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

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

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Conditions Neurotrophic Keratitis
Keratitis
Corneal Ulcer
Interventions Drug: rhNGF 10 μg/ml
Drug: rhNGF 20 μg/ml
Other: vehicle
Enrollment 174
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 Details 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
Hide 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
Reason Not Completed
decision unrelated to adverse event             0             0             0             1             1             1
Lack of Efficacy             0             0             0             2             1             0
Withdrawal by Subject             0             1             0             0             0             0
Adverse Event             1             0             2             3             9             1
Other causes             0             0             0             1             2             2
Period Title: Follow Up 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
Reason Not Completed
still in study after week 20             0             0             0             25             23             25
parent withdrew the consent to continue             0             1             0             0             0             0
Lack of Efficacy             0             0             0             0             0             1
Adverse Event             1             0             0             5             0             1
Lost to Follow-up             0             0             1             2             0             1
Other causes             0             0             0             1             3             5
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
Hide 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 Number of Baseline Participants 7 7 4 52 52 52 174
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous   [1] 
Mean (Standard Deviation)
Unit of measure:  Years
Age continuous Number Analyzed 7 participants 7 participants 4 participants 52 participants 52 participants 52 participants 174 participants
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)
[1]
Measure Analysis Population Description: The patients populations of Phase I and Phase II are different. The first consists of 18 individuals, the second of 156 individuals.
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 7 participants 7 participants 4 participants 52 participants 52 participants 52 participants 174 participants
Female
3
  42.9%
4
  57.1%
2
  50.0%
30
  57.7%
30
  57.7%
35
  67.3%
104
  59.8%
Male
4
  57.1%
3
  42.9%
2
  50.0%
22
  42.3%
22
  42.3%
17
  32.7%
70
  40.2%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 7 participants 7 participants 4 participants 52 participants 52 participants 52 participants 174 participants
Hispanic or Latino
1
  14.3%
0
   0.0%
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
 100.0%
42
  80.8%
42
  80.8%
41
  78.8%
141
  81.0%
Unknown or Not Reported
0
   0.0%
1
  14.3%
0
   0.0%
4
   7.7%
1
   1.9%
6
  11.5%
12
   6.9%
1.Primary Outcome
Title Percentage of Patients Achieving Healing of the Persistent Epithelial Defect (PED) or Corneal Ulcer
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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
Overall Number of Participants Analyzed 52 52 52
Measure Type: Number
Unit of Measure: percentage of subjects
Yes 55 58 20
No 45 42 80
Hide 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 [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in percentage
Estimated Value 35.3
Confidence Interval (2-Sided) 97.06%
15.88 to 54.71
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection 5_rhNGF20_Phase 2_treatment, 6_vehicle group_Phase 2_treatment
Comments [Not Specified]
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 [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in percentage
Estimated Value 38.4
Confidence Interval (2-Sided) 97.06%
18.96 to 57.83
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Percentage of Patients Experiencing Healing of the Persistent Epithelial Defect (PED) or Corneal Ulcer
Hide 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.
Hide Outcome Measure Data
Hide 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
Hide 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
Overall Number of Participants Analyzed 52 52 52
Measure Type: Number
Unit of Measure: percentage of subjects
Yes 52 61 26
No 48 39 74
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection 4_rhNGF10_Phase 2_treatment, 6_vehicle group_Phase 2_treatment
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value =0.016
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in percentage
Estimated Value 25.8
Confidence Interval (2-Sided) 97.06%
3.66 to 47.87
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection 5_rhNGF20_Phase 2_treatment, 6_vehicle group_Phase 2_treatment
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value =0.002
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in percentage
Estimated Value 34.7
Confidence Interval (2-Sided) 97.06%
11.91 to 57.41
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Percentage of Patients Experiencing Complete Healing of the Persistent Epithelial Defect (PED) or Corneal Ulcer
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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
Overall Number of Participants Analyzed 52 52 52
Measure Type: Number
Unit of Measure: percentage of subjects
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
Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value =0.818
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter difference in percentage
Estimated Value 2.4
Confidence Interval (2-Sided) 97.06%
-20.30 to 25.08
Estimation Comments [Not Specified]
Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value =0.571
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter difference in percentage
Estimated Value -6.3
Confidence Interval (2-Sided) 97.06%
-30.62 to 17.96
Estimation Comments [Not Specified]
Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value =0.064
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in percentage
Estimated Value 20.3
Confidence Interval (2-Sided) 97.06%
-3.11 to 43.79
Estimation Comments [Not Specified]
Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value =0.041
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in percentage
Estimated Value 23.1
