Clincosm LogoSign in Get a demo

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

Sponsor
Dompé Farmaceutici S.p.A (Industry)
Overall Status
Completed
CT.gov ID
NCT01756456
Collaborator
(none)
174
Enrollment
34
Locations
6
Arms
40
Actual Duration (Months)
5.1
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

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
  • 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

Study Design

Study Type:
Interventional
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 :
Jan 1, 2013
Actual Primary Completion Date :
Apr 1, 2015
Actual Study Completion Date :
May 1, 2016

Arms and Interventions

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 Names:
  • 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 Names:
  • 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 Names:
  • 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 Names:
  • 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 Names:
  • 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 Names:
  • placebo

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Percentage of Patients Achieving Healing of the Persistent Epithelial Defect (PED) or Corneal Ulcer [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 [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 [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 [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) [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 [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 [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 [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 [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 [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) [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) [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 [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 [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

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 CHU de Dijon - Service ophtalmologie Dijon France 21000
    2 CHU Dupuytren - Service Ophtalmologie Limoges Cedex France 87042
    3 Centre Hospitalier National d'Ophtalmologie - Service d'ophtalmologie Paris France 75 571
    4 "Fondation Ophtalmologique Adolphe de Rothschild - "Unité de Recherche Clinique Paris France 75019
    5 "CHU Toulouse-Purpan - Service Ophtalmologie Toulouse France 31059
    6 University Eye Clinic in Düsseldorf Düsseldorf Germany 50924
    7 Universitätsklinikum Erlangen Erlangen Germany 91054
    8 Universitäts-Augenklinik Freiburg Freiburg Germany 79106
    9 Universität zu Köln - Zentrum für Augenheilkunde am Universitätsklinikum Köln Köln Germany 50924
    10 Johannes-Gutenberg-Universität Augenklinik und Poliklinik - Department of Ophthalmology Mainz Germany 55131
    11 Klinikum der Universität München - Augenklinik der Ludwig-Maximilians-Universtiät München Munchen Germany 80336
    12 OSPEDALE SAN RAFFAELE di Milano Milan Lombardy Italy 20132
    13 Università G. D' Annunzio - Clinica Oftalmologica - Centro regionale di Eccellenza in Oftalmologia Chieti Italy 66100
    14 Azienda Ospedaliero Universitaria Careggi Florence Italy 50124
    15 Dipartimento di Scienze Neurologiche Oftalmologia e Genetica - Universtità di Genova Genoa Italy 16132
    16 Azienda Ospedaliero Universitaria di Messina - Dipartimento Specialità Chirurgiche Ambulatorio Studio delle Malattie dela Superficie Oculare Unità Operativa Complessa di Oftalmologia Messina Italy 98125
    17 Azienda Ospedaliera San Paolo - U.O. Oculistica Milano Italy 20142
    18 Azienda ospedaliera di Padova - Clinica Oculistica Policlinico 7° Piano Padova Italy 35128
    19 Università Campus Bio-Medico di Roma Rome Italy 00128
    20 Policlinico Umberto I Rome Italy 00161
    21 District Railway Hospital Katowice - Department of Ophthalmology Katowice Poland 40-760
    22 "SPKSO Szpital Okulistyczny ul. - SPKSO Szpital Okulistyczny Warsawa Poland 03-709
    23 Vissum Corporación Oftalmológica de Alicante Alicante Spain 03016
    24 Hospital de Cruces - Oftalmología Barakaldo Spain 48903
    25 Barraquer Eye center Barcelona Spain 08021
    26 Hospital Clinic de Barcelona - Oftalmología Barcelona Spain 08028
    27 Hospital Clínico San Carlos - Oftalmología. Unidad de Superficie Ocular Madrid Spain 28040
    28 Instituto Oftalmológico Fernández-Vega - Oftalmología Oviedo Spain 33012
    29 Cartuja Visión - Oftalmología Sevilla Spain 41092
    30 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
    31 Moorfields Eye Hospital - Moorfields Eye Hospital London United Kingdom EC1V 2PD
    32 Manchester Royal Eye Hospital - Manchester Royal Eye Hospital Manchester United Kingdom M13 9WL
    33 Royal Victoria Infirmary - Dept. of Ophthalmology Newcastle upon Tyne United Kingdom NE1 4LP
    34 University of Southampton Southampton General Hospital - MP104, Eye Unit Southampton United Kingdom SO16 6YD

    Sponsors and Collaborators

    • Dompé Farmaceutici S.p.A

    Investigators

    • Study Director: Francesco Sinigaglia, MD, Dompé s.p.a., Milan

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Dompé Farmaceutici S.p.A
    ClinicalTrials.gov Identifier:
    NCT01756456
    Other Study ID Numbers:
    • NGF0212
    • 2012-002527-15
    First Posted:
    Dec 27, 2012
    Last Update Posted:
    Jul 29, 2019
    Last Verified:
    Feb 1, 2017
    Keywords provided by Dompé Farmaceutici S.p.A
    Keratitis
    Corneal Ulcer
    Additional relevant MeSH terms:
    Corneal Ulcer
    Keratitis
    Pharmaceutical Solutions
    Mitogens

    Study Results

    Participant Flow

    Recruitment Details The study consisted of 2 periods: 8week PhaseI/controlled treatment period and 48/56-week FU period. In the Phase1 patients were randomized into 2 cohorts (of 9 pts each). In phase 2 pts were randomized in a 1:1:1 ratio (52 pts each group). Data refer to the 1st database lock when the last patient in Phase2 had completed 12 weeks of FU period.
    Pre-assignment Detail The inclusion/exclusion criteria were designed to include individuals 18 years of age or older with Stage 2 (PED) or Stage 3 (corneal ulcer) NK involving only 1 eye and to exclude those with Stage 2 or 3 NK affecting both eyes, any active ocular infection or inflammation not related to NK, or any ocular disease or severe vision loss.
    Arm/Group Title 1_rhNGF 10µg/ml Phase 1_treatment 2_rhNGF 20 µg/ml_Phase 1_treatment 3_vehicle group_Phase 1_treatment 4_rhNGF10_Phase 2_treatment 5_rhNGF20_Phase 2_treatment 6_vehicle group_Phase 2_treatment
    Arm/Group Description rhNGF 10 µg/ml eye drops solution, one drop 6 times a day for 8 weeks in the affected eye only rhNGF 20 µg/ml eye drops solution, one drop 6 times a day for 8 weeks in the affected eye only Placebo eye drops solution, one drop 6 times a day for 8 weeks in the affected eye only active treatment with rhNGF 10 μg/ml. One drop six times a day (one 35 μl drop equals to 0.35 μg of rhNGF) active treatment with rhNGF 20 μg/ml. One drop 6 times a day (one 35 μl drop equals to 0.70 μg of rhNGF) 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
    Period Title: Treatment Period: Phase I/II
    STARTED 7 7 4 52 52 52
    COMPLETED 6 6 2 45 39 48
    NOT COMPLETED 1 1 2 7 13 4
    Period Title: Treatment Period: Phase I/II
    STARTED 6 6 2 45 39 48
    COMPLETED 5 5 1 12 13 15
    NOT COMPLETED 1 1 1 33 26 33

    Baseline Characteristics

    Arm/Group Title 1_rhNGF10_Phase 1_treatment 2_rhNGF20_Phase 1_treatment 3_vehicle group_Phase 1_treatment 4_rhNGF10_Phase 2_treatment 5_rhNGF20_Phase 2_treatment 6_vehicle group_Phase 2_treatment Total
    Arm/Group Description rhNGF 10 µg/ml eye drops solution, one drop 6 times a day for 8 weeks in the affected eye only rhNGF 20 µg/ml eye drops solution, one drop 6 times a day for 8 weeks in the affected eye only Placebo eye drops solution, one drop 6 times a day for 8 weeks in the affected eye only rhNGF 10 µg/ml eye drops solution: rhNGF 10 µg/ml eye drops solution, one drop 6 times a day for 8 weeks in the affected eye only rhNGF 20 µg/ml eye drops solution: rhNGF 20 µg/ml eye drops solution, one drop 6 times a day for 8 weeks in the affected eye only Placebo: Placebo eye drops solution, one drop 6 times a day for 8 weeks in the affected eye only. Total of all reporting groups
    Overall Participants 7 7 4 52 52 52 174
    Age (years) [Mean (Standard Deviation) ]
    Age continuous
    61.7
    (21.47)
    52.0
    (17.24)
    64.3
    (24.06)
    59.0
    (17.17)
    62.5
    (14.01)
    60.4
    (16.78)
    58.5
    (19.98)
    Sex: Female, Male (Count of Participants)
    Female
    3
    42.9%
    4
    57.1%
    2
    50%
    30
    57.7%
    30
    57.7%
    35
    67.3%
    104
    59.8%
    Male
    4
    57.1%
    3
    42.9%
    2
    50%
    22
    42.3%
    22
    42.3%
    17
    32.7%
    70
    40.2%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    1
    14.3%
    0
    0%
    0
    0%
    6
    11.5%
    9
    17.3%
    5
    9.6%
    21
    12.1%
    Not Hispanic or Latino
    6
    85.7%
    6
    85.7%
    4
    100%
    42
    80.8%
    42
    80.8%
    41
    78.8%
    141
    81%
    Unknown or Not Reported
    0
    0%
    1
    14.3%
    0
    0%
    4
    7.7%
    1
    1.9%
    6
    11.5%
    12
    6.9%

