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

Primary Purpose

Neurotrophic Keratitis, Keratitis, Corneal Ulcer

Status
Completed
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
rhNGF 10 μg/ml
rhNGF 20 μg/ml
vehicle
Sponsored by
Dompé Farmaceutici S.p.A
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Neurotrophic Keratitis focused on measuring Keratitis, Corneal Ulcer

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Patients 18 years of age or older.
  2. 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.
  3. 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).
  4. 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.
  5. 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.
  6. No objective clinical evidence of improvement in the PED or corneal ulceration within the 2 weeks prior to study enrolment.
  7. 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.
  8. Patients must have the ability and willingness to comply with study procedures.
  9. Patients must be eligible for the National Health Insurance (where applicable).

Exclusion Criteria:

  1. Patients with stage 2 or 3 NK affecting both eyes.
  2. Any active ocular infection (bacterial, viral, fungal or protozoal) or active ocular inflammation not related to NK in the affected eye.
  3. 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.
  4. 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.
  5. Schirmer test without anesthesia ≤3 mm/5 minutes in the affected eye.
  6. Patients with severe blepharitis and/or severe meibomian gland disease in the affected eye.
  7. 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.
  8. 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.
  9. Use of therapeutic contact lenses or contact lens wear for refractive correction during the study treatment periods in the eye with NK.
  10. 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.
  11. Evidence of corneal ulceration involving the posterior third of the corneal stroma, corneal melting or perforation in the affected eye.
  12. 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).
  13. 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.
  14. Known hypersensitivity to one of the components of the study or procedural medications (e.g. fluorescein).
  15. History of drug, medication or alcohol abuse or addiction.
  16. Use of any investigational agent within 4 weeks of screening visit.
  17. Participation in another clinical study at the same time as the present study.
  18. 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.

Sites / Locations

  • CHU de Dijon - Service ophtalmologie
  • CHU Dupuytren - Service Ophtalmologie
  • Centre Hospitalier National d'Ophtalmologie - Service d'ophtalmologie
  • "Fondation Ophtalmologique Adolphe de Rothschild - "Unité de Recherche Clinique
  • "CHU Toulouse-Purpan - Service Ophtalmologie
  • University Eye Clinic in Düsseldorf
  • Universitätsklinikum Erlangen
  • Universitäts-Augenklinik Freiburg
  • Universität zu Köln - Zentrum für Augenheilkunde am Universitätsklinikum Köln
  • Johannes-Gutenberg-Universität Augenklinik und Poliklinik - Department of Ophthalmology
  • Klinikum der Universität München - Augenklinik der Ludwig-Maximilians-Universtiät München
  • OSPEDALE SAN RAFFAELE di Milano
  • Università G. D' Annunzio - Clinica Oftalmologica - Centro regionale di Eccellenza in Oftalmologia
  • Azienda Ospedaliero Universitaria Careggi
  • Dipartimento di Scienze Neurologiche Oftalmologia e Genetica - Universtità di Genova
  • Azienda Ospedaliero Universitaria di Messina - Dipartimento Specialità Chirurgiche Ambulatorio Studio delle Malattie dela Superficie Oculare Unità Operativa Complessa di Oftalmologia
  • Azienda Ospedaliera San Paolo - U.O. Oculistica
  • Azienda ospedaliera di Padova - Clinica Oculistica Policlinico 7° Piano
  • Università Campus Bio-Medico di Roma
  • Policlinico Umberto I
  • District Railway Hospital Katowice - Department of Ophthalmology
  • "SPKSO Szpital Okulistyczny ul. - SPKSO Szpital Okulistyczny
  • Vissum Corporación Oftalmológica de Alicante
  • Hospital de Cruces - Oftalmología
  • Barraquer Eye center
  • Hospital Clinic de Barcelona - Oftalmología
  • Hospital Clínico San Carlos - Oftalmología. Unidad de Superficie Ocular
  • Instituto Oftalmológico Fernández-Vega - Oftalmología
  • Cartuja Visión - Oftalmología
  • University of Birmingham - Academic Unit of Ophthalmology, School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham
  • Moorfields Eye Hospital - Moorfields Eye Hospital
  • Manchester Royal Eye Hospital - Manchester Royal Eye Hospital
  • Royal Victoria Infirmary - Dept. of Ophthalmology
  • University of Southampton Southampton General Hospital - MP104, Eye Unit

