Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu
Trial record 1 of 1 for:    reparo
Previous Study | Return to List | Next Study

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01756456
Recruitment Status : Completed
First Posted : December 27, 2012
Results First Posted : July 29, 2019
Last Update Posted : July 29, 2019
Sponsor:
Information provided by (Responsible Party):
Dompé Farmaceutici S.p.A

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

Condition or disease Intervention/treatment Phase
Neurotrophic Keratitis Keratitis Corneal Ulcer Drug: rhNGF 10 μg/ml Drug: rhNGF 20 μg/ml Other: vehicle Phase 1 Phase 2

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


Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 174 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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
Actual Study Start Date : January 2013
Actual Primary Completion Date : April 2015
Actual Study Completion Date : May 2016

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: 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).
Drug: 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)
Other Name: recombinant human nerve growth factor 10 µg/ml solution

Experimental: 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)
Drug: rhNGF 20 μg/ml
one drop 6 times a day (one 35 μl drop equals to 0.70 μg of rhNGF)
Other Name: recombinant human nerve growth factor 20 µg/ml solution

Placebo Comparator: 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
Other: vehicle
ophthalmic solution of the same composition as the test product without rhNGF
Other Name: placebo

Experimental: 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)
Drug: 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)
Other Name: recombinant human nerve growth factor 10 µg/ml solution

Experimental: 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)
Drug: rhNGF 20 μg/ml
one drop 6 times a day (one 35 μl drop equals to 0.70 μg of rhNGF)
Other Name: recombinant human nerve growth factor 20 µg/ml solution

Placebo Comparator: 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
Other: vehicle
ophthalmic solution of the same composition as the test product without rhNGF
Other Name: placebo




Primary Outcome Measures :
  1. Percentage of Patients Achieving Healing of the Persistent Epithelial Defect (PED) or Corneal Ulcer [ Time Frame: at 4 weeks of treatment ]

    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 :
  1. Percentage of Patients Experiencing Healing of the Persistent Epithelial Defect (PED) or Corneal Ulcer [ Time Frame: at 4 weeks of study treatment. ]

    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.


  2. Percentage of Patients Experiencing Complete Healing of the Persistent Epithelial Defect (PED) or Corneal Ulcer [ Time Frame: at 6 and 8 weeks after start of the treatment ]

    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.


  3. Percentage of Patients Experiencing Complete Corneal Clearing [ Time Frame: at 4, 6 and 8 weeks after start of the treatment ]

    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.


  4. Mean Change in Best Corrected Distance Visual Acuity (BCDVA) [ Time Frame: At screening and at week 8 ]
    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.

  5. Percentage of Patients That Achieve an Improvement in Corneal Sensitivity [ Time Frame: at 4, 6 and 8 weeks. ]
    Percentage of patients that achieve an improvement in corneal sensitivity as measured by the Cochet-Bonnet aesthesiometer

  6. Percentage of Patients Experiencing Deterioration in Stage 2 or 3 NK [ Time Frame: from baseline to Week 4, 6, and 8. ]
    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.

  7. 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 [ Time Frame: at week 20/28, 32/40, 44/52, and 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

  8. Percentage of Patients Experiencing a Different Level of Efficacy at 4 and 8 Weeks [ Time Frame: at week 4 and 8 ]
    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.

  9. Change From Baseline in Visual Analogue Scale (VAS) for Ocular Tolerability [ Time Frame: at baseline and at weeks 8 and 20 ]

    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).


  10. Change From Baseline in Best Corrected Distance Visual Acuity (BCDVA) [ Time Frame: at baseline and at period 1 (8 weeks) and 2 (Follow Up period of 12 weeks, until week 20) ]
    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).

  11. Change From Baseline in Intraocular Pressure (IOP) [ Time Frame: Baseline, period 1 (8 weeks) and 2 (Follow Up period of 12 weeks, until week 20). ]
    IOP was measured using a Goldmann applanation tonometer, a handheld applanation tonometer [eg, Tonopen], or other tonometer, after the instillation of a topical anesthetic.

  12. Percentage of Participants With Abnormal Eye Structures by Dilated Fundus Ophthalmoscopy [ Time Frame: At week 8 (Phase 1 and Phase 2) ]

    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.



