36 included. TBUT is Tear Breakup Time. Tear break-up time (TBUT) will be measured by determining the time to tear break-up. The examiner will monitor the integrity of the tear film, noting the time it takes to form lacunae (clear spaces in the tear film) from the time that the eye is opened after the last blink.
A higher value means longer time to tear break-up which is better. A positive change from baseline (Period 1) or from Month 12 (Period 2) will indicate improvement.
Efficacy Secondary Outcome Measures in Period 2: Change from Month 12 visit in TBUT at each visit in Period 2
Period 2 is Month 12 excluded to Month 36 included. TBUT is Tear Breakup Time. Tear break-up time (TBUT) will be measured by determining the time to tear break-up. The examiner will monitor the integrity of the tear film, noting the time it takes to form lacunae (clear spaces in the tear film) from the time that the eye is opened after the last blink.
A higher value means longer time to tear break-up which is better. A positive change from baseline (Period 1) or from Month 12 (Period 2) will indicate improvement.
Efficacy Secondary Outcome Measures in Period 2: Schirmer test at Month 24 and Month 36 visits
The rounded bent end of a sterile strip will be inserted into the lower conjunctival sac over the temporal one-third of the lower eyelid margin. After 5 minutes have elapsed the Schirmer test strip will be removed and the length of the tear absorption on the strip will be measured.
A higher value means higher tear absorption which is better. A positive change from baseline (Period 1) or from Month 12 (Period 2) will indicate improvement.
Efficacy Secondary Outcome Measures in Period 2: Change from Month 12 visit in Schirmer test at Month 24 and Month 36 visits
The rounded bent end of a sterile strip will be inserted into the lower conjunctival sac over the temporal one-third of the lower eyelid margin. After 5 minutes have elapsed the Schirmer test strip will be removed and the length of the tear absorption on the strip will be measured.
A higher value means higher tear absorption which is better. A positive change from baseline (Period 1) or from Month 12 (Period 2) will indicate improvement.
Efficacy Secondary Outcome Measures in Period 2: Use of Artificial Tears over the last week, at each visit in Period 2
Period 2 is Month 12 excluded to Month 36 included. The use of artificial tears will be monitored over the course of the study for each patient. Patients will be asked about the average number of times per day artificial tears was used over the last week, and number of days they were not used during the week preceding the visits.
Efficacy Secondary Outcome Measures in Period 2: Change from Month 12 visit in Use of Artificial Tears over the last week, at each visit in Period 2
Period 2 is Month 12 excluded to Month 36 included. The use of artificial tears will be monitored over the course of the study for each patient. Patients will be asked about the average number of times per day artificial tears was used over the last week, and number of days they were not used during the week preceding the visits.
Efficacy Secondary Outcome Measures in Period 2: Occurrence of relapse in Period 2
Period 2 is Month 12 excluded to Month 36 included. Relapse is defined as an increase of CFS score of 2 or more on the modified Oxford scale
Efficacy Secondary Outcome Measures in Period 2: time to relapse in Period 2
Period 2 is Month 12 excluded to Month 36 included. Relapse is defined as an increase of CFS score of 2 or more on the modified Oxford scale
Efficacy Secondary Outcome Measures in Entire study: CFS score at each visit in Entire study
CFS is Corneal Fluorescein Score. Staining using fluorescein (provided by the Sponsor) will be graded using the modified Oxford scale (7-point ordinal scale, score 0, 0.5, and 1 to 5 per area [cornea + nasal and temporal conjunctiva]) for cornea and conjunctiva separately. On this modified scale, the score 0 corresponds to no staining dots and the score 0.5 corresponds to one staining dot per area.
A CFS grade of 0 represents complete corneal clearing.
Efficacy Secondary Outcome Measures in Entire study: Change from baseline in CFS score at each visit in Entire study
CFS is Corneal Fluorescein Score. Staining using fluorescein (provided by the Sponsor) will be graded using the modified Oxford scale (7-point ordinal scale, score 0, 0.5, and 1 to 5 per area [cornea + nasal and temporal conjunctiva]) for cornea and conjunctiva separately. On this modified scale, the score 0 corresponds to no staining dots and the score 0.5 corresponds to one staining dot per area.
