Keratoconjunctivitis Sicca
Conditions
Keywords
Keratoconjunctivitis Sicca, KCS, Dry Eye
Brief summary
This is a Phase 2, randomized, double-masked, placebo-controlled, parallel-group study in adult males and females, aged 18 years and over, with a diagnosis of moderate-to-severe keratoconjunctivitis sicca (KCS). Patients will be randomized to receive either CF101 1 mg or matching placebo, given orally every 12 hours (q12h) for 12 weeks. A Screening Period of up to 4 weeks that includes a 2-week run-in period will precede a 12-week treatment period, followed by a 2-week follow-up period.
Detailed description
At a Screening Visit, patients who provide written informed consent will have screening procedures performed, including a complete medical history, medication history, physical examination, including height, weight, sitting blood pressure, pulse rate and temperature, and clinical laboratory tests. Disease activity will be assessed using tear meniscus (TM) height, tear break-up time (BUT), fluorescein staining (FS), Schirmer test, and the Dry Eye Symptom Score (DESS). Doses of artificial tears must be stable for \>2 weeks prior to the Screening Visit. Eligible patients will begin a 2-week run-in period, during which time they will be instructed to discontinue use of all topical ophthalmic medications except for lubricant eye drops. Patients who successfully complete the 2-week run-in period will be randomized to their assigned medication (CF101 1 mg or matching placebo) to be taken orally every q12h for 12 weeks. Patients will return for assessments and a new supply of study medication at Weeks 2, 4, 8 and 12, and at Week 14 for a final follow-up assessment.
Interventions
DRUGCF101
Orally CF101 1mg
DRUGPlacebo
Orally matching Placebo
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 KCS as defined by: (1) Schirmer Test (ST) (without anesthesia) \< 7 mm/5 min in either eye; AND (2) Positive FS, defined as a corneal punctate fluorescein staining score of ≥1 in either eye, where 0 = none and 3= severe; AND (3) At least 1 of the following ocular symptoms scored at ≥2, where 0 = none and 4 = very severe/interferes with normal activities: photophobia, blurred vision, foreign body sensation, soreness or pain, itching, burning, dryness; * Willing to use no topical ocular treatments except for the unpreserved artificial tears; * Doses of unpreserved artificial tears have been stable for \>2 weeks prior to Screening Visit; * 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
* Has Sjögren's Syndrome with significant systemic non-exocrine gland involvement; * Has Stevens-Johnson Syndrome; * If KCS is due to rheumatoid arthritis or other autoimmune diseases, patient may not be receiving disease-modifying drugs, including methotrexate and biological agents; * Use of systemic immunosuppressive drugs; * Use of oral corticosteroids \>10 mg prednisone, or equivalent, per day; * Use of topical steroids within 2 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; * Presence of chronic ocular disease other than KCS requiring topical treatment; * Presence of post-burn ocular injury; * Ocular herpes simplex virus infection; * Concomitant use of contact lenses; * Persistent intraocular inflammation or infection; * Active blepharitis; * Recent surgical occlusion of the lacrimal puncta; * Subepithelial corneal scarring; * Anesthetic or neurotrophic corneas; * Hemoglobin level \<9.0 gm/L; * Platelet count \<125,000/mm\^3; * White blood cell count \<3500/mm\^3; * Serum creatinine level outside the laboratory's normal limits; * Liver aminotransferase levels greater than 2 times the laboratory's upper limit of normal; * Pregnancy, planned pregnancy, lactation, or inadequate contraception as judged by the Investigator; * History of malignancy within the past 5 years (excluding basal cell carcinoma of the skin); * Significant acute or chronic medical, ophthalmic, or psychiatric illness that, in the judgment of the Investigator, could compromise patient safety, limit the patient's ability to complete the study, and/or compromise the objectives of the study; * Participation in another investigational drug or vaccine trial concurrently or within 30 days; or * Other conditions which would confound the study evaluations or endanger the safety of the patient.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 12 in Schirmer Test (ST) Score in Millimeters | 12 weeks | Involved placing a standardized paper tear strip inside the lower eyelid for 5 minutes. The tear strip was then removed and the length of the strip that was wet from tears was measured in millimeters. Change from baseline is calculated. Scores range 0-35 mm, with higher scores indicating more (better) tear production. |
