A Study to Evaluate the Performance and Safety of CBL-101 Versus Vismed® Multi Eye Drops in the Management of Dry Eye

The primary objectives of this investigation are to show that the performance of CBL-101 Eye Drops is non-inferior to that of Vismed® Multi eye drops in subjects with moderate to severe keratoconjunctivitis sicca after 28 days, and to assess the safety of CBL-101 Eye Drops during a 90-day period with treatment administered 3 to 6 times per day.

Study Overview

• Status: Completed
• Conditions: Dry Eye
• Intervention / Treatment: Device: CBL-101 Eye Drops; Device: Vismed® Multi Eye Drops

Detailed Description

Participants in this multicenter, randomized study had a screening visit, then were randomized on Day 0 with follow-up visits on Day 7 (±1), Day 28 (± 3) and Day 90 (±10).

• Study Type: Interventional
• Enrollment (Actual): 87
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Belgium
  • Huy, Belgium
    • Dr. Nyst private office
• France
  • Bordeaux, France, 33000
    • Pr Mortemousque private office

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Subjects must be of legal age (at least 18) on the date the Informed Consent Form (ICF) is signed and with the capacity to provide voluntary informed consent
2. Subjects must be able to read, understand, and provide written informed consent on the Ethics Committee (EC) approved ICF
3. Subjects who are able and willing to comply with all treatment and follow-up, study procedures
4. Subjects who have been using tear substitutes for at least 3 months prior to inclusion, and who will use multidose preservative-free artificial tear (Aqualarm U.P. povidone 2% eye drops in 10 mL bottles) up to 6 times a day for at least 2 weeks immediately prior to randomization
5. Subjects with a score ≥ 1 for at least 2 out of the 7 following symptoms (rated 0 to 4): sensation of dryness, foreign body, burning, stinging, itching, blurred vision, sensitivity to light

6. Subjects with at least 1 eye with the following signs of keratoconjunctivitis sicca :

   • Tear break-up time of ≤ 10sec (mean of 3 measurements) at both screening visit and inclusion visit
   • Total ocular surface staining score ≥ 4 and ≤ 9 at both screening visit and inclusion visit. This assessment combines corneal, nasal and temporal bulbar conjunctival fluorescein staining, each graded 0-5 according to the Oxford Scheme
7. Subjects who have a decimal visual acuity (VA) with habitual correction equal to or better than 0.1 (Monoyer chart) in both eyes
8. Subjects with no systemic treatment or who are receiving stable systemic treatment (unchanged for 1 month or longer)
9. Female subjects who are not of childbearing potential or who have a negative urine pregnancy test result at screening

Exclusion Criteria:

Ocular Exclusion Criteria

1. Subjects with moderate or severe blepharitis defined by at least moderate (a score of ≥ 2 from a range of 0 to 3) eyelid margin hyperemia or moderate eyelid swelling or both and at least moderate eyelid debris or moderate plugging of meibomian glands or both

2. Subjects who have severe ocular dryness accompanied by one of the following:

   • Lid abnormality (except mild blepharitis)
   • Corneal disease
   • Ocular surface metaplasia
   • Filamentary keratitis
   • Corneal neovascularization
3. Subjects who currently wear contact lenses or have worn contact lenses within 90 days prior to study start
4. Subjects who have received ocular surgery, including laser surgery, in either eye within 180 days prior to study start
5. Subjects with a history of ocular trauma, non-dry eye ocular inflammation, or ocular infection within 90 days prior to study start
6. Subjects with a history of ocular allergic disease or ocular herpes within 1 year prior to study start

7. Subjects with a history of any inflammatory ulcerative keratitis, recurrent corneal erosion, or uveitis

   Treatment Exclusion Criteria

8. Subjects with known hypersensitivity or contraindications to any of the ingredients in the test or comparator products or ART
9. Subjects with initiation of, or changes to, concomitant medication that could affect dry eye within 30 days prior to Visit 1 (Screening) or with planned initiation or changes of such medications during the study
10. Subjects who have received ocular therapy (either eye) with any ophthalmic medication, except tear substitutes, within 2 weeks prior to study start
11. Subjects expected to receive ocular therapy during the study
12. Subjects treated with topical ocular steroidal or non-steroidal antiinflammatory medication within 30 days prior to study start
13. Subjects expected to receive ocular therapy with immunosuppressants (e.g. cyclosporine) during the study or who have used ocular immunosuppressants within 90 days prior to study start

