Evaluation of Efficacy of 20 µg/ml rhNGF New Formulation (With Anti-oxidant) in Patients With Stage 2 and 3 NK

• Sponsor: Dompé Farmaceutici S.p.A (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02227147
• Collaborator: (none)
• Enrollment: 48
• Locations: 12
• Arms: 2
• Duration (Months): 19
• Patients Per Site: 4
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The primary objective of this study is to evaluate the efficacy of 20 µg/ml 6 times a day of rhNGF eye drops solution (formulation containing anti-oxidant) compared to vehicle (formulation containing anti-oxidant) given 6 times a day. The evaluation of efficacy is intended as:

• complete healing of stage 2 (persistent epithelial defect) and 3 (corneal ulcer) neurotrophic keratitis (NK) as measured by the central reading center using corneal fluorescein staining,

• assessing the duration of complete healing,

• improvement in visual acuity and improvement in corneal sensitivity.

Condition or Disease	Intervention/Treatment	Phase
Neurotrophic Keratitis	Drug: rhNGF 20µg/ml; Other: Placebo	Phase 2

Detailed Description

An 8-week phase II, multicenter, randomized, double-masked, vehicle-controlled, parallel group study with a 24 or 32 week follow-up period to evaluate the efficacy of a formulation containing anti-oxidant of recombinant human nerve growth factor (rhNGF) in 20 μg/ml, eye drops solution versus vehicle containing anti-oxidant in patients with Stage 2 and 3 Neurotrophic Keratitis. The primary objective was to evaluate the efficacy of 20 μg/ml 6 times a day of recombinant human nerve growth factor (rhNGF) containing anti-oxidant, eye drops solution compared to vehicle (formulation containing anti-oxidant) given 6 times a day in inducing a complete healing of stage 2 (PED) and 3 (corneal ulcer) NK as measured by the central reading center, evaluating the clinical pictures of corneal fluorescein staining.

Secondary objectives were to assess the duration of complete healing, improvement in visual acuity and improvement in corneal sensitivity, and percentage of patients achieving complete corneal clearing defined as complete absence of staining on the modified Oxford Scale.

Study Design

• Study Type: Interventional
• Actual Enrollment: 48 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: An 8-week Phase II, Multicenter, Randomized, Double-masked, Vehicle Controlled Parallel Group Study With a 24 or 32 Week Follow-up to Evaluate the Efficacy of rhNGF 20 µg/ml vs Vehicle in Patients With Stage 2 and 3 Neurotrophic Keratitis
• Study Start Date: Feb 1, 2015
• Actual Primary Completion Date: Jun 1, 2016
• Actual Study Completion Date: Sep 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: rhNGF 20 µg/ml rhNGF 20 µg/ml eye drops solution, formulation containing anti-oxidant	Drug: rhNGF 20µg/ml; Other Names: cenegermin
Placebo Comparator: Placebo Vehicle: formulation containing anti-oxidant	Other: Placebo; Formulation containing antioxidant; Other Names: Vehicle

Outcome Measures

Primary Outcome Measures

1. Complete Healing of the Persistent Epithelial Defect (PED) or Corneal Ulcer Defined by Central Reviewer [Week 8]

   Percentage of patients achieving complete healing of the PED or corneal ulcer determined by corneal fluorescein staining at 8 weeks as defined by the central reading center on clinical pictures.

Secondary Outcome Measures

1. Complete Healing of the Persistent Epithelial Defect (PED) or Corneal Ulcer Defined by the Investigator [Week 8]

   Percentage of patients experiencing complete healing of the PED or corneal ulcer determined by corneal fluorescein staining at 8 weeks as measured by the investigator.

2. Complete Healing of the Persistent Epithelial Defect (PED) or Corneal Ulcer Defined by Central Reading Center and Investigator. [At weeks 4 and 6]

   Percentage of patients experiencing complete healing of the PED or corneal ulcer at 4, and 6 weeks as measured by the central reading center evaluating the clinical pictures and investigator.

3. Percentage of Patients With Complete Corneal Clearing [at weeks 4, 6, and 8]

   Percentage of patients with complete corneal clearing at weeks 4, 6, and 8 defined as grade 0 on the modified Oxford scale. Grade 0 indicates the absence of conjunctival staining; grade V indicates severe conjunctival staining.

4. Mean Change From Baseline in Best Corrected Distance Visual Acuity (BCDVA) [Baseline, Week 8]

   Change in Best Corrected Distance Visual Acuity (BCDVA) from baseline to Week 8. Best Corrected Distance Visual Acuity consists of letters read at 4m only.

5. Percentage of Patients That Achieve a 15 Letter Gain in BCDVA [Weeks 4, week 6 and week 8]

   Percentage of patients that achieve a 15 letter gain in Best Corrected Distance Visual Acuity (BCDVA) at 4 weeks, 6 weeks, 8 weeks

6. Improvement in Corneal Sensitivity [At 4, 6 and 8 weeks after start of the treatment]

   Improvement in corneal sensitivity was measured by the Cochet-Bonnet aesthesiometer at 4, 6 and 8 weeks. Corneal sensitivity is measured continuously in each patient in cm: Area of the Persistent Epithelial Defect (PED) or corneal ulcer All quadrants, but outside the PED or corneal ulcer area: Superior nasal, inferior nasal, superior temporal, inferior temporal. Improvement is defined as an increase of at least 0.5 cm in the location of concern.

