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Neurotrophic KeratitisPhase 1/2REPARONCT01756456

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

A Phase 1/2 study testing rhNGF 10 μg/ml and rhNGF 20 μg/ml in people with Neurotrophic Keratitis and Keratitis, run by Dompé Farmaceutici S.p.A at 34 sites in 6 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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 Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Neurotrophic Keratitis, Keratitis, Corneal Ulcer
What is being tested?
rhNGF 10 μg/ml and rhNGF 20 μg/ml
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
174 participants
Where
34 sitesin 6 countries
Study dates
Jan 2013to May 2016
Phase
Phase 1/2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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.
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  • 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).

Who cannot join

  • 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.
Show all 18Show fewer
  • 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.

Trial locations and contacts

34 sites in 6 countries.

34 sites in 6 countries

Italy9 sites

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

    Chieti, 66100

  • Azienda Ospedaliero Universitaria Careggi

    Florence, 50124

  • Dipartimento di Scienze Neurologiche Oftalmologia e Genetica - Universtità di Genova

    Genoa, 16132

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

    Messina, 98125

  • OSPEDALE SAN RAFFAELE di Milano

    Milan, Lombardy, 20132

  • Azienda Ospedaliera San Paolo - U.O. Oculistica

    Milan, 20142

  • Azienda ospedaliera di Padova - Clinica Oculistica Policlinico 7° Piano

    Padova, 35128

  • Università Campus Bio-Medico di Roma

    Rome, 00128

  • Policlinico Umberto I

    Rome, 00161

Other trials in Italy

Spain7 sites

  • Vissum Corporación Oftalmológica de Alicante

    Alicante, 03016

  • Hospital de Cruces - Oftalmología

    Barakaldo, 48903

  • Barraquer Eye center

    Barcelona, 08021

  • Hospital Clinic de Barcelona - Oftalmología

    Barcelona, 08028

  • Hospital Clínico San Carlos - Oftalmología. Unidad de Superficie Ocular

    Madrid, 28040

  • Instituto Oftalmológico Fernández-Vega - Oftalmología

    Oviedo, 33012

  • Cartuja Visión - Oftalmología

    Seville, 41092

Other trials in Spain

Germany6 sites

  • Universität zu Köln - Zentrum für Augenheilkunde am Universitätsklinikum Köln

    Cologne, 50924

  • University Eye Clinic in Düsseldorf

    Düsseldorf, 50924

  • Universitätsklinikum Erlangen

    Erlangen, 91054

  • Universitäts-Augenklinik Freiburg

    Freiburg im Breisgau, 79106

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

    Mainz, 55131

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

    München, 80336

Other trials in Germany

France5 sites

  • CHU de Dijon - Service ophtalmologie

    Dijon, 21000

  • CHU Dupuytren - Service Ophtalmologie

    Limoges, 87042

  • Centre Hospitalier National d'Ophtalmologie - Service d'ophtalmologie

    Paris, 75 571

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

    Paris, 75019

  • "CHU Toulouse-Purpan - Service Ophtalmologie

    Toulouse, 31059

Other trials in France

United Kingdom5 sites

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

    Birmingham, "B15 2TT

  • Moorfields Eye Hospital - Moorfields Eye Hospital

    London, EC1V 2PD

  • Manchester Royal Eye Hospital - Manchester Royal Eye Hospital

    Manchester, M13 9WL

  • Royal Victoria Infirmary - Dept. of Ophthalmology

    Newcastle upon Tyne, NE1 4LP

  • University of Southampton Southampton General Hospital - MP104, Eye Unit

    Southampton, SO16 6YD

Other trials in United Kingdom

Poland2 sites

  • District Railway Hospital Katowice - Department of Ophthalmology

    Katowice, 40-760

  • "SPKSO Szpital Okulistyczny ul. - SPKSO Szpital Okulistyczny

    Warsaw, 03-709

Other trials in Poland

About this study

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

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

Read the 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

Being tested
rhNGF 10 μg/ml, rhNGF 20 μg/ml, vehicle
Keywords
Keratitis, Corneal Ulcer
Medical subject headings
Keratitis, Corneal Ulcer

