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

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

The study was designed to demonstrate the safety and efficacy of two dose concentrations of SAF312 eye drops (5 mg/mL and 15 mg/mL) in subjects with CICP persisting at least for 4 months after refractive or cataract surgery and chronicity confirmed during the observational period. The study also determined the optimal dose to carry forward for further development.

Study Overview

• Status: Completed
• Conditions: Chronic Ocular Pain
• Intervention / Treatment: Drug: SAF312; Other: SAF312 Placebo

Detailed Description

This was a Phase II randomized, double-masked, multi-center, parallel group, placebo-controlled study to evaluate 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. The study consisted of a 12-week observation period starting from Screening Visit (Visit 1) until the Baseline/Randomization Visit (Visit 2). Subjects who met eligibility criteria at Visit 2 were randomized to one of the three treatment arms (SAF312 5 mg/mL, SAF312 15 mg/mL, Placebo) in a 1:1:1 ratio. Subjects who qualified for randomization had visits every 2 weeks for the first 4 weeks, and then monthly visits for the remainder of the 12-week treatment period.

• Study Type: Interventional
• Enrollment (Actual): 153
• Phase: Phase 2

Contacts and Locations

Study Locations

• Japan
  • Hokkaido
    • Sapporo city, Hokkaido, Japan, 060 8648
      • Novartis Investigative Site
  • Tokyo
    • Shinagawa, Tokyo, Japan, 141-0022
      • Novartis Investigative Site
• United Kingdom
  • Newcastle Upon Tyne, United Kingdom, NE1 4LP
    • Novartis Investigative Site
  • West Midlands
    • Birmingham, West Midlands, United Kingdom, B75 6QW
      • Novartis Investigative Site
• United States
  • California
    • Mission Hills, California, United States, 91345
      • North Valley Eye Medical Group
    • Newport Beach, California, United States, 92660
      • NVISION Eye Centers
    • Palo Alto, California, United States, 94303
      • Stanford Eye Laser Center
    • San Diego, California, United States, 92122
      • Gordon Schanzlin New Vision Inst
  • Florida
    • Coral Springs, Florida, United States, 33067
      • Novartis Investigative Site
    • Jacksonville, Florida, United States, 32256
      • Novartis Investigative Site
    • Miami, Florida, United States, 33136
      • Novartis Investigative Site
  • Massachusetts
    • Boston, Massachusetts, United States, 02111
      • Tufts Medical Center
    • Needham, Massachusetts, United States, 02494
      • Boston Sight
  • Michigan
    • Ann Arbor, Michigan, United States, 48105
      • Univ of MI Kellogg Eye Center .
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke Univ Medical Center Ophthalmology
  • North Dakota
    • Fargo, North Dakota, United States, 58103
      • Bergstrom Eye Research LLC
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania .
  • Tennessee
    • Chattanooga, Tennessee, United States, 37411
      • Chattanooga Eye Institute
    • Memphis, Tennessee, United States, 38119
      • Novartis Investigative Site
    • Smyrna, Tennessee, United States, 37167
      • Advancing Vision Research LLC
  • Texas
    • Houston, Texas, United States, 77030
      • Novartis Investigative Site
    • Houston, Texas, United States, 77025
      • Novartis Investigative Site
    • Houston, Texas, United States, 77074
      • Novartis Investigative Site
    • Lakeway, Texas, United States, 78738
      • Lake Travis Eye and Laser Ctr
  • Utah
    • Salt Lake City, Utah, United States, 84117
      • Stacy R Smith MD PC
  • Virginia
    • Lynchburg, Virginia, United States, 24502
      • Piedmont Eye Center
  • Washington
    • Renton, Washington, United States, 98057
      • Rainier Clinical Research Center Inc .
    • Seattle, Washington, United States, 98119
      • Periman Eye Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: SAF312 Placebo; Randomized to a 1:1:1 topical eye drops, twice daily	Other: SAF312 Placebo; Topical ocular, suspension eye drops; Other Names: Artificial tears
Experimental: SAF312 5 mg/mL; Randomized to a 1:1:1 topical eye drops, twice daily	Drug: SAF312; Topical ocular, suspension eye drops
Experimental: SAF312 15 mg/mL; Randomized to a 1:1:1 topical eye drops, twice daily	Drug: SAF312; Topical ocular, suspension eye drops