7. Patients Experiencing Deterioration [from baseline to Week 8.]

   Number of patients experiencing deterioration (increase in lesion size ≥ 1mm and/or decrease in BCDVA by >5 Early Treatment Diabetic Retinopathy Study (ETDRS) letters and/or progression in lesion depth to corneal melting or perforation and/or onset of infection) in stage 2 or 3 NK from baseline to Week 8.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Patients 18 years of age or older.

• Patients with stage 2 (persistent epithelial defect, PED) or stage 3 (corneal ulcer) neurotrophic keratitis (NK).

• PED or corneal ulceration of at least 2 weeks duration refractory to one or more conventional non-surgical treatments for neurotrophic keratitis.

• Evidence of decreased corneal sensitivity (≤ 4 cm using the Cochet-Bonnet aesthesiometer) within the area of the PED or corneal ulcer and outside of the area of the defect in at least one corneal quadrant.

• Best corrected distance visual acuity (BCDVA) score ≤ 75 ETDRS (Early Treatment Diabetic Retinopathy Study)letters, (≥ 0.2 LogMAR, ≤ 20/32 Snellen or ≤ 0.625 decimal fraction) in the affected eye(s).

• No objective clinical evidence of improvement in the PED or corneal ulceration within the 2 weeks prior to study enrolment.

• Only patients who satisfy all Informed Consent requirements may be included in the study. The patient and/or his/her legal representative must read, sign and date the Informed Consent document before any study-related procedures are performed. The Informed Consent form signed by patients and/or legal representative must have been approved by the IRB (Institutional Review Board) for the current study.

• Patients must have the ability and willingness to comply with study procedures.

Exclusion Criteria:

• Any active ocular infection or active ocular inflammation not related to NK in the affected eye(s).

• Any other ocular disease requiring topical ocular treatment during the course of the study treatment period. No topical treatments other than the study medications provided by the study sponsor and allowed by the study protocol can be administered in the affected eye(s) during the course of the study treatment periods.

• Patients with severe vision loss with no potential for visual improvement in the opinion of the investigator as a result of the study treatment.

• Schirmer test without anesthesia ≤3 mm/5 minutes.

• Patients with severe blepharitis and/or severe meibomian gland disease.

• History of any ocular surgery (including laser or refractive surgical procedures) within the three months before study enrolment. (An exception to the preceding statement will be allowed if the ocular surgery is considered to be the cause of the stage 2 or 3 NK). Ocular surgery will not be allowed during the study treatment period and elective ocular surgery procedures should not be planned during the duration of the follow-up period.

• Prior surgical procedure(s) for the treatment of NK 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 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.

• Anticipated need to use therapeutic contact lenses or contact lens wear for refractive correction during the study treatment period in the eye(s) with NK.

• Anticipated need for punctual occlusion during the study treatment period. Patients with punctual occlusion or punctual plugs inserted prior to the study are eligible for enrolment provided that the punctual occlusion is maintained during the study.

• Evidence of corneal ulceration involving the posterior third of the corneal stroma, corneal melting or perforation.

• 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.

• Any need for or anticipated change in the dose of systemic medications known to impair the function of the trigeminal nerve. These treatments are allowed during the study if initiated prior study enrolment provided they remain stable throughout the course of the study treatment periods.

• Known hypersensitivity to one of the components of the study or procedural medications (e.g. fluorescein).

• History of drug, medication or alcohol abuse or addiction.

• Use of any investigational agent within 4 weeks of screening visit.

• Participation in another clinical study at the same time as the present study.

• Females of childbearing potential 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 are not willing to use highly effective birth control measures.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Loma Linda University Ophthalmology	Loma Linda	California	United States	92354
2	Jules Stein Eye Institute	Los Angeles	California	United States	90095
3	Shiley Eye Center University of California	San Diego	California	United States	92093
4	Bascom Palmer Eye Institute University of Miami	Miami	Florida	United States	33324
5	Tufts Medical Center	Boston	Massachusetts	United States	02111
6	Massachusetts Eye & Ear Infirmary	Boston	Massachusetts	United States	02114
7	Massachusetts Eye Research and Surgery Institution	Cambridge	Massachusetts	United States	02451
8	Mayo Clinic	Rochester	Minnesota	United States	55905
9	New York Eye and Ear Infirmary	New York	New York	United States	10003
10	Penn Eye Care Scheie Eye Institute	Philadelphia	Pennsylvania	United States	19104
11	UPMC eye center, department of ophthalmology, University of Pittsburgh	Pittsburgh	Pennsylvania	United States	15213
12	Baylor College of Medicine	Houston	Texas	United States	77030

Sponsors and Collaborators

• Dompé Farmaceutici S.p.A

Investigators

• Study Director: Flavio Mantelli, MD, PhD, Dompé farmaceutici 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: NCT02227147
• Other Study ID Numbers: NGF0214
• First Posted: Aug 27, 2014
• Last Update Posted: Apr 4, 2022
• Last Verified: Mar 1, 2022

• Keywords provided by Dompé Farmaceutici S.p.A: Neurotrophic Keratitis
• Additional relevant MeSH terms: Keratitis

Study Results

Participant Flow

Recruitment Details	Recruitment was competitive among the study sites, until the planned number of patients were randomized. Competitive recruitment was chosen to increase the speed of recruitment and to account for any difference in enrolment rate among study sites.

