Evaluation of Safety and Efficacy of rhNGF in Patients With Stage 2 and 3 Neurotrophic Keratitis.

Study Overview
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Brief Summary
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This study is aimed at assessing the safety and the efficacy of two dose regimens of recombinant human nerve growth factor (rhNGF) eye drops solution compared to vehicle for inducing a complete healing of stage 2 (persistent epithelial defect) and 3 (corneal ulcer) neurotrophic keratitis

Detailed Description
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The primary objective of this study is to assess the safety and the efficacy of two dose regimens (10 µg/ml or 20 µg/ml 6 times a day) of recombinant human nerve growth factor (rhNGF) eye drops solution compared to vehicle for inducing a complete healing of stage 2 (persistent epithelial defect) and 3 (corneal ulcer) neurotrophic keratitis (NK) as measured by the Reading Center evaluating the clinical pictures of corneal fluorescein staining. Secondary objectives of the study are to assess the duration of complete healing, improvement in visual acuity and improvement in corneal sensitivity following treatment with rhNGF eye drops solution This is a combined phase I/II study. The phase I and II segments of the study will be conducted as an 8 week, randomized, double-masked, vehicle controlled, parallel group study (referred to as the controlled treatment period) followed by a 48 or 56 week follow-up period The design of the phase I and phase II segments of the study are identical with the exception that in the phase I segment of the study the randomization scheme is different and patients will be followed with additional safety assessments and blood samples for PK (pharmacokinetic) profiling In the ascending dose Phase I segment of the study two doses of rhNGF 10 and 20 µg/ml will be evaluated in a sequential manner

Official Title
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An 8-week Phase I/II, Multicenter, Randomized, Double-masked, Vehicle Controlled Parallel Group Study to Evaluate the Safety and Efficacy of Two Doses of Recombinant Human Nerve Growth Factor in Patients With Stage 2 and 3 of NK

Conditions
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Keratitis, Neurotrophic Keratitis, Corneal Ulcer

Intervention / Treatment
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* Drug: rhNGF 10 μg/ml
* Drug: rhNGF 20 μg/ml
* Other: vehicle


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 involving only one eye. . Patients with Controlateral eye affected with stage 1 NK can be enrolled. PED or corneal ulceration of at least 2 weeks duration refractory to one or more conventional non-surgical treatments for neurotrophic keratitis (e.g., preservative-free artificial tears, gels or ointments; discontinuation of preserved topical drops and medications that can decrease corneal sensitivity; therapeutic contact lenses). 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 letters, (≥ 0.2 LogMAR, ≤ 20/32 Snellen or ≤ 0.625 decimal fraction) in the affected eye. 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 IEC/IRB for the current study. Patients must have the ability and willingness to comply with study procedures. Patients must be eligible for the National Health Insurance (where applicable). Exclusion Criteria: Patients with stage 2 or 3 NK affecting both eyes. Any active ocular infection (bacterial, viral, fungal or protozoal) or active ocular inflammation not related to NK in the affected eye. Any other ocular disease requiring topical ocular treatment in the affected eye during the course of the study treatment period. No topical treatments other than the study medications provided by the study sponsor or allowed by the study protocol can be administered in the affected eye during the course of the study treatment periods. Patients with severe vision loss in the affected eye 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 in the affected eye. Patients with severe blepharitis and/or severe meibomian gland disease in the affected eye. History of any ocular surgery (including laser or refractive surgical procedures) in the affected eye 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 in the affected eye 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 (e.g. complete tarsorraphy, conjunctival flap, etc) in the affected eye 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 (botulinum toxin) 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. Use of therapeutic contact lenses or contact lens wear for refractive correction during the study treatment periods in the eye 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 in the affected eye. 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 (e.g. progressive or degenerative corneal or retinal conditions, uveitis, optic neuritis, poorly controlled diabetes, autoimmune disease, systemic infection, neoplastic diseases). Any need for or anticipated change in the dose of systemic medications known to impair the function of the trigeminal nerve (e.g. neuroleptics, antipsychotic and antihistamine drugs). These treatments are allowed during the study if initiated prior to 30 days before 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 (those who are not surgically sterilized or post-menopausal for at least 1 year) 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 not willing to use highly effective birth control measures, such as: Hormonal contraceptives -oral, implanted, transdermal, or injected and/or Mechanical barrier methods -spermicide in conjunction with a barrier such as a condom or diaphragm or IUD during the entire course of and 30 days after the study treatment periods.