Confidence Interval (2-Sided) 97.06%
-0.89 to 47.04
Estimation Comments [Not Specified]
Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value =0.031
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in percentage
Estimated Value 21.9
Confidence Interval (2-Sided) 97.06%
0.07 to 43.64
Estimation Comments [Not Specified]
Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value =0.008
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter difference in percentage
Estimated Value 26.9
Confidence Interval (2-Sided) 97.06%
5.57 to 48.28
Estimation Comments [Not Specified]
Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value =0.011
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in percentage
Estimated Value 26.1
Confidence Interval (2-Sided) 97.06%
4.18 to 48.01
Estimation Comments [Not Specified]
Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value =0.014
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in percentage
Estimated Value 25.9
Confidence Interval (2-Sided) 97.06%
3.55 to 48.33
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Percentage of Patients Experiencing Complete Corneal Clearing
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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

Overall Number of Participants Analyzed 7 7 4 52 52 52
Measure Type: Number
Unit of Measure: percentage of subjects
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
Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value =0.065
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter difference in percentage
Estimated Value 13.7
Confidence Interval (2-Sided) 95%
-0.19 to 27.57
Estimation Comments [Not Specified]
Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value =0.097
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter difference in percentage
Estimated Value 12.4
Confidence Interval (2-Sided) 95%
-2.05 to 26.78
Estimation Comments [Not Specified]
Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value =0.036
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter difference in percentage
Estimated Value 16.9
Confidence Interval (2-Sided) 95%
1.97 to 31.92
Estimation Comments [Not Specified]
Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value =0.054
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter difference in percentage
Estimated Value 15.6
Confidence Interval (2-Sided) 95%
0.04 to 31.12
Estimation Comments [Not Specified]
Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value =0.043
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter difference in percentage
Estimated Value 17.1
Confidence Interval (2-Sided) 95%
1.45 to 32.72
Estimation Comments [Not Specified]
Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value =0.157
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter difference in percentage
Estimated Value 11.4
Confidence Interval (2-Sided) 95%
-4.08 to 26.93
Estimation Comments [Not Specified]
5.Secondary Outcome
Title Mean Change in Best Corrected Distance Visual Acuity (BCDVA)
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
ITT population
Arm/Group Title 4_rhNGF10_Phase 2_treatment 5_rhNGF20_Phase 2_treatment 6_vehicle group_Phase 2_treatment
Hide 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
Overall Number of Participants Analyzed 52 52 52
Least Squares Mean (Standard Error)
Unit of Measure: LogMAR
15.8  (2.58) 11.9  (2.80) 6.9  (2.83)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection 4_rhNGF10_Phase 2_treatment, 6_vehicle group_Phase 2_treatment
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value =0.022
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter least square mean difference
Estimated Value 8.9
Confidence Interval (2-Sided) 95%
1.33 to 16.50
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection 5_rhNGF20_Phase 2_treatment, 6_vehicle group_Phase 2_treatment
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value =0.213
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter least square mean difference
Estimated Value 5.0
Confidence Interval (2-Sided) 95%
-2.90 to 12.88
Estimation Comments [Not Specified]
6.Secondary Outcome
Title Percentage of Patients That Achieve an Improvement in Corneal Sensitivity
Hide 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.
Hide Outcome Measure Data
Hide 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
Hide 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

Overall Number of Participants Analyzed 7 7 4 52 52 52
Measure Type: Number
Unit of Measure: percentage of subjects
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
Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value =0.592
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter difference in percentage
Estimated Value 5.5
Confidence Interval (2-Sided) 95%
-14.53 to 25.48
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection 5_rhNGF20_Phase 2_treatment, 6_vehicle group_Phase 2_treatment
Comments [Not Specified]
Type of Statistical Test Superiority
Comments week 4
Statistical Test of Hypothesis P-Value =0.835
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter difference in percentage
Estimated Value -2.3
Confidence Interval (2-Sided) 95%
-24.01 to 19.40
Estimation Comments [Not Specified]
Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value =0.008
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter difference in percentage
Estimated Value 27.7
Confidence Interval (2-Sided) 95%
8.10 to 47.22
Estimation Comments [Not Specified]
Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value =0.282
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter difference in percentage
Estimated Value 12.4
Confidence Interval (2-Sided) 95%
-9.91 to 34.68
Estimation Comments [Not Specified]
Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection 4_rhNGF10_Phase 2_treatment, 6_vehicle group_Phase 2_treatment
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value =0.303
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter difference in percentage
Estimated Value 10.2
Confidence Interval (2-Sided) 95%
-9.15 to 29.45
Estimation Comments [Not Specified]
Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value =0.442
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter difference in percentage
Estimated Value 7.9
Confidence Interval (2-Sided) 95%
-12.13 to 27.92
Estimation Comments [Not Specified]
7.Secondary Outcome
Title Percentage of Patients Experiencing Deterioration in Stage 2 or 3 NK
Hide 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.
