Dry Eye Disease With Severe Keratitis Clinical Trial
Official title:
A Phase IIIb, Prospective, Interventional, Multicentre, 3-year Study to Explore the Long-term Evolution of Sign and Symptoms, and Occurence of Complications in Dry Eye Patients With Severe Keratitis Receiving Ikervis® (1mg/mL Ciclosporin)
| Verified date | May 2022 |
| Source | Santen SAS |
| Contact | n/a |
| Is FDA regulated | No |
| Health authority | |
| Study type | Interventional |
The proposed 36-month Post Approval Efficacy Study (PAES) is a prospective, interventional, multicentre study to explore the long-term evolution of signs and symptoms, and occurrence of complications in Dry Eye Disease (DED) patients with severe keratitis receiving Ikervis® (1mg/mL ciclosporin) eye drops administered once daily
| Status | Completed |
| Enrollment | 350 |
| Est. completion date | July 14, 2023 |
| Est. primary completion date | July 14, 2023 |
| Accepts healthy volunteers | No |
| Gender | All |
| Age group | 18 Years and older |
| Eligibility | Inclusion Criteria: 1. In the opinion of the investigator, the patient is capable of understanding and complying with protocol requirements. 2. The patient has signed and dated a written informed consent form and any required privacy authorization prior to the initiation of any study procedures. 3. Male or female patient is aged 18 years or above. 4. At least 4 weeks of use of tear substitutes prior to the Baseline Visit 5. DED patients with severe keratitis defined as the following: - CFS score of 3, 4 or 5 on the modified Oxford scale in at least one eye at Baseline Visits, AND - Schirmer test without anaesthesia scored <10 mm/5min in the same eye at Baseline Visit, AND - At least two moderate to very severe symptoms of dry eye disease with a score =2 (severity graded on a 0 to 4 grade scale), among the following symptoms: burning/stinging, foreign body sensation, eye dryness, eye pain and blurred/poor vision at Baseline Visit. 6. Patient must be willing and able to undergo and return for scheduled study-related examinations. Exclusion Criteria: 1. Active herpes keratitis or history of ocular herpes. 2. History of ocular trauma or ocular infection (viral, bacterial, fungal, protozoal) within 90 days before the Baseline Visit. 3. Any ocular diseases other than DED requiring topical ocular treatment during the course of the study. Patients taking preservative-free IOP lowering medications are eligible for study enrolment. 4. Concurrent ocular allergy (including seasonal conjunctivitis) or chronic conjunctivitis other than dry eye. 5. Anticipated use of temporary punctal plugs during the study. Patients with punctal plugs placed prior to the Baseline Visit are eligible for enrolment; however, punctal plugs must remain in place during the study. 6. Best corrected distance visual acuity (BCDVA) score = 20/200 Snellen in each eye. 7. Presence or history of any systemic or ocular disorder, condition or disease that could possibly interfere with the conduct of the required study procedures or the interpretation of study results or judged by the investigator to be incompatible with the study (e.g., diabetes with glycemia out of range, thyroid malfunction, uncontrolled autoimmune disease, current systemic infections, ocular infection…). 8. Known hypersensitivity to one of the components of the study or procedural medications (e.g., fluorescein, etc.). 9. History of ophthalmic malignancy 10. History of malignancy (other than ophthalmic) in the last 5 years. 11. Anticipated change during course of the study in the dose of systemic medications that could affect a dry eye condition [mainly, estrogen-progesterone or other estrogen derivatives (only allowed for post-menopausal women), pilocarpine, isotretinoine, tetracycline, antihistamines, tricyclic antidepressants, anxiolytics, antimuscarinics, beta-blocking agents, phenothiazines, omega-3, systemic corticosteroids]. These treatments are allowed during the study provided they remain stable throughout the course of the study. 12. Use of topical ciclosporin in the past 3 months prior to Baseline visit. 13. Any change in systemic immunosuppressant drugs within 30 days before the Baseline Visit or anticipated change during the course of the study. 14. Pregnancy or lactation at the Baseline Visit. 15. Women of childbearing potential not using a medically acceptable, highly effective method of birth control (such as hormonal implants, injectable or oral contraceptives together with condoms, some intrauterine devices, sexual abstinence or vasectomised partner) from the Baseline Visit throughout the conduct of the study treatment periods and up to 2 weeks after the study end. Post-menopausal women (two years without menstruation) do not need to use any method of birth control. 16. Participation in a clinical trial with an investigational substance within the past 30 days prior to Baseline Visit. 17. Participation in another clinical study at the same time as the present study. |
| Country | Name | City | State |
|---|---|---|---|
| Czechia | Fakultní Nemocnice Brno | Brno | Jihomoravský |
| Czechia | University Hospital Hradec Kralove | Hradec Králové | Nový Hradec Králové |
| Czechia | Fakultni Nemocnice Ostrava, Ocní Klinika | Ostrava | Moravskoslezský |
| Czechia | Ocni klinika OFTEX | Pardubice | Pardubický |