    Outcome Measures

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

    Outcome Measure Data

    Analysis Population Description
    Phase II patients who achieved complete healing at Week 4 (last observation carried forward - LOCF) as determined by the reading center (ITT population).
    Arm/Group Title 4_rhNGF10_Phase 2_treatment 5_rhNGF20_Phase 2_treatment 6_vehicle group_Phase 2_treatment
    Arm/Group Description active treatment with rhNGF 10 μg/ml. One drop six times a day (one 35 μl drop equals to 0.35 μg of rhNGF) active treatment with rhNGF 20 μg/ml. One drop 6 times a day (one 35 μl drop equals to 0.70 μg of rhNGF) 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
    Measure Participants 52 52 52
    Yes
    55
    58
    20
    No
    45
    42
    80
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection 4_rhNGF10_Phase 2_treatment, 6_vehicle group_Phase 2_treatment
    Comments Phase II
    Type of Statistical Test Superiority
    Comments Each of the comparisons was conducted on the data for the Phase II segment of the study using a 2 × 2 chi-square test, based on the null hypothesis that there is no association between treatment (rhNGF or Vehicle Control) and response (Complete Healing at Week 4 [Yes/No]).
    Statistical Test of Hypothesis p-Value <0.001
    Comments
    Method Chi-squared
    Comments
    Method of Estimation Estimation Parameter Difference in percentage
    Estimated Value 35.3
    Confidence Interval (2-Sided) 97.06%
    15.88 to 54.71
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection 5_rhNGF20_Phase 2_treatment, 6_vehicle group_Phase 2_treatment
    Comments
    Type of Statistical Test Superiority
    Comments Each of the comparisons was conducted on the data for the Phase II segment of the study using a 2 × 2 chi-square test, based on the null hypothesis that there is no association between treatment (rhNGF or Vehicle Control) and response (Complete Healing at Week 4 [Yes/No]).
    Statistical Test of Hypothesis p-Value =0.001
    Comments
    Method Chi-squared
    Comments
    Method of Estimation Estimation Parameter Difference in percentage
    Estimated Value 38.4
    Confidence Interval (2-Sided) 97.06%
    18.96 to 57.83
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    2. Secondary Outcome
    Title Percentage of Patients Experiencing Healing of the Persistent Epithelial Defect (PED) or Corneal Ulcer
    Description 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.
    Time Frame at 4 weeks of study treatment.

    Outcome Measure Data

    Analysis Population Description
    Phase II patients who achieved complete healing at Week 4 (last observation carried forward - LOCF) as determined by the reading center (ITT population).
    Arm/Group Title 4_rhNGF10_Phase 2_treatment 5_rhNGF20_Phase 2_treatment 6_vehicle group_Phase 2_treatment
    Arm/Group Description active treatment with rhNGF 10 μg/ml. One drop six times a day (one 35 μl drop equals to 0.35 μg of rhNGF) active treatment with rhNGF 20 μg/ml. One drop 6 times a day (one 35 μl drop equals to 0.70 μg of rhNGF) 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
    Measure Participants 52 52 52
    Yes
    52
    61
    26
    No
    48
    39
    74
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection 4_rhNGF10_Phase 2_treatment, 6_vehicle group_Phase 2_treatment
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value =0.016
    Comments
    Method Chi-squared
    Comments
    Method of Estimation Estimation Parameter Difference in percentage
    Estimated Value 25.8
    Confidence Interval (2-Sided) 97.06%
    3.66 to 47.87
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection 5_rhNGF20_Phase 2_treatment, 6_vehicle group_Phase 2_treatment
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value =0.002
    Comments
    Method Chi-squared
    Comments
    Method of Estimation Estimation Parameter Difference in percentage
    Estimated Value 34.7
    Confidence Interval (2-Sided) 97.06%
    11.91 to 57.41
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    3. Secondary Outcome
    Title Percentage of Patients Experiencing Complete Healing of the Persistent Epithelial Defect (PED) or Corneal Ulcer
    Description 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.
    Time Frame at 6 and 8 weeks after start of the treatment

    Outcome Measure Data

    Analysis Population Description
    Phase II patients who achieved complete healing at Week 4 (last observation carried forward - LOCF) as determined by the reading center (ITT population).
    Arm/Group Title 4_rhNGF10_Phase 2_treatment 5_rhNGF20_Phase 2_treatment 6_vehicle group_Phase 2_treatment
    Arm/Group Description active treatment with rhNGF 10 μg/ml. One drop six times a day (one 35 μl drop equals to 0.35 μg of rhNGF) active treatment with rhNGF 20 μg/ml. One drop 6 times a day (one 35 μl drop equals to 0.70 μg of rhNGF) 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
    Measure Participants 52 52 52
    week 6 - central reading center - yes
    68
    60
    66
    week 6 - central reading center - no
    32
    40
    34
    week 6 - investigator - yes
    61
    64
    41
    week 6 - investigator - no
    39
    36
    59
    week 8 - central reading center - yes
    78
    83
    56
    week 8 - central reading center - no
    22
    17
    44
    week 8 - investigator - yes
    79
    79
    53
    week 8 - investigator - no
    21
    21
    47
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection 4_rhNGF10_Phase 2_treatment, 6_vehicle group_Phase 2_treatment
    Comments At week 6 - reading center
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value =0.818
    Comments
    Method Chi-squared
    Comments
    Method of Estimation Estimation Parameter difference in percentage
    Estimated Value 2.4
    Confidence Interval (2-Sided) 97.06%
    -20.30 to 25.08
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection 5_rhNGF20_Phase 2_treatment, 6_vehicle group_Phase 2_treatment
    Comments at week 6 - central reading center
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value =0.571
    Comments
    Method Chi-squared
    Comments
    Method of Estimation Estimation Parameter difference in percentage
    Estimated Value -6.3
    Confidence Interval (2-Sided) 97.06%
    -30.62 to 17.96
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection 4_rhNGF10_Phase 2_treatment, 6_vehicle group_Phase 2_treatment
    Comments week 6 - investigator
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value =0.064
    Comments
    Method Chi-squared
    Comments
    Method of Estimation Estimation Parameter Difference in percentage
    Estimated Value 20.3
    Confidence Interval (2-Sided) 97.06%
    -3.11 to 43.79
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection 5_rhNGF20_Phase 2_treatment, 6_vehicle group_Phase 2_treatment
    Comments week 6 - investigator
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value =0.041
    Comments
    Method Chi-squared
    Comments
    Method of Estimation Estimation Parameter Difference in percentage
    Estimated Value 23.1
    Confidence Interval (2-Sided) 97.06%
    -0.89 to 47.04
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection 4_rhNGF10_Phase 2_treatment, 6_vehicle group_Phase 2_treatment
    Comments week 8 - central reading center
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value =0.031
    Comments
    Method Chi-squared
    Comments
    Method of Estimation Estimation Parameter Difference in percentage
    Estimated Value 21.9
    Confidence Interval (2-Sided) 97.06%
    0.07 to 43.64
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection 5_rhNGF20_Phase 2_treatment, 6_vehicle group_Phase 2_treatment
    Comments week 8 - central reading center
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value =0.008
    Comments
    Method Chi-squared
    Comments
    Method of Estimation Estimation Parameter difference in percentage
    Estimated Value 26.9
    Confidence Interval (2-Sided) 97.06%
    5.57 to 48.28
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 7
    Statistical Analysis Overview Comparison Group Selection 4_rhNGF10_Phase 2_treatment, 6_vehicle group_Phase 2_treatment
    Comments week 8 - investigator
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value =0.011
    Comments
    Method Chi-squared
    Comments
    Method of Estimation Estimation Parameter Difference in percentage
    Estimated Value 26.1
    Confidence Interval (2-Sided) 97.06%
    4.18 to 48.01
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 8
    Statistical Analysis Overview Comparison Group Selection 5_rhNGF20_Phase 2_treatment, 6_vehicle group_Phase 2_treatment
    Comments week 8 - investigator
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value =0.014
    Comments
    Method Chi-squared
    Comments
    Method of Estimation Estimation Parameter Difference in percentage
    Estimated Value 25.9
    Confidence Interval (2-Sided) 97.06%
    3.55 to 48.33
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    4. Secondary Outcome
    Title Percentage of Patients Experiencing Complete Corneal Clearing
    Description 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.
    Time Frame at 4, 6 and 8 weeks after start of the treatment

    Outcome Measure Data

    Analysis Population Description
    ITT population
    Arm/Group Title 1_rhNGF10_Phase 1_treatment 2_rhNGF20_Phase 1_treatment 3_vehicle group_Phase 1_treatment 4_rhNGF10_Phase 2_treatment 5_rhNGF20_Phase 2_treatment 6_vehicle group_Phase 2_treatment
    Arm/Group Description active treatment with rhNGF 10 μg/ml. One drop six times a day (one 35 μl drop equals to 0.35μg of rhNGF). 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) active treatment with rhNGF 20 μg/ml. One drop 6 times a day (one 35 μl drop equals to 0.70 μg of rhNGF) rhNGF 20 μg/ml: one drop 6 times a day (one 35 μl drop equals to 0.70 μg of rhNGF) 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 vehicle: ophthalmic solution of the same composition as the test product without rhNGF active treatment with rhNGF 10 μg/ml. One drop six times a day (one 35 μl drop equals to 0.35 μg of rhNGF) 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) active treatment with rhNGF 20 μg/ml. One drop 6 times a day (one 35 μl drop equals to 0.70 μg of rhNGF) rhNGF 20 μg/ml: one drop 6 times a day (one 35 μl drop equals to 0.70 μg of rhNGF) 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 vehicle: ophthalmic solution of the same composition as the test product without rhNGF
    Measure Participants 7 7 4 52 52 52
    week 4 - yes
    0
    17
    33
    21
    20
    7
    week 4 - no
    100
    83
    67
    79
    80
    93
    week 6 - yes
    17
    14
    0
    24
    23
    8
    week 6 - no
    83
    86
    100
    76
    77
    92
    week 8 -yes
    17
    14
    0
    27
    21
    10
    week 8 - no
    83
    86
    100
    73
    79
    90
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection 4_rhNGF10_Phase 2_treatment, 6_vehicle group_Phase 2_treatment
    Comments week 4
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value =0.065
    Comments
    Method Chi-squared
    Comments
    Method of Estimation Estimation Parameter difference in percentage
    Estimated Value 13.7
    Confidence Interval (2-Sided) 95%
    -0.19 to 27.57
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection 5_rhNGF20_Phase 2_treatment, 6_vehicle group_Phase 2_treatment
    Comments week 4
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value =0.097
    Comments
    Method Chi-squared
    Comments
    Method of Estimation Estimation Parameter difference in percentage
    Estimated Value 12.4
    Confidence Interval (2-Sided) 95%
    -2.05 to 26.78
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection 4_rhNGF10_Phase 2_treatment, 6_vehicle group_Phase 2_treatment
    Comments week 6
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value =0.036
    Comments
    Method Chi-squared
    Comments
    Method of Estimation Estimation Parameter difference in percentage
    Estimated Value 16.9
    Confidence Interval (2-Sided) 95%
    1.97 to 31.92
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection 5_rhNGF20_Phase 2_treatment, 6_vehicle group_Phase 2_treatment
    Comments week 6
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value =0.054
    Comments
    Method Chi-squared
    Comments
    Method of Estimation Estimation Parameter difference in percentage
    Estimated Value 15.6
    Confidence Interval (2-Sided) 95%
    0.04 to 31.12
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection 4_rhNGF10_Phase 2_treatment, 6_vehicle group_Phase 2_treatment
    Comments week 8
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value =0.043
    Comments
    Method Chi-squared
    Comments
    Method of Estimation Estimation Parameter difference in percentage
    Estimated Value 17.1
    Confidence Interval (2-Sided) 95%
    1.45 to 32.72
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection 5_rhNGF20_Phase 2_treatment, 6_vehicle group_Phase 2_treatment
    Comments week 8
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value =0.157
    Comments
    Method Chi-squared
    Comments
    Method of Estimation Estimation Parameter difference in percentage
    Estimated Value 11.4
    Confidence Interval (2-Sided) 95%
    -4.08 to 26.93
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    5. Secondary Outcome
    Title Mean Change in Best Corrected Distance Visual Acuity (BCDVA)
    Description 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.
    Time Frame At screening and at week 8

