Keratoconjunctivitis Sicca
Conditions
Keywords
Dry eye disease, KCS, Aqueous Deficient Dry Eye
Brief summary
Eligible patients with dry eye will be treated with CF101 or placebo twice daily for 24 weeks. Disease activity will be assessed using evaluations of ocular surface integrity, tear production, and patient symptoms.
Detailed description
Patients will be randomized to receive either CF101 0.1 mg, CF101 1.0 mg, or matching placebo, given orally twice daily (BID) for 24 weeks. A Screening Period of up to 4 weeks that includes a 2-week run-in period will precede a 24-week treatment period, followed by a 2-week follow-up period. At a Screening Visit, patients will undergo complete medical and ophthalmologic history, medication history, physical examination (including height, weight, sitting blood pressure, pulse rate and temperature), ophthalmic examination, and clinical laboratory tests. Disease activity will be assessed using fluorescein staining, Schirmer test with and without anesthesia, Ocular Surface Disease Index©, and tear break-up time. Eligible patients will begin a 2-week run-in period during the 4-week screening period, during which time they will be instructed to discontinue use of all topical ophthalmic medications except for REFRESH TEARS® Lubricant Eye Drops. At the Baseline Visit, patients who successfully complete the 2-week run-in period and re-qualify for entry will be randomized to their assigned medication (CF101 0.1 mg, CF101 1.0 mg, or matching placebo) to be taken orally twice daily BID for 24 weeks. Patients will return for assessments and a new supply of study medication at Weeks 2, 4, 8, 12, 16, and 20; at Week 24 for a final on-treatment assessment; and at Week 26 for the 2-week off-treatment follow-up visit.
Interventions
DRUGCF101
orally q12h
Sponsors
Can-Fite BioPharma
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female, 18 years of age and over; * Have a diagnosis of moderate-to-severe Aqueous-Deficient Dry Eye (including Sjögren's Syndrome dry eye), as defined by: 1. Positive corneal fluorescein staining (FS), defined as a corneal punctate fluorescein staining score of ≥4 in either eye by the National Eye Institute evaluation scale summed over 5 areas each with a 0-3 scoring scale; AND 2. FS score of ≥2 in at least one corneal region; AND 3. Schirmer Test (ST) score (without anesthesia) ≥1 mm and \< 7 mm/5 min in either eye; AND 4. OSDI score of ≥20; * Central corneal FS score of ≥2 in at least 1 eye; * Willing to use no topical ocular treatments, other than REFRESH® unpreserved artificial tears up to a maximum of 4 times daily, for the duration of the trial (including the 2-week run-in period, the 24-week treatment period and the 2-week follow-up period); * Willing to forego periocular cosmetic application for the duration of the trial; * Females of child-bearing potential must have a negative urine pregnancy test at screening and throughout the study, to be eligible for, and continue participation in, the study; * Females of child-bearing potential must be willing to use 2 methods of contraception deemed adequate by the Investigator (for example oral contraceptive pills plus a barrier method) to be eligible for, and continue participation in, the study; * Ability to complete the study in compliance with the protocol; and * Ability to understand and provide written informed consent.