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • rhNGF 10 μg/mlDrug

    Also called recombinant human nerve growth factor 10 µg/ml solution

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

  • rhNGF 20 μg/mlDrug

    Also called recombinant human nerve growth factor 20 µg/ml solution

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

  • vehicleOther

    Also called placebo

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

Study groups in NCT01756456
Study groupRoleWhat they receive
1_rhNGF10_Phase 1_treatmentExperimentalactive treatment with rhNGF 10 μg/ml. One drop six times a day (one 35 μl drop equals to 0.35μg of rhNGF).
Receives: Drug: rhNGF 10 μg/ml
2_rhNGF20_Phase 1_treatmentExperimentalactive treatment with rhNGF 20 μg/ml. One drop 6 times a day (one 35 μl drop equals to 0.70 μg of rhNGF)
Receives: Drug: rhNGF 20 μg/ml
3_vehicle group_Phase 1_treatmentPlacebo comparatorvehicle 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
Receives: Other: vehicle
4_rhNGF10_Phase 2_treatmentExperimentalactive treatment with rhNGF 10 μg/ml. One drop six times a day (one 35 μl drop equals to 0.35 μg of rhNGF)
Receives: Drug: rhNGF 10 μg/ml
5_rhNGF20_Phase 2_treatmentExperimentalactive treatment with rhNGF 20 μg/ml. One drop 6 times a day (one 35 μl drop equals to 0.70 μg of rhNGF)
Receives: Drug: rhNGF 20 μg/ml
6_vehicle group_Phase 2_treatmentPlacebo comparatorvehicle 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
Receives: Other: vehicle

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: at 4 weeks of treatment

Secondary outcomes (12)

  1. 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.

    Measured: at 4 weeks of study treatment.

  2. 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.

    Measured: at 6 and 8 weeks after start of the treatment

  3. 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.

    Measured: at 4, 6 and 8 weeks after start of the treatment

  4. 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.

    Measured: At screening and at week 8

  5. 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

    Measured: at 4, 6 and 8 weeks.

  6. 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.

    Measured: 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

    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

    Measured: at week 20/28, 32/40, 44/52, and 56/64

  8. 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.

    Measured: at week 4 and 8

  9. 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).

    Measured: at baseline and at weeks 8 and 20

  10. 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).

    Measured: at baseline and at period 1 (8 weeks) and 2 (Follow Up period of 12 weeks, until week 20)

  11. 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.

    Measured: Baseline, period 1 (8 weeks) and 2 (Follow Up period of 12 weeks, until week 20).

  12. 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.

    Measured: At week 8 (Phase 1 and Phase 2)

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted27 Dec 2012 (estimated)
  2. Study startJan 2013
  3. Primary completionApr 2015
  4. Study completionMay 2016

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
174 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01756456
Sponsor's protocol ID
NGF0212
Other IDs
2012-002527-15
Acronym
REPARO
Status last verified
Feb 2017
First submitted
20 Dec 2012
Last updated
19 Apr 2024
Data monitoring committee
Yes

Publications

  • 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.

    PubMed 26448169

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing rhNGF 10 μg/ml and rhNGF 20 μg/ml in people with Neurotrophic Keratitis and Keratitis, run by Dompé Farmaceutici S.p.A at 34 sites in 6 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 9 inclusion and 18 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 19 Apr 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 34 sites in Italy, Spain, Germany, France, United Kingdom and 1 more country. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 29 Jul 2019). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Percentage of Patients Achieving Healing of the Persistent Epithelial Defect (PED) or Corneal Ulcer (time frame: at 4 weeks of treatment). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01756456, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Apr 2024.

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