Hide Outcome Measure Data
Hide 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
Hide 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

Overall Number of Participants Analyzed 7 7 4 52 52 52
Measure Type: Number
Unit of Measure: percentage of subjects
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
Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value =0.597
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter difference in percentage
Estimated Value -2.6
Confidence Interval (2-Sided) 95%
-22.87 to 17.71
Estimation Comments [Not Specified]
Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value >0.999
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter difference in percentage
Estimated Value -2.3
Confidence Interval (2-Sided) 95%
-23.26 to 18.71
Estimation Comments [Not Specified]
Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value =0.183
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter difference in percentage
Estimated Value -7.8
Confidence Interval (2-Sided) 95%
-28.70 to 13.76
Estimation Comments [Not Specified]
Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value =0.116
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter difference in percentage
Estimated Value -10.0
Confidence Interval (2-Sided) 95%
-31.41 to 11.88
Estimation Comments [Not Specified]
Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value =0.134
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter difference in percentage
Estimated Value -10.8
Confidence Interval (2-Sided) 95%
-31.30 to 10.35
Estimation Comments [Not Specified]
Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value =0.307
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter difference in percentage
Estimated Value -7.9
Confidence Interval (2-Sided) 95%
-29.51 to 13.52
Estimation Comments [Not Specified]
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
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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

Overall Number of Participants Analyzed 7 7 4 52 52 52
Measure Type: Number
Unit of Measure: percentage of subjects
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
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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

Overall Number of Participants Analyzed 7 7 4 52 52 52
Measure Type: Number
Unit of Measure: percentage of subjects
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
Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value =0.041
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 2.18
Confidence Interval (2-Sided) 95%
1.03 to 4.62
Estimation Comments [Not Specified]
Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value =0.081
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.95
Confidence Interval (2-Sided) 95%
0.92 to 4.11
Estimation Comments [Not Specified]
Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value =0.040
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 2.47
Confidence Interval (2-Sided) 95%
1.04 to 5.88
Estimation Comments [Not Specified]
Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value =0.132
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.93
Confidence Interval (2-Sided) 95%
0.82 to 4.52
Estimation Comments [Not Specified]
10.Secondary Outcome
Title Change From Baseline in Visual Analogue Scale (VAS) for Ocular Tolerability
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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
Overall Number of Participants Analyzed 7 7 4 52 52 52 6 6 2 45 39 48
Mean (Standard Deviation)
Unit of Measure: VAS score
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)
Hide 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)
Hide Outcome Measure Data
Hide 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
Hide 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
Overall Number of Participants Analyzed 7 7 4 52 52 52 6 6 2 45 39 48
Mean (Standard Deviation)
Unit of Measure: Number of ETDRS letters
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)
Hide 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).