| Czechia | Axon clinical s.r.o. | Prague | Praha |
| Czechia | MEDOKO s.r.o. | Prague | Praha |
| Czechia | Nemocnice Teplice, Ocni Oddeleni | Teplice | Ústecký |
| Czechia | Masarykova nemocnice, Ocni oddeleni | Ústí Nad Labem | Ustecky |
| France | Hopitaux Universitaires Paris-Sud - Hopital Bicetre | Le Kremlin-Bicêtre | Île-de-France |
| France | Hospices Civils de Lyon - Hopital de la Croix-Rousse | Lyon | Rhône-Alpes |
| France | Hôpital des Quinze-Vingts | Paris | Île-de-France |
| France | Hopitaux Universitaires Paris Nord Val de Seine - Hopital Bichat - Claude Bernard | Paris | Île-de-France |
| Italy | Azienda Ospedaliera Universitaria Policlinico Gaetano Martino - Messina | Messina | Sicilia |
| Italy | ASST Santi Paolo e Carlo - Ospedale San Paolo Polo Universitario - Clinica Oculistica III | Milan | Lombardia |
| Italy | Polo Universita degli Studi di Milano - Ospedale Luigi Sacco - Clinica Oculistica (Eye Clinic) | Milan | Lombardia |
| Italy | Universita degli Studi di Milano - Clinica Oculistica I | Milan | Lombardia |
| Italy | Universita degli Studi di Milano - Ospedale San Giuseppe - Clinica Oculistica (University Eye Clinic) | Milan | Lombardia |
| Italy | Universita degli Studi di Padova - Azienda Ospedaliera di Padova - Clinica Oculistica | Padova | Veneto |
| Italy | Universita degli Studi di Pavia - Fondazione IRCCS Policlinico San Matteo - Clinica Oculistic | Pavia | Lombardia |
| Poland | Gabinet Okulistyczny Prof. Edward Wylegala | Katowice | Silesia |
| Poland | Uniwersyteckie Centrum Kliniczne Slaskiego Uniwersytetu Medycznego w Katowicach | Katowice | Silesia |
| Poland | Niepubliczny Zaklad Opieki Zdrowotnej Oko-Laser | Kraków | Malopolskie |
| Poland | Samodzielny Publiczny Szpital Kliniczny Nr 1 Klinika Diagnostyki i Mikrochirurgii Jaskry Oddzial Okulistyki | Lublin | Lubelskie |
| Poland | Retina Szpital Okulistyczny | Warszawa | Warszawskie |
| Poland | Uniwersytecki Szpital Kiliniczny IM. Jana Milkulicza-Radeckiego we Wroclawiu | Wroclaw | Wroclawiu |
| Russian Federation | Federal State Institution Intersectoral Research and Technology Complex Eye microsurgery n.a. academician S.N. Fyodorov - Cheboksary | Cheboksary | Chuvashia |
| Russian Federation | Ivanovo Regional Clinical Hospital | Ivanov | Ivanovo |
| Russian Federation | NMRC ISTC Eye Microsurgery n. a. Fyodorov - Moscow | Moscow | Moskva |
| Russian Federation | State Budget Educational Institution of High Professional Education Moscow State Medical Stomatology University named after A.I.Evdokimov of MoH of RF | Moskow | Moskva |
| Russian Federation | FSBI The Academician S.N. Fyodorov IRTC Eye Microsurgery of the Minzdrava - Novosibirsk | Novosibirsk | |
| Russian Federation | GBOU VPO Omsk State Medical Academy, Ophthalmology Department | Omsk | |
| Russian Federation | First Saint Petersburg State Medical University named after academician I.P. Pavlov | Saint Petersburg | Sankt-Peterburg |
| Russian Federation | Saint Petersburg State Pediatric Medical University | Saint Petersburg | Sankt-Peterburg |
| Russian Federation | Saratov Railway Clinic | Saratov | |
| Spain | Centro de Oftalmología Barraquer | Barcelona | Catalunya |
| Spain | Hospital Clinic de Barcelona (Hospital Clinic i Provincial) | Barcelona | Catalunya |
| Spain | Institut Catala de Retina | Barcelona | Catalunya |
| Spain | Hospital Universitario Donostia, Oftalmalogia | San Sebastián | Euskal Autonomia Erkidegoa |
| Spain | Cartujavision Oftalmologia | Sevilla | Andalucia |
| Spain | Fundación Oftalmológica del Mediterráneo | Valencia | |
| Spain | Hospital Clinico Universitario Lozano Blesa de Zaragoza | Zaragosa | Aragon |
| Turkey | Bayindir Kavaklidere Hospital Ophthalmology department | Ankara | Anatolia |
| Turkey | Ege Universitesi Tip Fakultesi Hastanesi Goz Hastaliklari Anabilim Dali | Bornova | Izmir |
| Turkey | Selcuk University School of Medicine Ophthalmology department | Konya | Selcuklu |
| Turkey | Ankara Üniversitesi Tip Fakültesi Göz Hastaliklari Anabilim Dali Vehbi Koç Göz Hastanesi | Mamak | Ankara |
| Lead Sponsor | Collaborator |
|---|---|
| Santen SAS |
Czechia, France, Italy, Poland, Russian Federation, Spain, Turkey,
| Type | Measure | Description | Time frame | Safety issue |
|---|---|---|---|---|
| Primary | The correlation between mean change from baseline in CFS score and SANDE symptoms score at each visit. | CFS is corneal Fluorescein Staining, SANDE is Symptom Assessment iN Dry Eye | 36 months | |
| Primary | The cross correlation of sign at visit X versus symptoms at visit X+i (i starting from 0), if any. | 36 months | ||
| Primary | The incident rate of ocular surface complications | Ocular surface complications are defined as corneal ulceration, corneal perforation, loss of visual acuity and ocular infection | 36 months | |
| Primary | The time to onset of ocular surface complications | Ocular surface complications are defined as corneal ulceration, corneal perforation, loss of visual acuity and ocular infection | 36 months | |
| Secondary | 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. |
12 months (Period 1) | |
| Secondary | 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. |
12 months (Period 1) | |
| Secondary | 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. |
12 months (Period 1) | |
| Secondary | 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. |