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline at Week 12 in Ocular Pain Severity Visual Analog Scale (VAS)	The pain severity Visual Analogue Scale (VAS) was completed by the subject using an electronic diary. A vertical mark was 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, with a range from 0 (min) to 100 (max). Higher scores indicate higher pain severity. A negative change from baseline is a positive outcome.	Baseline, Week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ocular Pain Severity Visual Analog Scale (VAS): Summary Statistics of Change From Baseline at Day 7 and Day 14	The pain severity Visual Analogue Scale (VAS) was completed by the subject using an electronic diary. A vertical mark was 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, with a range from 0 (min) to 100 (max). Higher scores indicate higher pain severity. A negative change from baseline is a positive outcome.	Baseline, Days 7 and 14
Ocular Pain Frequency Visual Analog Scale (VAS): Summary Statistics of Weekly Mean Change From Baseline to Week 12	The pain frequency Visual Analogue Scale (VAS) was completed by the subject using an electronic diary. A vertical mark was placed on the horizontal scoring line (anchored with 'No Pain' on the left and 'Very Frequent' pain on the right) to score the frequency of ocular pain over the past 24 hours, with a range from 0 (min) to 100 (max). Higher scores indicate higher pain frequency. A negative change from baseline is a positive outcome.	Baseline, Weeks 1 to 12
Ocular Pain Assessment Scale (OPAS) Subscale Quality of Life: Summary Statistics of Change From Baseline to Week 12	Each question in the Ocular Pain Assessment Survey (OPAS) quality of life subscale was scored by the subject on a line marked from 0 (not at all) to 10 (completely) that described how much pain interfered with or affected a particular activity (max score= 10/question). A higher score suggests a higher impact by pain on a particular activity. A negative change from baseline is a positive outcome. There are 7 questions in total regarding Quality of Life. The average score of the 7 Quality of Life questions is reported (mean (SD)).	Baseline, Weeks 2, 4, 8, 12
Ocular Surface Parameters: Summary Statistics of Change From Baseline by Week - Conjunctival Redness - Nasal (Oculus Dexter (OD) = Right Eye)	Conjunctival redness in each of two regions (nasal and temporal) was 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). A negative change from baseline is a positive outcome.	Baseline, Weeks 2, 4, 8, 12
Ocular Surface Parameters: Summary Statistics of Change From Baseline by Week - Conjunctival Redness - Nasal (Oculus Sinister (OS) = Left Eye)	Conjunctival redness in each of two regions (nasal and temporal) was 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). A negative change from baseline is a positive outcome.	Baseline, Weeks 2, 4, 8, 12
Ocular Surface Parameters: Summary Statistics of Change From Baseline by Week - Conjunctival Redness - Temporal (Oculus Dexter (OD) = Right Eye)	The pain severity Visual Analogue Scale (VAS) was completed by the subject using an electronic diary. A vertical mark was 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, with a range from 0 (min) to 100 (max). Higher scores indicate higher pain severity. A negative change from baseline is a positive outcome. A negative change from baseline is a positive outcome.	Baseline, Weeks 2, 4, 8, 12
Ocular Surface Parameters: Summary Statistics of Change From Baseline by Week - Conjunctival Redness - Temporal (Oculus Sinister (OS) = Left Eye)	Conjunctival redness in each of two regions (nasal and temporal) was 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). A negative change from baseline is a positive outcome.	Baseline, Weeks 2, 4, 8, 12
Ocular Surface Parameters: Summary Statistics of Change From Baseline by Week - Conjunctival Staining (Oculus Dexter (OD) = Right Eye)	The degree of lissamine conjunctival staining in two regions (temporal and nasal) was graded on a scale from 0 to 4 (max score = 8/eye). Higher scores suggest higher degrees of corneal staining (worsening). A negative change from baseline is a positive outcome.	Baseline, Weeks 2, 4, 8, 12
Ocular Surface Parameters: Summary Statistics of Change From Baseline by Week - Conjunctival Staining (Oculus Sinister (OS) = Left Eye)	The degree of lissamine conjunctival staining in two regions (temporal and nasal) was graded on a scale from 0 to 4 (max score = 8/eye). Higher scores suggest higher degrees of corneal staining (worsening). A negative change from baseline is a positive outcome.	Baseline, Weeks 2, 4, 8, 12