Exclusion criteria
* Sjögren's Syndrome with significant systemic non-exocrine gland involvement which, in the investigators opinion, would interfere with the conduct of the trial; * Stevens-Johnson Syndrome; * Use of methotrexate or systemic cyclosporine within the 3 months prior to the Screening Visit; * of any other disease-modifying anti-rheumatic therapy within 2 months prior to the Screening Visit; * Use of any anti-rheumatic biological agent within 2 months, or 5 half-lives, whichever is longer, prior to the Screening Visit; * Use of oral corticosteroids \>10 mg prednisone, or equivalent, per day; * Use of topical steroids within 4 weeks prior to the Screening Visit and for the duration of the study; * Receipt of topical cyclosporine eye drops within 3 months prior to the Screening Visit and for the duration of the trial; * Use of oral statin or preparation containing omega-3 fatty acid unless dose has been stable for at least 3 months and will remain so during the course of the trial; * Presence of chronic ocular disease other than Aqueous-Deficient Dry Eye requiring topical treatment; * Presence of post-burn ocular injury; * Ocular herpes simplex virus infection; * Concomitant use of contact lenses or use within 3 months prior to the Screening Visit; * Persistent intraocular inflammation or infection; * Active anterior blepharitis of greater than mild degree, defined as minimal crust at the base of the eyelashes and no signs of inflammation; * Meibomian gland dysfunction (MGD) of greater than mild degree, defined as mild plugging of the Meibomian glands without lid margin inflammation; * Surgical occlusion of the lacrimal puncta, including the insertion of punctual plugs, within 3 months of the Screening Visit.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects Who Achieved Complete Clearing of Corneal Staining (i.e., Total Corneal FS Score = 0) at Week 24 | 24 weeks | Complete clearing of corneal staining by fluorescein staining (FS). The primary efficacy analysis was performed for 1eye (target eye), defined as the eye with the larger corneal FS value at Baseline. If both eyes had the same corneal FS value at baseline, the target eye was considered the eye with the larger central corneal staining value at Baseline. Corneal FS defined as a corneal punctate fluorescein staining score of ≥4 in either eye by the National Eye Institute evaluation scale summed over 5 areas each with a 0-3 scoring scale |
| Number of Subjects With Adverse Events | 24 weeks | Determine the safety of oral CF 101 in this subject population. Adverse Events (AEs) and changes in vital signs, physical examination, clinical laboratory tests (liver, kidney, hematology, chemistry and urinalysis), electrocardiogram (ECG) findings, slit lamp and ophthalmic examination, visual acuity, and intraocular pressure measurements. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects Who Achieve an Increase in Schirmer Test Tearing by >9mm Over Baseline | 24 weeks | ST wetting increase over Baseline of ≥10 mm with or without anesthesia in either eye at Week 24, using a strip of filter paper placed inside the lower eyelid |
| Ocular Surface Disease Index | 24 weeks | The Ocular Surface Disease Index is assessed on a scale of 0 to 100, with higher scores representing greater disability. The subtotal score is based on 12 questions with answers ranging from 0 - none the time, to 4 - all of the time. The number of questions answered is totaled (0 - 12). The OSDI is calculated using the sum of subtotal scores (0-48) multiplied by 25, divided by number of questions answered (0-12). (i.e., if a participant answers all 12 questions with a severe outcome of 4, their respected OSDI = \[(4 x 12) x 25\] / 12 = \[48 x 25\] / 12 = 100) The outcome measured is the Mean Change from Baseline in Ocular Surface Disease Index at Week 24 |
Countries
Israel
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| CF101 0.1 mg CF101: orally q12h | 77 |
| CF101 1 mg CF101: orally q12h | 78 |
| Placebo CF101: orally q12h | 81 |
| Total | 236 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 2 | 1 |
Baseline characteristics