    Outcome Measure Data

    Analysis Population Description
    ITT population
    Arm/Group Title 4_rhNGF10_Phase 2_treatment 5_rhNGF20_Phase 2_treatment 6_vehicle group_Phase 2_treatment
    Arm/Group Description active treatment with rhNGF 10 μg/ml. One drop six times a day (one 35 μl drop equals to 0.35 μg of rhNGF) active treatment with rhNGF 20 μg/ml. One drop 6 times a day (one 35 μl drop equals to 0.70 μg of rhNGF) 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
    Measure Participants 52 52 52
    Least Squares Mean (Standard Error) [LogMAR]
    15.8
    (2.58)
    11.9
    (2.80)
    6.9
    (2.83)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection 4_rhNGF10_Phase 2_treatment, 6_vehicle group_Phase 2_treatment
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value =0.022
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter least square mean difference
    Estimated Value 8.9
    Confidence Interval (2-Sided) 95%
    1.33 to 16.50
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection 5_rhNGF20_Phase 2_treatment, 6_vehicle group_Phase 2_treatment
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value =0.213
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter least square mean difference
    Estimated Value 5.0
    Confidence Interval (2-Sided) 95%
    -2.90 to 12.88
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    6. Secondary Outcome
    Title Percentage of Patients That Achieve an Improvement in Corneal Sensitivity
    Description Percentage of patients that achieve an improvement in corneal sensitivity as measured by the Cochet-Bonnet aesthesiometer
    Time Frame at 4, 6 and 8 weeks.

    Outcome Measure Data

    Analysis Population Description
    ITT population
    Arm/Group Title 1_rhNGF10_Phase 1_treatment 2_rhNGF20_Phase 1_treatment 3_vehicle group_Phase 1_treatment 4_rhNGF10_Phase 2_treatment 5_rhNGF20_Phase 2_treatment 6_vehicle group_Phase 2_treatment
    Arm/Group Description active treatment with rhNGF 10 μg/ml. One drop six times a day (one 35 μl drop equals to 0.35μg of rhNGF). 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) active treatment with rhNGF 20 μg/ml. One drop 6 times a day (one 35 μl drop equals to 0.70 μg of rhNGF) rhNGF 20 μg/ml: one drop 6 times a day (one 35 μl drop equals to 0.70 μg of rhNGF) 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 vehicle: ophthalmic solution of the same composition as the test product without rhNGF active treatment with rhNGF 10 μg/ml. One drop six times a day (one 35 μl drop equals to 0.35 μg of rhNGF) 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) active treatment with rhNGF 20 μg/ml. One drop 6 times a day (one 35 μl drop equals to 0.70 μg of rhNGF) rhNGF 20 μg/ml: one drop 6 times a day (one 35 μl drop equals to 0.70 μg of rhNGF) 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 vehicle: ophthalmic solution of the same composition as the test product without rhNGF
    Measure Participants 7 7 4 52 52 52
    week 4 - yes
    67
    50
    50
    69
    61
    63
    week 4 - no
    33
    50
    50
    31
    39
    37
    week 6 - yes
    67
    50
    50
    83
    68
    55
    week 6 - no
    33
    50
    50
    17
    32
    45
    week 8 -yes
    67
    60
    100
    79
    76
    68
    week 8 - no
    33
    40
    0
    21
    24
    32
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection 4_rhNGF10_Phase 2_treatment, 6_vehicle group_Phase 2_treatment
    Comments week 4
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value =0.592
    Comments
    Method Chi-squared
    Comments
    Method of Estimation Estimation Parameter difference in percentage
    Estimated Value 5.5
    Confidence Interval (2-Sided) 95%
    -14.53 to 25.48
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection 5_rhNGF20_Phase 2_treatment, 6_vehicle group_Phase 2_treatment
    Comments
    Type of Statistical Test Superiority
    Comments week 4
    Statistical Test of Hypothesis p-Value =0.835
    Comments
    Method Chi-squared
    Comments
    Method of Estimation Estimation Parameter difference in percentage
    Estimated Value -2.3
    Confidence Interval (2-Sided) 95%
    -24.01 to 19.40
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection 4_rhNGF10_Phase 2_treatment, 6_vehicle group_Phase 2_treatment
    Comments week 6
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value =0.008
    Comments
    Method Chi-squared
    Comments
    Method of Estimation Estimation Parameter difference in percentage
    Estimated Value 27.7
    Confidence Interval (2-Sided) 95%
    8.10 to 47.22
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection 5_rhNGF20_Phase 2_treatment, 6_vehicle group_Phase 2_treatment
    Comments week 6
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value =0.282
    Comments
    Method Chi-squared
    Comments
    Method of Estimation Estimation Parameter difference in percentage
    Estimated Value 12.4
    Confidence Interval (2-Sided) 95%
    -9.91 to 34.68
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection 4_rhNGF10_Phase 2_treatment, 6_vehicle group_Phase 2_treatment
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value =0.303
    Comments
    Method Chi-squared
    Comments
    Method of Estimation Estimation Parameter difference in percentage
    Estimated Value 10.2
    Confidence Interval (2-Sided) 95%
    -9.15 to 29.45
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection 5_rhNGF20_Phase 2_treatment, 6_vehicle group_Phase 2_treatment
    Comments week 8
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value =0.442
    Comments
    Method Chi-squared
    Comments
    Method of Estimation Estimation Parameter difference in percentage
    Estimated Value 7.9
    Confidence Interval (2-Sided) 95%
    -12.13 to 27.92
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    7. Secondary Outcome
    Title Percentage of Patients Experiencing Deterioration in Stage 2 or 3 NK
    Description 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.
    Time Frame from baseline to Week 4, 6, and 8.

    Outcome Measure Data

    Analysis Population Description
    ITT population
    Arm/Group Title 1_rhNGF10_Phase 1_treatment 2_rhNGF20_Phase 1_treatment 3_vehicle group_Phase 1_treatment 4_rhNGF10_Phase 2_treatment 5_rhNGF20_Phase 2_treatment 6_vehicle group_Phase 2_treatment
    Arm/Group Description active treatment with rhNGF 10 μg/ml. One drop six times a day (one 35 μl drop equals to 0.35μg of rhNGF). 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) active treatment with rhNGF 20 μg/ml. One drop 6 times a day (one 35 μl drop equals to 0.70 μg of rhNGF) rhNGF 20 μg/ml: one drop 6 times a day (one 35 μl drop equals to 0.70 μg of rhNGF) 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 vehicle: ophthalmic solution of the same composition as the test product without rhNGF active treatment with rhNGF 10 μg/ml. One drop six times a day (one 35 μl drop equals to 0.35 μg of rhNGF) 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) active treatment with rhNGF 20 μg/ml. One drop 6 times a day (one 35 μl drop equals to 0.70 μg of rhNGF) rhNGF 20 μg/ml: one drop 6 times a day (one 35 μl drop equals to 0.70 μg of rhNGF) 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 vehicle: ophthalmic solution of the same composition as the test product without rhNGF
    Measure Participants 7 7 4 52 52 52
    week 4 - yes
    0
    0
    0
    2
    2
    5
    week 4 - no
    100
    100
    100
    98
    98
    95
    week 6 - yes
    0
    0
    0
    2
    0
    10
    week 6 - no
    100
    100
    100
    98
    100
    90
    week 8 -yes
    0
    14
    0
    4
    7
    15
    week 8 - no
    100
    86
    100
    96
    93
    85
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection 4_rhNGF10_Phase 2_treatment, 6_vehicle group_Phase 2_treatment
    Comments week 4
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value =0.597
    Comments
    Method Chi-squared
    Comments
    Method of Estimation Estimation Parameter difference in percentage
    Estimated Value -2.6
    Confidence Interval (2-Sided) 95%
    -22.87 to 17.71
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection 5_rhNGF20_Phase 2_treatment, 6_vehicle group_Phase 2_treatment
    Comments week 4
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value >0.999
    Comments
    Method Chi-squared
    Comments
    Method of Estimation Estimation Parameter difference in percentage
    Estimated Value -2.3
    Confidence Interval (2-Sided) 95%
    -23.26 to 18.71
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection 4_rhNGF10_Phase 2_treatment, 6_vehicle group_Phase 2_treatment
    Comments week 6
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value =0.183
    Comments
    Method Chi-squared
    Comments
    Method of Estimation Estimation Parameter difference in percentage
    Estimated Value -7.8
    Confidence Interval (2-Sided) 95%
    -28.70 to 13.76
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection 5_rhNGF20_Phase 2_treatment, 6_vehicle group_Phase 2_treatment
    Comments week 6
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value =0.116
    Comments
    Method Chi-squared
    Comments
    Method of Estimation Estimation Parameter difference in percentage
    Estimated Value -10.0
    Confidence Interval (2-Sided) 95%
    -31.41 to 11.88
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection 4_rhNGF10_Phase 2_treatment, 6_vehicle group_Phase 2_treatment
    Comments week 8
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value =0.134
    Comments
    Method Chi-squared
    Comments
    Method of Estimation Estimation Parameter difference in percentage
    Estimated Value -10.8
    Confidence Interval (2-Sided) 95%
    -31.30 to 10.35
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection 5_rhNGF20_Phase 2_treatment, 6_vehicle group_Phase 2_treatment
    Comments week 8
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value =0.307
    Comments
    Method Chi-squared
    Comments
    Method of Estimation Estimation Parameter difference in percentage
    Estimated Value -7.9
    Confidence Interval (2-Sided) 95%
    -29.51 to 13.52
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    8. Secondary Outcome
    Title 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
    Description 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
    Time Frame at week 20/28, 32/40, 44/52, and 56/64