Arm/Group Title	rhNGF 20 µg/ml	Vehicle
Arm/Group Description	rhNGF 20 µg/ml eye drops solution, formulation containing anti-oxidant rhNGF 20µg/ml	vehicle, formulation containing anti-oxidant Placebo Vehicle
Period Title: Controlled Treatment Period
STARTED	24	24
COMPLETED	18	21
NOT COMPLETED	6	3
Period Title: Controlled Treatment Period
STARTED	18	21
COMPLETED	15	16
NOT COMPLETED	3	5

Baseline Characteristics

Arm/Group Title	rhNGF 20 µg/ml	Vehicle	Total
Arm/Group Description	rhNGF 20 µg/ml eye drops solution, formulation containing anti-oxidant rhNGF 20µg/ml	vehicle, formulation containing anti-oxidant Placebo Vehicle	Total of all reporting groups
Overall Participants	24	24	48
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	11 45.8%	13 54.2%	24 50%
>=65 years	13 54.2%	11 45.8%	24 50%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	65.9 (13.85)	54.5 (14.15)	65.2 (13.87)
Sex: Female, Male (Count of Participants)
Female	14 58.3%	15 62.5%	29 60.4%
Male	10 41.7%	9 37.5%	19 39.6%
Region of Enrollment (Count of Participants)
United States	24 100%	24 100%	48 100%

Outcome Measures

1. Primary Outcome

Title	Complete Healing of the Persistent Epithelial Defect (PED) or Corneal Ulcer Defined by Central Reviewer
Description	Percentage of patients achieving complete healing of the PED or corneal ulcer determined by corneal fluorescein staining at 8 weeks as defined by the central reading center on clinical pictures.
Time Frame	Week 8

Outcome Measure Data

Analysis Population Description

ITT population, LOCF. One patient (randomized to rhNGF although not eligible) had no post-baseline data, was assumed to be missing, and was excluded from the analyses.

Arm/Group Title	rhNGF 20 µg/ml	Vehicle
Arm/Group Description	rhNGF 20 µg/ml eye drops solution, formulation containing anti-oxidant rhNGF 20µg/ml	vehicle, formulation containing anti-oxidant Placebo Vehicle
Measure Participants	23	24
Completely healed	70 291.7%	29 120.8%
Not completely healed	30 125%	71 295.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	rhNGF 20 µg/ml, Vehicle
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.006
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Difference in percentage
	Estimated Value	40.4
	Confidence Interval	(2-Sided) 90.00%; 14.2 to 66.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Complete Healing of the Persistent Epithelial Defect (PED) or Corneal Ulcer Defined by the Investigator
Description	Percentage of patients experiencing complete healing of the PED or corneal ulcer determined by corneal fluorescein staining at 8 weeks as measured by the investigator.
Time Frame	Week 8

Outcome Measure Data

Analysis Population Description

ITT population, LOCF. One patient (randomized to rhNGF although not eligible) had no post-baseline data, was assumed to be missing, and was excluded from the analyses.

Arm/Group Title	rhNGF 20 µg/ml	Vehicle
Arm/Group Description	rhNGF 20 µg/ml eye drops solution, formulation containing anti-oxidant rhNGF 20µg/ml	vehicle, formulation containing anti-oxidant Placebo Vehicle
Measure Participants	23	24
Completely healed	65 270.8%	29 120.8%
Not completely healed	35 145.8%	71 295.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	rhNGF 20 µg/ml, Vehicle
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.013
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Difference in percentage
	Estimated Value	36.1
	Confidence Interval	(2-Sided) 95.0%; 9.4 to 62.7
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Complete Healing of the Persistent Epithelial Defect (PED) or Corneal Ulcer Defined by Central Reading Center and Investigator.
Description	Percentage of patients experiencing complete healing of the PED or corneal ulcer at 4, and 6 weeks as measured by the central reading center evaluating the clinical pictures and investigator.
Time Frame	At weeks 4 and 6

Outcome Measure Data

Analysis Population Description

LOCF, ITT population. One patient (randomized to rhNGF although not eligible) had no post-baseline data, was assumed to be missing, and was excluded from the analyses.

Arm/Group Title	rhNGF 20 µg/ml	Placebo
Arm/Group Description	rhNGF 20 µg/ml eye drops solution, formulation containing anti-oxidant rhNGF 20µg/ml	Vehicle: formulation containing anti-oxidant Placebo: Formulation containing antioxidant
Measure Participants	23	24
Week 4 - central reviewer - yes	56 233.3%	38 158.3%
Week 4 - central reviewer - no	44 183.3%	62 258.3%
Week 6 - central reviewer - yes	56 233.3%	46 191.7%
Week 6 - central reviewer - no	44 183.3%	54 225%
Week 4 - investigator - yes	56 233.3%	42 175%
Week 4 - investigator - no	44 183.3%	58 241.7%
Week 6 - investigator - yes	65 270.8%	42 175%
Week 6 - investigator - no	35 145.8%	58 241.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	rhNGF 20 µg/ml, Vehicle
	Comments	week 4 - central reviewer
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.191
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	difference in percentage
	Estimated Value	19.0
	Confidence Interval	(2-Sided) 95%; -9.0 to 47.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	rhNGF 20 µg/ml, Vehicle
	Comments	week 6 - central reviewer
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.464
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	difference in percentage
	Estimated Value	10.7
	Confidence Interval	(2-Sided) 95%; -17.7 to 39.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	rhNGF 20 µg/ml, Vehicle
	Comments	week 4 - investigator
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.308
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	difference in percentage
	Estimated Value	14.9
	Confidence Interval	(2-Sided) 95%; -13.4 to 43.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	rhNGF 20 µg/ml, Vehicle
	Comments	week 6 - investigator
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.106
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	difference in percentage
	Estimated Value	23.6
	Confidence Interval	(2-Sided) 95%; -4.2 to 51.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Percentage of Patients With Complete Corneal Clearing
Description	Percentage of patients with complete corneal clearing at weeks 4, 6, and 8 defined as grade 0 on the modified Oxford scale. Grade 0 indicates the absence of conjunctival staining; grade V indicates severe conjunctival staining.
Time Frame	at weeks 4, 6, and 8