| Change From Baseline to Week 12 in Tear Break-Up Time (BUT) in Seconds | 12 weeks | Time elapsed between a complete blink and the development of the first random dry spot on the tear film as seen under fluorescent light. Change from baseline is calculated. Scores range 0-30 seconds, with higher scores indicating better tear composition and function. |
| Number of Subjects With >25% Improvement in Fluorescein Staining of the Cornea (FS) at Week 12 | 12 weeks | Severity of corneal epithelial loss as graded by Fluorescein Staining of the cornea, assessed on a 0-4+ scale with 0 = none and 4+ = severe de-epithelialization (in other words, higher scores indicate worse disease), expressed as number of participants with \>25% improvement at Week 12 relative to baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects Experiencing Clinical Success at Week 12 | 12 weeks | Proportion of subjects experiencing improvement of ≥25% over baseline at Week 12 in (a) tear breakup time (BUT), (b) superficial punctate keratitis as assessed by fluorescein staining (FS), or Schirmer Test (ST) |
| Percent Change From Baseline to Week 12 in the Use of Artificial Tears | 12 weeks | Daily use of REFRESH TEARS® Lubricant Eye Drops artificial tears supplied to each patient was recorded in diaries provided to patients. Percent change from baseline is calculated. |
| Change From Baseline to 12 Weeks in Dry Eye Symptom Score (DESS) | 12 weeks | DESS consists of 12 questions designed to assess the symptoms of ocular irritation, covering three areas: ocular symptoms, environmental triggers and vision-related function. Each of the 12 symptoms can be graded 0-4, with 0 indicating no symptoms over the past week, and 4 meaning constant symptoms over the past week. Scores from all answered questions are summed. The final score is multiplied by (25/number of questions answered) to give an outcome between 0 (no symptoms) to 100 (worst possible symptoms). Change from baseline is calculated. |
| Change From Baseline to Week 12 in Tear Meniscus (TM) Height | 12 weeks | Indicator of tear volume. TM was recorded on a scale from 0-3, with 0=none, 1=trace, 2=normal, and 3=high, with higher scores meaning better tear production and integrity. Change from baseline. |
Countries
Israel
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| CF101 1 mg CF101 1 mg q12 hours | 42 |
| Placebo Placebo tablets q12 hours for 12 weeks | 38 |
| Total | 80 |
Baseline characteristics
| Characteristic | CF101 1 mg | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 56.2 Years STANDARD_DEVIATION 14.4 | 61.4 Years STANDARD_DEVIATION 1311.7 | 58.7 Years STANDARD_DEVIATION 13.4 |
| Region of Enrollment Israel | 42 participants | 38 participants | 80 participants |
| Sex: Female, Male Female | 24 Participants | 28 Participants | 52 Participants |
| Sex: Female, Male Male | 18 Participants | 10 Participants | 28 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 20 / 39 | 8 / 37 |
| serious Total, serious adverse events | 0 / 39 | 0 / 37 |
Outcome results
Primary
Change From Baseline to Week 12 in Schirmer Test (ST) Score in Millimeters
Involved placing a standardized paper tear strip inside the lower eyelid for 5 minutes. The tear strip was then removed and the length of the strip that was wet from tears was measured in millimeters. Change from baseline is calculated. Scores range 0-35 mm, with higher scores indicating more (better) tear production.
Time frame: 12 weeks
Population: ITT
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| CF101 1 mg | Change From Baseline to Week 12 in Schirmer Test (ST) Score in Millimeters | 1.25 Millimeters | Standard Error 0.765 |
| Placebo | Change From Baseline to Week 12 in Schirmer Test (ST) Score in Millimeters | 3.81 Millimeters | Standard Error 0.814 |
p-value: 0.027ANCOVA
Primary
Change From Baseline to Week 12 in Tear Break-Up Time (BUT) in Seconds
Time elapsed between a complete blink and the development of the first random dry spot on the tear film as seen under fluorescent light. Change from baseline is calculated. Scores range 0-30 seconds, with higher scores indicating better tear composition and function.