12 months (Period 1) | |
| Secondary | 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. |
12 months (Period 1) | |
| Secondary | 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. |
12 months (Period 1) | |
| Secondary | 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. |
12 months (Period 1) | |
| Secondary | 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. |
12 months (Period 1) | |
| Secondary | 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. | 12 months (Period 1) | |
| Secondary | 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. | 12 months (Period 1) | |
| Secondary | 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. |
12 months (Period 1) | |
| Secondary | 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. |
12 months (Period 1) | |
| Secondary | 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. |
visit Month 12 | |
| Secondary | 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. |
visit Month 12 | |
| Secondary | 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. | 12 months (Period 1) | |
| Secondary | 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. | 12 months (Period 1) | |
| Secondary | 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. |
24 months (Period 2) | |
| Secondary | 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. |
24 months (Period 2) | |
| Secondary | 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. |
24 months (Period 2) | |
| Secondary | 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. |
24 months (Period 2) | |
| Secondary | 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. |
24 months (Period 2) | |
| Secondary | 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. |
24 months (Period 2) | |
| Secondary | 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. |
24 months (Period 2) | |
| Secondary | 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. |
24 months (Period 2) | |
| Secondary | 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. |
24 months (Period 2) | |
| Secondary | 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. |
24 months (Period 2) | |
| Secondary | 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. |
Month 24 and Month 36 visits | |
| Secondary | 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. |
Month 24 and Month 36 visits | |
| Secondary | 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. | 24 months (Period 2) | |
| Secondary | 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. | 24 months (Period 2) | |
| Secondary | 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 | 24 months (Period 2) | |
| Secondary | 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 | 24 months (Period 2) | |
| Secondary | 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. |
36 months (Periods 1 + 2) | |
| Secondary | 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. |
36 months (Periods 1 + 2) | |
| Secondary | 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. |
36 months (Periods 1 + 2) | |
| Secondary | 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. |
36 months (Periods 1 + 2) | |
| Secondary | 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. |
36 months (Periods 1 + 2) | |
| Secondary | 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. |
36 months (Periods 1 + 2) | |
| Secondary | 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. |
36 months (Periods 1 + 2) | |
| Secondary | 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. |
36 months (Periods 1 + 2) | |
| Secondary | 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. |
36 months (Periods 1 + 2) | |
| Secondary | 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. |
36 months (Periods 1 + 2) | |
| Secondary | 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. |
Month 12, Month 24 and Month 36 visits | |
| Secondary | 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. |
Month 12, Month 24 and Month 36 visits | |
| Secondary | 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. | 36 months (Periods 1 + 2) | |
| Secondary | 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. | 36 months (Periods 1 + 2) | |
| Secondary | 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. | Month 6, Month 12, Month 18, Month 24, Month 30 and Month 36 Visits. | |
| Secondary | 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. | Month 6, Month 12, Month 18, Month 24, Month 30 and Month 36 Visits | |
| Secondary | Safety and Tolerability Outcome: IOP at Month 12, Month 24 and Month 36 visits | IOP is Intraocular pressure | Month 12, Month 24 and Month 36 visits | |
| Secondary | Safety and Tolerability Outcome: Change from Baseline in IOP at Month 12, Month 24 and Month 36 visits | IOP is Intraocular pressure | Month 12, Month 24 and Month 36 visits | |
| Secondary | 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. | Month 6, Month 12, Month 24 and Month 36 visits | |
| Secondary | 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. | Month 6, Month 12, Month 24 and Month 36 visits | |
| Secondary | Safety and Tolerability Outcome: Incidence of ocular and systemic AEs over the three-year study period. | AE is Adverse Event | 36 months (Periods 1 + 2) | |
| Secondary | Safety and Tolerability Outcome: Severity of ocular and systemic AEs over the three-year study period. | AE is Adverse Event | 36 months (Periods 1 + 2) |