Study of Efficacy and Safety of SAF312 Eye Drops in Subjects With Post-operative Corneal Induced Chronic Pain (CICP)

Study Overview
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Brief Summary
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The study is designed to demonstrate the safety and efficacy of two dose concentrations of SAF312 eye drops (dose 1 and dose 2) in subjects with CICP persisting at least for 4 months after refractive or cataract surgery and chronicity confirmed during the observational period. The study will also determine the optimal dose to carry forward for further development.

Detailed Description
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This study is a Phase 2 randomized, double-blinded, multi-center, parallel group, placebo-controlled evaluation of the safety and efficacy of SAF312, 5 mg/ml and 15 mg/ml eye drops versus placebo used twice-daily in both eyes for 12 weeks. Eligible subjects will have undergone refractive surgery (i.e., PRK, LASIK, LASEK, RK, or SMILE) in both eyes or cataract surgery in both eyes with or without refractive enhancement in one or both eyes at least 4 months prior to Screening, and have been suffering from chronic ocular pain as a result of their surgery. Eligible patients must also demonstrate chronicity of the pain at Baseline Visit as described in inclusion criteria. Overall approximately 150 subjects will be enrolled in the study and randomized to one of 3 study arms in 1:1:1 ratio

Official Title
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A 12-week Parallel Group, Randomized, Placebo-controlled, Double-blinded, Multi-center Study to Evaluate Efficacy and Safety of 2 Concentrations of SAF312 Eye Drops (5 mg/ml and 15 mg/ml) Used Twice-daily in the Treatment of Post-operative Corneal Induced Chronic Pain (CICP) Following Photorefractive Keratectomy (PRK) or Laser-assisted in Situ Keratomileusis (LASIK) Surgeries

Conditions
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Chronic Ocular Pain

Intervention / Treatment
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* Other: SAF312 Placebo
* Drug: SAF312


