Trial Outcomes & Findings for Safety and Efficacy of rhNGF Eye Drops at Different Doses in Patients With Dry Eye (NCT NCT02101281)

Last Updated: 2024-04-19

Results Overview

The SANDE is a short questionnaire to evaluate the frequency of ocular dryness and/or irritation symptoms. For the assessment, the patients mark on a 100 mm Visual Analogue Scale (VAS) line the point that they feel represents their perception of their current state. The VAS score is determined by measuring in millimetres from the left hand end of the line to the point that the patient marks. The SANDE scores (0-100) will be then evaluated for frequency per day.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

40 participants

Primary outcome timeframe

Baseline, Day 1, Day 8, Day 29 and Day 56

Results posted on

2024-04-19

Participant Flow

The investigator included in the study 40 subjects. After inclusion, all the 40 subjects took the study treatment. In detail, the first 20 enrolled subjects received rhNGF 20 μg/mL eye drops (Group 1) and the last 20 enrolled subjects received rhNGF 4 μg/mL eye drops (Group 2).

Participant milestones

Participant milestones
Measure	Group 1 - rhNGF 20 μg/mL (first planned dose): one drop (35 μL) corresponding to 0.70 μg of rhNGF was instilled into each eye twice a day (b.i.d.) every 12±2 h for a total daily dose of 2.8 μg (both eyes), for 28 consecutive days. Total dose was 78.4 μg/28 days. rhNGF 20 µg/mL: 1 drop for each eye, twice daily for 28 day	Group 2 - rhNGF 4 μg/mL after completion of Group 1 treatment, one drop (35 μL) corresponding to 0.14 μg of rhNGF was instilled into each eye b.i.d. every 12±2 h for a total daily dose of 0.56 μg, for 28 consecutive days. Total dose was 15.68 μg/28 days. rhNGF 4 µg/mL: 1 drop each eye, twice daily for 28 day
Overall Study STARTED	20	20
Overall Study COMPLETED	20	19
Overall Study NOT COMPLETED	0	1

Reasons for withdrawal

Reasons for withdrawal
Measure	Group 1 - rhNGF 20 μg/mL (first planned dose): one drop (35 μL) corresponding to 0.70 μg of rhNGF was instilled into each eye twice a day (b.i.d.) every 12±2 h for a total daily dose of 2.8 μg (both eyes), for 28 consecutive days. Total dose was 78.4 μg/28 days. rhNGF 20 µg/mL: 1 drop for each eye, twice daily for 28 day	Group 2 - rhNGF 4 μg/mL after completion of Group 1 treatment, one drop (35 μL) corresponding to 0.14 μg of rhNGF was instilled into each eye b.i.d. every 12±2 h for a total daily dose of 0.56 μg, for 28 consecutive days. Total dose was 15.68 μg/28 days. rhNGF 4 µg/mL: 1 drop each eye, twice daily for 28 day
Overall Study Adverse Event	0	1

Baseline Characteristics

Safety and Efficacy of rhNGF Eye Drops at Different Doses in Patients With Dry Eye

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Group 1 - rhNGF 20 μg/mL n=20 Participants (first planned dose): one drop (35 μL) corresponding to 0.70 μg of rhNGF was instilled into each eye twice a day (b.i.d.) every 12±2 h for a total daily dose of 2.8 μg (both eyes), for 28 consecutive days. Total dose was 78.4 μg/28 days. rhNGF 20 µg/mL: 1 drop for each eye, twice daily for 28 day	Group 2 - rhNGF 4 μg/mL n=20 Participants after completion of Group 1 treatment, one drop (35 μL) corresponding to 0.14 μg of rhNGF was instilled into each eye b.i.d. every 12±2 h for a total daily dose of 0.56 μg, for 28 consecutive days. Total dose was 15.68 μg/28 days. rhNGF 4 µg/mL: 1 drop each eye, twice daily for 28 day	Total n=40 Participants Total of all reporting groups
Age, Continuous	48.4 years STANDARD_DEVIATION 12.0 • n=5 Participants	55.9 years STANDARD_DEVIATION 14.8 • n=7 Participants	52.1 years STANDARD_DEVIATION 13.8 • n=5 Participants
Sex: Female, Male Female	16 Participants n=5 Participants	17 Participants n=7 Participants	33 Participants n=5 Participants
Sex: Female, Male Male	4 Participants n=5 Participants	3 Participants n=7 Participants	7 Participants n=5 Participants
Region of Enrollment Austria	20 participants n=5 Participants	20 participants n=7 Participants	40 participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline, Day 1, Day 8, Day 29 and Day 56

Population: FAS subjects: all enrolled patients, who received at least one dose of the IMP. This analysis set was used for the efficacy analysis

