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

NCT ID: NCT01756456

Last Updated: 2024-04-19

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 174 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-01-31
• Study Completion Date: 2016-05-31

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

Conditions

Neurotrophic Keratitis; Keratitis; Corneal Ulcer

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

1_rhNGF10_Phase 1_treatment

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

Group Type: EXPERIMENTAL

rhNGF 10 μg/ml

Intervention Type: DRUG

rhNGF 10 μg/ml : one drop 6 times a day (one 35 μl drop equals to 0.35 μg of rhNGF)

2_rhNGF20_Phase 1_treatment

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

Group Type: EXPERIMENTAL

rhNGF 20 μg/ml

Intervention Type: DRUG

one drop 6 times a day (one 35 μl drop equals to 0.70 μg of rhNGF)

3_vehicle group_Phase 1_treatment

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

Group Type: PLACEBO_COMPARATOR

vehicle

Intervention Type: OTHER

ophthalmic solution of the same composition as the test product without rhNGF

4_rhNGF10_Phase 2_treatment

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

Group Type: EXPERIMENTAL

rhNGF 10 μg/ml

Intervention Type: DRUG

rhNGF 10 μg/ml : one drop 6 times a day (one 35 μl drop equals to 0.35 μg of rhNGF)

5_rhNGF20_Phase 2_treatment

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

Group Type: EXPERIMENTAL

rhNGF 20 μg/ml

Intervention Type: DRUG

one drop 6 times a day (one 35 μl drop equals to 0.70 μg of rhNGF)

6_vehicle group_Phase 2_treatment

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

Group Type: PLACEBO_COMPARATOR

vehicle

Intervention Type: OTHER

ophthalmic solution of the same composition as the test product without rhNGF

Interventions

rhNGF 10 μg/ml

rhNGF 10 μg/ml : one drop 6 times a day (one 35 μl drop equals to 0.35 μg of rhNGF)

Intervention Type: DRUG

rhNGF 20 μg/ml

one drop 6 times a day (one 35 μl drop equals to 0.70 μg of rhNGF)

Intervention Type: DRUG

vehicle

ophthalmic solution of the same composition as the test product without rhNGF

Intervention Type: OTHER

Other Intervention Names

recombinant human nerve growth factor 10 µg/ml solution; recombinant human nerve growth factor 20 µg/ml solution; placebo

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Dompé Farmaceutici S.p.A

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Francesco Sinigaglia, MD

Role: STUDY_DIRECTOR

Dompé s.p.a., Milan

Locations

CHU de Dijon - Service ophtalmologie

Dijon, , France

CHU Dupuytren - Service Ophtalmologie

Limoges, , France

Centre Hospitalier National d'Ophtalmologie - Service d'ophtalmologie

Paris, , France

"Fondation Ophtalmologique Adolphe de Rothschild - "Unité de Recherche Clinique

Paris, , France

"CHU Toulouse-Purpan - Service Ophtalmologie

Toulouse, , France

Universität zu Köln - Zentrum für Augenheilkunde am Universitätsklinikum Köln

Cologne, , Germany

University Eye Clinic in Düsseldorf

Düsseldorf, , Germany

Universitätsklinikum Erlangen

Erlangen, , Germany

Universitäts-Augenklinik Freiburg

Freiburg im Breisgau, , Germany

Johannes-Gutenberg-Universität Augenklinik und Poliklinik - Department of Ophthalmology

Mainz, , Germany

Klinikum der Universität München - Augenklinik der Ludwig-Maximilians-Universtiät München

München, , Germany

OSPEDALE SAN RAFFAELE di Milano

Milan, Lombardy, Italy

Università G. D' Annunzio - Clinica Oftalmologica - Centro regionale di Eccellenza in Oftalmologia

Chieti, , Italy

Azienda Ospedaliero Universitaria Careggi

Florence, , Italy

Dipartimento di Scienze Neurologiche Oftalmologia e Genetica - Universtità di Genova

Genoa, , Italy

Azienda Ospedaliero Universitaria di Messina - Dipartimento Specialità Chirurgiche Ambulatorio Studio delle Malattie dela Superficie Oculare Unità Operativa Complessa di Oftalmologia

Messina, , Italy

Azienda Ospedaliera San Paolo - U.O. Oculistica

Milan, , Italy

Azienda ospedaliera di Padova - Clinica Oculistica Policlinico 7° Piano

Padua, , Italy

Università Campus Bio-Medico di Roma

Rome, , Italy

Policlinico Umberto I

Rome, , Italy

District Railway Hospital Katowice - Department of Ophthalmology

Katowice, , Poland

"SPKSO Szpital Okulistyczny ul. - SPKSO Szpital Okulistyczny

Warsaw, , Poland

Vissum Corporación Oftalmológica de Alicante

Alicante, , Spain

Hospital de Cruces - Oftalmología

Barakaldo, , Spain

Barraquer Eye center

Barcelona, , Spain

Hospital Clinic de Barcelona - Oftalmología

Barcelona, , Spain

Hospital Clínico San Carlos - Oftalmología. Unidad de Superficie Ocular

Madrid, , Spain

Instituto Oftalmológico Fernández-Vega - Oftalmología

Oviedo, , Spain

Cartuja Visión - Oftalmología

Seville, , Spain

University of Birmingham - Academic Unit of Ophthalmology, School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham

Birmingham, , United Kingdom

Moorfields Eye Hospital - Moorfields Eye Hospital

London, , United Kingdom

Manchester Royal Eye Hospital - Manchester Royal Eye Hospital

Manchester, , United Kingdom

Royal Victoria Infirmary - Dept. of Ophthalmology

Newcastle upon Tyne, , United Kingdom

University of Southampton Southampton General Hospital - MP104, Eye Unit

Southampton, , United Kingdom

Countries

France; Germany; Italy; Poland; Spain; United Kingdom

References

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.

Reference Type: DERIVED

PMID: 26448169 (View on PubMed)

Other Identifiers

2012-002527-15

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

NGF0212

Identifier Type: -

Identifier Source: org_study_id