| Characteristic | CF101 1 mg | Placebo | CF101 0.1 mg | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 22 Participants | 22 Participants | 20 Participants | 64 Participants |
| Age, Categorical Between 18 and 65 years | 56 Participants | 59 Participants | 57 Participants | 172 Participants |
| Age, Continuous | 54.5 years | 55.1 years | 56.8 years | 55.5 years |
| Region of Enrollment Israel | 78 participants | 81 participants | 77 participants | 236 participants |
| Sex: Female, Male Female | 62 Participants | 71 Participants | 55 Participants | 188 Participants |
| Sex: Female, Male Male | 16 Participants | 10 Participants | 22 Participants | 48 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 9 / 77 | 13 / 78 | 9 / 81 |
| serious Total, serious adverse events | 6 / 77 | 0 / 78 | 1 / 81 |
Outcome results
Primary
Number of Subjects Who Achieved Complete Clearing of Corneal Staining (i.e., Total Corneal FS Score = 0) at Week 24
Complete clearing of corneal staining by fluorescein staining (FS). The primary efficacy analysis was performed for 1eye (target eye), defined as the eye with the larger corneal FS value at Baseline. If both eyes had the same corneal FS value at baseline, the target eye was considered the eye with the larger central corneal staining value at Baseline. Corneal FS defined as a corneal punctate fluorescein staining score of ≥4 in either eye by the National Eye Institute evaluation scale summed over 5 areas each with a 0-3 scoring scale
Time frame: 24 weeks
Population: The Number of Subjects Who Achieved Complete Clearing of Corneal Staining in Target Eye Using NRI at 24 weeks (ITT Population)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| CF101 0.1 mg | Number of Subjects Who Achieved Complete Clearing of Corneal Staining (i.e., Total Corneal FS Score = 0) at Week 24 | Complete clearing of corneal staining in target eye using NRI - YES | 15 participants |
| CF101 0.1 mg | Number of Subjects Who Achieved Complete Clearing of Corneal Staining (i.e., Total Corneal FS Score = 0) at Week 24 | Complete clearing of corneal staining in target eye using NRI - NO | 61 participants |
| CF101 1 mg | Number of Subjects Who Achieved Complete Clearing of Corneal Staining (i.e., Total Corneal FS Score = 0) at Week 24 | Complete clearing of corneal staining in target eye using NRI - YES | 13 participants |
| CF101 1 mg | Number of Subjects Who Achieved Complete Clearing of Corneal Staining (i.e., Total Corneal FS Score = 0) at Week 24 | Complete clearing of corneal staining in target eye using NRI - NO | 64 participants |
| Placebo | Number of Subjects Who Achieved Complete Clearing of Corneal Staining (i.e., Total Corneal FS Score = 0) at Week 24 | Complete clearing of corneal staining in target eye using NRI - YES | 21 participants |
| Placebo | Number of Subjects Who Achieved Complete Clearing of Corneal Staining (i.e., Total Corneal FS Score = 0) at Week 24 | Complete clearing of corneal staining in target eye using NRI - NO | 55 participants |
Primary
Number of Subjects With Adverse Events
Determine the safety of oral CF 101 in this subject population. Adverse Events (AEs) and changes in vital signs, physical examination, clinical laboratory tests (liver, kidney, hematology, chemistry and urinalysis), electrocardiogram (ECG) findings, slit lamp and ophthalmic examination, visual acuity, and intraocular pressure measurements.
Time frame: 24 weeks
Population: Safety Population - Adverse Events
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| CF101 0.1 mg | Number of Subjects With Adverse Events | Psychiatric disorders | 1 Participants |
| CF101 0.1 mg | Number of Subjects With Adverse Events | General disorders and administration site conditions | 1 Participants |
| CF101 0.1 mg | Number of Subjects With Adverse Events | Any AEs | 29 Participants |
| CF101 0.1 mg | Number of Subjects With Adverse Events | Nervous system disorders | 4 Participants |
| CF101 0.1 mg | Number of Subjects With Adverse Events | Immune system disorders | 1 Participants |
| CF101 0.1 mg | Number of Subjects With Adverse Events | Ear and labyrinth disorders | 1 Participants |