Outcome measures

Outcome measures
Measure	SANDE Changes From Baseline With rhNGF 20 μg/mL n=20 Participants Mean (±SD) changes from baseline and the outcome of their comparison with baseline after treatment with rhNGF 20 μg/mL - Day 1, 8, 29, 56	SANDE Changes From Baseline With rhNGF 4 μg/mL n=20 Participants Mean (±SD) changes from baseline and the outcome of their comparison with baseline after treatment with rhNGF 4 μg/mL - Day 1, 8, 29, 56
Change From Baseline in Frequency of Dry Eye Symptoms (SANDE) Day 1	-8.0 Frequency of symptoms per day Standard Deviation 15.9	-10.0 Frequency of symptoms per day Standard Deviation 24.8
Change From Baseline in Frequency of Dry Eye Symptoms (SANDE) Day 8	-15.0 Frequency of symptoms per day Standard Deviation 20.1	-23.4 Frequency of symptoms per day Standard Deviation 26.0
Change From Baseline in Frequency of Dry Eye Symptoms (SANDE) Day 29	-26.9 Frequency of symptoms per day Standard Deviation 24.5	-24.5 Frequency of symptoms per day Standard Deviation 22.2
Change From Baseline in Frequency of Dry Eye Symptoms (SANDE) Day 56	-30.1 Frequency of symptoms per day Standard Deviation 18.3	-28.0 Frequency of symptoms per day Standard Deviation 23.6

PRIMARY outcome

Timeframe: Baseline, Day 1, Day 8, Day 29 and Day 56

Population: FAS subjects: all enrolled patients, who received at least one dose of the IMP. This analysis set was used for the efficacy analysis

The SANDE is a short questionnaire to evaluate the severity of ocular dryness and/or irritation symptoms. For the assessment, the patients mark on the 100 mm VAS line the point that they feel represents their perception of their current state. The VAS score is determined by measuring in millimetres from the left-hand end of the line to the point that the patient marks. The SANDE scores (0-100) will be then evaluated for severity. The higher the score, the worse the outcome.

Outcome measures

Outcome measures
Measure	SANDE Changes From Baseline With rhNGF 20 μg/mL n=20 Participants Mean (±SD) changes from baseline and the outcome of their comparison with baseline after treatment with rhNGF 20 μg/mL - Day 1, 8, 29, 56	SANDE Changes From Baseline With rhNGF 4 μg/mL n=20 Participants Mean (±SD) changes from baseline and the outcome of their comparison with baseline after treatment with rhNGF 4 μg/mL - Day 1, 8, 29, 56
Change From Baseline in Severity of Dry Eye Symptoms (SANDE) Day 1	-7.6 units on a scale Standard Deviation 20.1	-9.9 units on a scale Standard Deviation 21.9
Change From Baseline in Severity of Dry Eye Symptoms (SANDE) Day 8	-11.7 units on a scale Standard Deviation 19.9	-21.1 units on a scale Standard Deviation 29.6
Change From Baseline in Severity of Dry Eye Symptoms (SANDE) Day 29	-27.0 units on a scale Standard Deviation 28.4	-28.9 units on a scale Standard Deviation 28.4
Change From Baseline in Severity of Dry Eye Symptoms (SANDE) Day 56	-29.0 units on a scale Standard Deviation 23.9	-28.2 units on a scale Standard Deviation 26.9

PRIMARY outcome

Timeframe: Baseline, Day 1, Day 8, Day 29 and Day 56

Population: FAS subjects: all enrolled patients, who received at least one dose of the IMP. This analysis set was used for the efficacy analysis

The cornea is divided into five sectors (central, superior, inferior, nasal and temporal), each of which is scored on a scale of 0-3, with a maximal score of 15. Both nasally and temporally, the conjunctiva is divided into a superior paralimbal area, an inferior paralimbal area and a peripheral area with a grading scale of 0-3 and with a maximal score of 9 for the nasal and temporal conjunctiva. Staining was derived as the sum of scores in the various sectors. The higher the total score the more compromised is the ocular surface.