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: 1_rhNGF10_Phase 1_treatment<br>active treatment with rhNGF 10 μg/ml. One drop six times a day (one 35 μl drop equals to 0.35μg of rhNGF). | Drug: rhNGF 10 μg/ml<br>* rhNGF 10 μg/ml : one drop 6 times a day (one 35 μl drop equals to 0.35 μg of rhNGF)<br>* Other names: recombinant human nerve growth factor 10 µg/ml solution;|
| Experimental: 2_rhNGF20_Phase 1_treatment<br>active treatment with rhNGF 20 μg/ml. One drop 6 times a day (one 35 μl drop equals to 0.70 μg of rhNGF) | Drug: rhNGF 20 μg/ml<br>* one drop 6 times a day (one 35 μl drop equals to 0.70 μg of rhNGF)<br>* Other names: recombinant human nerve growth factor 20 µg/ml solution;|
| Placebo Comparator: 3_vehicle group_Phase 1_treatment<br>vehicle control arm. Ophthalmic solution of the same composition as the test product with the exception of rhNGF. One drop six times a day for the entire period | Other: vehicle<br>* ophthalmic solution of the same composition as the test product without rhNGF<br>* Other names: placebo;|
| Experimental: 4_rhNGF10_Phase 2_treatment<br>active treatment with rhNGF 10 μg/ml. One drop six times a day (one 35 μl drop equals to 0.35 μg of rhNGF) | Drug: rhNGF 10 μg/ml<br>* rhNGF 10 μg/ml : one drop 6 times a day (one 35 μl drop equals to 0.35 μg of rhNGF)<br>* Other names: recombinant human nerve growth factor 10 µg/ml solution;|
| Experimental: 5_rhNGF20_Phase 2_treatment<br>active treatment with rhNGF 20 μg/ml. One drop 6 times a day (one 35 μl drop equals to 0.70 μg of rhNGF) | Drug: rhNGF 20 μg/ml<br>* one drop 6 times a day (one 35 μl drop equals to 0.70 μg of rhNGF)<br>* Other names: recombinant human nerve growth factor 20 µg/ml solution;|
| Placebo Comparator: 6_vehicle group_Phase 2_treatment<br>vehicle control arm. Ophthalmic solution of the same composition as the test product with the exception of rhNGF. One drop six times a day for the entire period | Other: vehicle<br>* ophthalmic solution of the same composition as the test product without rhNGF<br>* Other names: placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Patients Achieving Healing of the Persistent Epithelial Defect (PED) or Corneal Ulcer | Complete healing of the PED or corneal ulcer was determined by corneal fluorescein staining at 4 weeks as defined by the reading center evaluating the clinical pictures. Complete healing was defined as the greatest diameter of the corneal fluorescein staining in the area of the PED or corneal ulcer being less than 0.5 mm at the Week 4 visit. The primary efficacy variable was analyzed after 4 weeks of treatment only for the Phase II segment of the study. That's why the Phase I groups/arms are not included in this analysis. | at 4 weeks of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Patients Experiencing Healing of the Persistent Epithelial Defect (PED) or Corneal Ulcer | Complete healing of the PED or corneal ulcer at 4 weeks as defined by the Investigator. The complete healing was defined as the greatest diameter of the corneal fluorescein staining in the area of the PED or corneal ulcer, being less than 0.5 mm at the Week 4 visit. This secondary outcome was analyzed after 4 weeks of treatment only for the Phase II segment of the study. That's why the Phase I groups/arms are not included in this analysis. | at 4 weeks of study treatment. | 
| Percentage of Patients Experiencing Complete Healing of the Persistent Epithelial Defect (PED) or Corneal Ulcer | Complete healing of the PED or corneal ulcer at 6 and 8 weeks measured by both the central reading center and Investigator. Complete healing was defined as the greatest diameter of the corneal fluorescein staining in the area of the PED or corneal ulcer being less than 0.5 mm. This outcome was analyzed after 6 and 8 weeks of treatment only for the Phase II segment of the study. That's why the Phase I groups/arms are not included in this analysis. | at 6 and 8 weeks after start of the treatment | 