Time frame: 12 weeks
Population: ITT
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| CF101 1 mg | Change From Baseline to Week 12 in Tear Break-Up Time (BUT) in Seconds | 2.83 seconds | Standard Error 0.906 |
| Placebo | Change From Baseline to Week 12 in Tear Break-Up Time (BUT) in Seconds | 0.48 seconds | Standard Error 0.083 |
p-value: 0.083ANCOVA
Primary
Number of Subjects With >25% Improvement in Fluorescein Staining of the Cornea (FS) at Week 12
Severity of corneal epithelial loss as graded by Fluorescein Staining of the cornea, assessed on a 0-4+ scale with 0 = none and 4+ = severe de-epithelialization (in other words, higher scores indicate worse disease), expressed as number of participants with \>25% improvement at Week 12 relative to baseline.
Time frame: 12 weeks
Population: ITT
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CF101 1 mg | Number of Subjects With >25% Improvement in Fluorescein Staining of the Cornea (FS) at Week 12 | 22 participants |
| Placebo | Number of Subjects With >25% Improvement in Fluorescein Staining of the Cornea (FS) at Week 12 | 12 participants |
p-value: 0.028Fisher Exact
Secondary
Change From Baseline to 12 Weeks in Dry Eye Symptom Score (DESS)
DESS consists of 12 questions designed to assess the symptoms of ocular irritation, covering three areas: ocular symptoms, environmental triggers and vision-related function. Each of the 12 symptoms can be graded 0-4, with 0 indicating no symptoms over the past week, and 4 meaning constant symptoms over the past week. Scores from all answered questions are summed. The final score is multiplied by (25/number of questions answered) to give an outcome between 0 (no symptoms) to 100 (worst possible symptoms). Change from baseline is calculated.
Time frame: 12 weeks
Population: ITT
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CF101 1 mg | Change From Baseline to 12 Weeks in Dry Eye Symptom Score (DESS) | 34.44 score on a scale | Standard Deviation 25.393 |
| Placebo | Change From Baseline to 12 Weeks in Dry Eye Symptom Score (DESS) | 34.53 score on a scale | Standard Deviation 20.605 |
p-value: 0.387ANCOVA
Secondary
Change From Baseline to Week 12 in Tear Meniscus (TM) Height
Indicator of tear volume. TM was recorded on a scale from 0-3, with 0=none, 1=trace, 2=normal, and 3=high, with higher scores meaning better tear production and integrity. Change from baseline.
Time frame: 12 weeks
Population: ITT
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CF101 1 mg | Change From Baseline to Week 12 in Tear Meniscus (TM) Height | 0.38 units on a scale | Standard Deviation 0.637 |
| Placebo | Change From Baseline to Week 12 in Tear Meniscus (TM) Height | 0.13 units on a scale | Standard Deviation 0.694 |
p-value: 0.203Wilcoxon (Mann-Whitney)
Secondary
Number of Subjects Experiencing Clinical Success at Week 12
Proportion of subjects experiencing improvement of ≥25% over baseline at Week 12 in (a) tear breakup time (BUT), (b) superficial punctate keratitis as assessed by fluorescein staining (FS), or Schirmer Test (ST)
Time frame: 12 weeks
Population: ITT
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CF101 1 mg | Number of Subjects Experiencing Clinical Success at Week 12 | 24 Participants |
| Placebo | Number of Subjects Experiencing Clinical Success at Week 12 | 20 Participants |
p-value: 0.655Fisher Exact
Secondary
Percent Change From Baseline to Week 12 in the Use of Artificial Tears
Daily use of REFRESH TEARS® Lubricant Eye Drops artificial tears supplied to each patient was recorded in diaries provided to patients. Percent change from baseline is calculated.
Time frame: 12 weeks
Population: ITT
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| CF101 1 mg | Percent Change From Baseline to Week 12 in the Use of Artificial Tears | 355625.0 percentage change from baseline | Standard Error 410162 |
| Placebo | Percent Change From Baseline to Week 12 in the Use of Artificial Tears | 187883.1 percentage change from baseline | Standard Error 477720.08 |
p-value: 0.807ANCOVA