| CF101 0.1 mg | Number of Subjects With Adverse Events | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | 1 Participants |
| CF101 0.1 mg | Number of Subjects With Adverse Events | Infections and infestations | 3 Participants |
| CF101 0.1 mg | Number of Subjects With Adverse Events | Vascular disorders | 2 Participants |
| CF101 0.1 mg | Number of Subjects With Adverse Events | Musculoskeletal and connective tissue disorders | 2 Participants |
| CF101 0.1 mg | Number of Subjects With Adverse Events | Investigations | 4 Participants |
| CF101 0.1 mg | Number of Subjects With Adverse Events | Respiratory, thoracic and mediastinal disorders | 2 Participants |
| CF101 0.1 mg | Number of Subjects With Adverse Events | Endocrine disorders | 1 Participants |
| CF101 0.1 mg | Number of Subjects With Adverse Events | Skin and subcutaneous tissue disorders | 2 Participants |
| CF101 0.1 mg | Number of Subjects With Adverse Events | Reproductive system and breast disorders | 2 Participants |
| CF101 0.1 mg | Number of Subjects With Adverse Events | Eye disorders | 6 Participants |
| CF101 0.1 mg | Number of Subjects With Adverse Events | Cardiac disorders | 4 Participants |
| CF101 0.1 mg | Number of Subjects With Adverse Events | Renal and urinary disorders | 10 Participants |
| CF101 0.1 mg | Number of Subjects With Adverse Events | Gastrointestinal disorders | 3 Participants |
| CF101 0.1 mg | Number of Subjects With Adverse Events | Blood and lymphatic system disorders | 1 Participants |
| CF101 1 mg | Number of Subjects With Adverse Events | Respiratory, thoracic and mediastinal disorders | 1 Participants |
| CF101 1 mg | Number of Subjects With Adverse Events | Any AEs | 37 Participants |
| CF101 1 mg | Number of Subjects With Adverse Events | Blood and lymphatic system disorders | 0 Participants |
| CF101 1 mg | Number of Subjects With Adverse Events | Cardiac disorders | 6 Participants |
| CF101 1 mg | Number of Subjects With Adverse Events | Ear and labyrinth disorders | 1 Participants |
| CF101 1 mg | Number of Subjects With Adverse Events | Endocrine disorders | 1 Participants |
| CF101 1 mg | Number of Subjects With Adverse Events | Eye disorders | 8 Participants |
| CF101 1 mg | Number of Subjects With Adverse Events | Gastrointestinal disorders | 5 Participants |
| CF101 1 mg | Number of Subjects With Adverse Events | General disorders and administration site conditions | 4 Participants |
| CF101 1 mg | Number of Subjects With Adverse Events | Immune system disorders | 0 Participants |
| CF101 1 mg | Number of Subjects With Adverse Events | Infections and infestations | 2 Participants |
| CF101 1 mg | Number of Subjects With Adverse Events | Investigations | 9 Participants |
| CF101 1 mg | Number of Subjects With Adverse Events | Musculoskeletal and connective tissue disorders | 5 Participants |
| CF101 1 mg | Number of Subjects With Adverse Events | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | 0 Participants |
| CF101 1 mg | Number of Subjects With Adverse Events | Nervous system disorders | 6 Participants |
| CF101 1 mg | Number of Subjects With Adverse Events | Psychiatric disorders | 1 Participants |
| CF101 1 mg | Number of Subjects With Adverse Events | Renal and urinary disorders | 16 Participants |
| CF101 1 mg | Number of Subjects With Adverse Events | Reproductive system and breast disorders | 3 Participants |
| CF101 1 mg | Number of Subjects With Adverse Events | Skin and subcutaneous tissue disorders | 5 Participants |
| CF101 1 mg | Number of Subjects With Adverse Events | Vascular disorders | 4 Participants |
| Placebo | Number of Subjects With Adverse Events | Blood and lymphatic system disorders | 3 Participants |
| Placebo | Number of Subjects With Adverse Events | Nervous system disorders | 4 Participants |
| Placebo | Number of Subjects With Adverse Events | Gastrointestinal disorders | 4 Participants |
| Placebo | Number of Subjects With Adverse Events | Vascular disorders | 4 Participants |
| Placebo | Number of Subjects With Adverse Events | Psychiatric disorders | 0 Participants |
| Placebo | Number of Subjects With Adverse Events | Eye disorders | 3 Participants |