Outcome Measure Data

Analysis Population Description

LOCF, ITT population. Two patients (randomized to rhNGF although not eligible) had no post-baseline data, were assumed to be missing, and were excluded from the analyses.

Arm/Group Title	rhNGF 20 µg/ml	Placebo
Arm/Group Description	rhNGF 20 µg/ml eye drops solution, formulation containing anti-oxidant rhNGF 20µg/ml	Vehicle: formulation containing anti-oxidant Placebo: Formulation containing antioxidant
Measure Participants	22	24
Week 4 - yes	14 58.3%	4 16.7%
Week 4 - no	86 358.3%	96 400%
Week 6 - yes	9 37.5%	8 33.3%
Week 6 - no	91 379.2%	92 383.3%
Week 8 - yes	23 95.8%	4 16.7%
Week 8 - no	77 320.8%	96 400%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	rhNGF 20 µg/ml, Vehicle
	Comments	week 4
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.255
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	difference in percentage
	Estimated Value	9.5
	Confidence Interval	(2-Sided) 95%; -6.9 to 25.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	rhNGF 20 µg/ml, Vehicle
	Comments	week 6
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.927
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	difference in percentage
	Estimated Value	0.8
	Confidence Interval	(2-Sided) 95%; -15.6 to 17.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	rhNGF 20 µg/ml, Vehicle
	Comments	week 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.062
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	difference in percentage
	Estimated Value	18.6
	Confidence Interval	(2-Sided) 95%; -0.7 to 37.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Mean Change From Baseline in Best Corrected Distance Visual Acuity (BCDVA)
Description	Change in Best Corrected Distance Visual Acuity (BCDVA) from baseline to Week 8. Best Corrected Distance Visual Acuity consists of letters read at 4m only.
Time Frame	Baseline, Week 8

Outcome Measure Data

Analysis Population Description

LOCF, ITT Population

Arm/Group Title	rhNGF 20 µg/ml	Placebo
Arm/Group Description	rhNGF 20 µg/ml eye drops solution, formulation containing anti-oxidant rhNGF 20µg/ml	Vehicle: formulation containing anti-oxidant Placebo: Formulation containing antioxidant
Measure Participants	23	24
Mean (Standard Deviation) [letters read correctly]	4.48 (9.25)	4.33 (10.399)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	rhNGF 20 µg/ml, Vehicle
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.745
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	difference in least square means
	Estimated Value	1.1
	Confidence Interval	(2-Sided) 95%; -5.6 to 7.7
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Percentage of Patients That Achieve a 15 Letter Gain in BCDVA
Description	Percentage of patients that achieve a 15 letter gain in Best Corrected Distance Visual Acuity (BCDVA) at 4 weeks, 6 weeks, 8 weeks
Time Frame	Weeks 4, week 6 and week 8

Outcome Measure Data

Analysis Population Description

LOCF, ITT population

Arm/Group Title	rhNGF 20 µg/ml	Placebo
Arm/Group Description	rhNGF 20 µg/ml eye drops solution, formulation containing anti-oxidant rhNGF 20µg/ml	Vehicle: formulation containing anti-oxidant Placebo: Formulation containing antioxidant
Measure Participants	24	24
week 4 - yes	9	12
week 4 - no	91	88
week 6 - yes	13	12
week 6 - no	87	88
week 8 -yes	13	17
week 8 - no	87	83

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	rhNGF 20 µg/ml, Vehicle
	Comments	week 4
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.672
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	difference in percentage
	Estimated Value	-3.8
	Confidence Interval	(2-Sided) 95%; -21.3 to 13.7
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	rhNGF 20 µg/ml, Vehicle
	Comments	week 6
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.955
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	difference in percentage
	Estimated Value	0.5
	Confidence Interval	(2-Sided) 95%; -18.5 to 19.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	rhNGF 20 µg/ml, Vehicle
	Comments	week 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.727
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	difference in percentage
	Estimated Value	-3.6
	Confidence Interval	(2-Sided) 95%; -23.9 to 16.7
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Improvement in Corneal Sensitivity
Description	Improvement in corneal sensitivity was measured by the Cochet-Bonnet aesthesiometer at 4, 6 and 8 weeks. Corneal sensitivity is measured continuously in each patient in cm: Area of the Persistent Epithelial Defect (PED) or corneal ulcer All quadrants, but outside the PED or corneal ulcer area: Superior nasal, inferior nasal, superior temporal, inferior temporal. Improvement is defined as an increase of at least 0.5 cm in the location of concern.
Time Frame	At 4, 6 and 8 weeks after start of the treatment

