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

Dompé Farmaceutici S.p.A85 enrolled

Overview

Primary Objectives: * To compare the efficacy of cenegermin vs vehicle in Schirmer I test (without anaesthesia) \> 10 mm/5 min at Week 4 by testing the superiority. * To compare the efficacy of cenegermin vs vehicle in Symptom Assessment in Dry Eye questionnaire (SANDE) global score at Week 12 by testing the superiority. Secondary Objectives: * To compare the efficacy of cenegermin vs vehicle in Schirmer I test at Week 4, 8, 12 and 16 by testing the superiority. * To compare the efficacy of cenegermin vs vehicle in Cornea and conjunctiva vital staining with fluorescein (National Eye Institute \[NEI\] scales) at Week 4, 8, 12 and 16 by testing the superiority. * To compare the efficacy of cenegermin vs vehicle in Tear Film Break-Up Time (TFBUT) at Week 4, 8, 12 and 16 by testing the superiority. * To compare the efficacy of cenegermin vs vehicle in SANDE scores at Week 8, 12 and 16 by testing the superiority. * To compare the efficacy of cenegermin vs vehicle in worsening in symptom scores (SANDE) and/or NEI score at Week 4 by testing the superiority. * To compare the efficacy of cenegermin vs vehicle in impact of dry eye on everyday life (IDEEL) questionnaire at Week 4, 8, 12 and 16 by testing the superiority.

This was a 4 week phase III, multicenter, double-masked, vehicle-controlled study to evaluate safety and efficacy of cenegermin ophthalmic solution at 20 mcg/mL solution versus vehicle, in patients with severe Sjogren's dry eye disease under treatment with Ciclosporine A (or other drugs of the same class). During the Screening all procedures for inclusion and exclusion were performed. From the day of screening, the patients stopped any kind of further treatment, except CsA and commercially available preservative-free artificial tears provided by the Sponsor for a period of 8 days and 10 days as maximum. At the end of the washout period, patients still meeting the entry criteria for this study were randomized 1:1 and treated for 4 weeks with either cenegermin ophthalmic solution 20 mcg/mL three times a day (TID) or vehicle TID. In addition to topical CsA eye drops (both groups continued with topical CsA eye drops, or other topical ophthalmic treatment of the same class), during the 4 weeks of masked treatment, only the administration of investigational medicinal product (IMP) was allowed. During the follow up period, the patient could administer additional preservative-free artificial tear eye drops, provided by the Sponsor, only if strictly needed, and had to document in the patient's Diary the number of additional drops administered for each eye. Patients were then followed-up for efficacy and safety endpoints until Week 16 and for safety endpoints until Week 24. The total duration of the study was 25 weeks including 1 week of screening.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Male or female aged ≥ 18 years. 2. Patients with a confirmed diagnosis of Sjögren's syndrome or other autoimmune disease known to induce Sjögren's DED. 3. Patients with severe Sjögren's DED characterized by the following clinical features: 1. Corneal and/or conjunctival staining with fluorescein using National Eye Institute (NEI) grading system ≥ 3. 2. SANDE questionnaire \>25 mm. 3. Schirmer test I (without anaesthesia) ≥ 2 ≤ 5 mm/5 min. 4. The same eye (eligible eye) must fulfil all the above criteria. 5. Patients diagnosed with severe Sjögren's DED at least 3 months before enrolment (current use or recommended use of artificial tears for the treatment of Sjögren's related DE). 6. Best corrected distance visual acuity (BCDVA) score of ≥ 0.1 decimal units (20/200 Snellen value) in each eye at the time of study enrolment. 7. If a female of childbearing potential, have a negative urine pregnancy test and use a highly effective method to avoid pregnancy for the duration of the trial and 30 days after the study treatment period. Males of reproductive potential should use effective contraception during treatment and 30 days after the study treatment period. 8. Patients who have given written informed consent before any study-related procedures not part of standard medical care are performed. 9. Patients must have the ability and willingness to comply with study procedures. 10. Patients under treatment with topical cyclosporine (CsA), or topical ophthalmic treatments of the same class for at least 30 days before Screening Visit (Day -8). Exclusion Criteria: 1. Inability to speak and understand the local language sufficiently to understand the nature of the study, to provide written informed consent, and to allow the completion of all study assessments. 2. Evidence of an active ocular infection, in either eye. 3. Presence of any other ocular disorder or condition requiring topical medication during the entire duration of study in either eye. 4. History of severe systemic allergy or of ocular allergy (including seasonal conjunctivitis) or chronic conjunctivitis and/or keratitis other than dry eye. 5. Intraocular inflammation defined as Tyndall score \> 0. 6. History of malignancy in the last 5 years. 7. Systemic disease not stabilized within 1 month before Screening Visit (e.g., diabetes with glycemia out of range, thyroid malfunction) or judged by the Investigator to be incompatible with the study (e.g., current systemic infections) or with a condition incompatible with the frequent assessment required by the study. 8. Patient had a serious adverse reaction or significant hypersensitivity to any drug or chemically related compounds or had a clinically significant allergy to drugs, foods, amide local anaesthetics or other materials including commercial artificial tears (in the opinion of the Investigator). 9. Females of childbearing potential (those who are not surgically sterilized or post-menopausal for at least 1 year) were excluded from participation in the study if they met any one of the following conditions: 1. were currently pregnant or, 2. had a positive result at the urine pregnancy test (Baseline/Day 1) or, 3. intended to become pregnant during the study treatment period or, 4. were breast-feeding or, 5. were not willing to use highly effective birth control measures, such as: combined (oestrogen and progesterone containing) hormonal contraceptives associated with inhibition of ovulation (oral, intravaginal, transdermal), progestogen-only hormonal contraception associated with inhibition of ovulation (oral, implantable, injectable), intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomised partner, sexual abstinence - during the entire course of and 30 days after the study treatment period. 10. Any concurrent medical condition, that in the judgment of the PI, might interfere with the conduct of the study, confound the interpretation of the study results, or endanger the patient's well-being. 11. Use of topical corticosteroids, lifitegrast, autologous serum tears in either eye during the study (previous use not an exclusion criteria but must be discontinued at the Screening Visit). 12. Contact lenses, True Tear device, moisture goggles, sutureless amniotic membrane or punctum plug use during the study (previous use not an exclusion criteria but must be discontinued at the Screening Visit). 13. History of drug addiction or alcohol abuse in the last 2 years. 14. Any prior ocular surgery (including refractive, palpebral and cataract surgery) if within 90 days before the Screening Visit. 15. Participation in a clinical trial with a new active substance during the past 3 months. 16. Participation in another clinical trial study at the same time as the present study.

