Dry Eye Disease With Severe Keratitis
Conditions
Brief summary
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
Interventions
DRUGOpen-label Ikervis
NOVA22007, IKERVIS® is a sterile, ophthalmic cationic oil-in-water emulsion containing 1mg/ml CsA.
DRUGMasked Ikervis
NOVA22007, IKERVIS® is a sterile, ophthalmic cationic oil-in-water emulsion containing 1mg/ml CsA.
OTHERVehicle Comparator: Masked Vehicle
Vehicle of IKERVIS® - sterile, ophthalmic cationic oil-in-water emulsion containing no active substance.
Sponsors
Santen SAS
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Intervention model description
In order to assess the response to IKERVIS® for DED patients with severe keratitis, after 12-month IKERVIS® (once daily) treatment, patients who have shown a marked improvement at Month 12 (as defined below) will be randomised to receive IKERVIS® or Vehicle (ration 3:2) in double-masked fashion.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Correlation Between Mean Change From Baseline in Corneal Fluorescein Staining (CFS) Score and Symptom Assessment iN Dry Eye (SANDE) Symptoms Score at Each Visit. | Months 3, 6, 9, and 12 | For analysis, SCC (Spearman Correlation Coefficient) and its 95% Confidence Interval were calculated for the correlation analysis between change from baseline in CFS (Corneal Fluorescein Staining) score at visit X and SANDE (Symptom Assessment iN Dry Eye) symptoms score using the FAS (Full Analysis Set) Period 1 Population. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Corneal Fluorescein Staining (CFS) Score and Change From Baseline by Visit | Baseline, Months 3, 6, 9 and 12 | Period 1 is Baseline to Month 12 included. CFS is Corneal Fluorescein Score. Staining using fluorescein was 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. |
Countries
Czechia, France, Italy, Poland, Russia, Spain, Turkey (Türkiye)
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Period 1 Open-Label Treatment Ikervis Period 1 for all patients: IKERVIS® (1mg/ml CsA). Instillation of one drop in each affected eye, once daily at bedtime. From Baseline for the first 12 months of treatment.
Open-Label Ikervis: NOVA22007, IKERVIS® is a sterile, ophthalmic cationic oil-in-water emulsion containing 1mg/ml CsA. | 350 |
| Total | 350 |
Baseline characteristics
| Characteristic | Period 1 Open-Label Treatment Ikervis |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 141 Participants |
| Age, Categorical Between 18 and 65 years | 209 Participants |
| Age, Continuous | 59.4 years STANDARD_DEVIATION 13.39 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 51 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 298 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 3 Participants |
| Race (NIH/OMB) Asian | 4 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 11 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 331 Participants |
| Region of Enrollment Czechia | 65 participants |
| Region of Enrollment Italy | 57 participants |
| Region of Enrollment Poland | 83 participants |
| Region of Enrollment Russia | 61 participants |
| Region of Enrollment Spain | 74 participants |
| Region of Enrollment Turkey | 10 participants |
| Sex: Female, Male Female | 302 Participants |
| Sex: Female, Male Male | 48 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 344 | 0 / 148 | 0 / 97 |
| other Total, other adverse events | 138 / 344 | 58 / 148 | 39 / 97 |
| serious Total, serious adverse events | 15 / 344 | 12 / 148 | 9 / 97 |
Outcome results
Primary
The Correlation Between Mean Change From Baseline in Corneal Fluorescein Staining (CFS) Score and Symptom Assessment iN Dry Eye (SANDE) Symptoms Score at Each Visit.
For analysis, SCC (Spearman Correlation Coefficient) and its 95% Confidence Interval were calculated for the correlation analysis between change from baseline in CFS (Corneal Fluorescein Staining) score at visit X and SANDE (Symptom Assessment iN Dry Eye) symptoms score using the FAS (Full Analysis Set) Period 1 Population.