Other Outcome Measures:
  1. Percentage of Patients That Achieved a ≥15 Letter Gain in BCDVA [ Time Frame: at 4, 6 and 8 weeks ]
    Percentage of patients that achieved a ≥15 letter gain in best corrected distance visual acuity (BCDVA) at 4, 6, and 8 weeks



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01756456


Locations
Layout table for location information
France
CHU de Dijon - Service ophtalmologie
Dijon, France, 21000
CHU Dupuytren - Service Ophtalmologie
Limoges Cedex, France, 87042
Centre Hospitalier National d'Ophtalmologie - Service d'ophtalmologie
Paris, France, 75 571
"Fondation Ophtalmologique Adolphe de Rothschild - "Unité de Recherche Clinique
Paris, France, 75019
"CHU Toulouse-Purpan - Service Ophtalmologie
Toulouse, France, 31059
Germany
University Eye Clinic in Düsseldorf
Düsseldorf, Germany, 50924
Universitätsklinikum Erlangen
Erlangen, Germany, 91054
Universitäts-Augenklinik Freiburg
Freiburg, Germany, 79106
Universität zu Köln - Zentrum für Augenheilkunde am Universitätsklinikum Köln
Köln, Germany, 50924
Johannes-Gutenberg-Universität Augenklinik und Poliklinik - Department of Ophthalmology
Mainz, Germany, 55131
Klinikum der Universität München - Augenklinik der Ludwig-Maximilians-Universtiät München
Munchen, Germany, 80336
Italy
OSPEDALE SAN RAFFAELE di Milano
Milan, Lombardy, Italy, 20132
Università G. D' Annunzio - Clinica Oftalmologica - Centro regionale di Eccellenza in Oftalmologia
Chieti, Italy, 66100
Azienda Ospedaliero Universitaria Careggi
Florence, Italy, 50124
Dipartimento di Scienze Neurologiche Oftalmologia e Genetica - Universtità di Genova
Genoa, Italy, 16132
Azienda Ospedaliero Universitaria di Messina - Dipartimento Specialità Chirurgiche Ambulatorio Studio delle Malattie dela Superficie Oculare Unità Operativa Complessa di Oftalmologia
Messina, Italy, 98125
Azienda Ospedaliera San Paolo - U.O. Oculistica
Milano, Italy, 20142
Azienda ospedaliera di Padova - Clinica Oculistica Policlinico 7° Piano
Padova, Italy, 35128
Università Campus Bio-Medico di Roma
Rome, Italy, 00128
Policlinico Umberto I
Rome, Italy, 00161
Poland
District Railway Hospital Katowice - Department of Ophthalmology
Katowice, Poland, 40-760
"SPKSO Szpital Okulistyczny ul. - SPKSO Szpital Okulistyczny
Warsawa, Poland, 03-709
Spain
Vissum Corporación Oftalmológica de Alicante
Alicante, Spain, 03016
Hospital de Cruces - Oftalmología
Barakaldo, Spain, 48903
Barraquer Eye center
Barcelona, Spain, 08021
Hospital Clinic de Barcelona - Oftalmología
Barcelona, Spain, 08028
Hospital Clínico San Carlos - Oftalmología. Unidad de Superficie Ocular
Madrid, Spain, 28040
Instituto Oftalmológico Fernández-Vega - Oftalmología
Oviedo, Spain, 33012
Cartuja Visión - Oftalmología
Sevilla, Spain, 41092
United Kingdom
University of Birmingham - Academic Unit of Ophthalmology, School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham
Birmingham, United Kingdom, "B15 2TT
Moorfields Eye Hospital - Moorfields Eye Hospital
London, United Kingdom, EC1V 2PD
Manchester Royal Eye Hospital - Manchester Royal Eye Hospital
Manchester, United Kingdom, M13 9WL
Royal Victoria Infirmary - Dept. of Ophthalmology
Newcastle upon Tyne, United Kingdom, NE1 4LP
University of Southampton Southampton General Hospital - MP104, Eye Unit
Southampton, United Kingdom, SO16 6YD
Sponsors and Collaborators
Dompé Farmaceutici S.p.A
Investigators
Layout table for investigator information
Study Director: Francesco Sinigaglia, MD Dompé s.p.a., Milan

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Layout table for additonal information
Responsible Party: Dompé Farmaceutici S.p.A
ClinicalTrials.gov Identifier: NCT01756456     History of Changes
Other Study ID Numbers: NGF0212
2012-002527-15 ( EudraCT Number )
First Posted: December 27, 2012    Key Record Dates
Results First Posted: July 29, 2019
Last Update Posted: July 29, 2019
Last Verified: February 2017
Keywords provided by Dompé Farmaceutici S.p.A:
Keratitis
Corneal Ulcer
Additional relevant MeSH terms:
Layout table for MeSH terms
Corneal Ulcer
Keratitis
Corneal Diseases
Eye Diseases
Eye Infections
Infection
Ophthalmic Solutions
Pharmaceutical Solutions
Mitogens
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action