Ocular Surface Parameters: Summary Statistics of Change From Baseline by Week - Corneal Staining (Oculus Dexter (OD) = Right Eye)	The degree of corneal fluorescein staining in each of five regions (superior, inferior, nasal, temporal, and central) was graded on a scale from 0 to 4 (max score=20/eye). Higher scores suggest higher degrees of corneal staining (worsening). A negative change from baseline is a positive outcome.	Baseline, Weeks 2, 4, 8, 12
Ocular Surface Parameters: Summary Statistics of Change From Baseline by Week - Corneal Staining (Oculus Sinister (OS) = Left Eye)	The degree of corneal fluorescein staining in each of five regions (superior, inferior, nasal, temporal, and central) was graded on a scale from 0 to 4 (max score=20/eye). Higher scores suggest higher degrees of corneal staining (worsening). A negative change from baseline is a positive outcome.	Baseline, Weeks 2, 4, 8, 12
Ocular Surface Parameters: Summary Statistics of Change From Baseline by Week of Tear Production - Schirmer Test (mm) (Oculus Dexter (OD) = Right Eye)	The Schirmer's test was performed without anesthetic. Tear secretion was 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). A negative change from baseline is a positive outcome.	Baseline, Weeks 2, 4, 8, 12
Ocular Surface Parameters: Summary Statistics of Change From Baseline by Week of Tear Production - Schirmer Test (mm) (Oculus Sinister (OS) = Left Eye)	The Schirmer's test was performed without anesthetic. Tear secretion was 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). A negative change from baseline is a positive outcome.	Baseline, Weeks 2, 4, 8, 12
Number of Participants With Treatment Emergent Adverse Events	An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and unintended sign [including abnormal laboratory findings], symptom or disease) in a clinical investigation participant after providing written informed consent for participation in the study.	Adverse events were reported from first dose of study treatment until end of study treatment plus 30 days post treatment, up to a maximum timeframe of 119 days (approximately 4 months).
Ocular Treatment Emergent Adverse Events, by Primary System Organ Class (SOC) and Preferred Term (PT)	An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and unintended sign [including abnormal laboratory findings], symptom or disease) in a clinical investigation participant after providing written informed consent for participation in the study. MedDRA Version 26.0 was used for the reporting of adverse events.	Adverse events were reported from first dose of study treatment until end of study treatment plus 30 days post treatment, up to a maximum timeframe of 119 days (approximately 4 months).
Summary of Non-ocular Treatment Emergent Adverse Events	An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and unintended sign [including abnormal laboratory findings], symptom or disease) in a clinical investigation participant after providing written informed consent for participation in the study.	Adverse events were reported from first dose of study treatment until end of study treatment plus 30 days post treatment, up to a maximum timeframe of 119 days (approximately 4 months).

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Investigators: Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Publications and helpful links

Helpful Links

• A Plain Language Trial Summary is available on www.novctrd.com

Study record dates

Study Major Dates

• Study Start (Actual): April 21, 2021
• Primary Completion (Actual): June 7, 2023
• Study Completion (Actual): June 8, 2023

Study Registration Dates

• First Submitted: November 12, 2020
• First Submitted That Met QC Criteria: November 12, 2020
• First Posted (Actual): November 16, 2020

Study Record Updates

• Last Update Posted (Estimated): October 9, 2024
• Last Update Submitted That Met QC Criteria: October 7, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Keywords: 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
• Additional Relevant MeSH Terms: Pain; Neurologic Manifestations; Chronic Pain; Pharmaceutical Solutions; Ophthalmic Solutions; Lubricant Eye Drops
• Other Study ID Numbers: CSAF312B12201; 2021-005857-97 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on https://www.clinicalstudydatarequest.com/.

Drug and device information, study documents

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