Clinical trial NCT01756456: Evaluation of Safety and Efficacy of rhNGF in Patients With Stage 2 and 3 Neurotrophic Keratitis.
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
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Neurotrophic Keratitis
Keratitis
Corneal Ulcer
Keywords: Keratitis
Corneal Ulcer
Lead sponsor: Dompé Farmaceutici S.p.A
Sponsor class: INDUSTRY
First posted: 2012-12-27
Enrollment: 174
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

Eligibility criteria: 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.

Primary outcomes:
measure: Percentage of Patients Achieving Healing of the Persistent Epithelial Defect (PED) or Corneal Ulcer
timeFrame: at 4 weeks of treatment
Secondary outcomes:
measure: Percentage of Patients Experiencing Healing of the Persistent Epithelial Defect (PED) or Corneal Ulcer
timeFrame: at 4 weeks of study treatment.
measure: Percentage of Patients Experiencing Complete Healing of the Persistent Epithelial Defect (PED) or Corneal Ulcer
timeFrame: at 6 and 8 weeks after start of the treatment
measure: Percentage of Patients Experiencing Complete Corneal Clearing
timeFrame: at 4, 6 and 8 weeks after start of the treatment
measure: Mean Change in Best Corrected Distance Visual Acuity (BCDVA)
timeFrame: At screening and at week 8
measure: Percentage of Patients That Achieve an Improvement in Corneal Sensitivity
timeFrame: at 4, 6 and 8 weeks.
measure: Percentage of Patients Experiencing Deterioration in Stage 2 or 3 NK
timeFrame: from baseline to Week 4, 6, and 8.
measure: 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
timeFrame: at week 20/28, 32/40, 44/52, and 56/64
measure: Percentage of Patients Experiencing a Different Level of Efficacy at 4 and 8 Weeks
timeFrame: at week 4 and 8
measure: Change From Baseline in Visual Analogue Scale (VAS) for Ocular Tolerability
timeFrame: at baseline and at weeks 8 and 20
measure: Change From Baseline in Best Corrected Distance Visual Acuity (BCDVA)
timeFrame: at baseline and at period 1 (8 weeks) and 2 (Follow Up period of 12 weeks, until week 20)
measure: Change From Baseline in Intraocular Pressure (IOP)
timeFrame: Baseline, period 1 (8 weeks) and 2 (Follow Up period of 12 weeks, until week 20).
measure: Percentage of Participants With Abnormal Eye Structures by Dilated Fundus Ophthalmoscopy
timeFrame: At week 8 (Phase 1 and Phase 2)
Other outcomes:
measure: Percentage of Patients That Achieved a ≥15 Letter Gain in BCDVA
timeFrame: at 4, 6 and 8 weeks
Locations:
city: Dijon
country: France
facility: CHU de Dijon - Service ophtalmologie
city: Limoges Cedex
country: France
facility: CHU Dupuytren - Service Ophtalmologie
city: Paris
country: France
facility: Centre Hospitalier National d'Ophtalmologie - Service d'ophtalmologie
city: Paris
country: France
facility: "Fondation Ophtalmologique Adolphe de Rothschild - "Unité de Recherche Clinique
city: Toulouse
country: France
facility: "CHU Toulouse-Purpan - Service Ophtalmologie
city: Düsseldorf
country: Germany
facility: University Eye Clinic in Düsseldorf
city: Erlangen
country: Germany
facility: Universitätsklinikum Erlangen
city: Freiburg
country: Germany
facility: Universitäts-Augenklinik Freiburg
city: Köln
country: Germany
facility: Universität zu Köln - Zentrum für Augenheilkunde am Universitätsklinikum Köln
city: Mainz
country: Germany
facility: Johannes-Gutenberg-Universität Augenklinik und Poliklinik - Department of Ophthalmology
city: Munchen
country: Germany
facility: Klinikum der Universität München - Augenklinik der Ludwig-Maximilians-Universtiät München
city: Milan
country: Italy
facility: OSPEDALE SAN RAFFAELE di Milano
state: Lombardy
city: Chieti
country: Italy
facility: Università G. D' Annunzio - Clinica Oftalmologica - Centro regionale di Eccellenza in Oftalmologia
city: Florence
country: Italy
facility: Azienda Ospedaliero Universitaria Careggi
city: Genoa
country: Italy
facility: Dipartimento di Scienze Neurologiche Oftalmologia e Genetica - Universtità di Genova
city: Messina
country: Italy
facility: Azienda Ospedaliero Universitaria di Messina - Dipartimento Specialità Chirurgiche Ambulatorio Studio delle Malattie dela Superficie Oculare Unità Operativa Complessa di Oftalmologia
city: Milano
country: Italy
facility: Azienda Ospedaliera San Paolo - U.O. Oculistica
city: Padova
country: Italy
facility: Azienda ospedaliera di Padova - Clinica Oculistica Policlinico 7° Piano
city: Rome
country: Italy
facility: Università Campus Bio-Medico di Roma
city: Rome
country: Italy
facility: Policlinico Umberto I
city: Katowice
country: Poland
facility: District Railway Hospital Katowice - Department of Ophthalmology
city: Warsawa
country: Poland
facility: "SPKSO Szpital Okulistyczny ul. - SPKSO Szpital Okulistyczny
city: Alicante
country: Spain
facility: Vissum Corporación Oftalmológica de Alicante
city: Barakaldo
country: Spain
facility: Hospital de Cruces - Oftalmología
city: Barcelona
country: Spain
facility: Barraquer Eye center
city: Barcelona
country: Spain
facility: Hospital Clinic de Barcelona - Oftalmología
city: Madrid
country: Spain
facility: Hospital Clínico San Carlos - Oftalmología. Unidad de Superficie Ocular
city: Oviedo
country: Spain
facility: Instituto Oftalmológico Fernández-Vega - Oftalmología
city: Sevilla
country: Spain
facility: Cartuja Visión - Oftalmología
city: Birmingham
country: United Kingdom
facility: University of Birmingham - Academic Unit of Ophthalmology, School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham
city: London
country: United Kingdom
facility: Moorfields Eye Hospital - Moorfields Eye Hospital
city: Manchester
country: United Kingdom
facility: Manchester Royal Eye Hospital - Manchester Royal Eye Hospital
city: Newcastle upon Tyne
country: United Kingdom
facility: Royal Victoria Infirmary - Dept. of Ophthalmology
city: Southampton
country: United Kingdom
facility: University of Southampton Southampton General Hospital - MP104, Eye Unit
Study officials:
affiliation: Dompé s.p.a., Milan
name: Francesco Sinigaglia, MD
role: STUDY_DIRECTOR
References:
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.