    Outcome Measure Data

    Analysis Population Description
    ITT population
    Arm/Group Title 1_rhNGF10_Phase 1_treatment 2_rhNGF20_Phase 1_treatment 3_vehicle group_Phase 1_treatment 4_rhNGF10_Phase 2_treatment 5_rhNGF20_Phase 2_treatment 6_vehicle group_Phase 2_treatment
    Arm/Group Description active treatment with rhNGF 10 μg/ml. One drop six times a day (one 35 μl drop equals to 0.35μg of rhNGF). 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) active treatment with rhNGF 20 μg/ml. One drop 6 times a day (one 35 μl drop equals to 0.70 μg of rhNGF) rhNGF 20 μg/ml: one drop 6 times a day (one 35 μl drop equals to 0.70 μg of rhNGF) 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 vehicle: ophthalmic solution of the same composition as the test product without rhNGF active treatment with rhNGF 10 μg/ml. One drop six times a day (one 35 μl drop equals to 0.35 μg of rhNGF) 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) active treatment with rhNGF 20 μg/ml. One drop 6 times a day (one 35 μl drop equals to 0.70 μg of rhNGF) rhNGF 20 μg/ml: one drop 6 times a day (one 35 μl drop equals to 0.70 μg of rhNGF) 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 vehicle: ophthalmic solution of the same composition as the test product without rhNGF
    Measure Participants 7 7 4 52 52 52
    week 20/28 - yes
    100
    75
    100
    87
    89
    100
    week 20/28 - no
    0
    25
    0
    13
    11
    0
    week 32/40 - yes
    100
    75
    100
    78
    92
    100
    week 32/40 - no
    0
    25
    0
    22
    8
    0
    week 44/52 - yes
    100
    80
    100
    67
    88
    100
    week 44/52 - no
    0
    20
    0
    33
    12
    0
    week 56/64 - yes
    100
    80
    100
    67
    82
    100
    week 56/64 - no
    0
    20
    0
    33
    18
    0
    9. Secondary Outcome
    Title Percentage of Patients Experiencing a Different Level of Efficacy at 4 and 8 Weeks
    Description 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.
    Time Frame at week 4 and 8

    Outcome Measure Data

    Analysis Population Description
    ITT population
    Arm/Group Title 1_rhNGF10_Phase 1_treatment 2_rhNGF20_Phase 1_treatment 3_vehicle group_Phase 1_treatment 4_rhNGF10_Phase 2_treatment 5_rhNGF20_Phase 2_treatment 6_vehicle group_Phase 2_treatment
    Arm/Group Description active treatment with rhNGF 10 μg/ml. One drop six times a day (one 35 μl drop equals to 0.35μg of rhNGF). 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) active treatment with rhNGF 20 μg/ml. One drop 6 times a day (one 35 μl drop equals to 0.70 μg of rhNGF) rhNGF 20 μg/ml: one drop 6 times a day (one 35 μl drop equals to 0.70 μg of rhNGF) 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 vehicle: ophthalmic solution of the same composition as the test product without rhNGF active treatment with rhNGF 10 μg/ml. One drop six times a day (one 35 μl drop equals to 0.35 μg of rhNGF) 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) active treatment with rhNGF 20 μg/ml. One drop 6 times a day (one 35 μl drop equals to 0.70 μg of rhNGF) rhNGF 20 μg/ml: one drop 6 times a day (one 35 μl drop equals to 0.70 μg of rhNGF) 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 vehicle: ophthalmic solution of the same composition as the test product without rhNGF
    Measure Participants 7 7 4 52 52 52
    week 4 - very good
    17
    29
    67
    40
    34
    26
    week 4 - good
    33
    43
    0
    38
    49
    35
    week 4 - moderate
    17
    0
    0
    15
    7
    21
    week 4 - poor
    33
    29
    0
    6
    10
    19
    week 4 - non-evaluable
    0
    0
    33
    2
    0
    0
    week 8 - very good
    17
    29
    50
    48
    40
    40
    week 8 - good
    33
    43
    50
    31
    45
    20
    week 8 - moderate
    33
    0
    0
    12
    5
    12
    week 8 - poor
    17
    29
    0
    4
    10
    28
    week 8 - non-evaluable
    0
    0
    0
    4
    0
    0
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection 4_rhNGF10_Phase 2_treatment, 6_vehicle group_Phase 2_treatment
    Comments week 4
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value =0.041
    Comments
    Method Chi-squared
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 2.18
    Confidence Interval (2-Sided) 95%
    1.03 to 4.62
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection 5_rhNGF20_Phase 2_treatment, 6_vehicle group_Phase 2_treatment
    Comments week 4
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value =0.081
    Comments
    Method Chi-squared
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 1.95
    Confidence Interval (2-Sided) 95%
    0.92 to 4.11
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection 4_rhNGF10_Phase 2_treatment, 6_vehicle group_Phase 2_treatment
    Comments week 8
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value =0.040
    Comments
    Method Chi-squared
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 2.47
    Confidence Interval (2-Sided) 95%
    1.04 to 5.88
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection 5_rhNGF20_Phase 2_treatment, 6_vehicle group_Phase 2_treatment
    Comments week 8
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value =0.132
    Comments
    Method Chi-squared
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 1.93
    Confidence Interval (2-Sided) 95%
    0.82 to 4.52
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    10. Secondary Outcome
    Title Change From Baseline in Visual Analogue Scale (VAS) for Ocular Tolerability
    Description 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).
    Time Frame at baseline and at weeks 8 and 20

    Outcome Measure Data

    Analysis Population Description
    Safety population
    Arm/Group Title 1_rhNGF10_Phase 1_treatment 2_rhNGF20_Phase 1_treatment 3_vehicle group_Phase 1_treatment 4_rhNGF10_Phase 2_treatment 5_rhNGF20_Phase 2_treatment 6_vehicle group_Phase 2_treatment 1_rhNGF10_Phase 1_FU 2_rhNGF20_Phase 1_FU 3_vehicle group_Phase 1_FU 4_rhNGF10_Phase 2_FU 5_rhNGF20_Phase 2_FU 6_vehicle_Phase 2_FU
    Arm/Group Description active treatment with rhNGF 10 μg/ml. One drop six times a day (one 35 μl drop equals to 0.35μg of rhNGF). 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) active treatment with rhNGF 20 μg/ml. One drop 6 times a day (one 35 μl drop equals to 0.70 μg of rhNGF) rhNGF 20 μg/ml: one drop 6 times a day (one 35 μl drop equals to 0.70 μg of rhNGF) 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 vehicle: ophthalmic solution of the same composition as the test product without rhNGF active treatment with rhNGF 10 μg/ml. One drop six times a day (one 35 μl drop equals to 0.35 μg of rhNGF) 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) active treatment with rhNGF 20 μg/ml. One drop 6 times a day (one 35 μl drop equals to 0.70 μg of rhNGF) rhNGF 20 μg/ml: one drop 6 times a day (one 35 μl drop equals to 0.70 μg of rhNGF) 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 vehicle: ophthalmic solution of the same composition as the test product without rhNGF Follow up for Phase 1 active treatment with rhNGF 10 μg/ml Follow up for Phase 1 active treatment with rhNGF 20 μg/ml Follow up for Phase 1 vehicle control arm Follow up for Phase 2 active treatment with rhNGF 10 μg/ml Follow up for Phase 2 active treatment with rhNGF 20 μg/ml Follow up for Phase 2 vehicle control arm
    Measure Participants 7 7 4 52 52 52 6 6 2 45 39 48
    Foreign Body Sensation_Baseline
    50.4
    (25.68)
    24
    (19.76)
    20.5
    (29.23)
    34.8
    (29.4)
    35.4
    (34.79)
    37.7
    (36.49)
    50.4
    (25.68)
    24
    (19.76)
    20.5
    (29.23)
    34.8
    (29.4)
    35.4
    (34.79)
    37.7
    (36.49)
    Foreign Body Sensation_CFB
    -21.2
    (25.96)
    -12.9
    (17.03)
    -16
    (65.05)
    -8.8
    (34.68)
    -16.5
    (36.87)
    -20.9
    (35.86)
    -20
    (30.32)
    -13
    (25.3)
    -52
    (0)
    -16.6
    (31.26)
    -22.4
    (38.77)
    -20.7
    (30.57)
    burning/stinging_baseline
    41.4
    (30.85)
    30.7
    (38.78)
    18
    (28.57)
    32.5
    (32.88)
    26.5
    (30.86)
    30.2
    (32.21)
    41.4
    (30.85)
    30.7
    (38.78)
    18
    (28.57)
    32.5
    (32.88)
    26.5
    (30.86)
    30.2
    (32.21)
    burning/stinging_CFB
    -14.7
    (38.02)
    -12.1
    (28.27)
    -28.5
    (23.33)
    -3.8
    (42.13)
    -2.5
    (26.76)
    -18
    (32.97)
    -18
    (41.65)
    -16.5
    (17.13)
    -12
    (0)
    -14.9
    (40.35)
    -10.8
    (31.51)
    -14.7
    (37.54)
    itching_baseline
    17
    (27.4)
    18.7
    (19.62)
    7.8
    (15.5)
    24.1
    (27.48)
    21.8
    (28.68)
    22.9
    (28.43)
    17
    (27.4)
    18.7
    (19.62)
    7.8
    (15.5)
    24.1
    (27.48)
    21.8
    (28.68)
    22.9
    (28.43)
    itching_CFB
    -3
    (17.93)
    -10
    (23.1)
    -15.5
    (21.92)
    -10.8
    (29.25)
    -7.3
    (22.67)
    -8.9
    (25.59)
    -7.8
    (27.18)
    -4.2
    (28.51)
    -31
    (0)
    -10.2
    (30.62)
    -11.9
    (23.05)
    -4.8
    (30.71)
    ocular pain_baseline
    34.1
    (36.96)
    33.6
    (34.73)
    19
    (38)
    32.8
    (34.86)
    21.1
    (28.38)
    28.8
    (32.82)
    34.1
    (36.96)
    33.6
    (34.73)
    19
    (38)
    32.8
    (34.86)
    21.1
    (28.38)
    28.8
    (32.82)
    ocular pain_CFB
    -21.2
    (28.96)
    -6
    (30.72)
    -23
    (32.53)
    -2
    (43)
    2
    (37.25)
    -16.3
    (30.52)
    -16
    (28.59)
    -9.3
    (11.86)
    -26
    (0)
    -16.7
    (34.66)
    -12.1
    (31.25)
    -18.3
    (34.3)
    sticky feeling_baseline
    47.6
    (34.14)
    32.1
    (35.34)
    15.5
    (23.69)
    26.6
    (29.65)
    17.4
    (22.07)
    26.1
    (31.93)
    47.6
    (34.14)
    32.1
    (35.34)
    15.5
    (23.69)
    26.6
    (29.65)
    17.4
    (22.07)
    26.1
    (31.93)
    sticky feeling_CFB
    -7.2
    (42.82)
    -18.7
    (38.32)
    -11
    (5.66)
    -11.7
    (30.17)
    -4.3
    (29.55)
    -10.7
    (29.95)
    -19.8
    (22.18)
    -0.7
    (12.52)
    -2
    (0)
    -13.3
    (30.75)
    -11.4
    (31.11)
    -8.3
    (30.62)
    blurred vision_baseline
    71
    (38.37)
    85.7
    (14.74)
    93.5
    (7.9)
    80.2
    (25.18)
    83.2
    (24.45)
    78.5
    (24.68)
    71
    (38.37)
    85.7
    (14.74)
    93.5
    (7.9)
    80.2
    (25.18)
    83.2
    (24.45)
    78.5
    (24.68)
    blurred vision_CFB
    -25.7
    (34.37)
    -25
    (32.15)
    -22
    (31.11)
    -24.9
    (35.33)
    -26.2
    (31.58)
    -17.4
    (28.55)
    -26.5
    (31.18)
    -26.2
    (17.93)
    -14
    (0)
    -16.5
    (38.42)
    -25.7
    (34.41)
    -17.4
    (27.14)
    photophobia_baseline
    64.7
    (42.9)
    66.6
    (29.85)
    30.3
    (26.21)
    64.3
    (32.07)
    57.6
    (36.1)
    65.2
    (34.71)
    64.7
    (42.9)
    66.6
    (29.85)
    30.3
    (26.21)
    64.3
    (32.07)
    57.6
    (36.1)
    65.2
    (34.71)
    photophobia_CFB
    -19.5
    (27.98)
    -20.7
    (34.13)
    -30.5
    (43.13)
    -17.8
    (41.23)
    -13.2
    (40.44)
    -17.5
    (29.02)
    -20.3
    (28.63)
    -26
    (39.88)
    -61
    (0)
    -24.2
    (37.51)
    -21
    (38.76)
    -14.6
    (29.19)
    11. Secondary Outcome
    Title Change From Baseline in Best Corrected Distance Visual Acuity (BCDVA)
    Description 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).
    Time Frame at baseline and at period 1 (8 weeks) and 2 (Follow Up period of 12 weeks, until week 20)