Time frame: Months 3, 6, 9, and 12
Population: Full Analysis Set (FAS). The number of analyzed data are participants evaluable for the outcome measure at Months 3, 6, 9, and 12.~Comment3: Overall Number of Participants analyzed were 336 who received at least one dose of the study medication and had at least one post-baseline sign or symptom assessment of the study eye during Period 1. However, the discrepancy between each specific time-frame is due to missing data or patients withdrawn. These statistical methods were defined in a SAP.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Period 1 Open-Label Treatment Ikervis | The Correlation Between Mean Change From Baseline in Corneal Fluorescein Staining (CFS) Score and Symptom Assessment iN Dry Eye (SANDE) Symptoms Score at Each Visit. | Month 3 / Month 3 | 0.169 Spearman Correlation Coefficient |
| Period 1 Open-Label Treatment Ikervis | The Correlation Between Mean Change From Baseline in Corneal Fluorescein Staining (CFS) Score and Symptom Assessment iN Dry Eye (SANDE) Symptoms Score at Each Visit. | Month 3 / Month 6 | 0.245 Spearman Correlation Coefficient |
| Period 1 Open-Label Treatment Ikervis | The Correlation Between Mean Change From Baseline in Corneal Fluorescein Staining (CFS) Score and Symptom Assessment iN Dry Eye (SANDE) Symptoms Score at Each Visit. | Month 3 / Month 9 | 0.274 Spearman Correlation Coefficient |
| Period 1 Open-Label Treatment Ikervis | The Correlation Between Mean Change From Baseline in Corneal Fluorescein Staining (CFS) Score and Symptom Assessment iN Dry Eye (SANDE) Symptoms Score at Each Visit. | Month 3 / Month 12 | 0.178 Spearman Correlation Coefficient |
| Period 1 Open-Label Treatment Ikervis | The Correlation Between Mean Change From Baseline in Corneal Fluorescein Staining (CFS) Score and Symptom Assessment iN Dry Eye (SANDE) Symptoms Score at Each Visit. | Month 6 / Month 6 | 0.258 Spearman Correlation Coefficient |
| Period 1 Open-Label Treatment Ikervis | The Correlation Between Mean Change From Baseline in Corneal Fluorescein Staining (CFS) Score and Symptom Assessment iN Dry Eye (SANDE) Symptoms Score at Each Visit. | Month 6 / Month 9 | 0.322 Spearman Correlation Coefficient |
| Period 1 Open-Label Treatment Ikervis | The Correlation Between Mean Change From Baseline in Corneal Fluorescein Staining (CFS) Score and Symptom Assessment iN Dry Eye (SANDE) Symptoms Score at Each Visit. | Month 6 / Month 12 | 0.274 Spearman Correlation Coefficient |
| Period 1 Open-Label Treatment Ikervis | The Correlation Between Mean Change From Baseline in Corneal Fluorescein Staining (CFS) Score and Symptom Assessment iN Dry Eye (SANDE) Symptoms Score at Each Visit. | Month 9 / Month 9 | 0.343 Spearman Correlation Coefficient |
| Period 1 Open-Label Treatment Ikervis | The Correlation Between Mean Change From Baseline in Corneal Fluorescein Staining (CFS) Score and Symptom Assessment iN Dry Eye (SANDE) Symptoms Score at Each Visit. | Month 9 / Month 12 | 0.332 Spearman Correlation Coefficient |
| Period 1 Open-Label Treatment Ikervis | The Correlation Between Mean Change From Baseline in Corneal Fluorescein Staining (CFS) Score and Symptom Assessment iN Dry Eye (SANDE) Symptoms Score at Each Visit. | Month 12 / Month 12 | 0.266 Spearman Correlation Coefficient |
Secondary
Corneal Fluorescein Staining (CFS) Score and Change From Baseline by Visit
Period 1 is Baseline to Month 12 included. CFS is Corneal Fluorescein Score. Staining using fluorescein was 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.
Time frame: Baseline, Months 3, 6, 9 and 12
Population: Full Analysis Set (FAS). The number of analyzed data are participants evaluable for the outcome measure at Baseline, Months 3, 6, 9, and 12.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Period 1 Open-Label Treatment Ikervis | Corneal Fluorescein Staining (CFS) Score and Change From Baseline by Visit | Month 6 change from baseline | -1.91 score on a scale | Standard Deviation 1.143 |
| Period 1 Open-Label Treatment Ikervis | Corneal Fluorescein Staining (CFS) Score and Change From Baseline by Visit | Observed Baseline | 3.62 score on a scale | Standard Deviation 0.667 |
| Period 1 Open-Label Treatment Ikervis | Corneal Fluorescein Staining (CFS) Score and Change From Baseline by Visit | Observed Month 3 | 2.24 score on a scale | Standard Deviation 1.072 |
| Period 1 Open-Label Treatment Ikervis | Corneal Fluorescein Staining (CFS) Score and Change From Baseline by Visit | Month 3 change from baseline | -1.38 score on a scale | Standard Deviation 0.995 |
| Period 1 Open-Label Treatment Ikervis | Corneal Fluorescein Staining (CFS) Score and Change From Baseline by Visit | Observed Month 6 | 1.72 score on a scale | Standard Deviation 1.137 |
| Period 1 Open-Label Treatment Ikervis | Corneal Fluorescein Staining (CFS) Score and Change From Baseline by Visit | Observed Month 9 | 1.42 score on a scale | Standard Deviation 1.094 |
| Period 1 Open-Label Treatment Ikervis | Corneal Fluorescein Staining (CFS) Score and Change From Baseline by Visit | Month 9 change from baseline | -2.20 score on a scale | Standard Deviation 1.123 |
| Period 1 Open-Label Treatment Ikervis | Corneal Fluorescein Staining (CFS) Score and Change From Baseline by Visit | Observed Month 12 | 1.14 score on a scale | Standard Deviation 1.008 |
| Period 1 Open-Label Treatment Ikervis | Corneal Fluorescein Staining (CFS) Score and Change From Baseline by Visit | Month 12 change from baseline | -2.49 score on a scale | Standard Deviation 0.981 |