Outcome measures

Outcome measures
Measure	SANDE Changes From Baseline With rhNGF 20 μg/mL n=20 Participants Mean (±SD) changes from baseline and the outcome of their comparison with baseline after treatment with rhNGF 20 μg/mL - Day 1, 8, 29, 56	SANDE Changes From Baseline With rhNGF 4 μg/mL n=20 Participants Mean (±SD) changes from baseline and the outcome of their comparison with baseline after treatment with rhNGF 4 μg/mL - Day 1, 8, 29, 56
Change From Baseline in Ocular Surface Vital Staining (National Eye Institute [NEI] Scale) Central cornea, Day 1 vs Day -15	-0.1 units on a scale Standard Deviation 0.8	0.0 units on a scale Standard Deviation 0.0
Change From Baseline in Ocular Surface Vital Staining (National Eye Institute [NEI] Scale) Central cornea, Day 8 vs Day -15	-0.4 units on a scale Standard Deviation 0.9	-0.2 units on a scale Standard Deviation 0.5
Change From Baseline in Ocular Surface Vital Staining (National Eye Institute [NEI] Scale) Central cornea, Day 29 vs Day -15	-0.7 units on a scale Standard Deviation 0.9	-0.3 units on a scale Standard Deviation 0.7
Change From Baseline in Ocular Surface Vital Staining (National Eye Institute [NEI] Scale) Central cornea, Day 56 vs Day -15	-0.8 units on a scale Standard Deviation 0.9	-0.4 units on a scale Standard Deviation 0.9
Change From Baseline in Ocular Surface Vital Staining (National Eye Institute [NEI] Scale) Superior cornea, Day 1 vs Day -15	0.2 units on a scale Standard Deviation 0.4	-0.1 units on a scale Standard Deviation 0.2
Change From Baseline in Ocular Surface Vital Staining (National Eye Institute [NEI] Scale) Superior cornea, Day 8 vs Day -15	-0.2 units on a scale Standard Deviation 0.7	-0.1 units on a scale Standard Deviation 0.7
Change From Baseline in Ocular Surface Vital Staining (National Eye Institute [NEI] Scale) Superior cornea, Day 29 vs Day -15	-0.4 units on a scale Standard Deviation 0.5	-0.3 units on a scale Standard Deviation 1.1
Change From Baseline in Ocular Surface Vital Staining (National Eye Institute [NEI] Scale) Superior cornea, Day 56 vs Day -15	-0.3 units on a scale Standard Deviation 0.6	-0.5 units on a scale Standard Deviation 0.8
Change From Baseline in Ocular Surface Vital Staining (National Eye Institute [NEI] Scale) Inferior cornea, Day 1 vs Day -15	-0.2 units on a scale Standard Deviation 0.7	-0.2 units on a scale Standard Deviation 0.5
Change From Baseline in Ocular Surface Vital Staining (National Eye Institute [NEI] Scale) Inferior cornea, Day 8 vs Day -15	-0.6 units on a scale Standard Deviation 0.7	-0.5 units on a scale Standard Deviation 0.5
Change From Baseline in Ocular Surface Vital Staining (National Eye Institute [NEI] Scale) Inferior cornea, Day 29 vs Day -15	-1.2 units on a scale Standard Deviation 0.5	-0.9 units on a scale Standard Deviation 0.8
Change From Baseline in Ocular Surface Vital Staining (National Eye Institute [NEI] Scale) Inferior cornea, Day 56 vs Day -15	-1.1 units on a scale Standard Deviation 0.5	-0.9 units on a scale Standard Deviation 0.9
Change From Baseline in Ocular Surface Vital Staining (National Eye Institute [NEI] Scale) Nasal cornea, Day 1 vs Day -15	-0.1 units on a scale Standard Deviation 0.6	0.0 units on a scale Standard Deviation 0.3
Change From Baseline in Ocular Surface Vital Staining (National Eye Institute [NEI] Scale) Nasal cornea, Day 8 vs Day -15	-0.7 units on a scale Standard Deviation 0.5	-0.2 units on a scale Standard Deviation 0.5
Change From Baseline in Ocular Surface Vital Staining (National Eye Institute [NEI] Scale) Nasal cornea, Day 29 vs Day -15	-1.0 units on a scale Standard Deviation 0.5	-0.7 units on a scale Standard Deviation 0.6
Change From Baseline in Ocular Surface Vital Staining (National Eye Institute [NEI] Scale) Nasal cornea, Day 56 vs Day -15	-1.0 units on a scale Standard Deviation 0.7	-0.5 units on a scale Standard Deviation 0.7
Change From Baseline in Ocular Surface Vital Staining (National Eye Institute [NEI] Scale) Temporal cornea, Day 1 vs Day -15	-0.3 units on a scale Standard Deviation 1	0.0 units on a scale Standard Deviation 0.3
Change From Baseline in Ocular Surface Vital Staining (National Eye Institute [NEI] Scale) Temporal cornea, Day 8 vs Day -15	-0.9 units on a scale Standard Deviation 0.7	-0.3 units on a scale Standard Deviation 0.6
Change From Baseline in Ocular Surface Vital Staining (National Eye Institute [NEI] Scale) Temporal cornea, Day 29 vs Day -15	-0.8 units on a scale Standard Deviation 0.6	-0.6 units on a scale Standard Deviation 0.6
Change From Baseline in Ocular Surface Vital Staining (National Eye Institute [NEI] Scale) Temporal cornea, Day 56 vs Day -15	-1.0 units on a scale Standard Deviation 0.6	-0.6 units on a scale Standard Deviation 0.8
Change From Baseline in Ocular Surface Vital Staining (National Eye Institute [NEI] Scale) Total score cornea, Day 1 vs Day -15	-0.4 units on a scale Standard Deviation 2.4	-0.2 units on a scale Standard Deviation 0.8
Change From Baseline in Ocular Surface Vital Staining (National Eye Institute [NEI] Scale) Total score cornea, Day 8 vs Day -15	-2.7 units on a scale Standard Deviation 1.7	-1.2 units on a scale Standard Deviation 1.4
Change From Baseline in Ocular Surface Vital Staining (National Eye Institute [NEI] Scale) Total score cornea, Day 29 vs Day -15	-4.0 units on a scale Standard Deviation 1.5	-2.9 units on a scale Standard Deviation 1.7
Change From Baseline in Ocular Surface Vital Staining (National Eye Institute [NEI] Scale) Total score cornea, Day 56 vs Day -15	-4.0 units on a scale Standard Deviation 1.7	-0.9 units on a scale Standard Deviation 2.5
Change From Baseline in Ocular Surface Vital Staining (National Eye Institute [NEI] Scale) Day 1 - Superior Paralimbal Nasal Conjunctiva	-0.3 units on a scale Standard Deviation 0.4	0.0 units on a scale Standard Deviation 0.5
Change From Baseline in Ocular Surface Vital Staining (National Eye Institute [NEI] Scale) Day 8 - Superior Paralimbal Nasal Conjunctiva	-0.4 units on a scale Standard Deviation 0.9	-0.3 units on a scale Standard Deviation 0.6
