Evaluation of Efficacy of 20 µg/ml rhNGF New Formulation (With Anti-oxidant) in Patients With Stage 2 and 3 NK

Study Overview
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Brief Summary
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The primary objective of this study is to evaluate the efficacy of 20 µg/ml 6 times a day of rhNGF eye drops solution (formulation containing anti-oxidant) compared to vehicle (formulation containing anti-oxidant) given 6 times a day. The evaluation of efficacy is intended as: complete healing of stage 2 (persistent epithelial defect) and 3 (corneal ulcer) neurotrophic keratitis (NK) as measured by the central reading center using corneal fluorescein staining, assessing the duration of complete healing, improvement in visual acuity and improvement in corneal sensitivity.

Detailed Description
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An 8-week phase II, multicenter, randomized, double-masked, vehicle-controlled, parallel group study with a 24 or 32 week follow-up period to evaluate the efficacy of a formulation containing anti-oxidant of recombinant human nerve growth factor (rhNGF) in 20 μg/ml, eye drops solution versus vehicle containing anti-oxidant in patients with Stage 2 and 3 Neurotrophic Keratitis. The primary objective was to evaluate the efficacy of 20 μg/ml 6 times a day of recombinant human nerve growth factor (rhNGF) containing anti-oxidant, eye drops solution compared to vehicle (formulation containing anti-oxidant) given 6 times a day in inducing a complete healing of stage 2 (PED) and 3 (corneal ulcer) NK as measured by the central reading center, evaluating the clinical pictures of corneal fluorescein staining. Secondary objectives were to assess the duration of complete healing, improvement in visual acuity and improvement in corneal sensitivity, and percentage of patients achieving complete corneal clearing defined as complete absence of staining on the modified Oxford Scale.

Official Title
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An 8-week Phase II, Multicenter, Randomized, Double-masked, Vehicle Controlled Parallel Group Study With a 24 or 32 Week Follow-up to Evaluate the Efficacy of rhNGF 20 µg/ml vs Vehicle in Patients With Stage 2 and 3 Neurotrophic Keratitis

Conditions
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Neurotrophic Keratitis

Intervention / Treatment
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* Drug: rhNGF 20µg/ml
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients 18 years of age or older. Patients with stage 2 (persistent epithelial defect, PED) or stage 3 (corneal ulcer) neurotrophic keratitis (NK). PED or corneal ulceration of at least 2 weeks duration refractory to one or more conventional non-surgical treatments for neurotrophic keratitis. Evidence of decreased corneal sensitivity (≤ 4 cm using the Cochet-Bonnet aesthesiometer) within the area of the PED or corneal ulcer and outside of the area of the defect in at least one corneal quadrant. Best corrected distance visual acuity (BCDVA) score ≤ 75 ETDRS (Early Treatment Diabetic Retinopathy Study)letters, (≥ 0.2 LogMAR, ≤ 20/32 Snellen or ≤ 0.625 decimal fraction) in the affected eye(s). No objective clinical evidence of improvement in the PED or corneal ulceration within the 2 weeks prior to study enrolment. Only patients who satisfy all Informed Consent requirements may be included in the study. The patient and/or his/her legal representative must read, sign and date the Informed Consent document before any study-related procedures are performed. The Informed Consent form signed by patients and/or legal representative must have been approved by the IRB (Institutional Review Board) for the current study. Patients must have the ability and willingness to comply with study procedures. Exclusion Criteria: Any active ocular infection or active ocular inflammation not related to NK in the affected eye(s). Any other ocular disease requiring topical ocular treatment during the course of the study treatment period. No topical treatments other than the study medications provided by the study sponsor and allowed by the study protocol can be administered in the affected eye(s) during the course of the study treatment periods. Patients with severe vision loss with no potential for visual improvement in the opinion of the investigator as a result of the study treatment. Schirmer test without anesthesia ≤3 mm/5 minutes. Patients with severe blepharitis and/or severe meibomian gland disease. History of any ocular surgery (including laser or refractive surgical procedures) within the three months before study enrolment. (An exception to the preceding statement will be allowed if the ocular surgery is considered to be the cause of the stage 2 or 3 NK). Ocular surgery will not be allowed during the study treatment period and elective ocular surgery procedures should not be planned during the duration of the follow-up period. Prior surgical procedure(s) for the treatment of NK with the exception of amniotic membrane transplantation. Patients previously treated with amniotic membrane transplantation may only be enrolled two weeks after the membrane has disappeared within the area of the PED or corneal ulcer or at least six weeks after the date of the amniotic membrane transplantation procedure. Patients previously treated with Botox injections used to induce pharmacologic blepharoptosis are eligible for enrolment only if the last injection was given at least 90 days prior to enrolment in the study. Anticipated need to use therapeutic contact lenses or contact lens wear for refractive correction during the study treatment period in the eye(s) with NK. Anticipated need for punctual occlusion during the study treatment period. Patients with punctual occlusion or punctual plugs inserted prior to the study are eligible for enrolment provided that the punctual occlusion is maintained during the study. Evidence of corneal ulceration involving the posterior third of the corneal stroma, corneal melting or perforation. Presence or history of any ocular or systemic disorder or condition that might hinder the efficacy of the study treatment or its evaluation, could possibly interfere with the interpretation of study results, or could be judged by the investigator to be incompatible with the study visit schedule or conduct. Any need for or anticipated change in the dose of systemic medications known to impair the function of the trigeminal nerve. These treatments are allowed during the study if initiated prior study enrolment provided they remain stable throughout the course of the study treatment periods. Known hypersensitivity to one of the components of the study or procedural medications (e.g. fluorescein). History of drug, medication or alcohol abuse or addiction. Use of any investigational agent within 4 weeks of screening visit. Participation in another clinical study at the same time as the present study. Females of childbearing potential are excluded from participation in the study if they meet any one of the following conditions: are currently pregnant or, have a positive result on the urine pregnancy test at the Randomization Visit or, intend to become pregnant during the study treatment period or, are breast-feeding or are not willing to use highly effective birth control measures.