    Outcome Measure Data

    Analysis Population Description
    Safety population
    Arm/Group Title 1_rhNGF10_Phase 1_treatment 2_rhNGF20_Phase 1_treatment 3_vehicle group_Phase 1_treatment 4_rhNGF10_Phase 2_treatment 5_rhNGF20_Phase 2_treatment 6_vehicle group_Phase 2_treatment 1_rhNGF10_Phase 1_FU 2_rhNGF20_Phase 1_FU 3_vehicle group_Phase 1_FU 4_rhNGF10_Phase 2_FU 5_rhNGF20_Phase 2_FU 6_vehicle_Phase 2_FU
    Arm/Group Description active treatment with rhNGF 10 μg/ml. One drop six times a day (one 35 μl drop equals to 0.35μg of rhNGF). 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) active treatment with rhNGF 20 μg/ml. One drop 6 times a day (one 35 μl drop equals to 0.70 μg of rhNGF) rhNGF 20 μg/ml: one drop 6 times a day (one 35 μl drop equals to 0.70 μg of rhNGF) 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 vehicle: ophthalmic solution of the same composition as the test product without rhNGF active treatment with rhNGF 10 μg/ml. One drop six times a day (one 35 μl drop equals to 0.35 μg of rhNGF) 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) active treatment with rhNGF 20 μg/ml. One drop 6 times a day (one 35 μl drop equals to 0.70 μg of rhNGF) rhNGF 20 μg/ml: one drop 6 times a day (one 35 μl drop equals to 0.70 μg of rhNGF) 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 vehicle: ophthalmic solution of the same composition as the test product without rhNGF Follow up for Phase 1 active treatment with rhNGF 10 μg/ml Follow up for Phase 1 active treatment with rhNGF 20 μg/ml Follow up for Phase 1 vehicle control arm Follow up for Phase 2 active treatment with rhNGF 10 μg/ml Follow up for Phase 2 active treatment with rhNGF 20 μg/ml Follow up for Phase 2 vehicle control arm
    Measure Participants 7 7 4 52 52 52 6 6 2 45 39 48
    Baseline
    42
    (28.25)
    30.4
    (24.85)
    9.5
    (11.96)
    30.7
    (28.35)
    24.2
    (25.88)
    32.4
    (26.07)
    42
    (28.25)
    30.4
    (24.85)
    9.5
    (11.96)
    30.7
    (28.35)
    24.2
    (25.88)
    32.4
    (26.07)
    Change from baseline
    9.3
    (5.89)
    8.7
    (12.41)
    -1
    (1.41)
    15.8
    (16.82)
    11.9
    (20.9)
    6.9
    (15.44)
    11.2
    (7.47)
    7
    (9.8)
    -6
    (0)
    13.2
    (16.8)
    14.2
    (19.6)
    8.8
    (14.27)
    12. Secondary Outcome
    Title Change From Baseline in Intraocular Pressure (IOP)
    Description IOP was measured using a Goldmann applanation tonometer, a handheld applanation tonometer [eg, Tonopen], or other tonometer, after the instillation of a topical anesthetic.
    Time Frame Baseline, period 1 (8 weeks) and 2 (Follow Up period of 12 weeks, until week 20).

    Outcome Measure Data

    Analysis Population Description
    safety population
    Arm/Group Title 1_rhNGF10_Phase 1_treatment 2_rhNGF20_Phase 1_treatment 3_vehicle group_Phase 1_treatment 4_rhNGF10_Phase 2_treatment 5_rhNGF20_Phase 2_treatment 6_vehicle group_Phase 2_treatment 1_rhNGF10_Phase 1_FU 2_rhNGF20_Phase 1_FU 3_vehicle group_Phase 1_FU 4_rhNGF10_Phase 2_FU 5_rhNGF20_Phase 2_FU 6_vehicle_Phase 2_FU
    Arm/Group Description active treatment with rhNGF 10 μg/ml. One drop six times a day (one 35 μl drop equals to 0.35μg of rhNGF). 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) active treatment with rhNGF 20 μg/ml. One drop 6 times a day (one 35 μl drop equals to 0.70 μg of rhNGF) rhNGF 20 μg/ml: one drop 6 times a day (one 35 μl drop equals to 0.70 μg of rhNGF) 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 vehicle: ophthalmic solution of the same composition as the test product without rhNGF active treatment with rhNGF 10 μg/ml. One drop six times a day (one 35 μl drop equals to 0.35 μg of rhNGF) 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) active treatment with rhNGF 20 μg/ml. One drop 6 times a day (one 35 μl drop equals to 0.70 μg of rhNGF) rhNGF 20 μg/ml: one drop 6 times a day (one 35 μl drop equals to 0.70 μg of rhNGF) 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 vehicle: ophthalmic solution of the same composition as the test product without rhNGF Follow up for Phase 1 active treatment with rhNGF 10 μg/ml Follow up for Phase 1 active treatment with rhNGF 20 μg/ml Follow up for Phase 1 vehicle control arm Follow up for Phase 2 active treatment with rhNGF 10 μg/ml Follow up for Phase 2 active treatment with rhNGF 20 μg/ml Follow up for Phase 2 vehicle control arm
    Measure Participants 7 7 4 52 52 52 6 6 2 45 39 48
    Baseline
    16.1
    (3.85)
    11.3
    (3.68)
    11.8
    (3.3)
    14.3
    (3.16)
    14
    (3.06)
    14.1
    (3.16)
    16.1
    (3.85)
    11.3
    (3.68)
    11.8
    (3.3)
    14.3
    (3.16)
    14
    (3.06)
    14.1
    (3.16)
    Change from baseline
    -1.8
    (2.48)
    1.9
    (5.24)
    3.5
    (2.12)
    -0.1
    (3.71)
    0.9
    (2.61)
    0.8
    (3.43)
    -2.2
    (2.49)
    2.3
    (3.78)
    -3
    (0)
    0.2
    (3.25)
    0.1
    (3.64)
    0.6
    (3.93)
    13. Secondary Outcome
    Title Percentage of Participants With Abnormal Eye Structures by Dilated Fundus Ophthalmoscopy
    Description 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.
    Time Frame At week 8 (Phase 1 and Phase 2)