| Percentage of Patients Experiencing Complete Corneal Clearing | Complete corneal clearing (grade 0 on the modified Oxford scale) at 4, 6 and 8 weeks. A patient was considered to have achieved complete corneal clearing if he/she had a Modified Oxford Scale recorded as Grade 0. The scale has the following grades: 0-1-2-3-4-5, where 5 represents the worst outcome value and 0 the best outcome value. | at 4, 6 and 8 weeks after start of the treatment | 
| Mean Change in Best Corrected Distance Visual Acuity (BCDVA) | Mean changes in Best-Corrected Distance Visual Acuity (BCDVA) from baseline to Week 8 are calculated as Least Square means. BCDVA consists of letters read at 4 meters only. Patients are scored by how many letters could be correctly identified. Therefore the higher the number of letters, the higher the visual acuity. | At screening and at week 8 | 
| Percentage of Patients That Achieve an Improvement in Corneal Sensitivity | Percentage of patients that achieve an improvement in corneal sensitivity as measured by the Cochet-Bonnet aesthesiometer | at 4, 6 and 8 weeks. | 
| Percentage of Patients Experiencing Deterioration in Stage 2 or 3 NK | Percentage of patients experiencing deterioration (increase in lesion size ≥ 1mm, decrease in BCDVA by >5 ETDRS letters, progression in lesion depth to corneal melting or perforation, onset of infection) in stage 2 or 3 NK from baseline to Week 4, 6, and 8. | from baseline to Week 4, 6, and 8. | 
| Percentage of Patients Achieving Complete Healing of the PED or Corneal Ulcer by Week 8/16 That Remain Healed at Weeks 20/28, 32/40, 44/52, 56/64 | Percentage of patients achieving complete healing of the PED or corneal ulcer by Week 8/16 that remain healed (ie, no recurrence of the PED and/or corneal ulcer) at Weeks 20/28, 32/40, 44/52, 56/64 | at week 20/28, 32/40, 44/52, and 56/64 | 
| Percentage of Patients Experiencing a Different Level of Efficacy at 4 and 8 Weeks | Global evaluation of efficacy as assessed by the Investigator at 4 and 8 weeks. The different level of efficacy were: very good; good; moderate; poor; non-evaluable. | at week 4 and 8 | 
| Change From Baseline in Visual Analogue Scale (VAS) for Ocular Tolerability | Ocular tolerability was recorded by the patient on a VAS scale from 0 to 100 mm, where a higher VAS score indicates worse ocular symptoms (0 means no symptoms and 100 means the worst possible discomfort). The overall VAS score for ocular tolerability was calculated as the mean of the individual VAS scores for the 7 different symptoms (foreign body sensation, burning/stinging, itching, ocular pain, sticky feeling, blurred vision and photophobia). Results are below reported as per symptoms at week 8 (for treatment period) and week 20 (for Follow Up period). | at baseline and at weeks 8 and 20 | 
| Change From Baseline in Best Corrected Distance Visual Acuity (BCDVA) | Best-Corrected Distance Visual Acuity (BCDVA) by means of the Early Treatment of Diabetic Retinopathy Study (ETDRS) visual acuity chart at 4 meters (13 feet). Data reported refers to week n° 8 (treatment group) and n°12/20 (FU group). | at baseline and at period 1 (8 weeks) and 2 (Follow Up period of 12 weeks, until week 20) | 
| Change From Baseline in Intraocular Pressure (IOP) | IOP was measured using a Goldmann applanation tonometer, a handheld applanation tonometer [eg, Tonopen], or other tonometer, after the instillation of a topical anesthetic. | Baseline, period 1 (8 weeks) and 2 (Follow Up period of 12 weeks, until week 20). | 
| Percentage of Participants With Abnormal Eye Structures by Dilated Fundus Ophthalmoscopy | Dilated fundus ophthalmoscopy was performed to assess the vitreous, retina, macula, choroid and optic nerve head after dilation of the pupil. Percentage of patients is summarized for each eye structure by treatment and visit for the controlled treatment period for Phase I and Phase II separately. The assessment time points were Baseline, weeks 2, 4 and 8 for Phase 1; Baseline and week 8 for Phase 2; and weeks 12 and 56 for follow up. Only results for eye structure at week 8 are reported. | At week 8 (Phase 1 and Phase 2) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Keratitis, Corneal Ulcer