Change From Baseline in Ocular Surface Vital Staining (National Eye Institute [NEI] Scale) Day 29 - Superior Paralimbal Nasal Conjunctiva	-0.9 units on a scale Standard Deviation 1.1	-0.4 units on a scale Standard Deviation 0.6
Change From Baseline in Ocular Surface Vital Staining (National Eye Institute [NEI] Scale) Day 56 - Superior Paralimbal Nasal Conjunctiva	-0.6 units on a scale Standard Deviation 0.9	-0.5 units on a scale Standard Deviation 0.6
Change From Baseline in Ocular Surface Vital Staining (National Eye Institute [NEI] Scale) Day 1 - Inferior Paralimbal Nasal Conjunctiva	-0.2 units on a scale Standard Deviation 0.7	0.1 units on a scale Standard Deviation 0.4
Change From Baseline in Ocular Surface Vital Staining (National Eye Institute [NEI] Scale) Day 8 - Inferior Paralimbal Nasal Conjunctiva	-0.5 units on a scale Standard Deviation 0.8	-0.4 units on a scale Standard Deviation 0.6
Change From Baseline in Ocular Surface Vital Staining (National Eye Institute [NEI] Scale) Day 29 - Inferior Paralimbal Nasal Conjunctiva	-0.9 units on a scale Standard Deviation 0.7	-0.4 units on a scale Standard Deviation 0.5
Change From Baseline in Ocular Surface Vital Staining (National Eye Institute [NEI] Scale) Day 56 - Inferior Paralimbal Nasal Conjunctiva	-0.5 units on a scale Standard Deviation 0.7	-0.3 units on a scale Standard Deviation 0.6
Change From Baseline in Ocular Surface Vital Staining (National Eye Institute [NEI] Scale) Peripheral Nasal Conjunctiva, Day 1 vs Day -15	0.0 units on a scale Standard Deviation 0.9	0.2 units on a scale Standard Deviation 0.6
Change From Baseline in Ocular Surface Vital Staining (National Eye Institute [NEI] Scale) Peripheral Nasal Conjunctiva, Day 8 vs Day -15	-0.5 units on a scale Standard Deviation 1.1	-0.4 units on a scale Standard Deviation 0.7
Change From Baseline in Ocular Surface Vital Staining (National Eye Institute [NEI] Scale) Peripheral Nasal Conjunctiva, Day 29 vs Day -15	-1.0 units on a scale Standard Deviation 0.8	-0.5 units on a scale Standard Deviation 0.8
Change From Baseline in Ocular Surface Vital Staining (National Eye Institute [NEI] Scale) Peripheral Nasal Conjunctiva, Day 56 vs Day -15	-0.7 units on a scale Standard Deviation 1.0	-0.7 units on a scale Standard Deviation 0.8
Change From Baseline in Ocular Surface Vital Staining (National Eye Institute [NEI] Scale) Day 1 - Superior Paralimbal Temporal Conjunctiva	-0.2 units on a scale Standard Deviation 0.7	0.1 units on a scale Standard Deviation 0.3
Change From Baseline in Ocular Surface Vital Staining (National Eye Institute [NEI] Scale) Day 8 - Superior Paralimbal Temporal Conjunctiva	-0.5 units on a scale Standard Deviation 0.8	-0.1 units on a scale Standard Deviation 0.7
Change From Baseline in Ocular Surface Vital Staining (National Eye Institute [NEI] Scale) Day 29 - Superior Paralimbal Temporal Conjunctiva	-0.9 units on a scale Standard Deviation 0.8	-0.4 units on a scale Standard Deviation 0.8
Change From Baseline in Ocular Surface Vital Staining (National Eye Institute [NEI] Scale) Day 56 - Superior Paralimbal Temporal Conjunctiva	-0.6 units on a scale Standard Deviation 0.9	-0.5 units on a scale Standard Deviation 0.7
Change From Baseline in Ocular Surface Vital Staining (National Eye Institute [NEI] Scale) Day 1 - Inferior Paralimbal Temporal Conjunctiva	-0.3 units on a scale Standard Deviation 0.6	0.2 units on a scale Standard Deviation 0.5
Change From Baseline in Ocular Surface Vital Staining (National Eye Institute [NEI] Scale) Day 8 - Inferior Paralimbal Temporal Conjunctiva	-0.6 units on a scale Standard Deviation 0.9	0.0 units on a scale Standard Deviation 0.5
Change From Baseline in Ocular Surface Vital Staining (National Eye Institute [NEI] Scale) Day 29 - Inferior Paralimbal Temporal Conjunctiva	-1.0 units on a scale Standard Deviation 0.8	-0.2 units on a scale Standard Deviation 0.7
Change From Baseline in Ocular Surface Vital Staining (National Eye Institute [NEI] Scale) Day 56 - Inferior Paralimbal Temporal Conjunctiva	-0.8 units on a scale Standard Deviation 1.0	-0.1 units on a scale Standard Deviation 0.8
Change From Baseline in Ocular Surface Vital Staining (National Eye Institute [NEI] Scale) Peripheral Temporal Conjunctiva, Day 1 vs Day -15	-0.4 units on a scale Standard Deviation 0.7	0.0 units on a scale Standard Deviation 0.6
Change From Baseline in Ocular Surface Vital Staining (National Eye Institute [NEI] Scale) Peripheral Temporal Conjunctiva, Day 8 vs Day -15	-0.9 units on a scale Standard Deviation 0.6	0.0 units on a scale Standard Deviation 0.8
Change From Baseline in Ocular Surface Vital Staining (National Eye Institute [NEI] Scale) Peripheral Temporal Conjunctiva, Day 29 vs Day -15	-1.1 units on a scale Standard Deviation 0.9	-0.2 units on a scale Standard Deviation 0.8
Change From Baseline in Ocular Surface Vital Staining (National Eye Institute [NEI] Scale) Peripheral Temporal Conjunctiva, Day 56 vs Day -15	-0.7 units on a scale Standard Deviation 1.0	-0.2 units on a scale Standard Deviation 0.8
Change From Baseline in Ocular Surface Vital Staining (National Eye Institute [NEI] Scale) Total Score Conjunctiva, Day 1 vs Day -15	-1.2 units on a scale Standard Deviation 2.5	0.5 units on a scale Standard Deviation 1.4
Change From Baseline in Ocular Surface Vital Staining (National Eye Institute [NEI] Scale) Total Score Conjunctiva, Day 8 vs Day -15	-3.3 units on a scale Standard Deviation 2.9	-1.1 units on a scale Standard Deviation 1.8
Change From Baseline in Ocular Surface Vital Staining (National Eye Institute [NEI] Scale) Total Score Conjunctiva, Day 29 vs Day -15	-5.6 units on a scale Standard Deviation 3.2	-2.2 units on a scale Standard Deviation 1.8
Change From Baseline in Ocular Surface Vital Staining (National Eye Institute [NEI] Scale) Total Score Conjunctiva, Day 56 vs Day -15	-3.9 units on a scale Standard Deviation 3.3	-2.2 units on a scale Standard Deviation 2.0