14. Subjects who have received occlusion therapy with lacrimal or punctum plugs within 90 days prior to study start

    General Exclusion Criteria

15. Female subjects who are sexually active and who do not fall into 1 of the following categories:

    • Post-menopausal
    • Surgically sterile
    • Using one of the following birth control methods throughout the duration of the study: Intrauterine device (at least for 14 days prior to study start) or Barrier method (condom or diaphragm) with spermicide (at least for 14 days prior to study start) or Hormonal contraception (same dose and same formulation for at least 6 months)
16. Females who are breastfeeding
17. Subjects participating in any drug or device clinical investigation within 30 days prior to entry into this study and, or during the period of study participation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: CBL-101 Eye Drops; The test article, CBL-101 Eye Drops, is a CE-marked medical device containing 0.15% sodium hyaluronate and polyethylene glycol (PEG) 8000. An oxide (Oxyd®) used as a soft preservative, rapidly turns into oxygen, water and ions on contact with the eye. The formula is presented in 10 mL bottles.	Device: CBL-101 Eye Drops; CBL-101 Eye Drops 3 to 6 times per day for 3 months.
Active Comparator: Vismed® Multi Eye Drops; The comparator product, Vismed® Multi ophthalmic solution (CE marked), contains 0.18% sodium hyaluronate, is unpreserved and presented in 10 mL bottles.	Device: Vismed® Multi Eye Drops; Vismed® Multi 3 to 6 times per day for 3 months.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Ocular Surface Fluorescein Staining Score at Day 28	Mean change from baseline (CFB) in the study eye in Ocular Surface Fluorescein Staining (OSFS) scored according to the Oxford Scheme. The Oxford Scheme is a validated scale consisting of a series of panels labelled A to E in order of increasing severity. Grade 0 corresponds to panel A increasing to Grade 5 corresponding to more than Panel E, with punctate dots representing staining. The 3 regions, cornea, nasal and temporal bulbar conjunctiva are graded separately from 0 to 5, with the OSFS score ranging from 0 (best outcome) to 15 (worst outcome). The OSFS is the sum score of the 3 subscores (cornea, nasal and temporal regions). The study eye was the eligible eye with the highest OSFS score at baseline, which needed to be ≥4 and ≤9 on the 15-grade Oxford Scheme. If both eyes were eligible and had the same OSFS score, the study eye was the right eye.	Baseline (Day 0), Visit 4 (Day 28)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Ocular Surface Fluorescein Staining Score at Day 7 (Visit 3)	Mean change from baseline (CFB) in the study eye in Ocular Surface Fluorescein Staining (OSFS) scored according to the Oxford Scheme. The Oxford Scheme is a validated scale consisting of a series of panels labelled A to E in order of increasing severity. Grade 0 corresponds to panel A increasing to Grade 5 corresponding to more than Panel E, with punctate dots representing staining. The 3 regions, cornea, nasal and temporal bulbar conjunctiva are graded separately from 0 to 5, with the OSFS score ranging from 0 (best outcome) to 15 (worst outcome). The OSFS is the sum score of the 3 subscores (cornea, nasal and temporal regions). The study eye was the eligible eye with the highest OSFS score at baseline, which needed to be ≥4 and ≤9 on the 15-grade Oxford Scheme. If both eyes were eligible and had the same OSFS score, the study eye was the right eye.	Baseline (Day 0), Visit 3 (Day 7)
Change From Baseline in Ocular Surface Fluorescein Staining Score at Day 90 (Visit 5)	Mean change from baseline (CFB) in the study eye in Ocular Surface Fluorescein Staining (OSFS) scored according to the Oxford Scheme. The Oxford Scheme is a validated scale consisting of a series of panels labelled A to E in order of increasing severity. Grade 0 corresponds to panel A increasing to Grade 5 corresponding to more than Panel E, with punctate dots representing staining. The 3 regions, cornea, nasal and temporal bulbar conjunctiva are graded separately from 0 to 5, with the OSFS score ranging from 0 (best outcome) to 15 (worst outcome). The OSFS is the sum score of the 3 subscores (cornea, nasal and temporal regions). The study eye was the eligible eye with the highest OSFS score at baseline, which needed to be ≥4 and ≤9 on the 15-grade Oxford Scheme. If both eyes were eligible and had the same OSFS score, the study eye was the right eye.	Baseline (Day 0), Visit 5 (Day 90)
Change From Baseline in Corneal Fluorescein Staining Score at Day 7 (Visit 3)	Mean change from baseline (CFB) in the study eye in Corneal Fluorescein Staining scored according to the Oxford Scheme. The Oxford Scheme is a validated scale consisting of a series of panels labelled A to E in order of increasing severity. Grade 0 corresponds to panel A increasing to Grade 5 corresponding to more than Panel E, with punctate dots representing staining. The Corneal region is graded separately from 0 (best outcome) to 5 (worst outcome).	Baseline (Day 0), Visit 3 (Day 7)
Change From Baseline in Corneal Fluorescein Staining Score at Day 28 (Visit 4)	Mean change from baseline (CFB) in the study eye in Corneal Fluorescein Staining scored according to the Oxford Scheme. The Oxford Scheme is a validated scale consisting of a series of panels labelled A to E in order of increasing severity. Grade 0 corresponds to panel A increasing to Grade 5 corresponding to more than Panel E, with punctate dots representing staining. The Corneal region is graded separately from 0 (best outcome) to 5 (worst outcome).	Baseline (Day 0), Visit 4 (Day 28)
Change From Baseline in Corneal Fluorescein Staining Score at Day 90 (Visit 5)	Mean change from baseline (CFB) in the study eye in Corneal Fluorescein Staining scored according to the Oxford Scheme. The Oxford Scheme is a validated scale consisting of a series of panels labelled A to E in order of increasing severity. Grade 0 corresponds to panel A increasing to Grade 5 corresponding to more than Panel E, with punctate dots representing staining. The Corneal region is graded separately from 0 (best outcome) to 5 (worst outcome).	Baseline (Day 0), Visit 5 (Day 90)