    Outcome Measure Data

    Analysis Population Description
    safety population
    Arm/Group Title 1_rhNGF10_Phase 1_treatment 2_rhNGF20_Phase 1_treatment 3_vehicle group_Phase 1_treatment 4_rhNGF10_Phase 2_treatment 5_rhNGF20_Phase 2_treatment 6_vehicle group_Phase 2_treatment
    Arm/Group Description active treatment with rhNGF 10 μg/ml. One drop six times a day (one 35 μl drop equals to 0.35μg of rhNGF). 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) active treatment with rhNGF 20 μg/ml. One drop 6 times a day (one 35 μl drop equals to 0.70 μg of rhNGF) rhNGF 20 μg/ml: one drop 6 times a day (one 35 μl drop equals to 0.70 μg of rhNGF) 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 vehicle: ophthalmic solution of the same composition as the test product without rhNGF active treatment with rhNGF 10 μg/ml. One drop six times a day (one 35 μl drop equals to 0.35 μg of rhNGF) 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) active treatment with rhNGF 20 μg/ml. One drop 6 times a day (one 35 μl drop equals to 0.70 μg of rhNGF) rhNGF 20 μg/ml: one drop 6 times a day (one 35 μl drop equals to 0.70 μg of rhNGF) 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 vehicle: ophthalmic solution of the same composition as the test product without rhNGF
    Measure Participants 7 7 4 52 52 52
    Vitreous
    0
    0%
    0
    0%
    0
    0%
    14.7
    28.3%
    18.2
    35%
    10.3
    19.8%
    Retina macula
    25
    357.1%
    25
    357.1%
    100
    2500%
    17.6
    33.8%
    23.3
    44.8%
    28.6
    55%
    Choroid
    0
    0%
    25
    357.1%
    0
    0%
    8.8
    16.9%
    6.5
    12.5%
    14.8
    28.5%
    Optic nerve
    25
    357.1%
    0
    0%
    100
    2500%
    11.8
    22.7%
    12.5
    24%
    7.7
    14.8%
    14. Other Pre-specified Outcome
    Title Percentage of Patients That Achieved a ≥15 Letter Gain in BCDVA
    Description Percentage of patients that achieved a ≥15 letter gain in best corrected distance visual acuity (BCDVA) at 4, 6, and 8 weeks
    Time Frame at 4, 6 and 8 weeks

    Outcome Measure Data

    Analysis Population Description
    ITT population
    Arm/Group Title 1_rhNGF10_Phase 1_treatment 2_rhNGF20_Phase 1_treatment 3_vehicle group_Phase 1_treatment 4_rhNGF10_Phase 2_treatment 5_rhNGF20_Phase 2_treatment 6_vehicle group_Phase 2_treatment
    Arm/Group Description active treatment with rhNGF 10 μg/ml. One drop six times a day (one 35 μl drop equals to 0.35μg of rhNGF). 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) active treatment with rhNGF 20 μg/ml. One drop 6 times a day (one 35 μl drop equals to 0.70 μg of rhNGF) rhNGF 20 μg/ml: one drop 6 times a day (one 35 μl drop equals to 0.70 μg of rhNGF) 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 vehicle: ophthalmic solution of the same composition as the test product without rhNGF active treatment with rhNGF 10 μg/ml. One drop six times a day (one 35 μl drop equals to 0.35 μg of rhNGF) 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) active treatment with rhNGF 20 μg/ml. One drop 6 times a day (one 35 μl drop equals to 0.70 μg of rhNGF) rhNGF 20 μg/ml: one drop 6 times a day (one 35 μl drop equals to 0.70 μg of rhNGF) 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 vehicle: ophthalmic solution of the same composition as the test product without rhNGF
    Measure Participants 7 7 4 52 52 52
    week 4 - yes
    0
    29
    0
    37
    34
    21
    week 4 - no
    100
    71
    100
    63
    66
    79
    week 6 - yes
    17
    43
    0
    44
    38
    28
    week 6 - no
    83
    57
    100
    56
    62
    72
    week 8 -yes
    17
    43
    0
    50
    42
    22
    week 8 - no
    83
    57
    100
    50
    58
    78
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection 4_rhNGF10_Phase 2_treatment, 6_vehicle group_Phase 2_treatment
    Comments week 4
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value =0.097
    Comments
    Method Chi-squared
    Comments
    Method of Estimation Estimation Parameter difference in percentage
    Estimated Value 15.8
    Confidence Interval (2-Sided) 95%
    -2.36 to 33.97
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection 5_rhNGF20_Phase 2_treatment, 6_vehicle group_Phase 2_treatment
    Comments week 4
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value =0.175
    Comments
    Method Chi-squared
    Comments
    Method of Estimation Estimation Parameter difference in percentage
    Estimated Value 13.2
    Confidence Interval (2-Sided) 95%
    -5.72 to 32.15
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection 4_rhNGF10_Phase 2_treatment, 6_vehicle group_Phase 2_treatment
    Comments week 6
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value =0.105
    Comments
    Method Chi-squared
    Comments
    Method of Estimation Estimation Parameter difference in percentage
    Estimated Value 16.9
    Confidence Interval (2-Sided) 95%
    -3.11 to 37.00
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection 5_rhNGF20_Phase 2_treatment, 6_vehicle group_Phase 2_treatment
    Comments week 6
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value =0.300
    Comments
    Method Chi-squared
    Comments
    Method of Estimation Estimation Parameter difference in percentage
    Estimated Value 11.0
    Confidence Interval (2-Sided) 95%
    -9.64 to 31.57
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection 4_rhNGF10_Phase 2_treatment, 6_vehicle group_Phase 2_treatment
    Comments week 8
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value =0.008
    Comments
    Method Chi-squared
    Comments
    Method of Estimation Estimation Parameter difference in percentage
    Estimated Value 27.5
    Confidence Interval (2-Sided) 95%
    8.33 to 46.67
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection 5_rhNGF20_Phase 2_treatment, 6_vehicle group_Phase 2_treatment
    Comments week 8
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value =0.068
    Comments
    Method Chi-squared
    Comments
    Method of Estimation Estimation Parameter difference in percentage
    Estimated Value 19.0
    Confidence Interval (2-Sided) 95%
    -0.91 to 38.83
    Parameter Dispersion Type:
    Value:
    Estimation Comments