PRIMARY outcome

Timeframe: Baseline, Day 1, Day 8, Day 29 and Day 56

Population: FAS subjects:

The Schirmer test type I (without anaesthesia) was performed to measure aqueous tear secretion prior to the instillation of any dilating or anaesthetic eye drops. The rounded tip of a standardized paper strip is inserted into the lower fornix of the eye, and the wetted length extending out from the lower lid is recorded after 5 min of eye closure. Both eyes could be tested at the same time. Changes from baseline in values of Schirmer's test type I are summarised by eye and evaluation visit, and stratified by severity level. The longer the wetted length the healthier the status of the eye. Only study eye's results are reported hereunder.

Outcome measures

Outcome measures
Measure	SANDE Changes From Baseline With rhNGF 20 μg/mL n=20 Participants Mean (±SD) changes from baseline and the outcome of their comparison with baseline after treatment with rhNGF 20 μg/mL - Day 1, 8, 29, 56	SANDE Changes From Baseline With rhNGF 4 μg/mL n=20 Participants Mean (±SD) changes from baseline and the outcome of their comparison with baseline after treatment with rhNGF 4 μg/mL - Day 1, 8, 29, 56
Change From Baseline in Tear Wetting Distance as Determined by Schirmer Tear Test I - Study Eye Day 1 vs Day -15	1.3 millimeters Standard Deviation 4.9	1.4 millimeters Standard Deviation 5.2
Change From Baseline in Tear Wetting Distance as Determined by Schirmer Tear Test I - Study Eye Day 8 vs Day -15	4.5 millimeters Standard Deviation 7.2	0.8 millimeters Standard Deviation 5.6
Change From Baseline in Tear Wetting Distance as Determined by Schirmer Tear Test I - Study Eye Day 29 vs Day -15	5.3 millimeters Standard Deviation 6.5	3.2 millimeters Standard Deviation 6.0
Change From Baseline in Tear Wetting Distance as Determined by Schirmer Tear Test I - Study Eye Day 56 vs Day -15	4.6 millimeters Standard Deviation 8.3	4.6 millimeters Standard Deviation 6.7