Change From Baseline in Nasal Conjunctival Fluorescein Staining Score at Day 7 (Visit 3)	Mean change from baseline (CFB) in the study eye in Nasal conjunctival Fluorescein Staining scored according to the Oxford Scheme. The Oxford Scheme is a validated scale consisting of a series of panels labelled A to E in order of increasing severity. Grade 0 corresponds to panel A increasing to Grade 5 corresponding to more than Panel E, with punctate dots representing staining. The Nasal conjunctival region is graded separately from 0 (best outcome) to 5 (worst outcome).	Baseline (Day 0), Visit 3 (Day 7)
Change From Baseline in Nasal Conjunctival Fluorescein Staining Score at Day 28 (Visit 4)	Mean change from baseline (CFB) in the study eye in Nasal conjunctival Fluorescein Staining scored according to the Oxford Scheme. The Oxford Scheme is a validated scale consisting of a series of panels labelled A to E in order of increasing severity. Grade 0 corresponds to panel A increasing to Grade 5 corresponding to more than Panel E, with punctate dots representing staining. The Nasal conjunctival region is graded separately from 0 (best outcome) to 5 (worst outcome).	Baseline (Day 0), Visit 4 (Day 28)
Change From Baseline in Nasal Conjunctival Fluorescein Staining Score at Day 90 (Visit 5)	Mean change from baseline (CFB) in the study eye in Nasal Conjunctival Fluorescein Staining scored according to the Oxford Scheme. The Oxford Scheme is a validated scale consisting of a series of panels labelled A to E in order of increasing severity. Grade 0 corresponds to panel A increasing to Grade 5 corresponding to more than Panel E, with punctate dots representing staining. The Nasal conjunctival region is graded separately from 0 (best outcome) to 5 (worst outcome).	Baseline (Day 0), Visit 5 (Day 90)
Change From Baseline in Temporal Conjunctival Fluorescein Staining Score at Day 7 (Visit 3)	Mean change from baseline (CFB) in the study eye in Temporal Conjunctival Fluorescein Staining scored according to the Oxford Scheme. The Oxford Scheme is a validated scale consisting of a series of panels labelled A to E in order of increasing severity. Grade 0 corresponds to panel A increasing to Grade 5 corresponding to more than Panel E, with punctate dots representing staining. The Temporal conjunctival region is graded separately from 0 (best outcome) to 5 (worst outcome).	Baseline (Day 0), Visit 3 (Day 7)
Change From Baseline in Temporal Conjunctival Fluorescein Staining Score at Day 28 (Visit 4)	Mean change from baseline (CFB) in the study eye in Temporal Conjunctival Fluorescein Staining scored according to the Oxford Scheme. The Oxford Scheme is a validated scale consisting of a series of panels labelled A to E in order of increasing severity. Grade 0 corresponds to panel A increasing to Grade 5 corresponding to more than Panel E, with punctate dots representing staining. The Temporal conjunctival region is graded separately from 0 (best outcome) to 5 (worst outcome).	Baseline (Day 0), Visit 4 (Day 28)
Change From Baseline in Temporal Conjunctival Fluorescein Staining Score at Day 90 (Visit 5)	Mean change from baseline (CFB) in the study eye in Temporal Conjunctival Fluorescein Staining scored according to the Oxford Scheme. The Oxford Scheme is a validated scale consisting of a series of panels labelled A to E in order of increasing severity. Grade 0 corresponds to panel A increasing to Grade 5 corresponding to more than Panel E, with punctate dots representing staining. The Temporal conjunctival region is graded separately from 0 (best outcome) to 5 (worst outcome).	Baseline (Day 0), Visit 5 (Day 90)
Change From Baseline in Global Sum Score of Dry Eye Symptoms at Day 28 (Visit 4)	The global sum score (scale 0-28) of dry eye symptoms assessed 7 items: sensation of dryness, foreign body, burning, stinging, itching, blurred vision, sensitivity to light, each graded from 0 (absent) to 4(severe and/or disabling and constant).	Baseline, Visit 4 (Day 28)
Change From Baseline in Global Sum Score of Dry Eye Symptoms at Day 90 (Visit 5)	The global sum score (scale 0-28) of dry eye symptoms assessed 7 items: sensation of dryness, foreign body, burning, stinging, itching, blurred vision, sensitivity to light, each graded from 0 (absent) to 4 (severe and/or disabling and constant).	Baseline, Visit 5 (Day 90)
Change From Baseline in the Ocular Surface Disease-Quality of Life (OSD-QoL®) at Day 90 (Visit 5)	The OSD-QoL® questionnaire is a validated instrument for measuring dry eye severity and impairment. It includes 28 items divided into 7 dimensions: Daily activities, Difficulties with work and handicap, Giving up makeup, Acknowledgement of the disease, Acceptance of the disease, Fear for the future, and Emotional well-being. A Global Question: "How do you feel when considering your eye problems?" (included in the Fear for the future dimension) was also evaluated separately. The converted score for each dimension ranges from 0 to 100, with a higher score reflecting a better quality of life.	Baseline (Day 0), Visit 5 (Day 90)
Change From Baseline in Tear Film Break Up Time (TFBUT) at Day 7 (Visit 3)	The Tear Film Break Up Time (TFBUT) after fluorescein instillation, measured the time between the last blink and the first appearance of a dry spot or disruption of the tear film. The TFBUT was measured in tenths of seconds with a stopwatch provided to the sites. It was conducted 3 times and the mean was calculated.	Baseline (Day 0), Visit 3 (Day 7)
Change From Baseline in Tear Film Break Up Time (TFBUT) at Day 28 (Visit 4)	The Tear Film Break Up Time (TFBUT) after fluorescein instillation, measured the time between the last blink and the first appearance of a dry spot or disruption of the tear film. The TFBUT was measured in tenths of seconds with a stopwatch provided to the sites. It was conducted 3 times and the means was calculated.	Baseline (Day 0), Visit 4 (Day 28)
Change From Baseline in Tear Film Break Up Time (TFBUT) at Day 90 (Visit 5)	The Tear Film Break Up Time (TFBUT) after fluorescein instillation, measured the time between the last blink and the first appearance of a dry spot or disruption of the tear film. The TFBUT was measured in tenths of seconds with a stopwatch provided to the sites. It was conducted 3 times and the means was calculated.	Baseline (Day 0), Visit 5 (Day 90)
Change From Baseline in Schirmer Test at Day 28 (Visit 4)	Tear fluid secretion was assessed by the unanaesthetized Schirmer's test in the study eye with graduated strips in millimeters. Schirmer paper test strips were carefully inserted over the lower eyelid margin. The strips were removed after 5 minutes and the amount of tear fluid secretion read to the nearest mm from the graduated strip markings.	Baseline (Day 0), Visit 4 (Day 28)

