A Safety and Efficacy Study of 2 Dosing Regimens of Recombinant Human Nerve Growth Factor (rhNGF) Eye Drop Solution Compared With Vehicle in Patients With Dry Eye Disease. (REDUCO)

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

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

Study Overview

• Status: Completed
• Conditions: Dry Eye Disease
• Intervention / Treatment: Drug: rhNGF 5 μg/mL; Drug: rhNGF 10 μg/mL; Drug: Vehicle (Placebo 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.

• Study Type: Interventional
• Enrollment (Actual): 317
• Phase: Phase 2

Contacts and Locations

Study Locations

• Italy
  • Messina, Italy, 98124
    • Azienda Ospedaliera Universitaria Policlinico G Martino
  • Milan, Italy, 20123
    • Ospedale S. Giuseppe Multimedica
  • Roma, Italy, 00128
    • Fondazione Policlinico Universitario Campus Bio-Medico di Roma
  • Roma, Italy, 00161
    • Azienda Ospedaliero Universitario Policlinicol Umberto I
• United States
  • Arizona
    • Chandler, Arizona, United States, 85224
      • Arizona Eye Center
  • California
    • Torrance, California, United States, 90505
      • East West Eye Institute
  • Colorado
    • Colorado Springs, Colorado, United States, 80907
      • Vision Institute - Fontanero St
  • Florida
    • Boynton Beach, Florida, United States, 33437
      • Sibia Eye Institute
  • Georgia
    • Atlanta, Georgia, United States, 30339
      • Eye Consultants of Atlanta
  • Massachusetts
    • Boston, Massachusetts, United States, 02111
      • New England Eye Center - Boston
  • New Jersey
    • Dover, New Jersey, United States, 07801
      • Eye Associates of North Jersey
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • The Scheie Eye Institute
  • Tennessee
    • Memphis, Tennessee, United States, 38119
      • Total Eye Care PA
    • Nashville, Tennessee, United States, 37215
      • Toyos Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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:

  1. Symptoms Assessment in Dry Eye (SANDE) questionnaire global score ≥50, and
  2. Schirmer-I test without anesthesia >2 mm and <10 mm/5 minutes, and
  3. Total corneal fluorescein staining grade ≥3 (NEI scale) and/or total conjunctival lissamine green staining score ≥3 assessed by the NEI grading system, and
  4. 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.
• Have the ability and willingness to comply with study procedures.

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 >0.
• Medical history of tumor malignancy in the previous 3 years
• Systemic disease not stabilized within 1 month before the screening visit (e.g., diabetes with glycemia out of range, thyroid malfunction) or judged by the investigator to be incompatible with the study (e.g., current systemic infections) or with a condition incompatible with the frequent assessment required by the study.
• History of a serious adverse reaction or significant hypersensitivity to any drug or chemically related compounds or had a clinically significant allergy to drugs, foods, topical anesthetic eye drop or other local anesthetics or other materials, including ocular vital dyes, tropicamide eye drops, commercial artificial tears.
• Known or suspected allergy to sesame and other seeds, tree nuts, and/or peanuts, and/or any other component of the new rhNGF formulation.

• Fertile patients (i.e., not surgically sterilized, or postmenopausal women for at least 1 year) are excluded from participation in the study if they do not practice abstinence from heterosexual intercourse as per usual and customary lifestyle, or are unwilling to use an acceptable form of contraception such as condom with spermicidal cream or jelly for males, or for females if they meet any one of the following conditions:

  1. Currently pregnant (positive urine pregnancy test at screening or baseline visits) or planning to become pregnant during the duration of the treatment phase of the clinical trial.
  2. Participant is breastfeeding.
  3. Unwilling to use birth control measures such as mechanical barrier methods (spermicide in conjunction with a barrier such as a condom or diaphragm or intrauterine device) during the entire course of and 30 days after the study treatment period, or,
  4. Unwilling to continue to use highly effective birth control measures such as hormonal contraceptives (oral, implanted, transdermal, or injected) during the entire course of and 30 days after the study treatment period.
• Any concurrent medical condition that, in the judgment of the principal investigator, might interfere with the conduct of the study, confound the interpretation of the study results, or endanger the participant's well-being.
• Contact lenses or punctum plug use in either eye during the washout, treatment, and follow-up phases of the study (previous use is not an exclusion criteria but must be removed and discontinued at the Screening visit).
• Medical history of drug addiction or alcohol abuse (>1 drink /day for women and >2 drinks /day for men following USDA dietary Guidelines 2020-2025).
• Any prior ocular surgery, including but not limited to amniotic membrane transplant, refractive [PTK (Excimer Laser Phototherapeutic Keratectomy) / LASIK (Laser-Assisted In Situ Keratomileusis) / Epi-LASIK (Epithelial Laser In Situ Keratomileusis) / LASEK (Laser-Assisted Subepithelial Keratectomy) / SMILE (Small Incision Lenticule Extraction)], palpebral, cataract surgery, trabeculectomy, vitrectomy and Pan-Retinal Photocoagulation (PRP) within 90 days before the screening visit.
• Participation in a clinical trial with a new active substance, including medical devices, during the previous 60 days.
• Participation in another clinical trial study at the same time as the present study.