    Adverse Events

    Time Frame Adverse events were collected at each time point of Phase I and Phase II of the study. Phase I: Days 1, 2, Weeks 1, 2, 3, 4, 6, Day 55, Week 8 Phase II: Weeks 1, 2, 3, 4, 6, 8
    Adverse Event Reporting Description The definition of adverse event and/or serious adverse event used to collect adverse event information does not differ from the clinicaltrials.gov Definitions.
    Arm/Group Title 1_rhNGF10_Phase 1 2_rhNGF20_Phase 1 3_vehicle group_Phase 1 4_rhNGF10_Phase 2_treatment 5_rhNGF20_Phase 2_treatment 6_vehicle group_Phase 2_treatment
    Arm/Group Description rhNGF 10 µg/ml eye drops solution, one drop 6 times a day for 8 weeks in the affected eye only rhNGF 20 µg/ml eye drops solution, one drop 6 times a day for 8 weeks in the affected eye only Placebo eye drops solution, one drop 6 times a day for 8 weeks in the affected eye only rhNGF 10 µg/ml eye drops solution: rhNGF 10 µg/ml eye drops solution, one drop 6 times a day for 8 weeks in the affected eye only rhNGF 20 µg/ml eye drops solution: rhNGF 20 µg/ml eye drops solution, one drop 6 times a day for 8 weeks in the affected eye only Placebo: Placebo eye drops solution, one drop 6 times a day for 8 weeks in the affected eye only.
    All Cause Mortality
    1_rhNGF10_Phase 1 2_rhNGF20_Phase 1 3_vehicle group_Phase 1 4_rhNGF10_Phase 2_treatment 5_rhNGF20_Phase 2_treatment 6_vehicle group_Phase 2_treatment
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/7 (0%) 0/7 (0%) 0/4 (0%) 5/52 (9.6%) 2/52 (3.8%) 1/52 (1.9%)
    Serious Adverse Events
    1_rhNGF10_Phase 1 2_rhNGF20_Phase 1 3_vehicle group_Phase 1 4_rhNGF10_Phase 2_treatment 5_rhNGF20_Phase 2_treatment 6_vehicle group_Phase 2_treatment
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 3/7 (42.9%) 1/7 (14.3%) 3/4 (75%) 13/52 (25%) 14/52 (26.9%) 4/52 (7.7%)
    Cardiac disorders
    myocardial infarction 0/7 (0%) 0 1/7 (14.3%) 1 0/4 (0%) 0 2/52 (3.8%) 3 0/52 (0%) 0 0/52 (0%) 0
    Arrhythmia 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0 0/52 (0%) 0
    Cardiac failure 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0 0/52 (0%) 0
    Ear and labyrinth disorders
    Vertigo 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 0/52 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0
    Eye disorders
    visual acuity reduced 1/7 (14.3%) 1 0/7 (0%) 0 0/4 (0%) 0 0/52 (0%) 0 2/52 (3.8%) 2 1/52 (1.9%) 1
    Corneal endotheliitis 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0 0/52 (0%) 0
    Corneal epithelium defect 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 0/52 (0%) 0 1/52 (1.9%) 1 1/52 (1.9%) 1
    Corneal oedema 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 0/52 (0%) 0 0/52 (0%) 0 1/52 (1.9%) 1
    Eye inflammation 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 0/52 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0
    Corneal neovascularisation 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0 0/52 (0%) 0
    Corneal opacity 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0 0/52 (0%) 0
    Neurotrophic keratopathy 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0 0/52 (0%) 0
    Ulcerative keratitis 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0 0/52 (0%) 0
    Gastrointestinal disorders
    Diverticular perforation 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0 0/52 (0%) 0
    Nausea 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0 0/52 (0%) 0
    General disorders
    disease progression 2/7 (28.6%) 2 0/7 (0%) 0 1/4 (25%) 1 1/52 (1.9%) 1 3/52 (5.8%) 3 2/52 (3.8%) 2
    Impaired healing 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0 0/52 (0%) 0
    Immune system disorders
    Corneal graft rejection 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 0/52 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0
    Infections and infestations
    Diverticulitis 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0 0/52 (0%) 0
    Corneal abscess 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0 0/52 (0%) 0
    Herpes ophthalmic 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0 0/52 (0%) 0
    Injury, poisoning and procedural complications
    Femur fracture 0/7 (0%) 0 0/7 (0%) 0 1/4 (25%) 1 0/52 (0%) 0 0/52 (0%) 0 1/52 (1.9%) 1
    Clavicle fracture 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 0/52 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0
    Fall 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 0/52 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0
    Investigations
    Blood pressure increased 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0 0/52 (0%) 0
    Metabolism and nutrition disorders
    Decreased appetite 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0 0/52 (0%) 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant neoplasm progression 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 1/52 (1.9%) 1 1/52 (1.9%) 1 0/52 (0%) 0
    Nervous system disorders
    Syncope 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 0/52 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0
    Renal and urinary disorders
    renal failure 0/7 (0%) 0 0/7 (0%) 0 1/4 (25%) 1 0/52 (0%) 0 0/52 (0%) 0 0/52 (0%) 0
    Renal colic 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 0/52 (0%) 0 2/52 (3.8%) 2 0/52 (0%) 0
    Bladder prolapse 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0 0/52 (0%) 0
    Reproductive system and breast disorders
    Uterine prolapse 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0 0/52 (0%) 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary edema 0/7 (0%) 0 0/7 (0%) 0 1/4 (25%) 1 0/52 (0%) 0 0/52 (0%) 0 0/52 (0%) 0
    Respiratory distress 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0 0/52 (0%) 0
    Respiratory failure 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 0/52 (0%) 0 1/52 (1.9%) 1 1/52 (1.9%) 1
    Dyspnoea 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0 0/52 (0%) 0
    Epistaxis 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0 0/52 (0%) 0
    Vascular disorders
    Aortic dissection 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 1/52 (1.9%) 1 1/52 (1.9%) 1 0/52 (0%) 0
    Venous thrombosis 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 0/52 (0%) 0 1/52 (1.9%) 1 1/52 (1.9%) 1
    Aortic rupture 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0 0/52 (0%) 0
    Diabetic vascular disorder 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0 0/52 (0%) 0
    Shock haemorrhagic 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0 0/52 (0%) 0
    Other (Not Including Serious) Adverse Events
    1_rhNGF10_Phase 1 2_rhNGF20_Phase 1 3_vehicle group_Phase 1 4_rhNGF10_Phase 2_treatment 5_rhNGF20_Phase 2_treatment 6_vehicle group_Phase 2_treatment
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 3/7 (42.9%) 5/7 (71.4%) 1/4 (25%) 23/52 (44.2%) 23/52 (44.2%) 21/52 (40.4%)
    Blood and lymphatic system disorders
    Anaemia 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 1/52 (1.9%) 3 1/52 (1.9%) 1 0/52 (0%) 0
    Neutropenia 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 0/52 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0
    Cardiac disorders
    Cardiovascular disorder 0/7 (0%) 0 1/7 (14.3%) 1 0/4 (0%) 0 0/52 (0%) 0 0/52 (0%) 0 0/52 (0%) 0
    Arrhythmia 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 1/52 (1.9%) 1 1/52 (1.9%) 1 0/52 (0%) 0
    Myocardial infarction 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 2/52 (3.8%) 2 0/52 (0%) 0 0/52 (0%) 0
    Cardiac failure 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0 0/52 (0%) 0
    Ear and labyrinth disorders
    Vertigo 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0 0/52 (0%) 0
    Ear pain 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0 0/52 (0%) 0
    Eye disorders
    Eye pain 0/7 (0%) 0 3/7 (42.9%) 6 1/4 (25%) 2 2/52 (3.8%) 2 7/52 (13.5%) 7 5/52 (9.6%) 7
    Eye inflammation 0/7 (0%) 0 2/7 (28.6%) 2 1/4 (25%) 1 0/52 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0
    Visual acuity reduced 3/7 (42.9%) 4 1/7 (14.3%) 1 1/4 (25%) 1 2/52 (3.8%) 2 5/52 (9.6%) 5 2/52 (3.8%) 2
    Photophobia 0/7 (0%) 0 3/7 (42.9%) 3 0/4 (0%) 0 2/52 (3.8%) 2 0/52 (0%) 0 1/52 (1.9%) 1
    Conjunctival hyperaemia 1/7 (14.3%) 2 0/7 (0%) 0 0/4 (0%) 0 2/52 (3.8%) 2 1/52 (1.9%) 1 1/52 (1.9%) 1
    Corneal epithelium defect 0/7 (0%) 0 2/7 (28.6%) 2 0/4 (0%) 0 1/52 (1.9%) 1 5/52 (9.6%) 5 1/52 (1.9%) 2
    Corneal lesion 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 0/52 (0%) 0 0/52 (0%) 0 1/52 (1.9%) 1
    Dry eye 0/7 (0%) 0 1/7 (14.3%) 1 0/4 (0%) 0 2/52 (3.8%) 2 1/52 (1.9%) 1 3/52 (5.8%) 3
    Erythema of eyelid 1/7 (14.3%) 1 0/7 (0%) 0 0/4 (0%) 0 0/52 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0
    Eye irritation 0/7 (0%) 0 1/7 (14.3%) 1 0/4 (0%) 0 2/52 (3.8%) 2 1/52 (1.9%) 1 1/52 (1.9%) 1
    Eyelid margin crusting 0/7 (0%) 0 0/7 (0%) 0 1/4 (25%) 1 0/52 (0%) 0 0/52 (0%) 0 0/52 (0%) 0
    Foreign body sensation in eyes 0/7 (0%) 0 0/7 (0%) 0 1/4 (25%) 1 1/52 (1.9%) 1 0/52 (0%) 0 1/52 (1.9%) 1
    Iridocyclitis 0/7 (0%) 0 1/7 (14.3%) 1 0/4 (0%) 0 0/52 (0%) 0 0/52 (0%) 0 0/52 (0%) 0
    Photopsia 0/7 (0%) 0 1/7 (14.3%) 1 1/4 (25%) 1 0/52 (0%) 0 0/52 (0%) 0 0/52 (0%) 0
    Ulcerative keratitis 0/7 (0%) 0 1/7 (14.3%) 1 0/4 (0%) 0 4/52 (7.7%) 4 1/52 (1.9%) 1 0/52 (0%) 0
    Vision blurred 0/7 (0%) 0 0/7 (0%) 0 1/4 (25%) 1 2/52 (3.8%) 2 0/52 (0%) 0 2/52 (3.8%) 2
    Vitreous haemorrhage 0/7 (0%) 0 1/7 (14.3%) 1 0/4 (0%) 0 1/52 (1.9%) 2 0/52 (0%) 0 0/52 (0%) 0
    Corneal decompensation 0/7 (0%) 0 1/7 (14.3%) 1 0/4 (0%) 0 0/52 (0%) 0 0/52 (0%) 0 0/52 (0%) 0
    Corneal oedema 0/7 (0%) 0 1/7 (14.3%) 1 0/4 (0%) 0 0/52 (0%) 0 0/52 (0%) 0 1/52 (1.9%) 1
    Keratitis 0/7 (0%) 0 1/7 (14.3%) 1 0/4 (0%) 0 0/52 (0%) 0 4/52 (7.7%) 6 0/52 (0%) 0
    Ocular hyperemia 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 0/52 (0%) 0 1/52 (1.9%) 1 2/52 (3.8%) 2
    Retinal haemorrhage 0/7 (0%) 0 1/7 (14.3%) 1 0/4 (0%) 0 0/52 (0%) 0 0/52 (0%) 0 0/52 (0%) 0
    Blepharitis 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 3/52 (5.8%) 3 6/52 (11.5%) 6 1/52 (1.9%) 2
    Eye pruritus 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 2/52 (3.8%) 2 1/52 (1.9%) 1 1/52 (1.9%) 1
    Lacrimation increased 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 3/52 (5.8%) 3 0/52 (0%) 0 2/52 (3.8%) 2
    Lacrimation decreased 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 1/52 (1.9%) 1 1/52 (1.9%) 1 0/52 (0%) 0
    Corneal deposits 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 0/52 (0%) 0 2/52 (3.8%) 3 0/52 (0%) 0
    Eye discharge 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 1/52 (1.9%) 1 2/52 (3.8%) 2 0/52 (0%) 0
    Abnormal sensation in eye 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 0/52 (0%) 0 0/52 (0%) 0 1/52 (1.9%) 1
    Asthenopia 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 0/52 (0%) 0 0/52 (0%) 0 1/52 (1.9%) 1
    Conjunctival haemorrhage 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 2/52 (3.8%) 2 0/52 (0%) 0 1/52 (1.9%) 2
    Corneal endotheliitis 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0 0/52 (0%) 0
    Corneal opacity 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 1/52 (1.9%) 1 1/52 (1.9%) 1 0/52 (0%) 0
    Eye allergy 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0 0/52 (0%) 0
    Eyelid oedema 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 0/52 (0%) 0 1/52 (1.9%) 2 1/52 (1.9%) 1
    Eyelid pain 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 1/52 (1.9%) 2 0/52 (0%) 0 1/52 (1.9%) 1
    Eyelid ptosis 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0 0/52 (0%) 0
    Lagophthalmos 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0 0/52 (0%) 0
    Macular fibrosis 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 0/52 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0
    Ocular discomfort 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 0/52 (0%) 0 0/52 (0%) 0 2/52 (3.8%) 2
    Posterior capsule opacification 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 1/52 (1.9%) 2 0/52 (0%) 0 0/52 (0%) 0
    Lenticular opacities 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0 0/52 (0%) 0
    Meibomianitis 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 0/52 (0%) 0 0/52 (0%) 0 1/52 (1.9%) 1