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	rhNGF 20 µg/ml	Placebo
Arm/Group Description	rhNGF 20 µg/ml eye drops solution, formulation containing anti-oxidant rhNGF 20µg/ml	Vehicle: formulation containing anti-oxidant Placebo: Formulation containing antioxidant
Measure Participants	24	24
week 4	2.50 (1.821)	1.56 (1.983)
week 6	2.26 (2.009)	1.84 (2.150)
week 8	2.91 (2.144)	1.83 (1.952)
Change from baseline to week 8	1.88 (1.401)	1.00 (1.254)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	rhNGF 20 µg/ml, Vehicle
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.207
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	least square mean difference
	Estimated Value	0.6
	Confidence Interval	(2-Sided) 95%; -0.4 to 1.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Patients Experiencing Deterioration
Description	Number of patients experiencing deterioration (increase in lesion size ≥ 1mm and/or decrease in BCDVA by >5 Early Treatment Diabetic Retinopathy Study (ETDRS) letters and/or progression in lesion depth to corneal melting or perforation and/or onset of infection) in stage 2 or 3 NK from baseline to Week 8.
Time Frame	from baseline to Week 8.

Outcome Measure Data

Analysis Population Description

ITT population. As far as this endpoint is concerned, data are available (non-missing) for 18 patients out of 24 in the rhNGF group, and for 15 patients out of 24 for the vehicle group.

Arm/Group Title	rhNGF 20 µg/ml	Placebo
Arm/Group Description	rhNGF 20 µg/ml eye drops solution, formulation containing anti-oxidant rhNGF 20µg/ml	Vehicle: formulation containing anti-oxidant Placebo: Formulation containing antioxidant
Measure Participants	18	15
Deterioration	0	2
No deterioration	18	13