A CFS grade of 0 represents complete corneal clearing.
Efficacy Secondary Outcome Measures in Entire study: Conjunctival fluorescein staining score at each visit in Entire study
Staining using fluorescein (provided by the Sponsor) will be graded using the modified Oxford scale (7-point ordinal scale, score 0, 0.5, and 1 to 5 per area [cornea + nasal and temporal conjunctiva]) for cornea and conjunctiva separately. On this modified scale, the score 0 corresponds to no staining dots and the score 0.5 corresponds to one staining dot per area.
A CFS grade of 0 represents complete corneal clearing.
Efficacy Secondary Outcome Measures in Entire study: Change from Baseline in Conjunctival fluorescein staining score at each visit in Entire study
Staining using fluorescein (provided by the Sponsor) will be graded using the modified Oxford scale (7-point ordinal scale, score 0, 0.5, and 1 to 5 per area [cornea + nasal and temporal conjunctiva]) for cornea and conjunctiva separately. On this modified scale, the score 0 corresponds to no staining dots and the score 0.5 corresponds to one staining dot per area.
A CFS grade of 0 represents complete corneal clearing.
Efficacy Secondary Outcome Measures in Entire study: SANDE symptoms score at each visit in Entire study
SANDE is Symptom Assessment iN Dry Eye. The self-administered Symptom Assessment iN Dry Eye (SANDE) questionnaire must be completed by the patient him/herself.
SANDE questionnaire will be used to score both severity and frequency of dry eye symptoms. This 2-item frequency- and severity-based visual analogue scales (0-100mm ranging respectively from" rarely" to "all the time", and from "very mild" to "very severe") is short and quick, and provides reliable measure for Dry Eye Disease symptoms assessment. Symptoms will be evaluated for both eyes together.
A negative change from baseline (Period 1) or from Month 12 (Period 2) will indicate an improvement in dry eye disease symptoms.
Efficacy Secondary Outcome Measures in Entire study: Change from Baseline in SANDE symptoms score at each visit in Entire study
SANDE is Symptom Assessment iN Dry Eye. The self-administered Symptom Assessment iN Dry Eye (SANDE) questionnaire must be completed by the patient him/herself.
SANDE questionnaire will be used to score both severity and frequency of dry eye symptoms. This 2-item frequency- and severity-based visual analogue scales (0-100mm ranging respectively from" rarely" to "all the time", and from "very mild" to "very severe") is short and quick, and provides reliable measure for Dry Eye Disease symptoms assessment. Symptoms will be evaluated for both eyes together.
A negative change from baseline (Period 1) or from Month 12 (Period 2) will indicate an improvement in dry eye disease symptoms.
Efficacy Secondary Outcome Measures in Entire study: Symptoms score (5-point scale) at each visit, for each of the five symptoms assessed in Entire study
The 5-point Likert scales are a self-administered questionnaire and must be completed by the patient him/herself.
Burning/stinging, foreign body sensation, eye dryness, photophobia, pain and blurred/poor vision, will be assessed by the study patients using a 5-point Likert scale from none to very severe (0 to 4). Symptoms will be evaluated for both eyes together.
Efficacy Secondary Outcome Measures in Entire study: Change from Baseline in Symptoms score (5-point scale) at each visit, for each of the five symptoms assessed in Entire study
The 5-point Likert scales are a self-administered questionnaire and must be completed by the patient him/herself.
Burning/stinging, foreign body sensation, eye dryness, photophobia, pain and blurred/poor vision, will be assessed by the study patients using a 5-point Likert scale from none to very severe (0 to 4). Symptoms will be evaluated for both eyes together.
Efficacy Secondary Outcome Measures in Entire study: TBUT at each visit in Entire study
TBUT is Tear Breakup Time. Tear break-up time (TBUT) will be measured by determining the time to tear break-up. The examiner will monitor the integrity of the tear film, noting the time it takes to form lacunae (clear spaces in the tear film) from the time that the eye is opened after the last blink.
A higher value means longer time to tear break-up which is better. A positive change from baseline (Period 1) or from Month 12 (Period 2) will indicate improvement.
