| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Adult patients diagnosed with unilateral stage 2 (persistent epithelial defect) and stage 3 (corneal ulcer) NK refractory to one or more conventional non-surgical treatments. Patients with Controlateral eye affected with stage 1 NK can be enrolled. |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Eye Diseases [C11] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10032064 |
| E.1.2 | Term | Other forms of keratitis |
| E.1.2 | System Organ Class | 100000004853 |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The main objective of the Phase I segment of the study is safety, whereas the main objectives of the Phase II segment of the study are efficacy and safety. The 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 central reading center evaluating the clinical pictures of corneal fluorescein staining. |
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| E.2.2 | Secondary objectives of the trial |
| Secondary objectives of the study are to assess complete healing as measured by the investigator using corneal fluorescein staining, the duration of complete healing according to the central reading center, improvement in visual acuity and improvement in corneal sensitivity and percentage of patients achieving complete corneal clearing defined as grade 0 on the Modified Oxford Scale, following treatment with rhNGF eye drops solution. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 eyes. 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 using the Cochet-Bonnet esthesiometer) 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(s).
6. No objective clinical evidence of improvement in the PED or corneal ulceration within the 2 weeks prior to study enrolment.
7. In patients with bilateral disease, the same eye (worse eligible eye) must fulfill all the above criteria.
8. 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 IRB/IEC for the current study.
9. Patients must have the ability and willingness to comply with study procedures.
10. Patients must be eligible for the National Health Insurance (where applicable). |
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| E.4 | Principal 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 inflammation not related to NK in the affected eye(s).
3. Any other ocular disease requiring topical ocular treatment during the course of the study treatment period. No topical treatments other than the study medications provided by the study sponsor and allowed by the study protocol can be administered 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.
6. Patients with severe blepharitis and/or severe meibomian gland disease.
7. History of any ocular surgery (including laser or refractive surgical procedures) 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 will not be allowed during the study treatment period and elective ocular surgery procedures should not be planned during the duration of the open-label follow-up period.
8. Prior surgical procedure(s) for the treatment of NK (e.g. complete tarsorraphy, conjunctival flap, etc) 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(s) 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.
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:
a. are currently pregnant or,
b. have a positive result on the urine pregnancy test at the Randomisation Visit or,
c. intend to become pregnant during the study treatment period or,
d. are breast-feeding or,
e. 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.
Please refer to study protocol for full exclusion list. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Percentage of patients experiencing complete healing of the PED or corneal ulcer determined by corneal fluorescein staining at 4 weeks as defined by the central reading center evaluating the clinical pictures. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
Consistent with the study design the secondary efficacy endpoints are presented according to the two study treatment periods: the 8 week controlled treatment period (Controlled Treatment Period) and the 46 or 52 week open-label follow-up period (Open-Label Follow-up Period).
Secondary efficacy endpoints related to the Controlled Treatment Period
•Percentage of patients experiencing complete healing of the PED or
corneal ulcer determined by corneal fluorescein staining at 4 weeks as
defined by the Investigator.
•Percentage of patients experiencing complete healing of the PED or
corneal ulcer at 6 and 8 weeks as measured by both the central reading
center and Investigator.
•Percentage of patients experiencing complete corneal clearing (grade 0
on the modified Oxford scale) at 4, 6 and 8 weeks.
• Mean change in BCDVA from baseline to Week 8.
• Percentage of patients that achieve a ≥ 15 letter gain in BCDVA at 4
weeks, 6 weeks, 8 weeks.
• Percentage of patients that achieve an improvement in corneal
sensitivity as measured by the Cochet-Bonnet esthesiometer at 4, 6 and
8 weeks.
• Percentage of patients experiencing deterioration (increase in lesion
size ≥ 1 mm, 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 8.
• Time to onset of deterioration from baseline to Week 8.
• Investigator global evaluation of efficacy at 4, 6 and 8 weeks.
Secondary efficacy endpoints related to the Open-label Follow-up Period:
• Percentage of patients achieving complete healing of the PED or corneal ulcer by Week 8/16 that remain healed (i.e. no recurrence of the PED and/or corneal ulcer) at Weeks 20/28, 32/40, 44/52, 56/64.
• Mean change in BCDVA in patients achieving complete healing of the PED or corneal ulcer by Week 8/16 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 achieve a ≥ 15 letter gain in BCDVA 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 with no change or improved corneal sensitivity that show no change or further improvement 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 with no recurrence of stage 2 (PED) or stage 3 (corneal ulcer) at Weeks 20/28, 32/40, 44/52, 56/64.
• Time to recurrence of stage 2 (PED) or stage 3 (corneal ulcer) in patients achieving complete healing of the PED or corneal ulcer by Week 8/16, defined as the stage of NK recorded by the investigator as stage 2 or stage 3 after healing.
Exploratory efficacy variables
• Percentage of patients achieving complete corneal clearing (grade 0 on the modified Oxford scale) by Week 8/16 that maintain complete corneal clearing at Weeks 20/28, 32/40, 44/52, 56/64.
• Time to complete corneal clearing.
• Time to onset of healing (defined as a >20% reduction in the greatest diameter of the lesion) and time to complete healing of the PED or corneal ulcer as determined by the investigator.
• Change in Schirmers without anesthesia score from baseline at Weeks 4 and 8.
• Change in confocal microscopy from baseline to Week 8.
• Change in tear film osmolarity from baseline to Week 8.
• Change in NEI-VFQ and EQ5D (quality of life and health state questionnaires) scores from baseline to Week 8.
• Comparision of the safety and efficacy results in patients with and without punctual occlusion from baseline to Week 8.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Please refer to the descritpion of the secondary end point description |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
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| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Multicentric phase I/II with an open labelled follow-up period of 48/56 weeks |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 35 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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