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	rhNGF 20 µg/ml, Vehicle
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.110
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	difference in percentage
	Estimated Value	-13.3
	Confidence Interval	(2-Sided) 95%; -30.5 to 3.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Adverse events were analyzed by study period (Controlled Treatment Period, Follow-up Period and Uncontrolled Treatment Period).
Adverse Event Reporting Description	The number of Participants considered in the Adverse Event Section reflects the safety subset population of the study: 23 patients: rhNGF during the Controlled Treatment Period 24 patients: vehicle during the Controlled Treatment Period 18 patients: rhNGF during the Follow-up Period 21 patients: vehicle during the Follow-up Period 13 patients: vehicle during the Controlled Treatment Period and rhNGF during the Uncontrolled Treatment Period
Arm/Group Title	rhNGF 20 µg/ml - Controlled Treatment Period		Vehicle - Controlled Treatment Period		rhNGF 20 µg/ml - Follow-up Period		Vehicle - Follow-up Period		Uncontrolled Treatment Period
Arm/Group Description	rhNGF 20 µg/ml eye drops solution, formulation containing anti-oxidant rhNGF 20µg/ml		vehicle, formulation containing anti-oxidant Placebo Vehicle		rhNGF 20 µg/ml eye drops solution, formulation containing anti-oxidant rhNGF 20µg/ml		vehicle, formulation containing anti-oxidant Placebo Vehicle		rhNGF 20 µg/ml eye drops solution, formulation containing anti-oxidant Patients randomized to vehicle at baseline and not completely healed at week 8 who entered a 8-week treatment period before entering follow-up period
All Cause Mortality
	rhNGF 20 µg/ml - Controlled Treatment Period		Vehicle - Controlled Treatment Period		rhNGF 20 µg/ml - Follow-up Period		Vehicle - Follow-up Period		Uncontrolled Treatment Period
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/23 (0%)		0/24 (0%)		5/18 (27.8%)		2/21 (9.5%)		0/13 (0%)
Serious Adverse Events
	rhNGF 20 µg/ml - Controlled Treatment Period		Vehicle - Controlled Treatment Period		rhNGF 20 µg/ml - Follow-up Period		Vehicle - Follow-up Period		Uncontrolled Treatment Period
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/23 (17.4%)		4/24 (16.7%)		4/18 (22.2%)		2/21 (9.5%)		0/0 (NaN)
Eye disorders
Corneal Thinning	1/23 (4.3%)	1	0/24 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	0/0 (NaN)	0
decreased visual acuity	0/23 (0%)	0	1/24 (4.2%)	2	1/18 (5.6%)	1	1/21 (4.8%)	2	1/0 (Infinity)	2
Corneal perforation	0/23 (0%)	0	0/24 (0%)	0	2/18 (11.1%)	2	0/21 (0%)	0	0/0 (NaN)	0
Gastrointestinal disorders
ventral hernia	0/23 (0%)	0	1/24 (4.2%)	1	0/18 (0%)	0	0/21 (0%)	0	0/0 (NaN)	0
General disorders
Disease Progression	1/23 (4.3%)	1	2/24 (8.3%)	2	0/18 (0%)	0	0/21 (0%)	0	0/0 (NaN)	0
Death	0/23 (0%)	0	0/24 (0%)	0	1/18 (5.6%)	1	0/21 (0%)	0	0/0 (NaN)	0
Disease recurrence	0/23 (0%)	0	0/24 (0%)	0	0/18 (0%)	0	1/21 (4.8%)	1	1/0 (Infinity)	1
Infections and infestations
Viral gastroenteritis	0/23 (0%)	0	0/24 (0%)	0	1/18 (5.6%)	1	0/21 (0%)	0	0/0 (NaN)	0
Injury, poisoning and procedural complications
Aqueous Humour Leakage	1/23 (4.3%)	1	0/24 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	0/0 (NaN)	0
Nervous system disorders
Syncope	1/23 (4.3%)	1	0/24 (0%)	0	0/18 (0%)	0	0/21 (0%)	0	0/0 (NaN)	0
Other (Not Including Serious) Adverse Events
	rhNGF 20 µg/ml - Controlled Treatment Period		Vehicle - Controlled Treatment Period		rhNGF 20 µg/ml - Follow-up Period		Vehicle - Follow-up Period		Uncontrolled Treatment Period
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	21/23 (91.3%)		18/24 (75%)		14/14 (100%)		9/9 (100%)		7/13 (53.8%)
Ear and labyrinth disorders