Hide Outcome Measure Data
Hide 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
Hide 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
Overall Number of Participants Analyzed 7 7 4 52 52 52 6 6 2 45 39 48
Mean (Standard Deviation)
Unit of Measure: mmHg
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
Hide 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)
Hide Outcome Measure Data
Hide 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
Hide 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

Overall Number of Participants Analyzed 7 7 4 52 52 52
Measure Type: Number
Unit of Measure: percentage of participants
Vitreous 0 0 0 14.7 18.2 10.3
Retina macula 25 25 100 17.6 23.3 28.6
Choroid 0 25 0 8.8 6.5 14.8
Optic nerve 25 0 100 11.8 12.5 7.7
14.Other Pre-specified Outcome
Title Percentage of Patients That Achieved a ≥15 Letter Gain in BCDVA
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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

Overall Number of Participants Analyzed 7 7 4 52 52 52
Measure Type: Number
Unit of Measure: percentage of subjects
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
Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value =0.097
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter difference in percentage
Estimated Value 15.8
Confidence Interval (2-Sided) 95%
-2.36 to 33.97
Estimation Comments [Not Specified]
Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value =0.175
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter difference in percentage
Estimated Value 13.2
Confidence Interval (2-Sided) 95%
-5.72 to 32.15
Estimation Comments [Not Specified]
Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value =0.105
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter difference in percentage
Estimated Value 16.9
Confidence Interval (2-Sided) 95%
-3.11 to 37.00
Estimation Comments [Not Specified]
Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value =0.300
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter difference in percentage
Estimated Value 11.0
Confidence Interval (2-Sided) 95%
-9.64 to 31.57
Estimation Comments [Not Specified]
Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value =0.008
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter difference in percentage
Estimated Value 27.5
Confidence Interval (2-Sided) 95%
8.33 to 46.67
Estimation Comments [Not Specified]
Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value =0.068
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter difference in percentage
Estimated Value 19.0
Confidence Interval (2-Sided) 95%
-0.91 to 38.83
Estimation Comments [Not Specified]
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
Hide 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 (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/7 (0.00%)      0/7 (0.00%)      0/4 (0.00%)      5/52 (9.62%)      2/52 (3.85%)      1/52 (1.92%)    
Hide 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 (42.86%)      1/7 (14.29%)      3/4 (75.00%)      13/52 (25.00%)      14/52 (26.92%)      4/52 (7.69%)    
Cardiac disorders             
myocardial infarction  1  0/7 (0.00%)  0 1/7 (14.29%)  1 0/4 (0.00%)  0 2/52 (3.85%)  3 0/52 (0.00%)  0 0/52 (0.00%)  0
Arrhythmia  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 1/52 (1.92%)  1 0/52 (0.00%)  0 0/52 (0.00%)  0
Cardiac failure  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 1/52 (1.92%)  1 0/52 (0.00%)  0 0/52 (0.00%)  0
Ear and labyrinth disorders             
Vertigo  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 0/52 (0.00%)  0 1/52 (1.92%)  1 0/52 (0.00%)  0
Eye disorders             
visual acuity reduced  1  1/7 (14.29%)  1 0/7 (0.00%)  0 0/4 (0.00%)  0 0/52 (0.00%)  0 2/52 (3.85%)  2 1/52 (1.92%)  1
Corneal endotheliitis  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 1/52 (1.92%)  1 0/52 (0.00%)  0 0/52 (0.00%)  0
Corneal epithelium defect  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 0/52 (0.00%)  0 1/52 (1.92%)  1 1/52 (1.92%)  1
Corneal oedema  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 0/52 (0.00%)  0 0/52 (0.00%)  0 1/52 (1.92%)  1