| Placebo | Number of Subjects With Adverse Events | Skin and subcutaneous tissue disorders | 1 Participants |
| Placebo | Number of Subjects With Adverse Events | Renal and urinary disorders | 11 Participants |
| Placebo | Number of Subjects With Adverse Events | Endocrine disorders | 0 Participants |
| Placebo | Number of Subjects With Adverse Events | Any AEs | 29 Participants |
| Placebo | Number of Subjects With Adverse Events | Reproductive system and breast disorders | 1 Participants |
| Placebo | Number of Subjects With Adverse Events | Ear and labyrinth disorders | 0 Participants |
| Placebo | Number of Subjects With Adverse Events | Investigations | 1 Participants |
| Placebo | Number of Subjects With Adverse Events | Infections and infestations | 0 Participants |
| Placebo | Number of Subjects With Adverse Events | Cardiac disorders | 6 Participants |
| Placebo | Number of Subjects With Adverse Events | Musculoskeletal and connective tissue disorders | 1 Participants |
| Placebo | Number of Subjects With Adverse Events | Immune system disorders | 2 Participants |
| Placebo | Number of Subjects With Adverse Events | Respiratory, thoracic and mediastinal disorders | 7 Participants |
| Placebo | Number of Subjects With Adverse Events | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | 1 Participants |
| Placebo | Number of Subjects With Adverse Events | General disorders and administration site conditions | 2 Participants |
Secondary
Number of Subjects Who Achieve an Increase in Schirmer Test Tearing by >9mm Over Baseline
ST wetting increase over Baseline of ≥10 mm with or without anesthesia in either eye at Week 24, using a strip of filter paper placed inside the lower eyelid
Time frame: 24 weeks
Population: ITT Population
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| CF101 0.1 mg | Number of Subjects Who Achieve an Increase in Schirmer Test Tearing by >9mm Over Baseline | Number of subjects with ST wetting increase over baseline of >=10mm at 24 weeks | 15 Participants |
| CF101 0.1 mg | Number of Subjects Who Achieve an Increase in Schirmer Test Tearing by >9mm Over Baseline | Number of subjects without ST wetting increase over baseline of >=10mm at 24 weeks | 61 Participants |
| CF101 1 mg | Number of Subjects Who Achieve an Increase in Schirmer Test Tearing by >9mm Over Baseline | Number of subjects with ST wetting increase over baseline of >=10mm at 24 weeks | 13 Participants |
| CF101 1 mg | Number of Subjects Who Achieve an Increase in Schirmer Test Tearing by >9mm Over Baseline | Number of subjects without ST wetting increase over baseline of >=10mm at 24 weeks | 64 Participants |
| Placebo | Number of Subjects Who Achieve an Increase in Schirmer Test Tearing by >9mm Over Baseline | Number of subjects with ST wetting increase over baseline of >=10mm at 24 weeks | 13 Participants |
| Placebo | Number of Subjects Who Achieve an Increase in Schirmer Test Tearing by >9mm Over Baseline | Number of subjects without ST wetting increase over baseline of >=10mm at 24 weeks | 63 Participants |
Secondary
Ocular Surface Disease Index
The Ocular Surface Disease Index is assessed on a scale of 0 to 100, with higher scores representing greater disability. The subtotal score is based on 12 questions with answers ranging from 0 - none the time, to 4 - all of the time. The number of questions answered is totaled (0 - 12). The OSDI is calculated using the sum of subtotal scores (0-48) multiplied by 25, divided by number of questions answered (0-12). (i.e., if a participant answers all 12 questions with a severe outcome of 4, their respected OSDI = \[(4 x 12) x 25\] / 12 = \[48 x 25\] / 12 = 100) The outcome measured is the Mean Change from Baseline in Ocular Surface Disease Index at Week 24
Time frame: 24 weeks
Population: ITT Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CF101 0.1 mg | Ocular Surface Disease Index | -24.27 Score on a Scale - OSDI | Standard Deviation 17.99 |
| CF101 1 mg | Ocular Surface Disease Index | -25.63 Score on a Scale - OSDI | Standard Deviation 16.77 |
| Placebo | Ocular Surface Disease Index | -28.70 Score on a Scale - OSDI | Standard Deviation 19.08 |