Deafness bilateral	0/23 (0%)	0	0/24 (0%)	0	0/14 (0%)	0	1/9 (11.1%)	1	0/13 (0%)	0
motion sickness	0/23 (0%)	0	0/24 (0%)	0	0/14 (0%)	0	1/9 (11.1%)	1	0/13 (0%)	0
Eye disorders
Visual acuity reduced	5/23 (21.7%)	5	5/24 (20.8%)	7	1/14 (7.1%)	1	2/9 (22.2%)	2	2/13 (15.4%)	2
Eye pain	7/23 (30.4%)	11	2/24 (8.3%)	2	3/14 (21.4%)	3	2/9 (22.2%)	2	2/13 (15.4%)	2
Corneal Epithelium Defect	3/23 (13%)	3	2/24 (8.3%)	2	2/14 (14.3%)	2	1/9 (11.1%)	1	0/13 (0%)	0
Eye Inflammation	3/23 (13%)	3	2/24 (8.3%)	2	0/14 (0%)	0	0/9 (0%)	0	0/13 (0%)	0
Lacrimation Increased	4/23 (17.4%)	4	1/24 (4.2%)	1	2/14 (14.3%)	2	0/9 (0%)	0	0/13 (0%)	0
Ocular Hyperaemia	4/23 (17.4%)	4	1/24 (4.2%)	1	0/14 (0%)	0	2/9 (22.2%)	2	0/13 (0%)	0
Corneal Thinning	2/23 (8.7%)	2	2/24 (8.3%)	2	0/14 (0%)	0	0/9 (0%)	0	0/13 (0%)	0
Eye Irritation	0/23 (0%)	0	4/24 (16.7%)	5	1/14 (7.1%)	1	0/9 (0%)	0	0/13 (0%)	0
Ocular Discomfort	2/23 (8.7%)	2	2/24 (8.3%)	2	1/14 (7.1%)	1	0/9 (0%)	0	0/13 (0%)	0
Photophobia	2/23 (8.7%)	2	2/24 (8.3%)	2	0/14 (0%)	0	0/9 (0%)	0	0/13 (0%)	0
Cataract	3/23 (13%)	3	0/24 (0%)	0	0/14 (0%)	0	1/9 (11.1%)	1	0/13 (0%)	0
Foreign Body Sensation In Eyes	2/23 (8.7%)	2	0/24 (0%)	0	1/14 (7.1%)	1	0/9 (0%)	0	0/13 (0%)	0
Posterior Capsule Opacification	1/23 (4.3%)	1	1/24 (4.2%)	1	0/14 (0%)	0	0/9 (0%)	0	0/13 (0%)	0
Anterior Chamber Inflammation	1/23 (4.3%)	1	0/24 (0%)	0	0/14 (0%)	0	0/9 (0%)	0	1/13 (7.7%)	1
Conjunctivitis Allergic	1/23 (4.3%)	1	0/24 (0%)	0	0/14 (0%)	0	0/9 (0%)	0	0/13 (0%)	0
Corneal Deposits	1/23 (4.3%)	1	0/24 (0%)	0	0/14 (0%)	0	0/9 (0%)	0	0/13 (0%)	0
Corneal Neovascularisation	0/23 (0%)	0	1/24 (4.2%)	2	0/14 (0%)	0	0/9 (0%)	0	0/13 (0%)	0
Corneal Perforation	0/23 (0%)	0	1/24 (4.2%)	1	0/14 (0%)	0	0/9 (0%)	0	0/13 (0%)	0
Eye Discharge	1/23 (4.3%)	1	0/24 (0%)	0	1/14 (7.1%)	1	0/9 (0%)	0	0/13 (0%)	0
Eye Pruritus	0/23 (0%)	0	1/24 (4.2%)	1	0/14 (0%)	0	0/9 (0%)	0	1/13 (7.7%)	1
Eye Swelling	1/23 (4.3%)	1	0/24 (0%)	0	0/14 (0%)	0	0/9 (0%)	0	0/13 (0%)	0
Eyelid Oedema	1/23 (4.3%)	1	0/24 (0%)	0	1/14 (7.1%)	1	0/9 (0%)	0	0/13 (0%)	0
Eyelid Pain	1/23 (4.3%)	2	0/24 (0%)	0	0/14 (0%)	0	0/9 (0%)	0	1/13 (7.7%)	1
Hyphaema	1/23 (4.3%)	1	0/24 (0%)	0	0/14 (0%)	0	0/9 (0%)	0	0/13 (0%)	0
Iritis	0/23 (0%)	0	1/24 (4.2%)	1	0/14 (0%)	0	0/9 (0%)	0	0/13 (0%)	0
Keratitis	1/23 (4.3%)	1	0/24 (0%)	0	0/14 (0%)	0	0/9 (0%)	0	0/13 (0%)	0
Macular Fibrosis	0/23 (0%)	0	1/24 (4.2%)	1	0/14 (0%)	0	0/9 (0%)	0	0/13 (0%)	0
Meibomian Gland Dysfunction	0/23 (0%)	0	1/24 (4.2%)	1	0/14 (0%)	0	1/9 (11.1%)	1	0/13 (0%)	0
Punctate Keratitis	0/23 (0%)	0	1/24 (4.2%)	1	0/14 (0%)	0	0/9 (0%)	0	0/13 (0%)	0
Trichiasis	1/23 (4.3%)	1	0/24 (0%)	0	1/14 (7.1%)	1	0/9 (0%)	0	0/13 (0%)	0
Ulcerative Keratitis	0/23 (0%)	0	1/24 (4.2%)	1	1/14 (7.1%)	1	0/9 (0%)	0	0/13 (0%)	0
Vision Blurred	0/23 (0%)	0	1/24 (4.2%)	1	0/14 (0%)	0	0/9 (0%)	0	0/13 (0%)	0
Vitreous Floaters	1/23 (4.3%)	1	0/24 (0%)	0	0/14 (0%)	0	0/9 (0%)	0	0/13 (0%)	0
Blepharitis	0/23 (0%)	0	0/24 (0%)	0	1/14 (7.1%)	1	0/9 (0%)	0	0/13 (0%)	0
Chalazion	0/23 (0%)	0	0/24 (0%)	0	1/14 (7.1%)	1	0/9 (0%)	0	0/13 (0%)	0
Conjunctivochalasis	0/23 (0%)	0	0/24 (0%)	0	1/14 (7.1%)	1	0/9 (0%)	0	0/13 (0%)	0
Corneal opacity	0/23 (0%)	0	0/24 (0%)	0	1/14 (7.1%)	1	0/9 (0%)	0	0/13 (0%)	0
Dry eye	0/23 (0%)	0	0/24 (0%)	0	1/14 (7.1%)	1	0/9 (0%)	0	0/13 (0%)	0
Floppy eyelid syndrome	0/23 (0%)	0	0/24 (0%)	0	1/14 (7.1%)	1	0/9 (0%)	0	0/13 (0%)	0
Gastrointestinal disorders
Abdominal Hernia	0/23 (0%)	0	1/24 (4.2%)	1	0/14 (0%)	0	0/9 (0%)	0	0/13 (0%)	0
Lip Swelling	0/23 (0%)	0	1/24 (4.2%)	1	0/14 (0%)	0	0/9 (0%)	0	0/13 (0%)	0
Nausea	1/23 (4.3%)	1	0/24 (0%)	0	0/14 (0%)	0	0/9 (0%)	0	0/13 (0%)	0
Noninfective gingivitis	0/23 (0%)	0	0/24 (0%)	0	1/14 (7.1%)	1	0/9 (0%)	0	0/13 (0%)	0
General disorders