Eye inflammation  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 0/52 (0.00%)  0 1/52 (1.92%)  1 0/52 (0.00%)  0
Corneal neovascularisation  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 1/52 (1.92%)  1 0/52 (0.00%)  0 0/52 (0.00%)  0
Corneal opacity  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 1/52 (1.92%)  1 0/52 (0.00%)  0 0/52 (0.00%)  0
Neurotrophic keratopathy  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 1/52 (1.92%)  1 0/52 (0.00%)  0 0/52 (0.00%)  0
Ulcerative keratitis  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 1/52 (1.92%)  1 0/52 (0.00%)  0 0/52 (0.00%)  0
Gastrointestinal disorders             
Diverticular perforation  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 1/52 (1.92%)  1 0/52 (0.00%)  0 0/52 (0.00%)  0
Nausea  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 1/52 (1.92%)  1 0/52 (0.00%)  0 0/52 (0.00%)  0
General disorders             
disease progression  1  2/7 (28.57%)  2 0/7 (0.00%)  0 1/4 (25.00%)  1 1/52 (1.92%)  1 3/52 (5.77%)  3 2/52 (3.85%)  2
Impaired healing  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 1/52 (1.92%)  1 0/52 (0.00%)  0 0/52 (0.00%)  0
Immune system disorders             
Corneal graft rejection  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 0/52 (0.00%)  0 1/52 (1.92%)  1 0/52 (0.00%)  0
Infections and infestations             
Diverticulitis  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 1/52 (1.92%)  1 0/52 (0.00%)  0 0/52 (0.00%)  0
Corneal abscess  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 1/52 (1.92%)  1 0/52 (0.00%)  0 0/52 (0.00%)  0
Herpes ophthalmic  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 1/52 (1.92%)  1 0/52 (0.00%)  0 0/52 (0.00%)  0
Injury, poisoning and procedural complications             
Femur fracture  1  0/7 (0.00%)  0 0/7 (0.00%)  0 1/4 (25.00%)  1 0/52 (0.00%)  0 0/52 (0.00%)  0 1/52 (1.92%)  1
Clavicle fracture  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 0/52 (0.00%)  0 1/52 (1.92%)  1 0/52 (0.00%)  0
Fall  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 0/52 (0.00%)  0 1/52 (1.92%)  1 0/52 (0.00%)  0
Investigations             
Blood pressure increased  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 1/52 (1.92%)  1 0/52 (0.00%)  0 0/52 (0.00%)  0
Metabolism and nutrition disorders             
Decreased appetite  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 1/52 (1.92%)  1 0/52 (0.00%)  0 0/52 (0.00%)  0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)             
Malignant neoplasm progression  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 1/52 (1.92%)  1 1/52 (1.92%)  1 0/52 (0.00%)  0
Nervous system disorders             
Syncope  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 0/52 (0.00%)  0 1/52 (1.92%)  1 0/52 (0.00%)  0
Renal and urinary disorders             
renal failure  1  0/7 (0.00%)  0 0/7 (0.00%)  0 1/4 (25.00%)  1 0/52 (0.00%)  0 0/52 (0.00%)  0 0/52 (0.00%)  0
Renal colic  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 0/52 (0.00%)  0 2/52 (3.85%)  2 0/52 (0.00%)  0
Bladder prolapse  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 1/52 (1.92%)  1 0/52 (0.00%)  0 0/52 (0.00%)  0
Reproductive system and breast disorders             
Uterine prolapse  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 1/52 (1.92%)  1 0/52 (0.00%)  0 0/52 (0.00%)  0
Respiratory, thoracic and mediastinal disorders             
Pulmonary edema  1  0/7 (0.00%)  0 0/7 (0.00%)  0 1/4 (25.00%)  1 0/52 (0.00%)  0 0/52 (0.00%)  0 0/52 (0.00%)  0
Respiratory distress  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 1/52 (1.92%)  1 0/52 (0.00%)  0 0/52 (0.00%)  0
Respiratory failure  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 0/52 (0.00%)  0 1/52 (1.92%)  1 1/52 (1.92%)  1
Dyspnoea  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 1/52 (1.92%)  1 0/52 (0.00%)  0 0/52 (0.00%)  0
Epistaxis  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 1/52 (1.92%)  1 0/52 (0.00%)  0 0/52 (0.00%)  0
Vascular disorders             
Aortic dissection  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 1/52 (1.92%)  1 1/52 (1.92%)  1 0/52 (0.00%)  0