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm Type

Experimental

Experimental

Placebo Comparator

Experimental

Experimental

Placebo Comparator

Arm Label

1_rhNGF10_Phase 1_treatment

2_rhNGF20_Phase 1_treatment

3_vehicle group_Phase 1_treatment

4_rhNGF10_Phase 2_treatment

5_rhNGF20_Phase 2_treatment

6_vehicle group_Phase 2_treatment

Arm Description

active treatment with rhNGF 10 μg/ml. One drop six times a day (one 35 μl drop equals to 0.35μg of rhNGF).

active treatment with rhNGF 20 μg/ml. One drop 6 times a day (one 35 μl drop equals to 0.70 μg of rhNGF)

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

active treatment with rhNGF 10 μg/ml. One drop six times a day (one 35 μl drop equals to 0.35 μg of rhNGF)

active treatment with rhNGF 20 μg/ml. One drop 6 times a day (one 35 μl drop equals to 0.70 μg of rhNGF)

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

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.
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.
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.
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.
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
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.
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
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.
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).
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).
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.
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.

Full Information

First Posted
December 20, 2012
Last Updated
July 26, 2019
Sponsor
Dompé Farmaceutici S.p.A
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1. Study Identification

Unique Protocol Identification Number
NCT01756456
Brief Title
Evaluation of Safety and Efficacy of rhNGF in Patients With Stage 2 and 3 Neurotrophic Keratitis.
Acronym
REPARO
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
February 2017
Overall Recruitment Status
Completed
Study Start Date
January 2013 (Actual)
Primary Completion Date
April 2015 (Actual)
Study Completion Date
May 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Dompé Farmaceutici S.p.A

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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
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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Neurotrophic Keratitis, Keratitis, Corneal Ulcer
Keywords
Keratitis, Corneal Ulcer

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
174 (Actual)