Disease Progression	2/23 (8.7%)	2	4/24 (16.7%)	4	0/14 (0%)	0	0/9 (0%)	0	0/13 (0%)	0
Sensation Of Foreign Body	2/23 (8.7%)	2	2/24 (8.3%)	2	0/14 (0%)	0	0/9 (0%)	0	1/13 (7.7%)	1
Chest Pain	0/23 (0%)	0	1/24 (4.2%)	1	0/14 (0%)	0	0/9 (0%)	0	0/13 (0%)	0
Disease progression	0/23 (0%)	0	0/24 (0%)	0	0/14 (0%)	0	1/9 (11.1%)	1	0/13 (0%)	0
Sensation of foreign body	0/23 (0%)	0	0/24 (0%)	0	1/14 (7.1%)	1	0/9 (0%)	0	0/13 (0%)	0
Infections and infestations
Eye Infection Intraocular	1/23 (4.3%)	1	0/24 (0%)	0	0/14 (0%)	0	0/9 (0%)	0	0/13 (0%)	0
Hordeolum	0/23 (0%)	0	1/24 (4.2%)	1	0/14 (0%)	0	0/9 (0%)	0	0/13 (0%)	0
Ophthalmic Herpes Zoster	1/23 (4.3%)	1	0/24 (0%)	0	0/14 (0%)	0	0/9 (0%)	0	0/13 (0%)	0
Respiratory Tract Infection	0/23 (0%)	0	1/24 (4.2%)	1	0/14 (0%)	0	0/9 (0%)	0	0/13 (0%)	0
Urinary Tract Infection	1/23 (4.3%)	1	0/24 (0%)	0	0/14 (0%)	0	0/9 (0%)	0	0/13 (0%)	0
Vulvovaginal Mycotic Infection	1/23 (4.3%)	1	0/24 (0%)	0	0/14 (0%)	0	0/9 (0%)	0	0/13 (0%)	0
Bronchitis	0/23 (0%)	0	0/24 (0%)	0	0/14 (0%)	0	2/9 (22.2%)	2	0/13 (0%)	0
Conjunctivitis	0/23 (0%)	0	0/24 (0%)	0	1/14 (7.1%)	1	0/9 (0%)	0	0/13 (0%)	0
Mastoiditis	0/23 (0%)	0	0/24 (0%)	0	0/14 (0%)	0	1/9 (11.1%)	1	0/13 (0%)	0
Nasopharyngitis	0/23 (0%)	0	0/24 (0%)	0	1/14 (7.1%)	1	0/9 (0%)	0	1/13 (7.7%)	1
Ophthalmic herpes simplex	0/23 (0%)	0	0/24 (0%)	0	1/14 (7.1%)	1	0/9 (0%)	0	0/13 (0%)	0
Upper respiratory tract infection	0/23 (0%)	0	0/24 (0%)	0	1/14 (7.1%)	1	0/9 (0%)	0	0/13 (0%)	0
Injury, poisoning and procedural complications
Animal Bite	1/23 (4.3%)	1	0/24 (0%)	0	0/14 (0%)	0	0/9 (0%)	0	0/13 (0%)	0
Aqueous Humour Leakage	1/23 (4.3%)	1	0/24 (0%)	0	0/14 (0%)	0	0/9 (0%)	0	0/13 (0%)	0
Foot Fracture	1/23 (4.3%)	1	0/24 (0%)	0	0/14 (0%)	0	0/9 (0%)	0	0/13 (0%)	0
Contusion	0/23 (0%)	0	0/24 (0%)	0	0/14 (0%)	0	1/9 (11.1%)	1	0/13 (0%)	0
Investigations
Intraocular Pressure Increased	3/23 (13%)	4	2/24 (8.3%)	2	2/14 (14.3%)	2	0/9 (0%)	0	0/13 (0%)	0
Metabolism and nutrition disorders
Hyperkalaemia	0/23 (0%)	0	0/24 (0%)	0	0/14 (0%)	0	1/9 (11.1%)	1	0/13 (0%)	0
Hypoglycaemia	0/23 (0%)	0	0/24 (0%)	0	0/14 (0%)	0	0/9 (0%)	0	1/13 (7.7%)	1
Musculoskeletal and connective tissue disorders
Joint Swelling	1/23 (4.3%)	2	0/24 (0%)	0	0/14 (0%)	0	0/9 (0%)	0	0/13 (0%)	0
Osteoporosis	1/23 (4.3%)	1	0/24 (0%)	0	0/14 (0%)	0	0/9 (0%)	0	0/13 (0%)	0
Pain In Extremity	1/23 (4.3%)	1	0/24 (0%)	0	0/14 (0%)	0	0/9 (0%)	0	0/13 (0%)	0
Bursitis	0/23 (0%)	0	0/24 (0%)	0	1/14 (7.1%)	1	0/9 (0%)	0	0/13 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Papilloma	0/23 (0%)	0	0/24 (0%)	0	1/14 (7.1%)	1	0/9 (0%)	0	0/13 (0%)	0
Nervous system disorders
Headache	1/23 (4.3%)	1	2/24 (8.3%)	2	0/14 (0%)	0	0/9 (0%)	0	1/13 (7.7%)	1
Diabetic Neuropathy	1/23 (4.3%)	1	0/24 (0%)	0	0/14 (0%)	0	0/9 (0%)	0	0/13 (0%)	0
Dizziness	1/23 (4.3%)	1	0/24 (0%)	0	0/14 (0%)	0	0/9 (0%)	0	0/13 (0%)	0
Paraesthesia	1/23 (4.3%)	1	0/24 (0%)	0	0/14 (0%)	0	0/9 (0%)	0	0/13 (0%)	0
Syncope	1/23 (4.3%)	1	0/24 (0%)	0	0/14 (0%)	0	0/9 (0%)	0	0/13 (0%)	0
Migrane	0/23 (0%)	0	0/24 (0%)	0	1/14 (7.1%)	1	0/9 (0%)	0	0/13 (0%)	0
Renal and urinary disorders
Renal Impairment	0/23 (0%)	0	1/24 (4.2%)	1	0/14 (0%)	0	0/9 (0%)	0	0/13 (0%)	0
Respiratory, thoracic and mediastinal disorders
Cough	0/23 (0%)	0	1/24 (4.2%)	1	0/14 (0%)	0	0/9 (0%)	0	0/13 (0%)	0
Nasal septum deviation	0/23 (0%)	0	0/24 (0%)	0	0/14 (0%)	0	0/9 (0%)	0	1/13 (7.7%)	1
Skin and subcutaneous tissue disorders
Blister	1/23 (4.3%)	1	0/24 (0%)	0	0/14 (0%)	0	0/9 (0%)	0	0/13 (0%)	0
Pruritus	1/23 (4.3%)	1	0/24 (0%)	0	0/14 (0%)	0	0/9 (0%)	0	0/13 (0%)	0
erythema	0/23 (0%)	0	0/24 (0%)	0	1/14 (7.1%)	1	0/9 (0%)	0	0/13 (0%)	0

Limitations/Caveats

LImitations and caveats non specified

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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.