PRIMARY outcome

Timeframe: Throughout the study up to day 56

Population: Safety set: all patients who received at least one dose of the IMP. This analysis set was used for the safety analysis

The treatment-emergent adverse events were recorded throughout the whole study.

Outcome measures

Outcome measures
Measure	SANDE Changes From Baseline With rhNGF 20 μg/mL n=20 Participants Mean (±SD) changes from baseline and the outcome of their comparison with baseline after treatment with rhNGF 20 μg/mL - Day 1, 8, 29, 56	SANDE Changes From Baseline With rhNGF 4 μg/mL n=20 Participants Mean (±SD) changes from baseline and the outcome of their comparison with baseline after treatment with rhNGF 4 μg/mL - Day 1, 8, 29, 56
Number of Participants With Treatment-emergent Adverse Events (TEAEs),	14 Participants	15 Participants

SECONDARY outcome

Timeframe: Baseline, Day 1, Day 8, Day 29 and Day 56

Population: FAS: all enrolled patients, who received at least one dose of the IMP. This analysis set was used for the efficacy analysis

A ocular tolerability score was determined using a 100 mm VAS on which 0 meant No symptoms and 100 meant the Worst possible discomfort. The patients subjectively evaluated their ocular symptoms (foreign body sensation, burning or stinging, itching, pain, sticky feeling, blurred vision and photophobia) using the VAS giving the value they were feeling from none to an extreme value. The ocular symptoms were evaluated by the patients through the scale. Only the study eye's results are reported hereunder.