Venous thrombosis  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 0/52 (0.00%)  0 1/52 (1.92%)  1 1/52 (1.92%)  1
Aortic rupture  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 1/52 (1.92%)  1 0/52 (0.00%)  0 0/52 (0.00%)  0
Diabetic vascular disorder  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 1/52 (1.92%)  1 0/52 (0.00%)  0 0/52 (0.00%)  0
Shock haemorrhagic  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 1/52 (1.92%)  1 0/52 (0.00%)  0 0/52 (0.00%)  0
1
Term from vocabulary, MedDRA 15.1
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 1%
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 (42.86%)      5/7 (71.43%)      1/4 (25.00%)      23/52 (44.23%)      23/52 (44.23%)      21/52 (40.38%)    
Blood and lymphatic system disorders             
Anaemia  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 1/52 (1.92%)  3 1/52 (1.92%)  1 0/52 (0.00%)  0
Neutropenia  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 0/52 (0.00%)  0 1/52 (1.92%)  1 0/52 (0.00%)  0
Cardiac disorders             
Cardiovascular disorder  1  0/7 (0.00%)  0 1/7 (14.29%)  1 0/4 (0.00%)  0 0/52 (0.00%)  0 0/52 (0.00%)  0 0/52 (0.00%)  0
Arrhythmia  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 1/52 (1.92%)  1 1/52 (1.92%)  1 0/52 (0.00%)  0
Myocardial infarction  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 2/52 (3.85%)  2 0/52 (0.00%)  0 0/52 (0.00%)  0
Cardiac failure  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 1/52 (1.92%)  1 0/52 (0.00%)  0 0/52 (0.00%)  0
Ear and labyrinth disorders             
Vertigo  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 1/52 (1.92%)  1 0/52 (0.00%)  0 0/52 (0.00%)  0
Ear pain  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 1/52 (1.92%)  1 0/52 (0.00%)  0 0/52 (0.00%)  0
Eye disorders             
Eye pain  1  0/7 (0.00%)  0 3/7 (42.86%)  6 1/4 (25.00%)  2 2/52 (3.85%)  2 7/52 (13.46%)  7 5/52 (9.62%)  7
Eye inflammation  1  0/7 (0.00%)  0 2/7 (28.57%)  2 1/4 (25.00%)  1 0/52 (0.00%)  0 1/52 (1.92%)  1 0/52 (0.00%)  0
Visual acuity reduced  1  3/7 (42.86%)  4 1/7 (14.29%)  1 1/4 (25.00%)  1 2/52 (3.85%)  2 5/52 (9.62%)  5 2/52 (3.85%)  2
Photophobia  1  0/7 (0.00%)  0 3/7 (42.86%)  3 0/4 (0.00%)  0 2/52 (3.85%)  2 0/52 (0.00%)  0 1/52 (1.92%)  1
Conjunctival hyperaemia  1  1/7 (14.29%)  2 0/7 (0.00%)  0 0/4 (0.00%)  0 2/52 (3.85%)  2 1/52 (1.92%)  1 1/52 (1.92%)  1
Corneal epithelium defect  1  0/7 (0.00%)  0 2/7 (28.57%)  2 0/4 (0.00%)  0 1/52 (1.92%)  1 5/52 (9.62%)  5 1/52 (1.92%)  2
Corneal lesion  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 0/52 (0.00%)  0 0/52 (0.00%)  0 1/52 (1.92%)  1
Dry eye  1  0/7 (0.00%)  0 1/7 (14.29%)  1 0/4 (0.00%)  0 2/52 (3.85%)  2 1/52 (1.92%)  1 3/52 (5.77%)  3
Erythema of eyelid  1  1/7 (14.29%)  1 0/7 (0.00%)  0 0/4 (0.00%)  0 0/52 (0.00%)  0 1/52 (1.92%)  1 0/52 (0.00%)  0
Eye irritation  1  0/7 (0.00%)  0 1/7 (14.29%)  1 0/4 (0.00%)  0 2/52 (3.85%)  2 1/52 (1.92%)  1 1/52 (1.92%)  1
Eyelid margin crusting  1  0/7 (0.00%)  0 0/7 (0.00%)  0 1/4 (25.00%)  1 0/52 (0.00%)  0 0/52 (0.00%)  0 0/52 (0.00%)  0
Foreign body sensation in eyes  1  0/7 (0.00%)  0 0/7 (0.00%)  0 1/4 (25.00%)  1 1/52 (1.92%)  1 0/52 (0.00%)  0 1/52 (1.92%)  1
Iridocyclitis  1  0/7 (0.00%)  0 1/7 (14.29%)  1 0/4 (0.00%)  0 0/52 (0.00%)  0 0/52 (0.00%)  0 0/52 (0.00%)  0
Photopsia  1  0/7 (0.00%)  0 1/7 (14.29%)  1 1/4 (25.00%)  1 0/52 (0.00%)  0 0/52 (0.00%)  0 0/52 (0.00%)  0
Ulcerative keratitis  1  0/7 (0.00%)  0 1/7 (14.29%)  1 0/4 (0.00%)  0 4/52 (7.69%)  4 1/52 (1.92%)  1 0/52 (0.00%)  0
Vision blurred  1  0/7 (0.00%)  0 0/7 (0.00%)  0 1/4 (25.00%)  1 2/52 (3.85%)  2 0/52 (0.00%)  0 2/52 (3.85%)  2
Vitreous haemorrhage  1  0/7 (0.00%)  0 1/7 (14.29%)  1 0/4 (0.00%)  0 1/52 (1.92%)  2 0/52 (0.00%)  0 0/52 (0.00%)  0
Corneal decompensation  1  0/7 (0.00%)  0 1/7 (14.29%)  1 0/4 (0.00%)  0 0/52 (0.00%)  0 0/52 (0.00%)  0 0/52 (0.00%)  0
Corneal oedema  1  0/7 (0.00%)  0 1/7 (14.29%)  1 0/4 (0.00%)  0 0/52 (0.00%)  0 0/52 (0.00%)  0 1/52 (1.92%)  1
Keratitis  1  0/7 (0.00%)  0 1/7 (14.29%)  1 0/4 (0.00%)  0 0/52 (0.00%)  0 4/52 (7.69%)  6 0/52 (0.00%)  0
