A 4-Week, Phase II, Multicenter, Randomized, Double-Masked, Vehicle-Controlled, Parallel Group Study With 4 Weeks of Follow-Up to Evaluate Safety and Efficacy of a New Formulation of Recombinant Human Nerve Growth Factor (rhNGF) Eye Drop Solution at Two Different Concentrations in Patients With Dry Eye Disease
Overview
- Phase
- Phase 2
- Intervention
- Vehicle (Placebo solution)
- Conditions
- Dry Eye Disease
- Sponsor
- Dompé Farmaceutici S.p.A
- Enrollment
- 317
- Locations
- 28
- Primary Endpoint
- Mean Change From Baseline to Week 8 in Symptoms of Dry Eye Assessed by Symptom Assessment in Dry Eye (SANDE) Global Score
- Status
- Completed
- Last Updated
- 2 months ago
Overview
Brief Summary
Primary objective
• To evaluate the efficacy of 5 μg/mL and 10 μg/mL concentrations of the new formulation of rhNGF ophthalmic solution versus vehicle, in order to demonstrate superiority of at least 1 of the concentrations over vehicle in the improvement of ocular symptoms of dry eye in participants with dry eye disease (DED)
Key secondary objectives
- To evaluate the efficacy of the new formulation of rhNGF ophthalmic solution in increasing the number of participants with improved reflex tear production as compared to vehicle at week 4
- To evaluate the efficacy of the new formulation of rhNGF ophthalmic solution in improving reflex tear production as compared to vehicle at week 4
- To evaluate the efficacy of the new formulation of rhNGF ophthalmic solution in improving ocular surface integrity (corneal epitheliopathy) as compared to vehicle at week 4
Secondary objectives
- To evaluate the efficacy of the new formulation of rhNGF ophthalmic solution in improving reflex tear production as compared to vehicle at week 8
- To evaluate the efficacy of the new formulation of rhNGF ophthalmic solution in improving tear film stability as compared to vehicle at weeks 4 and 8
- To evaluate the efficacy of the new formulation of rhNGF ophthalmic solution in improving ocular surface integrity (corneal and conjunctival epitheliopathy) as compared to vehicle at weeks 4 and 8
- To evaluate the efficacy of the new formulation of rhNGF ophthalmic solution in improving the severity and frequency of dry eye symptoms as compared to vehicle at weeks 4 and 8
- To evaluate the efficacy of the new formulation of rhNGF ophthalmic solution in improving dry eye symptoms as compared to vehicle at week 4
- To evaluate the efficacy of the new formulation of rhNGF ophthalmic solution in improving associated symptoms in DED as compared to vehicle at weeks 4 and 8
- To evaluate the efficacy of the new formulation of rhNGF ophthalmic solution in improving the quality of life in participants with DED as compared to vehicle at weeks 4 and 8
- To evaluate the efficacy of the new formulation of rhNGF ophthalmic solution in improving best corrected visual acuity in DED as compared to vehicle at weeks 4 and 8
Safety objectives
- To evaluate safety/tolerability of the new formulation of rhNGF ophthalmic solution
- To evaluate safety of the new formulation of rhNGF ophthalmic solution
- To evaluate tolerability of the new formulation of rhNGF ophthalmic solution
Detailed Description
This was a phase 2, multi-center, randomized, double-masked, parallel-arm, vehicle-controlled, dose-finding, clinical study to evaluate the safety and efficacy of 2 concentrations (5 μg/mL and 10 μg/mL) of a reconstituted lyophilized formulation of rhNGF, administered as 1 drop of an ophthalmic solution 3 times a day (TID) in both eyes for 4 weeks in participants with DED. Participants were evaluated at the screening visit (day -12 ± 2; visit 1), baseline (day 1; visit 2), week 2 (day 13 ± 1; visit 3), week 4 end of treatment (EOT; day 28 ± 1; visit 4), and week 8 end of follow-up and end of study (EOS; day 56 ± 2; visit 5). At the screening visit (visit 1), participants who signed informed consent and met all eligibility criteria were enrolled and instructed to discontinue all topical ophthalmic medications; during the run-in period, they were only allowed to use investigational product (vehicle) ophthalmic solution provided by the sponsor. The first eye drop of the vehicle was applied to both eyes of participants at the site by the investigator during visit 1. Participants were instructed on how to prepare the investigational product (vehicle) daily at home and then how to self-administer 1 drop TID in both eyes. A Patient Diary for the run-in phase was supplied to the participant. At the conclusion of the day 1 baseline visit (visit 2), participants still meeting all eligibility criteria