Outcome measures

Outcome measures
Measure	SANDE Changes From Baseline With rhNGF 20 μg/mL n=20 Participants Mean (±SD) changes from baseline and the outcome of their comparison with baseline after treatment with rhNGF 20 μg/mL - Day 1, 8, 29, 56	SANDE Changes From Baseline With rhNGF 4 μg/mL n=20 Participants Mean (±SD) changes from baseline and the outcome of their comparison with baseline after treatment with rhNGF 4 μg/mL - Day 1, 8, 29, 56
Change From Baseline in Ocular Tolerability (Visual Analogue Scale, VAS) Sticky feeling, Day 8 vs Day -15	-11.7 Units on a scale Standard Deviation 20.0	-16.9 Units on a scale Standard Deviation 27.1
Change From Baseline in Ocular Tolerability (Visual Analogue Scale, VAS) Sticky feeling, Day 29 vs Day -15	-12.7 Units on a scale Standard Deviation 22.1	-22.7 Units on a scale Standard Deviation 23.8
Change From Baseline in Ocular Tolerability (Visual Analogue Scale, VAS) Sticky feeling, Day 56 vs Day -15	-13.2 Units on a scale Standard Deviation 22.0	-22.6 Units on a scale Standard Deviation 22.5
Change From Baseline in Ocular Tolerability (Visual Analogue Scale, VAS) Blurred vision, Day 1 vs Day -15	-24.0 Units on a scale Standard Deviation 21.1	-7.0 Units on a scale Standard Deviation 17.6
Change From Baseline in Ocular Tolerability (Visual Analogue Scale, VAS) Foreign Body Sensation, Day 1 vs Day -15	-18.4 Units on a scale Standard Deviation 18.6	-1.2 Units on a scale Standard Deviation 22.8
Change From Baseline in Ocular Tolerability (Visual Analogue Scale, VAS) Foreign Body Sensation, Day 8 vs Day -15	-25.2 Units on a scale Standard Deviation 19.4	-19.9 Units on a scale Standard Deviation 24.0
Change From Baseline in Ocular Tolerability (Visual Analogue Scale, VAS) Foreign Body Sensation, Day 29 vs Day -15	-31.4 Units on a scale Standard Deviation 24.3	-30.4 Units on a scale Standard Deviation 33.5
Change From Baseline in Ocular Tolerability (Visual Analogue Scale, VAS) Foreign Body Sensation, Day 56 vs Day -15	-30.7 Units on a scale Standard Deviation 20.5	-29.9 Units on a scale Standard Deviation 28.2
Change From Baseline in Ocular Tolerability (Visual Analogue Scale, VAS) Burning/Stinging, Day 1vs Day -15	-21.3 Units on a scale Standard Deviation 21.1	-7.4 Units on a scale Standard Deviation 17.3
Change From Baseline in Ocular Tolerability (Visual Analogue Scale, VAS) Burning/Stinging, Day 8 vs Day -15	-25.9 Units on a scale Standard Deviation 21.1	-13.7 Units on a scale Standard Deviation 30.9
Change From Baseline in Ocular Tolerability (Visual Analogue Scale, VAS) Burning/Stinging, Day 29 vs Day -15	-32.7 Units on a scale Standard Deviation 21.8	-24.1 Units on a scale Standard Deviation 30.9
Change From Baseline in Ocular Tolerability (Visual Analogue Scale, VAS) Burning/Stinging, Day 56 vs Day -15	-30.2 Units on a scale Standard Deviation 19.6	-29.9 Units on a scale Standard Deviation 28.1
Change From Baseline in Ocular Tolerability (Visual Analogue Scale, VAS) Itching, Day 1 vs Day -15	-14.6 Units on a scale Standard Deviation 20.4	-14.0 Units on a scale Standard Deviation 22.3
Change From Baseline in Ocular Tolerability (Visual Analogue Scale, VAS) Itching, Day 8 vs Day -15	-23.8 Units on a scale Standard Deviation 18.2	-24.1 Units on a scale Standard Deviation 29.6
Change From Baseline in Ocular Tolerability (Visual Analogue Scale, VAS) Itching, Day 29 vs Day -15	-30.7 Units on a scale Standard Deviation 20.3	-33.9 Units on a scale Standard Deviation 32.8
Change From Baseline in Ocular Tolerability (Visual Analogue Scale, VAS) Itching, Day 56 vs Day -15	-26.0 Units on a scale Standard Deviation 25.8	-35.2 Units on a scale Standard Deviation 33.0
Change From Baseline in Ocular Tolerability (Visual Analogue Scale, VAS) Pain - Day 1 vs Day -15	-19.2 Units on a scale Standard Deviation 21.6	-2.5 Units on a scale Standard Deviation 14.9
Change From Baseline in Ocular Tolerability (Visual Analogue Scale, VAS) Pain, Day 8 vs Day -15	-15.4 Units on a scale Standard Deviation 30.0	-4.1 Units on a scale Standard Deviation 29.8
Change From Baseline in Ocular Tolerability (Visual Analogue Scale, VAS) Pain, Day 29 vs Day -15	-24.4 Units on a scale Standard Deviation 21.7	-14.9 Units on a scale Standard Deviation 28.9
Change From Baseline in Ocular Tolerability (Visual Analogue Scale, VAS) Pain, Day 56 vs Day -15	-24.9 Units on a scale Standard Deviation 20.1	-16.9 Units on a scale Standard Deviation 22.6
Change From Baseline in Ocular Tolerability (Visual Analogue Scale, VAS) Sticky feeling, Day 1 vs Day -15	-9.2 Units on a scale Standard Deviation 15.1	-1.4 Units on a scale Standard Deviation 26.0
Change From Baseline in Ocular Tolerability (Visual Analogue Scale, VAS) Blurred vision, Day 8 vs Day -15	-29.9 Units on a scale Standard Deviation 30.7	-17.2 Units on a scale Standard Deviation 25.9
Change From Baseline in Ocular Tolerability (Visual Analogue Scale, VAS) Blurred vision, Day 29 vs Day -15	-41.0 Units on a scale Standard Deviation 28.4	-31.6 Units on a scale Standard Deviation 28.3
Change From Baseline in Ocular Tolerability (Visual Analogue Scale, VAS) Blurred vision, Day 56 vs Day -15	-39.4 Units on a scale Standard Deviation 27.4	-28.4 Units on a scale Standard Deviation 27.2
Change From Baseline in Ocular Tolerability (Visual Analogue Scale, VAS) Photophobia, Day 1 vs Day -15	-21.0 Units on a scale Standard Deviation 23.1	5.0 Units on a scale Standard Deviation 23.9
Change From Baseline in Ocular Tolerability (Visual Analogue Scale, VAS) Photophobia, Day 8 vs Day -15	-27.1 Units on a scale Standard Deviation 22.8	-10.8 Units on a scale Standard Deviation 35.9
Change From Baseline in Ocular Tolerability (Visual Analogue Scale, VAS) Photophobia, Day 29 vs Day -15	-31.5 Units on a scale Standard Deviation 22.6	-20.8 Units on a scale Standard Deviation 42.8
Change From Baseline in Ocular Tolerability (Visual Analogue Scale, VAS) Photophobia, Day 56 vs Day -15	-32.3 Units on a scale Standard Deviation 21.9	-23.1 Units on a scale Standard Deviation 29.8

SECONDARY outcome

Timeframe: Baseline, Day 1, Day 8, Da 29 and Day 56

Population: FAS: all enrolled patients, who received at least one dose of the IMP. This analysis set was used for the efficacy analysis