Ocular hyperemia  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 0/52 (0.00%)  0 1/52 (1.92%)  1 2/52 (3.85%)  2
Retinal haemorrhage  1  0/7 (0.00%)  0 1/7 (14.29%)  1 0/4 (0.00%)  0 0/52 (0.00%)  0 0/52 (0.00%)  0 0/52 (0.00%)  0
Blepharitis  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 3/52 (5.77%)  3 6/52 (11.54%)  6 1/52 (1.92%)  2
Eye pruritus  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 2/52 (3.85%)  2 1/52 (1.92%)  1 1/52 (1.92%)  1
Lacrimation increased  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 3/52 (5.77%)  3 0/52 (0.00%)  0 2/52 (3.85%)  2
Lacrimation decreased  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 1/52 (1.92%)  1 1/52 (1.92%)  1 0/52 (0.00%)  0
Corneal deposits  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 0/52 (0.00%)  0 2/52 (3.85%)  3 0/52 (0.00%)  0
Eye discharge  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 1/52 (1.92%)  1 2/52 (3.85%)  2 0/52 (0.00%)  0
Abnormal sensation in eye  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 0/52 (0.00%)  0 0/52 (0.00%)  0 1/52 (1.92%)  1
Asthenopia  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 0/52 (0.00%)  0 0/52 (0.00%)  0 1/52 (1.92%)  1
Conjunctival haemorrhage  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 2/52 (3.85%)  2 0/52 (0.00%)  0 1/52 (1.92%)  2
Corneal endotheliitis  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 1/52 (1.92%)  1 0/52 (0.00%)  0 0/52 (0.00%)  0
Corneal opacity  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 1/52 (1.92%)  1 1/52 (1.92%)  1 0/52 (0.00%)  0
Eye allergy  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 1/52 (1.92%)  1 0/52 (0.00%)  0 0/52 (0.00%)  0
Eyelid oedema  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 0/52 (0.00%)  0 1/52 (1.92%)  2 1/52 (1.92%)  1
Eyelid pain  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 1/52 (1.92%)  2 0/52 (0.00%)  0 1/52 (1.92%)  1
Eyelid ptosis  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 1/52 (1.92%)  1 0/52 (0.00%)  0 0/52 (0.00%)  0
Lagophthalmos  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 1/52 (1.92%)  1 0/52 (0.00%)  0 0/52 (0.00%)  0
Macular fibrosis  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 0/52 (0.00%)  0 1/52 (1.92%)  1 0/52 (0.00%)  0
Ocular discomfort  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 0/52 (0.00%)  0 0/52 (0.00%)  0 2/52 (3.85%)  2
Posterior capsule opacification  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 1/52 (1.92%)  2 0/52 (0.00%)  0 0/52 (0.00%)  0
Lenticular opacities  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 1/52 (1.92%)  1 0/52 (0.00%)  0 0/52 (0.00%)  0
Meibomianitis  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 0/52 (0.00%)  0 0/52 (0.00%)  0 1/52 (1.92%)  1
Pseudopterygium  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 0/52 (0.00%)  0 1/52 (1.92%)  1 0/52 (0.00%)  0
Retinal cyst  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 1/52 (1.92%)  1 0/52 (0.00%)  0 0/52 (0.00%)  0
Cataract  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 3/52 (5.77%)  3 0/52 (0.00%)  0 0/52 (0.00%)  0
Corneal erosion  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 2/52 (3.85%)  5 1/52 (1.92%)  1 0/52 (0.00%)  0
Corneal neovascularisation  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 2/52 (3.85%)  2 2/52 (3.85%)  4 1/52 (1.92%)  1
Neurotrophic keratopathy  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 2/52 (3.85%)  3 1/52 (1.92%)  1 0/52 (0.00%)  0
Gastrointestinal disorders             
Conjunctivitis  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 1/52 (1.92%)  1 1/52 (1.92%)  1 0/52 (0.00%)  0
Nausea  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 2/52 (3.85%)  2 0/52 (0.00%)  0 0/52 (0.00%)  0
Toothache  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 1/52 (1.92%)  1 0/52 (0.00%)  0 0/52 (0.00%)  0
Vomiting  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 0/52 (0.00%)  0 1/52 (1.92%)  1 0/52 (0.00%)  0
Abdominal pain upper  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 0/52 (0.00%)  0 1/52 (1.92%)  1 0/52 (0.00%)  0