    Pseudopterygium 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 0/52 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0
    Retinal cyst 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0 0/52 (0%) 0
    Cataract 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 3/52 (5.8%) 3 0/52 (0%) 0 0/52 (0%) 0
    Corneal erosion 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 2/52 (3.8%) 5 1/52 (1.9%) 1 0/52 (0%) 0
    Corneal neovascularisation 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 2/52 (3.8%) 2 2/52 (3.8%) 4 1/52 (1.9%) 1
    Neurotrophic keratopathy 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 2/52 (3.8%) 3 1/52 (1.9%) 1 0/52 (0%) 0
    Gastrointestinal disorders
    Conjunctivitis 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 1/52 (1.9%) 1 1/52 (1.9%) 1 0/52 (0%) 0
    Nausea 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 2/52 (3.8%) 2 0/52 (0%) 0 0/52 (0%) 0
    Toothache 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0 0/52 (0%) 0
    Vomiting 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 0/52 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0
    Abdominal pain upper 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 0/52 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0
    Diverticular perforation 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0 0/52 (0%) 0
    Gastric polyps 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0 0/52 (0%) 0
    General disorders
    Disease progression 2/7 (28.6%) 2 0/7 (0%) 0 1/4 (25%) 1 4/52 (7.7%) 4 4/52 (7.7%) 6 6/52 (11.5%) 6
    Fatigue 0/7 (0%) 0 1/7 (14.3%) 1 0/4 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0 0/52 (0%) 0
    Instillation site pruritus 0/7 (0%) 0 1/7 (14.3%) 1 0/4 (0%) 0 0/52 (0%) 0 0/52 (0%) 0 0/52 (0%) 0
    Irritability 0/7 (0%) 0 1/7 (14.3%) 1 0/4 (0%) 0 0/52 (0%) 0 0/52 (0%) 0 0/52 (0%) 0
    Instillation site pain 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 0/52 (0%) 0 1/52 (1.9%) 1 1/52 (1.9%) 1
    Pyrexia 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0 0/52 (0%) 0
    Inflammation 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 1/52 (1.9%) 1 1/52 (1.9%) 1 0/52 (0%) 0
    Impaired healing 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 1/52 (1.9%) 1 1/52 (1.9%) 1 0/52 (0%) 0
    Hepatobiliary disorders
    Cholelithiasis 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 0/52 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0
    Immune system disorders
    Corneal graft rejection 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 1/52 (1.9%) 1 3/52 (5.8%) 4 1/52 (1.9%) 1
    Immunodeficiency 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 0/52 (0%) 0 1/52 (1.9%) 2 0/52 (0%) 0
    Infections and infestations
    Influenza 0/7 (0%) 0 1/7 (14.3%) 1 0/4 (0%) 0 0/52 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0
    Keratitis herpetic 0/7 (0%) 0 0/7 (0%) 0 1/4 (25%) 1 0/52 (0%) 0 2/52 (3.8%) 2 0/52 (0%) 0
    Corneal infection 0/7 (0%) 0 1/7 (14.3%) 1 0/4 (0%) 0 1/52 (1.9%) 1 1/52 (1.9%) 1 0/52 (0%) 0
    Nasopharyngitis 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 4/52 (7.7%) 4 3/52 (5.8%) 4 2/52 (3.8%) 2
    Gastroenteritis 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0 1/52 (1.9%) 1
    Conjunctivitis bacterial 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 0/52 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0
    Corneal abscess 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 1/52 (1.9%) 1 1/52 (1.9%) 1 0/52 (0%) 0
    Diverticulitis 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0 0/52 (0%) 0
    Lower respiratory tract infection 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 0/52 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0
    Oral herpes 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0 0/52 (0%) 0
    Staphylococcal infection 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0 0/52 (0%) 0
    Upper respiratory tract infection 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 0/52 (0%) 0 1/52 (1.9%) 2 0/52 (0%) 0
    Helicobacter gastritis 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 2/52 (3.8%) 2 0/52 (0%) 0 0/52 (0%) 0
    Herpes ophthalmic 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 2/52 (3.8%) 2 0/52 (0%) 0 0/52 (0%) 0
    Blister infected 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0 0/52 (0%) 0
    Catheter site infection 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0 0/52 (0%) 0
    Cystitis 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 0/52 (0%) 0 1/52 (1.9%) 2 0/52 (0%) 0
    Herpes simplex ophtalmic 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 0/52 (0%) 0 0/52 (0%) 0 1/52 (1.9%) 1
    Herpes zoster ophtalmic 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 0/52 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0
    Onychomycosis 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 0/52 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0
    Onychomycosis 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0 0/52 (0%) 0
    Tonsillitis 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 0/52 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0
    Urinary tract infection 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 0/52 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0
    Injury, poisoning and procedural complications
    Fall 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 1/52 (1.9%) 1 1/52 (1.9%) 1 0/52 (0%) 0
    Laceration 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 0/52 (0%) 0 0/52 (0%) 0 1/52 (1.9%) 1
    Periorbital haematoma 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0 0/52 (0%) 0
    Suture related complication 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 0/52 (0%) 0 0/52 (0%) 0 1/52 (1.9%) 2
    Clavicle fracture 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 0/52 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0
    Facial bones fracture 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 0/52 (0%) 0 0/52 (0%) 0 1/52 (1.9%) 1
    Femur fracture 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 0/52 (0%) 0 0/52 (0%) 0 1/52 (1.9%) 1
    Pelvic fracture 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0 0/52 (0%) 0
    Tibia fracture 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0 0/52 (0%) 0
    Transplant failure 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0 0/52 (0%) 0
    Upper limb fracture 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 0/52 (0%) 0 0/52 (0%) 0 1/52 (1.9%) 1
    Investigations
    Haematocrit decreased 0/7 (0%) 0 1/7 (14.3%) 1 0/4 (0%) 0 0/52 (0%) 0 0/52 (0%) 0 0/52 (0%) 0
    Intraocular pressure increased 1/7 (14.3%) 2 0/7 (0%) 0 0/4 (0%) 0 2/52 (3.8%) 2 4/52 (7.7%) 4 0/52 (0%) 0
    Alanine aminotransferase increased 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 0/52 (0%) 0 0/52 (0%) 0 1/52 (1.9%) 1
    Blood pressure increased 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 1/52 (1.9%) 1 1/52 (1.9%) 1 0/52 (0%) 0
    Blood creatine increased 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0 0/52 (0%) 0
    Heart rate increased 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 0/52 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0
    Vital dye staining cornea present 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0 0/52 (0%) 0
    Metabolism and nutrition disorders
    Folate deficiency 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 0/52 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0
    Hypercholesterolaemia 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 0/52 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0
    Hypertriglyceridaemia 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0 0/52 (0%) 0
    Iron deficiency 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 0/52 (0%) 0 0/52 (0%) 0 1/52 (1.9%) 1
    Vitamin B12 deficiency 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 0/52 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0
    Decreased appetite 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 1/52 (1.9%) 2 0/52 (0%) 0 0/52 (0%) 0
    Hyperuricaemia 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0 0/52 (0%) 0
    Hypokalaemia 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 0/52 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0
    Vitamin D deficiency 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 0/52 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0
    Musculoskeletal and connective tissue disorders
    Muscle spasms 0/7 (0%) 0 1/7 (14.3%) 1 0/4 (0%) 0 0/52 (0%) 0 0/52 (0%) 0 0/52 (0%) 0
    Intervertebral disc protrusion 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0 0/52 (0%) 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant neoplasm progression 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 1/52 (1.9%) 1 1/52 (1.9%) 1 0/52 (0%) 0
    Nervous system disorders
    headache 0/7 (0%) 0 2/7 (28.6%) 3 0/4 (0%) 0 2/52 (3.8%) 2 4/52 (7.7%) 4 2/52 (3.8%) 2
    Hypoaesthesia 0/7 (0%) 0 1/7 (14.3%) 1 0/4 (0%) 0 0/52 (0%) 0 0/52 (0%) 0 0/52 (0%) 0
    Neuralgia 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0 0/52 (0%) 0
    Trigeminal neuralgia 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0 0/52 (0%) 0
    Burning sensation 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0 0/52 (0%) 0
    Syncope 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 0/52 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0
    Psychiatric disorders
    Insomnia 0/7 (0%) 0 2/7 (28.6%) 2 0/4 (0%) 0 0/52 (0%) 0 0/52 (0%) 0 0/52 (0%) 0
    Anxiety 0/7 (0%) 0 1/7 (14.3%) 1 0/4 (0%) 0 0/52 (0%) 0 0/52 (0%) 0 0/52 (0%) 0
    Renal and urinary disorders
    Renal colic 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 1/52 (1.9%) 1 2/52 (3.8%) 2 0/52 (0%) 0
    Bladder prolapse 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0 0/52 (0%) 0
    Reproductive system and breast disorders
    Uterine prolapse 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0 0/52 (0%) 0
    Respiratory, thoracic and mediastinal disorders
    Dysphonia 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 0/52 (0%) 0 0/52 (0%) 0 1/52 (1.9%) 1
    Respiratory distress 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0 0/52 (0%) 0
    Respiratory failure 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 0/52 (0%) 0 1/52 (1.9%) 1 1/52 (1.9%) 1
    Dyspnoea 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0 0/52 (0%) 0
    Epistaxis 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0 0/52 (0%) 0
    Skin and subcutaneous tissue disorders
    Dry skin 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 0/52 (0%) 0 0/52 (0%) 0 1/52 (1.9%) 1
    Onychoclasis 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 0/52 (0%) 0 0/52 (0%) 0 1/52 (1.9%) 1
    Diabetic foot 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0 0/52 (0%) 0
    Vascular disorders
    Aortic dissection 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 1/52 (1.9%) 1 1/52 (1.9%) 1 0/52 (0%) 0
    Hypertension 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 2/52 (3.8%) 2 0/52 (0%) 0 0/52 (0%) 0
    Venous thrombosis 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 0/52 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0
    Aortic rupture 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0 0/52 (0%) 0
    Deep vein thrombosis 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0 0/52 (0%) 0
    Diabetic vascular disorder 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0 0/52 (0%) 0
    Diastolic hypotension 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0 0/52 (0%) 0
    Shock haemorrhagic 0/7 (0%) 0 0/7 (0%) 0 0/4 (0%) 0 1/52 (1.9%) 1 0/52 (0%) 0 0/52 (0%) 0

    Limitations/Caveats

    None reported

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Flavio Mantelli, MD, PhD
    Organization Dompè
    Phone +3902583831
    Email info@dompe.com
    Responsible Party:
    Dompé Farmaceutici S.p.A
    ClinicalTrials.gov Identifier:
    NCT01756456
    Other Study ID Numbers:
    • NGF0212
    • 2012-002527-15
    First Posted:
    Dec 27, 2012
    Last Update Posted:
    Jul 29, 2019
    Last Verified:
    Feb 1, 2017