Locations (10)

Lugene Eye Institute - Glendale Office

Glendale, California, United States

The Johns Hopkins University

Baltimore, Maryland, United States

Tufts University School of Medicine (TUSM) - New England Eye Center/Tufts Medical Center

Boston, Massachusetts, United States

OCLI (Ophthalmic Consultants of Long Island)

Garden City, New York, United States

Scheie Eye Institute

Philadelphia, Pennsylvania, United States

Houston Eye Associates HEA - Gramercy Location

Houston, Tennessee, United States

Toyos Clinic - Nashville

Nashville, Tennessee, United States

AOU Gaspare Rodolico - Ospedale San Marco

Catania, Italy

Università degli Studi di Milano - Ospedale San Giuseppe - UO Oculistica

Milan, Italy

AOU Policlinico Umberto I - Dipartimento Organi di Senso - Clinica Oculistica

Roma, Italy

Outcomes

Primary Outcomes

Number of Patients With Schirmer I Test (Without Anesthesia) >10mm/5min in the Eligible Eye at Week 4

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.

Time frame: At Week 4 (Visit 3)

Change From Baseline in Symptom Questionnaire (SANDE) Global Score at Week 12

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).

Time frame: At Week 12 (Visit 5 - Follow up)

Secondary Outcomes

Key Secondary Outcome: Number of Patients With Schirmer I Test (Without Anesthesia) >10mm/5min at Week 8

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.

Time frame: At Week 8 (Visit 4)

Key Secondary Outcome: Change From Baseline in Symptom Assessment in Dry Eye Questionnaire (SANDE) Score for Severity at Week 12

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.

Time frame: At Week 12 (Visit 5 - Follow-up)

Key Secondary Outcome: Change From Baseline in Symptoms Assessment in Dry Eye Questionnaire (SANDE) Score for Frequency at Week 12

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).

Time frame: At Week 12 (Visit 5 - Follow-up)

Key Secondary Outcome: Change From Baseline in "Quality of Life, Dry Eye Treatment Satisfaction & Bother and Dry Eye Symptom-Bother" Modules Measured by "Impact of Dry Eye on Everyday Life [IDEEL]" Questionnaire at Week 12 and at Week 4.

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: 1. Impact on Daily Activities 2. Emotional Impact 3. 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: 1. Satisfaction with Treatment Effectiveness 2. 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: 1. 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.

Time frame: At Week 12 (Visit 5 - Follow-up) and Week 4 (Visit 3)

Key Secondary Outcome: Change From Baseline in Tear Film Break-Up Time (TFBUT) at Week 4, Week 8 and Week 12

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.

Time frame: At week 4 (Visit 3) , Week 8 (Visit 4), and Week 12 (Visit 5 - Follow-up)

Change From Baseline in Schirmer I Test (Without Anaesthesia) at Week 4, Week 8, Week 12, and Week 16

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.

Time frame: At Week 4 (Visit 3), Week 8 (Visit 4), Week 12 (Visit 5), and Week 16 (Visit 6)

Change From Baseline in Cornea and Conjunctiva Vital Staining With Fluorescein (National Eye Institute [NEI] Scales) at Week 4, Week 8, Week 12 and Week 16

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.

Time frame: At Week 4 (Visit 3), Week 8 (Visit 4) , Week 12 (Visit 5) and Week 16 (Visit 6)

Change From Baseline in Tear Film Break-Up Time (TFBUT) at Week 4, Week 8, Week 12 and Week 16

Time frame: At Week 4 (Visit 3), Week 8 (Visit 4), Week 12 (Visit 5), and Week 16 (Visit 6)

Change From Baseline in Symptoms Questionnaire (SANDE) Global Scores, and for Severity and Frequency at Week 8, Week 12, and Week 16

Time frame: At Week 8 (Visit 4), Week 12 (Visit 5), and Week 16 (Visit 6)

Number of Patients Experienced a Worsening in Symptom Scores (SANDE Global Scores) and/or NEI Score ≥ 50% at Week 4

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.

Time frame: At Week 4 (Visit 3)

Change From Baseline in "Quality of Life, Dry Eye Treatment Satisfaction & Bother and Dry Eye Symptom-Bother" Modules Measured by "Impact of Dry Eye on Everyday Life [IDEEL]" Questionnaire at Week 4, Week, 8, Week 12, and Week 16

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: 1. Impact on Daily Activities 2. Emotional Impact 3. 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: 1. Satisfaction with Treatment Effectiveness 2. 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: 1. 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.

Time frame: At Week 4 (Visit 3), Week 8 (Visit 4), Week 12 (Visit 5), and Week 16 (Visit 6)

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

Overview

Conditions

Interventions

Eligibility

Locations (10)

Outcomes

Primary Outcomes

Secondary Outcomes