Diverticular perforation  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 1/52 (1.92%)  1 0/52 (0.00%)  0 0/52 (0.00%)  0
Gastric polyps  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 1/52 (1.92%)  1 0/52 (0.00%)  0 0/52 (0.00%)  0
General disorders             
Disease progression  1  2/7 (28.57%)  2 0/7 (0.00%)  0 1/4 (25.00%)  1 4/52 (7.69%)  4 4/52 (7.69%)  6 6/52 (11.54%)  6
Fatigue  1  0/7 (0.00%)  0 1/7 (14.29%)  1 0/4 (0.00%)  0 1/52 (1.92%)  1 0/52 (0.00%)  0 0/52 (0.00%)  0
Instillation site pruritus  1  0/7 (0.00%)  0 1/7 (14.29%)  1 0/4 (0.00%)  0 0/52 (0.00%)  0 0/52 (0.00%)  0 0/52 (0.00%)  0
Irritability  1  0/7 (0.00%)  0 1/7 (14.29%)  1 0/4 (0.00%)  0 0/52 (0.00%)  0 0/52 (0.00%)  0 0/52 (0.00%)  0
Instillation site pain  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 0/52 (0.00%)  0 1/52 (1.92%)  1 1/52 (1.92%)  1
Pyrexia  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 1/52 (1.92%)  1 0/52 (0.00%)  0 0/52 (0.00%)  0
Inflammation  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 1/52 (1.92%)  1 1/52 (1.92%)  1 0/52 (0.00%)  0
Impaired healing  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 1/52 (1.92%)  1 1/52 (1.92%)  1 0/52 (0.00%)  0
Hepatobiliary disorders             
Cholelithiasis  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 0/52 (0.00%)  0 1/52 (1.92%)  1 0/52 (0.00%)  0
Immune system disorders             
Corneal graft rejection  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 1/52 (1.92%)  1 3/52 (5.77%)  4 1/52 (1.92%)  1
Immunodeficiency  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 0/52 (0.00%)  0 1/52 (1.92%)  2 0/52 (0.00%)  0
Infections and infestations             
Influenza  1  0/7 (0.00%)  0 1/7 (14.29%)  1 0/4 (0.00%)  0 0/52 (0.00%)  0 1/52 (1.92%)  1 0/52 (0.00%)  0
Keratitis herpetic  1  0/7 (0.00%)  0 0/7 (0.00%)  0 1/4 (25.00%)  1 0/52 (0.00%)  0 2/52 (3.85%)  2 0/52 (0.00%)  0
Corneal infection  1  0/7 (0.00%)  0 1/7 (14.29%)  1 0/4 (0.00%)  0 1/52 (1.92%)  1 1/52 (1.92%)  1 0/52 (0.00%)  0
Nasopharyngitis  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 4/52 (7.69%)  4 3/52 (5.77%)  4 2/52 (3.85%)  2
Gastroenteritis  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 1/52 (1.92%)  1 0/52 (0.00%)  0 1/52 (1.92%)  1
Conjunctivitis bacterial  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 0/52 (0.00%)  0 1/52 (1.92%)  1 0/52 (0.00%)  0
Corneal abscess  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 1/52 (1.92%)  1 1/52 (1.92%)  1 0/52 (0.00%)  0
Diverticulitis  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 1/52 (1.92%)  1 0/52 (0.00%)  0 0/52 (0.00%)  0
Lower respiratory tract infection  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 0/52 (0.00%)  0 1/52 (1.92%)  1 0/52 (0.00%)  0
Oral herpes  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 1/52 (1.92%)  1 0/52 (0.00%)  0 0/52 (0.00%)  0
Staphylococcal infection  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 1/52 (1.92%)  1 0/52 (0.00%)  0 0/52 (0.00%)  0
Upper respiratory tract infection  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 0/52 (0.00%)  0 1/52 (1.92%)  2 0/52 (0.00%)  0
Helicobacter gastritis  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 2/52 (3.85%)  2 0/52 (0.00%)  0 0/52 (0.00%)  0
Herpes ophthalmic  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 2/52 (3.85%)  2 0/52 (0.00%)  0 0/52 (0.00%)  0
Blister infected  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 1/52 (1.92%)  1 0/52 (0.00%)  0 0/52 (0.00%)  0
Catheter site infection  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 1/52 (1.92%)  1 0/52 (0.00%)  0 0/52 (0.00%)  0
Cystitis  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 0/52 (0.00%)  0 1/52 (1.92%)  2 0/52 (0.00%)  0
Herpes simplex ophtalmic  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 0/52 (0.00%)  0 0/52 (0.00%)  0 1/52 (1.92%)  1
Herpes zoster ophtalmic  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 0/52 (0.00%)  0 1/52 (1.92%)  1 0/52 (0.00%)  0
Onychomycosis  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 0/52 (0.00%)  0 1/52 (1.92%)  1 0/52 (0.00%)  0
Onychomycosis  1  0/7 (0.00%)  0 0/7 (0.00%)  0 0/4 (0.00%)  0 1/52 (1.92%)  1 0/52 (0.00%)  0