Collaborators and Investigators

• Sponsor: Laboratoire Chauvin
• Collaborators: Bausch & Lomb Incorporated
• Investigators: Study Director: Raphaele Siou Mermet, MD, Laboratoire Chauvin

Publications and helpful links

General Publications

• Labetoulle M, Mortemousque B; CBL-101 Study Group. Performance and Safety of a Sodium Hyaluronate Tear Substitute with Polyethylene Glycol in Dry Eye Disease: A Multicenter, Investigator-Masked, Randomized, Noninferiority Trial. J Ocul Pharmacol Ther. 2022 Nov;38(9):607-616. doi: 10.1089/jop.2022.0048. Epub 2022 Oct 21.

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2017
• Primary Completion (Actual): September 17, 2019
• Study Completion (Actual): September 17, 2019

Study Registration Dates

• First Submitted: November 21, 2016
• First Submitted That Met QC Criteria: November 23, 2016
• First Posted (Estimated): November 29, 2016

Study Record Updates

• Last Update Posted (Actual): June 24, 2024
• Last Update Submitted That Met QC Criteria: January 15, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Eye Diseases; Lacrimal Apparatus Diseases; Keratoconjunctivitis; Conjunctivitis; Conjunctival Diseases; Keratitis; Corneal Diseases; Dry Eye Syndromes; Keratoconjunctivitis Sicca; Pharmaceutical Solutions; Ophthalmic Solutions
• Other Study ID Numbers: 2016-A01121-50

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No