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 |
| --- | --- |
| Experimental: rhNGF 20 µg/ml<br>rhNGF 20 µg/ml eye drops solution, formulation containing anti-oxidant | Drug: rhNGF 20µg/ml<br> <br> * Other names: cenegermin;|
| Placebo Comparator: Placebo<br>Vehicle: formulation containing anti-oxidant | Other: Placebo<br>* Formulation containing antioxidant<br>* Other names: Vehicle;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Healing of the Persistent Epithelial Defect (PED) or Corneal Ulcer Defined by Central Reviewer | Percentage of patients achieving complete healing of the PED or corneal ulcer determined by corneal fluorescein staining at 8 weeks as defined by the central reading center on clinical pictures. | Week 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Healing of the Persistent Epithelial Defect (PED) or Corneal Ulcer Defined by the Investigator | Percentage of patients experiencing complete healing of the PED or corneal ulcer determined by corneal fluorescein staining at 8 weeks as measured by the investigator. | Week 8 | 
| Complete Healing of the Persistent Epithelial Defect (PED) or Corneal Ulcer Defined by Central Reading Center and Investigator. | Percentage of patients experiencing complete healing of the PED or corneal ulcer at 4, and 6 weeks as measured by the central reading center evaluating the clinical pictures and investigator. | At weeks 4 and 6 | 
| Percentage of Patients With Complete Corneal Clearing | Percentage of patients with complete corneal clearing at weeks 4, 6, and 8 defined as grade 0 on the modified Oxford scale. Grade 0 indicates the absence of conjunctival staining; grade V indicates severe conjunctival staining. | at weeks 4, 6, and 8 | 
| Mean Change From Baseline in Best Corrected Distance Visual Acuity (BCDVA) | Change in Best Corrected Distance Visual Acuity (BCDVA) from baseline to Week 8. Best Corrected Distance Visual Acuity consists of letters read at 4m only. | Baseline, Week 8 | 
| Percentage of Patients That Achieve a 15 Letter Gain in BCDVA | Percentage of patients that achieve a 15 letter gain in Best Corrected Distance Visual Acuity (BCDVA) at 4 weeks, 6 weeks, 8 weeks | Weeks 4, week 6 and week 8 | 
| Improvement in Corneal Sensitivity | Improvement in corneal sensitivity was measured by the Cochet-Bonnet aesthesiometer at 4, 6 and 8 weeks. Corneal sensitivity is measured continuously in each patient in cm: Area of the Persistent Epithelial Defect (PED) or corneal ulcer All quadrants, but outside the PED or corneal ulcer area: Superior nasal, inferior nasal, superior temporal, inferior temporal. Improvement is defined as an increase of at least 0.5 cm in the location of concern. | At 4, 6 and 8 weeks after start of the treatment | 
| Patients Experiencing Deterioration | Number of patients experiencing deterioration (increase in lesion size ≥ 1mm and/or decrease in BCDVA by >5 Early Treatment Diabetic Retinopathy Study (ETDRS) letters and/or progression in lesion depth to corneal melting or perforation and/or onset of infection) in stage 2 or 3 NK from baseline to Week 8. | from baseline to Week 8. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Neurotrophic Keratitis