8. Arms, Groups, and Interventions

Arm Title
1_rhNGF10_Phase 1_treatment
Arm Type
Experimental
Arm Description
active treatment with rhNGF 10 μg/ml. One drop six times a day (one 35 μl drop equals to 0.35μg of rhNGF).
Arm Title
2_rhNGF20_Phase 1_treatment
Arm Type
Experimental
Arm Description
active treatment with rhNGF 20 μg/ml. One drop 6 times a day (one 35 μl drop equals to 0.70 μg of rhNGF)
Arm Title
3_vehicle group_Phase 1_treatment
Arm Type
Placebo Comparator
Arm Description
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
Arm Title
4_rhNGF10_Phase 2_treatment
Arm Type
Experimental
Arm Description
active treatment with rhNGF 10 μg/ml. One drop six times a day (one 35 μl drop equals to 0.35 μg of rhNGF)
Arm Title
5_rhNGF20_Phase 2_treatment
Arm Type
Experimental
Arm Description
active treatment with rhNGF 20 μg/ml. One drop 6 times a day (one 35 μl drop equals to 0.70 μg of rhNGF)
Arm Title
6_vehicle group_Phase 2_treatment
Arm Type
Placebo Comparator
Arm Description
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
Intervention Type
Drug
Intervention Name(s)
rhNGF 10 μg/ml
Other Intervention Name(s)
recombinant human nerve growth factor 10 µg/ml solution
Intervention Description
rhNGF 10 μg/ml : one drop 6 times a day (one 35 μl drop equals to 0.35 μg of rhNGF)
Intervention Type
Drug
Intervention Name(s)
rhNGF 20 μg/ml
Other Intervention Name(s)
recombinant human nerve growth factor 20 µg/ml solution
Intervention Description
one drop 6 times a day (one 35 μl drop equals to 0.70 μg of rhNGF)
Intervention Type
Other
Intervention Name(s)
vehicle
Other Intervention Name(s)
placebo
Intervention Description
ophthalmic solution of the same composition as the test product without rhNGF
Primary Outcome Measure Information:
Title
Percentage of Patients Achieving Healing of the Persistent Epithelial Defect (PED) or Corneal Ulcer
Description
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.
Time Frame
at 4 weeks of treatment
Secondary Outcome Measure Information:
Title
Percentage of Patients Experiencing Healing of the Persistent Epithelial Defect (PED) or Corneal Ulcer
Description
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.
Time Frame
at 4 weeks of study treatment.
Title
Percentage of Patients Experiencing Complete Healing of the Persistent Epithelial Defect (PED) or Corneal Ulcer
Description
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.
Time Frame
at 6 and 8 weeks after start of the treatment
Title
Percentage of Patients Experiencing Complete Corneal Clearing
Description
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.
Time Frame
at 4, 6 and 8 weeks after start of the treatment
Title
Mean Change in Best Corrected Distance Visual Acuity (BCDVA)
Description
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.
Time Frame
At screening and at week 8
Title
Percentage of Patients That Achieve an Improvement in Corneal Sensitivity
Description
Percentage of patients that achieve an improvement in corneal sensitivity as measured by the Cochet-Bonnet aesthesiometer
Time Frame
at 4, 6 and 8 weeks.
Title
Percentage of Patients Experiencing Deterioration in Stage 2 or 3 NK
Description
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.
Time Frame
from baseline to Week 4, 6, and 8.
Title
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
Description
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
Time Frame
at week 20/28, 32/40, 44/52, and 56/64
Title
Percentage of Patients Experiencing a Different Level of Efficacy at 4 and 8 Weeks
Description
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.
Time Frame
at week 4 and 8
Title
Change From Baseline in Visual Analogue Scale (VAS) for Ocular Tolerability
Description
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).
Time Frame
at baseline and at weeks 8 and 20
Title
Change From Baseline in Best Corrected Distance Visual Acuity (BCDVA)
Description
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).
Time Frame
at baseline and at period 1 (8 weeks) and 2 (Follow Up period of 12 weeks, until week 20)
Title
Change From Baseline in Intraocular Pressure (IOP)
Description
IOP was measured using a Goldmann applanation tonometer, a handheld applanation tonometer [eg, Tonopen], or other tonometer, after the instillation of a topical anesthetic.
Time Frame
Baseline, period 1 (8 weeks) and 2 (Follow Up period of 12 weeks, until week 20).
Title
Percentage of Participants With Abnormal Eye Structures by Dilated Fundus Ophthalmoscopy
Description
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.
Time Frame
At week 8 (Phase 1 and Phase 2)
Other Pre-specified Outcome Measures:
Title
Percentage of Patients That Achieved a ≥15 Letter Gain in BCDVA
Description
Percentage of patients that achieved a ≥15 letter gain in best corrected distance visual acuity (BCDVA) at 4, 6, and 8 weeks
Time Frame