were randomly assigned 1:1:1 to a 4-week treatment regimen of investigational product (vehicle, or rhNGF \[5 μg/mL or 10 μg/mL\]), administered as follows: * 1 drop of rhNGF ophthalmic solution at 5 μg/mL in each eye TID, at approximately 6-hour intervals, for 4 weeks * 1 drop of rhNGF ophthalmic solution at 10 μg/mL in each eye TID, at approximately 6-hour intervals, for 4 weeks * 1 drop of vehicle in each eye, TID, at approximately 6-hour intervals, for 4 weeks. Eligible participants were also dispensed a 2-week supply of the investigational product (vehicle or rhNGF) to administer at home between visits 2 and 3. They received another 2-week supply during visit 3. A Patient Diary for recording the treatment phase was supplied to the participant. At visit 2 (baseline visit) a study eye was determined. Namely, the study eye was the worse eye. Assuming that all inclusion/exclusion criteria were met in both eyes, the worse eye (study eye) was determined based on the lower Schirmer-I (without anesthesia) score. If the Schirmer-I score was identical in both eyes, the study eye was determined based on the worse score for corneal and conjunctival NEI staining (total score for corneal staining followed by total score for conjunctival). If the staining score was identical in both eyes, then the right eye was assigned as the study eye. Participants who prematurely discontinued the treatment (for any reason) were asked to complete the remaining assessments planned by the protocol and received commercially available preservative-free AT, TID, provided by the sponsor. In case of withdrawal from the study, participants were asked to complete the assessment expected for visit 4 as an Early Exit Visit. Following the completion of the treatment period, participants were followed up for an additional 4 weeks and were evaluated at 8 weeks (visit 5). During the 4-week follow-up period, no treatment was allowed except for commercially available preservative free AT TID provided by the sponsor. A Patient Diary for the follow-up period was supplied to the patient.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Male or female aged ≥18 years of any race/ethnicity and eye color.
- •A diagnosis of dry eye disease at least 6 months before enrollment (current use or recommended use of artificial tears for the treatment of dry eye).
- •Moderate-to-severe dry eye characterized by the following clinical features:
- •Symptoms Assessment in Dry Eye (SANDE) questionnaire global score ≥50, and
- •Schirmer-I test without anesthesia \>2 mm and \<10 mm/5 minutes, and
- •Total corneal fluorescein staining grade ≥3 (NEI scale) and/or total conjunctival lissamine green staining score ≥3 assessed by the NEI grading system, and
- •Fluorescein tear film break-up time (fTBUT) \< 10 seconds The same eye must have fulfilled all the above criteria.
- •Best corrected distance visual acuity (BCDVA) score on ETDRS chart of ≥0.1 decimal units (≤1.0 logarithm of the minimum angle of resolution \[logMAR\]) in each eye at the time of study enrollment
- •Negative pregnancy test in females of childbearing potential.
- •Only participants who satisfy all informed consent requirements were included in the study; the participant and/or his/her legal representative must have read, signed, and dated the informed consent document before any study-related procedures were performed; the informed consent form signed by participants and/or legal representatives must have been approved by the Institutional Review Board (IRB) for the current study.
Exclusion Criteria
- •Inability to speak and understand the local language sufficiently to understand the nature of the study, to provide written informed consent, and to allow the completion of all study assessments.
- •Evidence of an active ocular infection in either eye.
- •Presence of any other ocular disorder or condition requiring topical ocular medication during the entire duration of the study.
- •Possibility of the need for ocular surgery at the time of inclusion in the study or anticipated ocular surgery expected during the participation in the study
- •History of severe systemic allergy or severe ocular allergy \[including seasonal conjunctivitis, AKC (Atopic KeratoConjunctivitis), VKC (Vernal KeratoConjunctivitis)\] or chronic conjunctivitis and/or keratitis other than dry eye.
- •Ocular scarring due to irradiation, alkali burns, Stevens-Johnson syndrome and ocular cicatricial pemphigoid.
- •Destruction of conjunctival goblet cells such as in Vitamin A deficiency.
- •Severe blepharitis or obvious inflammation of the lid margin.