Efficacy Secondary Outcome Measures in Entire study: Change from Baseline in TBUT at each visit in Entire study
TBUT is Tear Breakup Time. Tear break-up time (TBUT) will be measured by determining the time to tear break-up. The examiner will monitor the integrity of the tear film, noting the time it takes to form lacunae (clear spaces in the tear film) from the time that the eye is opened after the last blink.
A higher value means longer time to tear break-up which is better. A positive change from baseline (Period 1) or from Month 12 (Period 2) will indicate improvement.
Efficacy Secondary Outcome Measures in Entire study: Schirmer test at Month 12, Month 24 and Month 36 visits
The rounded bent end of a sterile strip will be inserted into the lower conjunctival sac over the temporal one-third of the lower eyelid margin. After 5 minutes have elapsed the Schirmer test strip will be removed and the length of the tear absorption on the strip will be measured.
A higher value means higher tear absorption which is better. A positive change from baseline (Period 1) or from Month 12 (Period 2) will indicate improvement.
Efficacy Secondary Outcome Measures in Entire study: Change from Baseline in Schirmer test at Month 12, Month 24 and Month 36 visits
The rounded bent end of a sterile strip will be inserted into the lower conjunctival sac over the temporal one-third of the lower eyelid margin. After 5 minutes have elapsed the Schirmer test strip will be removed and the length of the tear absorption on the strip will be measured.
A higher value means higher tear absorption which is better. A positive change from baseline (Period 1) or from Month 12 (Period 2) will indicate improvement.
Efficacy Secondary Outcome Measures in Entire study: Use of Artificial Tears over the last week at each visit in Entire study
The use of artificial tears will be monitored over the course of the study for each patient. Patients will be asked about the average number of times per day artificial tears was used over the last week, and number of days they were not used during the week preceding the visits.
Efficacy Secondary Outcome Measures in Entire study: Change from Baseline in Use of Artificial Tears over the last week at each visit in Entire study
The use of artificial tears will be monitored over the course of the study for each patient. Patients will be asked about the average number of times per day artificial tears was used over the last week, and number of days they were not used during the week preceding the visits.
Quality of Life Outcome: DEQS overall score at Month 6, Month 12, Month 18, Month 24, Month 30 and Month 36 Visits.
DEQS is Dry Eye related Quality of life Score. The DEQS consists of 15 items related to dry eye symptoms and influence on daily life, and the overall degree of Quality of Life impairment is calculated as a summary score (0 to 100), lower score meaning better.
Quality of Life Outcome: Change from Baseline in DEQS at Month 6, Month 12, Month 18, Month 24, Month 30 and Month 36 Visits. Change from Month 12 will also be summarized for scores collected in Period 2.
DEQS is Dry Eye related Quality of life Score. The DEQS consists of 15 items related to dry eye symptoms and influence on daily life, and the overall degree of Quality of Life impairment is calculated as a summary score (0 to 100), lower score meaning better.
Safety and Tolerability Outcome: IOP at Month 12, Month 24 and Month 36 visits
IOP is Intraocular pressure
Safety and Tolerability Outcome: Change from Baseline in IOP at Month 12, Month 24 and Month 36 visits
IOP is Intraocular pressure
Safety and Tolerability Outcome: BCDVA at Month 6, Month 12, Month 24 and Month 36 visits
BCDVA is Best Corrected Distance Visual Acuity. Lowest visual acuity corresponds to Snellen value 20/200, while best visual acuity corresponds to Snellen value 20/20 or higher.
Safety and Tolerability Outcome: Change from Baseline in BCDVA at Month 6, Month 12, Month 24 and Month 36 visits
BCDVA is Best Corrected Distance Visual Acuity. Lowest visual acuity corresponds to Snellen value 20/200, while best visual acuity corresponds to Snellen value 20/20 or higher.
Safety and Tolerability Outcome: Incidence of ocular and systemic AEs over the three-year study period.
AE is Adverse Event
Safety and Tolerability Outcome: Severity of ocular and systemic AEs over the three-year study period.
AE is Adverse Event