at 4, 6 and 8 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Francesco Sinigaglia, MD
Organizational Affiliation
Dompé s.p.a., Milan
Official's Role
Study Director
Facility Information:
Facility Name
CHU de Dijon - Service ophtalmologie
City
Dijon
ZIP/Postal Code
21000
Country
France
Facility Name
CHU Dupuytren - Service Ophtalmologie
City
Limoges Cedex
ZIP/Postal Code
87042
Country
France
Facility Name
Centre Hospitalier National d'Ophtalmologie - Service d'ophtalmologie
City
Paris
ZIP/Postal Code
75 571
Country
France
Facility Name
"Fondation Ophtalmologique Adolphe de Rothschild - "Unité de Recherche Clinique
City
Paris
ZIP/Postal Code
75019
Country
France
Facility Name
"CHU Toulouse-Purpan - Service Ophtalmologie
City
Toulouse
ZIP/Postal Code
31059
Country
France
Facility Name
University Eye Clinic in Düsseldorf
City
Düsseldorf
ZIP/Postal Code
50924
Country
Germany
Facility Name
Universitätsklinikum Erlangen
City
Erlangen
ZIP/Postal Code
91054
Country
Germany
Facility Name
Universitäts-Augenklinik Freiburg
City
Freiburg
ZIP/Postal Code
79106
Country
Germany
Facility Name
Universität zu Köln - Zentrum für Augenheilkunde am Universitätsklinikum Köln
City
Köln
ZIP/Postal Code
50924
Country
Germany
Facility Name
Johannes-Gutenberg-Universität Augenklinik und Poliklinik - Department of Ophthalmology
City
Mainz
ZIP/Postal Code
55131
Country
Germany
Facility Name
Klinikum der Universität München - Augenklinik der Ludwig-Maximilians-Universtiät München
City
Munchen
ZIP/Postal Code
80336
Country
Germany
Facility Name
OSPEDALE SAN RAFFAELE di Milano
City
Milan
State/Province
Lombardy
ZIP/Postal Code
20132
Country
Italy
Facility Name
Università G. D' Annunzio - Clinica Oftalmologica - Centro regionale di Eccellenza in Oftalmologia
City
Chieti
ZIP/Postal Code
66100
Country
Italy
Facility Name
Azienda Ospedaliero Universitaria Careggi
City
Florence
ZIP/Postal Code
50124
Country
Italy
Facility Name
Dipartimento di Scienze Neurologiche Oftalmologia e Genetica - Universtità di Genova
City
Genoa
ZIP/Postal Code
16132
Country
Italy
Facility Name
Azienda Ospedaliero Universitaria di Messina - Dipartimento Specialità Chirurgiche Ambulatorio Studio delle Malattie dela Superficie Oculare Unità Operativa Complessa di Oftalmologia
City
Messina
ZIP/Postal Code
98125
Country
Italy
Facility Name
Azienda Ospedaliera San Paolo - U.O. Oculistica
City
Milano
ZIP/Postal Code
20142
Country
Italy
Facility Name
Azienda ospedaliera di Padova - Clinica Oculistica Policlinico 7° Piano
City
Padova
ZIP/Postal Code
35128
Country
Italy
Facility Name
Università Campus Bio-Medico di Roma
City
Rome
ZIP/Postal Code
00128
Country
Italy
Facility Name
Policlinico Umberto I
City
Rome
ZIP/Postal Code
00161
Country
Italy
Facility Name
District Railway Hospital Katowice - Department of Ophthalmology
City
Katowice
ZIP/Postal Code
40-760
Country
Poland
Facility Name
"SPKSO Szpital Okulistyczny ul. - SPKSO Szpital Okulistyczny
City
Warsawa
ZIP/Postal Code
03-709
Country
Poland
Facility Name
Vissum Corporación Oftalmológica de Alicante
City
Alicante
ZIP/Postal Code
03016
Country
Spain
Facility Name
Hospital de Cruces - Oftalmología
City
Barakaldo
ZIP/Postal Code
48903
Country
Spain
Facility Name
Barraquer Eye center
City
Barcelona
ZIP/Postal Code
08021
Country
Spain
Facility Name
Hospital Clinic de Barcelona - Oftalmología
City
Barcelona
ZIP/Postal Code
08028
Country
Spain
Facility Name
Hospital Clínico San Carlos - Oftalmología. Unidad de Superficie Ocular
City
Madrid
ZIP/Postal Code
28040
Country
Spain
Facility Name
Instituto Oftalmológico Fernández-Vega - Oftalmología
City
Oviedo
ZIP/Postal Code
33012
Country
Spain
Facility Name
Cartuja Visión - Oftalmología
City
Sevilla
ZIP/Postal Code
41092
Country
Spain
Facility Name
University of Birmingham - Academic Unit of Ophthalmology, School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham
City
Birmingham
ZIP/Postal Code
"B15 2TT
Country
United Kingdom
Facility Name
Moorfields Eye Hospital - Moorfields Eye Hospital
City
London
ZIP/Postal Code
EC1V 2PD
Country
United Kingdom
Facility Name
Manchester Royal Eye Hospital - Manchester Royal Eye Hospital
City
Manchester
ZIP/Postal Code
M13 9WL
Country
United Kingdom
Facility Name
Royal Victoria Infirmary - Dept. of Ophthalmology
City
Newcastle upon Tyne
ZIP/Postal Code
NE1 4LP
Country
United Kingdom
Facility Name
University of Southampton Southampton General Hospital - MP104, Eye Unit
City
Southampton
ZIP/Postal Code
SO16 6YD
Country
United Kingdom

12. IPD Sharing Statement

Citations:
PubMed Identifier
26448169
Citation
Yanai R, Nishida T, Chikama T, Morishige N, Yamada N, Sonoda KH. Potential New Modes of Treatment of Neurotrophic Keratopathy. Cornea. 2015 Nov;34 Suppl 11:S121-7. doi: 10.1097/ICO.0000000000000587.
Results Reference
derived

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

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