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
Experimental: rhNGF 5 μg/mL; IMP1	Drug: rhNGF 5 μg/mL; 1 drop of rhNGF ophthalmic solution at 5 μg/mL in each eye TID, at approximately 6-hour intervals, for 4 weeks of treatment.; Other Names: Recombinant Human Nerve Growth Factor
Experimental: rhNGF 10 μg/mL; IMP2	Drug: rhNGF 10 μg/mL; 1 drop of rhNGF ophthalmic solution at 10 μg/mL in each eye TID, at approximately 6-hour intervals, for 4 weeks of treatment.; Other Names: Recombinant Human Nerve Growth Factor
Placebo Comparator: Vehicle IMP; Vehicle	Drug: Vehicle (Placebo solution); Eye drop solution, containing no rhNGF. 1 drop of vehicle in each eye TID at approximately 6-hour intervals, for 4 weeks of treatment.; Other Names: Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Change From Baseline to Week 8 in Symptoms of Dry Eye Assessed by Symptom Assessment in Dry Eye (SANDE) Global Score	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.	Week 8 (V5)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Key Secondary Outcome: Percentage of Participants Improving to Schirmer-I Test Without Anesthesia ≥ 10 mm/5 Min in the Study Eye at Week 4	Schirmer-I test was performed without anesthesia to determine wetting of the strip within 5 minutes, the length of the moistened strip being measured in millimeters (mm). "Improvement" is defined as having a change from baseline at the corresponding visit >= 10 mm/5min in Schirmer-I test without anesthesia. Data analyzed and here reported were the data after having applied the predefined strategy to handle intercurrent events (ie, data for Schirmer-I Test collected in the week after an administration of a prohibited medication were set to missing under the hypothetical strategy while a treatment policy strategy was used for any other intercurrent event). Missing data for Schirmer-I Test were imputed employing an MI based on copy-reference approach assuming MNAR.	Week 4 (V4)
Key Secondary Outcome: Mean Change From Baseline to Week 4 in Schirmer-I Score Without Anesthesia in the Study Eye	The Schirmer test was used in ophthalmic examination to measure tear production for the diagnosis of several ocular conditions such as dry eye. Without previously instilling anesthetic drops, the Schirmer strip was inserted into the lower conjunctival sac at the junction of the lateral and middle thirds, avoiding touching the cornea, and the length of wetting strips in millimeters was recorded after 5 minutes. After 5 minutes had elapsed, the Schirmer test strip was removed and the length of the tear absorption on the strip was measured (millimeters/5 minutes). Cutoff values: <5 mm - pathologic dry eye 5-10 mm - marginal dry eye >10 and <30 mm - normal secretion The longer the moistened strip, the healthier the status of the eye. Adjusted means are reported. Data here reported are the data after having applied the predefined strategy to handle intercurrent events. Missing data for Schirmer-I Test were imputed employing an MI based on copy reference approach assuming MNAR.	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	Corneal fluorescein staining examination was performed at the slit-lamp using blue light. Corneal fluorescein staining was graded according to the NEI scale (5 zones, each zone scoring 0-3, with a total score ranging 0-15, with a higher number representing more staining). The five cornea zones are: central, superior, inferior, nasal and temporal. To avoid the phenomenon of quenching, which is increased in participants with dry eye, staining was assessed after 2-5 minutes from fluorescein instillation for fTBUT evaluation. Adjusted means are reported. Data here reported are the data after having applied the predefined strategy to handle intercurrent events. Missing data for The corneal fluorescein staining (NEI score) were imputed employing an MI based on copy reference approach assuming MNAR.	Week 4 (V4)
Mean Change From Baseline to Week 8 in Schirmer-I Score Without Anesthesia in the Study Eye	Schirmer-I test was performed without anesthesia to determine wetting of the strip within 5 minutes, the length of the moistened strip being measured in millimeters (mm). The longer the moistened strip, the better the outcome. The ones reported are adjusted means. Missing data for Schirmer-I Test were imputed employing an MI based on copy reference approach assuming MNAR.	Week 8 (V5)
Percentage of Participants Improving to Schirmer-I Test Without Anesthesia ≥ 10 mm/5min in the Study Eye at Week 8	Schirmer-I test was performed without anesthesia to determine wetting of the strip within 5 minutes, the length of the moistened strip being measured in millimeters (mm). "Improvement" is defined as having a change from baseline at the corresponding visit >= 10 mm/5min in Schirmer-I test without anesthesia. Missing data for Schirmer-I Score were imputed employing an MI based on copy-reference approach assuming MNAR. Samely, "Adjusted proportions" are reported, expressed under the term "mean" (the system doesn't provide the option "adjusted proportion").	Week 8 (V5)