- •Intraocular inflammation defined as Tyndall score \>
- •Medical history of tumor malignancy in the previous 3 years
Arms & Interventions
Vehicle IMP
Vehicle
Intervention: Vehicle (Placebo solution)
rhNGF 5 μg/mL
IMP1
Intervention: rhNGF 5 μg/mL
rhNGF 10 μg/mL
IMP2
Intervention: rhNGF 10 μg/mL
Outcomes
Primary Outcomes
Mean Change From Baseline to Week 8 in Symptoms of Dry Eye Assessed by Symptom Assessment in Dry Eye (SANDE) Global Score
Time Frame: Week 8 (V5)
SANDE questionnaire included 2 VAS-based questions that assessed: (i) DED symptom frequency (from 0 to 100) (ii) DED symptom severity (from 0 to 100) compiled by the participants. The global SANDE score (from 0 to 100, with 100 representing the most frequent and severe dry eye symptoms) was calculated by multiplying the frequency score by the severity score and obtaining the square root. For SANDE global Score, the lower the score, the better the outcome. Adjusted means are reported. Data here reported are the data after having applied the predefined strategy to handle intercurrent events (i.e. data for SANDE collected in the week after an administration of a prohibited medication are set to missing under the hypothetical strategy while a treatment policy strategy is used for any other intercurrent event). Missing data for SANDE Global Score are imputed employing Multiple Imputation (MI) based on copy-reference approach assuming MNAR.
Secondary Outcomes
- Key Secondary Outcome: Percentage of Participants Improving to Schirmer-I Test Without Anesthesia ≥ 10 mm/5 Min in the Study Eye at Week 4(Week 4 (V4))
- Key Secondary Outcome: Mean Change From Baseline to Week 4 in Schirmer-I Score Without Anesthesia in the Study Eye(Week 4 (V4))
- Key Secondary Outcome: Mean Change From Baseline to Week 4 in Total Corneal Fluorescein Staining (National Eye Institute NEI Scale) in the Study Eye as Assessed by the Investigator(Week 4 (V4))
- Mean Change From Baseline to Week 8 in Schirmer-I Score Without Anesthesia in the Study Eye(Week 8 (V5))
- Percentage of Participants Improving to Schirmer-I Test Without Anesthesia ≥ 10 mm/5min in the Study Eye at Week 8(Week 8 (V5))
- Mean Change From Baseline to Weeks 4 and 8 in Fluorescein Tear Break-up Time (fTBUT) in Study Eye(Week 4 (V4) and Week 8 (V5))
- Mean Change From Baseline to Weeks 4 and 8 in the Ocular Pain Assessment Survey (OPAS) Questionnaire's Ocular Pain and Quality of Life (QoL) Scores(Week 4 (V4) and week 8 (V5))
- Mean Change From Baseline to Week 8 in Total Corneal Fluorescein Staining (National Eye Institute NEI Scale) in the Study Eye as Assessed by the Investigator(Week 8 (V5))
- Mean Change From Baseline to Weeks 4 and 8 in Symptoms Questionnaire (SANDE) Scores for Severity(Week 4 (V4) and week 8 (V5))
- Mean Change From Baseline to Weeks 4 and 8 in Symptoms Questionnaire (SANDE) Scores for Frequency(Week 4 (V4) and week 8 (V5))
- Mean Change From Baseline to Week 4 in Symptoms of Dry Eye Assessed by SANDE Global Score(Week 4 (V4))
- Mean Change From Baseline to Weeks 4 and 8 in Best Corrected Distance Visual Acuity (BCDVA) Score in Study Eye(Week 4 (V4) and Week 8 (V5))
- Safety Outcome: Incidence of theTreatment-Emergent Adverse Events (TEAEs) Overall (Ocular and Non-ocular) Assessed Throughout the Study(Throughout the study, from baseline to the end of trial (Week 8,V5))
- Safety Outcome: Frequency of the Treatment-Emergent Adverse Events (TEAEs) (Ocular and Non-ocular) at Participant Level, Assessed Throughout the Study Including run-in Period(Throughout the study, including run-in period)
- Safety Outcome: Mean Change From Baseline to Week 8 in Corneal Endothelial Cell Density in Both Eyes (Study Eye and Fellow Eye)(Week 8 (V5))
- Safety Outcome: Percentage of Participants With Vitritis, Retinal or Vitreal Hemorrhages, Retinal or Posterior Vitreal Detachment, Retinal Tears, Maculopathy on Dilated Fundus Exam (DFE) in Both Eyes at Week 8(Week 8 (V5))
- Safety Outcome: Change From Baseline to Week 8 in Cup-to-disc Ratio in Both Eyes(Week 8 (V5))
- Safety Outcome: Mean Change From Baseline to Weeks 4 and 8 in Bulbar Conjunctival Redness (VBR 10 Score) in Both Eyes(Weeks 4 (V4) and 8 (V5))
- Percentage of Participants Who Discontinued the Treatment Due to Tolerability Issues(Throughout the study till week 8 (V5))