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Subjects who have undergone refractive surgery (i.e., PRK, LASIK, LASEK, RK, or SMILE) in both eyes or cataract surgery in both eyes, with or without refractive enhancement in one or both eyes, ≥4 months prior to Screening Visit and experiencing persistent ocular surface pain since the surgery, and have been seen by an ophthalmologist or optometrist at least once with complaint of continued ocular pain since surgery. Subjects who demonstrate a ≥ 60% reduction in ocular pain within 5 minutes after instillation of a single topical ocular anesthetic drop at Screening Visit. At Baseline Subjects with an average pain severity VAS score of ≥ 30 mm based on Daily eDiary for the last 7 days prior to Baseline Visit. Subjects who have reported pain severity >10 mm based on Daily eDiary for > 50% of the days of the observational period (Screening) Key Exclusion Criteria: Use of nerve growth factor eye drops within 14 days of the Screening Visit Seasonal allergic conjunctivitis, or other acute or seasonal ocular diagnosis that are active at the time of Screening or would be active during the course of the study. Any history of ocular herpes simplex virus or herpes zoster virus infection, or other severe ocular conditions such as graft versus host disease, Stevens-Johnson syndrome or sarcoidosis. Presence of any ocular infection (bacterial, viral, or fungal) within 30 days prior to Screening. Chronic topical ocular medications (ie. cyclosporine, lifitegrast) initiated <6 months prior to Screening Visit, or any anticipated change during the study. Use of ocular or nasal corticosteroids within 30 days of Screening Visit. Use of neuromodulatory medications (eg, gabapentin, pregabalin) or opioid use for non-ocular pain within 30 days of Screening Visit. Chronic medications (both over the counter and prescription) that have not been stable for at least 30 days prior to Screening Visit, or any anticipated change in the chronic medication regimen. Subjects requiring hospitalization within 6 months prior to screening for severe psychiatric disorders (e.g. psychosis, schizophrenia, mania, depression) or major psychiatric illness.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: SAF312 Placebo<br>Randomized to a 1:1:1 topical eye drops, twice daily | Other: SAF312 Placebo<br>* Topical ocular, suspension eye drops,<br>* Other names: Artificial tears;|
| Experimental: SAF312 dose 1<br>Randomized to a 1:1:1 topical eye drops, twice daily | Drug: SAF312<br>* Topical ocular, suspension eye drops<br>|
| Experimental: SAF312 dose 2<br>Randomized to a 1:1:1 topical eye drops, twice daily | Drug: SAF312<br>* Topical ocular, suspension eye drops<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in mean pain severity Visual Analog Scale | To demonstrate the efficacy of at least 1 of 2 concentrations of SAF312 (dose 1 or dose 2) with superiority to placebo in reducing ocular pain severity. The pain severity Visual Analogue Scale (VAS) is completed by the subject using an electronic diary. A vertical mark is placed on the horizontal scoring line (anchored with 'No Pain' on the left and 'Very Severe' pain on the right) to score the severity of ocular pain over the past 24 hours (max score=100). Higher scores indicate higher pain severity. | 84 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in pain severity Visual Analog Scale | To evaluate additional efficacy of 2 concentrations of SAF312 vs placebo (eg., time to pain severity improvement). The pain severity Visual Analogue Scale (VAS) is completed by the subject using an electronic diary. A vertical mark is placed on the horizontal scoring line (anchored with 'No Pain' on the left and 'Very Severe' pain on the right) to score the severity of ocular pain over the past 24 hours (max score=100). Higher scores indicate higher pain severity. | Baseline, Day 7 and Day 14 | 
| Change in pain frequency Visual Analog Scale | To evaluate additional efficacy of 2 concentrations of SAF312 vs placebo (eg., time to pain frequency improvement). The pain frequency Visual Analogue Scale (VAS) is completed by the subject using an electronic diary. A vertical mark is placed on the horizontal scoring line (anchored with 'Rarely' on the left and 'All the Time' on the right) to score the frequency of ocular pain over the past 24 hours (max score=100). Higher scores indicate higher pain frequency. | Baseline, Week 12 | 
| Change in Ocular Pain Assessment Scale (OPAS) sub-scale Quality of Life | To evaluate additional efficacy of 2 concentrations of SAF312 vs placebo (e.g., time to improvement in quality of life). Each question in the Ocular Pain Assessment Survey (OPAS) quality of life subscale is scored by the subject on a line marked from 0 (not at all) to 10 (completely) that describes how much pain has interfered with or affected a particular activity (max score= 10/question). A higher score suggests a higher impact by pain on a particular activity. | Baseline, Week 12 | 
| Change in ocular surface parameters as assessed by the corneal fluorescein staining | To evaluate if SAF312 has negative effects to the ocular surface after prolonged TRPV1 inhibition. The degree of corneal fluorescein staining in each of five regions (superior, inferior, nasal, temporal, and central) is graded on a scale from 0 to 4 (max score=20/eye). Higher scores suggest higher degrees of corneal staining (worsening). | Baseline, Week 12 | 
| Change in ocular surface parameters as assessed by lissamine staining | To evaluate if SAF312 has negative effects to the ocular surface after prolonged TRPV1 inhibition. The degree of lissamine conjunctival staining in two regions (temporal and nasal) is graded on a scale from 0 to 4 (max score = 8/eye). Higher scores suggest higher degrees of corneal staining (worsening). | Baseline, Week 12 | 
| Change in ocular surface parameters as assessed by Schirmer's testing | To evaluate if SAF312 has negative effects to the ocular surface after prolonged TRPV1 inhibition. The Schirmer's test will be performed without anesthetic. Tear secretion is measured in millimeters based on the length of strip wetted by tears (max score =35 mm/eye). Lower values indicate lower relative amounts of tear secretion (worsening). | Baseline, Week 12 | 
| Change in ocular surface parameters as evaluated by the investigator using the McMonnies redness photographic scale. | To evaluate if SAF312 has negative effects to the ocular surface after prolonged TRPV1 inhibition. Conjunctival redness in each of two regions (nasal and temporal) is graded on a scale from 0 to 5 using the McMonnies conjunctival redness photographic scale (max score=5/region). Higher scores suggest higher degrees of redness (worsening). | Baseline, Week 12 | 
| Comparison of adverse events rates between active and placebo | To evaluate the safety of 2 concentrations of SAF312 (dose 1 and dose 2). Ocular and non-ocular adverse events will be summarized separately. Separate summaries also will be provided for study treatment related adverse events, death, serious adverse events, and other significant adverse events leading to discontinuation. Higher rates of adverse events in the active group compared to the placebo may suggest potential safety signals. | Baseline, End of Study (Day 88) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Eye pain, Dry eye like symptoms, Ocular surface pain, Corneal induced chronic pain, neuropathic eye pain, post-operative corneal induced chronic pain, CICP, corneal, corneal pain