Mean Change From Baseline to Weeks 4 and 8 in Fluorescein Tear Break-up Time (fTBUT) in Study Eye	fTBUT was measured by determining the time to tear film break-up. fTBUT was measured after instilling one drop of fluorescein into the inferior conjunctival cul-de-sac of the study eye. After the participant blinked several times, the examiner waited ~30 seconds. Using a slit lamp (10X, cobalt blue), the examiner recorded the fTBUT as the time from the last blink to the first break in the tear film. The shorter the time, the worse the outcome. The fTBUT was measured twice during the first minute after the instillation. If the 2 readings differed by more than 2 seconds, then a third was taken. The fTBUT value was the average of the 2 or 3 measurements. Missing data for fluorescein tear break-up Time were imputed employing an MI based on copy-reference approach assuming MNAR. Two separate imputation models were used for each timepoint. Adjusted means are reported.	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	OPAS is a validated questionnaire. Administered to all patients, it was completed only by those that either had eye pain or had filled this form before. It has 7 domains: eye pain intensity over 24 hours and past two weeks; non-eye pain intensity; quality of life; aggravating factors; associated factors; symptomatic relief Each subscale score= sum of scores divided by number of questions answered within each subscale. % values were divided by 10 before applying the algorithm. Ocular Pain Score = sum of the scores for eye pain intensity at 24 hours and 2 weeks (questions 4-9) divided by the number of questions answered for questions 4-9. This subscore ranges 0-10, where the higher the score, the worse the outcome. QoL score = sum of the scores for QoL subscale (questions 13-19) divided by the number of questions answered for questions 13-19. QoL scores range 0-10 where the higher the score, the better the outcome. MI was applied. Adjusted means are reported.	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	Corneal fluorescein staining examination was performed at the slit-lamp using blue light. Corneal fluorescein staining was graded according to the NEI scale (5 zones, each zone scoring 0-3, with a total score ranging 0-15, with a higher number representing more staining). The five cornea zones are: central, superior, inferior, nasal and temporal. To avoid the phenomenon of quenching, which is increased in participants with dry eye, staining was assessed after 2-5 minutes from fluorescein instillation for fTBUT evaluation. Missing data for corneal fluorescein staining were imputed employing an MI based on copy-reference approach assuming MNAR. Adjusted means are reported.	Week 8 (V5)
Mean Change From Baseline to Weeks 4 and 8 in Symptoms Questionnaire (SANDE) Scores for Severity	The Symptom Assessment in Dry Eye (SANDE) questionnaire was a short questionnaire to evaluate both dry eye intensity/severity and frequency. This questionnaire used a 100 mm horizontal line (Visual Analogue Scale - VAS) for each of the 2 questions to assess ocular discomfort and/or dryness experienced by the patients. In the SANDE questionnaire, frequency of symptoms ranges from "rarely" to "all of the time" and the severity of symptoms ranged from "very mild" to "very severe". Patients were asked to place a mark on the two given lines based on the extent of their symptoms. The locations of the marks was measured in mm from left to right and recorded as frequency and severity scores, respectively. The SANDE scale ranged from 0, being the minimal amount of dry eye symptoms (best outcome) to 100, being the maximal amount of dry eye symptoms (worst outcome). In this outcome severity score was assessed. MI was applied. Adjusted means are reported.	Week 4 (V4) and week 8 (V5)
Mean Change From Baseline to Weeks 4 and 8 in Symptoms Questionnaire (SANDE) Scores for Frequency	SANDE was a short questionnaire to evaluate both dry eye intensity and frequency. It uses a 100 mm horizontal line (Visual Analogue Scale, VAS), for each of the 2 questions, to assess ocular discomfort and/or dryness. Frequency of symptoms ranged from "rarely" (best outcome) to "all of the time" (worst outcome), while the severity of symptoms ranged from "very mild" (best outcome) to "very severe" (worst outcome). Patients had to place a mark on the two given lines based on the extent of their symptoms. The locations of the marks was measured in mm from left to right and recorded as frequency and severity scores, respectively. The SANDE lines for intensity and for severity ranged from 0, being the minimal amount of dry eye symptoms (best outcome) to 100, being the maximal amount of dry eye symptoms (worst outcome). In this outcome frequency score was assessed. MI was applied. Adjusted means are reported.	Week 4 (V4) and week 8 (V5)
Mean Change From Baseline to Week 4 in Symptoms of Dry Eye Assessed by SANDE Global Score	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 based on copy-reference approach assuming MNAR. Adjusted means are reported.	Week 4 (V4)
Mean Change From Baseline to Weeks 4 and 8 in Best Corrected Distance Visual Acuity (BCDVA) Score in Study Eye	The BCDVA score is measured by ETDRS letter score. The score is given by the total number of letters read at 4-m distance. If 20 or more letters are read, then the score is given by the total number of letters read + 30. If less than 20 letters are read at 4-m distance, the score is given by the sum of the letters read at 4-m distance and the letters read at 1-m distance. The equivalent logMAR score is given by: logMAR = 1.7 - (0.02) x (ETDRS letter score). The higher the score the better the outcome. MI was applied. Adjusted means are reported.	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	TEAEs were defined as adverse events that were reported or worsened on or after the first dose of study treatment. Safety results are provided for overall (ocular and non-ocular) and separately for ocular and non-ocular adverse events.	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	TEAEs were defined as adverse events that were reported or worsened on or after the first dose of study treatment. Most frequently reported ocular adverse events (reported in > 1 participant in the total group) are reported here: at participant's level, for the "on treatment" and for the "follow-up" periods, while most frequently reported non-ocular adverse events (reported in > 1 participant in the total group) are reported at patient level for the overall 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)	Corneal Endothelial Cell Density (ECD) is a measure of the number of cells per square millimeter in the innermost layer of the cornea, which is crucial for maintaining corneal transparency and hydration. ECD is typically highest at birth (around 3,000 cells/mm2) and decreases with age, reaching approximately 2,500 cells/mm2) in adulthood. A critical minimum of 400-500 cells/mm2 is required to maintain proper function, and if the density falls below this level, it can lead to corneal edema and reduced vision. Results (absolute values and change from baseline) were summarized using descriptive statistics at each scheduled visit for both eyes. Herenuder only mean change from baseline to week 8 is reported.	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	A summary of dilated fundoscopy (DFE) results at week 8 for the following parameters: maculopathy, posterior vitreous detachment, optic nerve abnormal appearance, retinal or virtual hemorrhage, vitritis, in the SAF is presented for the study eye and for the fellow eye.	Week 8 (V5)
Safety Outcome: Change From Baseline to Week 8 in Cup-to-disc Ratio in Both Eyes	Change from baseline in cup-to-disc ratio in the SAF population is presented for the study eye and for the fellow eye. An increased cup-to-disc ratio means the "cup" (the central depression) of the optic nerve is larger relative to the "disc" (the entire nerve head), which can indicate a loss of nerve fibers and is often a sign of glaucoma. An increase in this ratio may indicate a decrease in the quantity of healthy neuroretinal cells. For the change from baseline, only patients with a value at both baseline visit and the postbaseline visit are included.	Week 8 (V5)
Safety Outcome: Mean Change From Baseline to Weeks 4 and 8 in Bulbar Conjunctival Redness (VBR 10 Score) in Both Eyes	Bulbar conjunctival redness was assessed at the slit-lamp using white light prior to vital dye instillation and graded according to the Validate Bulbar Redness (VBR 10) scale. The scale starts at grade 10 and has 10-point steps between reference images (score range 10-100). The VBR scale ranges from 10 to 100 with a higher score meaning more severe redness. The ocular areas where the redness is assessed for the study eye and the fellow eye are: Nasal conjunctiva; Temporal conjunctiva Please note that the results (absolute values and change from baseline) were summarized by conjunctiva, visit and eye using descriptive statistics.	Weeks 4 (V4) and 8 (V5)
Percentage of Participants Who Discontinued the Treatment Due to Tolerability Issues	The number and percentage of participants who discontinued study treatment due to tolerability were summarized as recorded in the eCRF EOT page.	Throughout the study till week 8 (V5)

Collaborators and Investigators

• Sponsor: Dompé Farmaceutici S.p.A
• Investigators: Study Director: Flavio Mantelli, MD, PhD, Dompé Farmaceutici S.p.A

Study record dates

Study Major Dates

• Study Start (Actual): January 22, 2024
• Primary Completion (Actual): December 4, 2024
• Study Completion (Actual): December 4, 2024

Study Registration Dates

• First Submitted: January 29, 2024
• First Submitted That Met QC Criteria: January 29, 2024
• First Posted (Actual): February 6, 2024

Study Record Updates

• Last Update Posted (Actual): February 13, 2026
• Last Update Submitted That Met QC Criteria: January 27, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Keywords: DED; rhNGF; Recombinant Human Nerve Growth Factor; Eye Drop Solution
• Additional Relevant MeSH Terms: Eye Diseases; Lacrimal Apparatus Diseases; Dry Eye Syndromes; cenegermin
• Other Study ID Numbers: NGF0123; 2023-507561-26-00 (Ctis)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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