SLE grading of the eyelids, lashes, conjunctiva, cornea, lens, iris and anterior chamber was done according to the following scales: Eyelid - Meibomian glands (evaluation of the central ten Meibomian gland openings in the mid-portion of the upper eyelid): 0, 1, 2, 3 = None, Mild, Moderate, Severe gland plugging Eyelid - Erythema 0, 1, 2, 3,4 = None, Mild, Moderate, Severe, Very severe redness of lid margin and/or skin Eyelid - Oedema 0, 1, 2, 3,4 = None, Mild, Moderate, Severe, Very severe oedema Lashes 0 = Normal 1 = Abnormal Conjunctiva - Erythema 0, 1, 2, 3, 4 = None, Mild, Moderate, Severe erythema Conjunctiva - Oedema 0, 1, 2, 3, 4 = None, Mild, Moderate, Severe, Very severe swelling Lens 0, 1, 2, 3 = No, Mild, Moderate, Severe opacification N/A = Patient with artificial lens Iris 0 = Normal 1 = Abnormal. Anterior Chamber Inflammation 0, 1, 2, 3, = No, Mild, Moderate, Severe, Very severe Tyndall effect Only the study eye's results are reported hereunder.

Outcome measures

Outcome measures
Measure	SANDE Changes From Baseline With rhNGF 20 μg/mL n=20 Participants Mean (±SD) changes from baseline and the outcome of their comparison with baseline after treatment with rhNGF 20 μg/mL - Day 1, 8, 29, 56	SANDE Changes From Baseline With rhNGF 4 μg/mL n=20 Participants Mean (±SD) changes from baseline and the outcome of their comparison with baseline after treatment with rhNGF 4 μg/mL - Day 1, 8, 29, 56
Change From Baseline in Slit Lamp Examination Eyelid - Meibomian glands, Day 1 vs Day -15	0.1 units on a scale Standard Deviation 0.6	-0.2 units on a scale Standard Deviation 0.4
Change From Baseline in Slit Lamp Examination Eyelid - Meibomian glands, Day 8 vs Day -15	-0.1 units on a scale Standard Deviation 0.6	-0.3 units on a scale Standard Deviation 0.6
Change From Baseline in Slit Lamp Examination Eyelid - Meibomian glands, Day 29 vs Day -15	-0.6 units on a scale Standard Deviation 0.8	-0.3 units on a scale Standard Deviation 0.7
Change From Baseline in Slit Lamp Examination Eyelid - Meibomian glands, Day 56 vs Day -15	-0.4 units on a scale Standard Deviation 0.9	-0.3 units on a scale Standard Deviation 0.7
Change From Baseline in Slit Lamp Examination Eyelid - erythema, Day 1 vs Day -15	-0.1 units on a scale Standard Deviation 0.6	-0.1 units on a scale Standard Deviation 0.2
Change From Baseline in Slit Lamp Examination Eyelid - erythema, Day 8 vs Day -15	-0.3 units on a scale Standard Deviation 0.7	0.0 units on a scale Standard Deviation 0.6
Change From Baseline in Slit Lamp Examination Eyelid - erythema, Day 29 vs Day -15	-0.8 units on a scale Standard Deviation 0.6	0.1 units on a scale Standard Deviation 0.7
Change From Baseline in Slit Lamp Examination Eyelid - erythema, Day 56 vs Day -15	-0.8 units on a scale Standard Deviation 0.7	-0.1 units on a scale Standard Deviation 0.6
Change From Baseline in Slit Lamp Examination Eyelid - Oedema, Day 1 vs Day -15	0.2 units on a scale Standard Deviation 0.5	0.0 units on a scale Standard Deviation 0.3
Change From Baseline in Slit Lamp Examination Eyelid - Oedema, Day 8 vs Day -15	-0.2 units on a scale Standard Deviation 0.5	0.2 units on a scale Standard Deviation 0.5
Change From Baseline in Slit Lamp Examination Eyelid - Oedema, Day 29 vs Day -15	-0.4 units on a scale Standard Deviation 0.5	0.2 units on a scale Standard Deviation 0.6
Change From Baseline in Slit Lamp Examination Eyelid - Oedema, Day 56 vs Day -15	-0.4 units on a scale Standard Deviation 0.5	0.0 units on a scale Standard Deviation 0.6
Change From Baseline in Slit Lamp Examination Lashes, Day 1 vs Day -15	0.0 units on a scale Standard Deviation 0.0	0.0 units on a scale Standard Deviation 0.0
Change From Baseline in Slit Lamp Examination Lashes, Day 8 vs Day -15	0.0 units on a scale Standard Deviation 0.0	0.0 units on a scale Standard Deviation 0.0
Change From Baseline in Slit Lamp Examination Lashes, Day 29 vs Day -15	0.0 units on a scale Standard Deviation 0.0	-0.3 units on a scale Standard Deviation 0.7
Change From Baseline in Slit Lamp Examination Lashes, Day 56 vs Day -15	0.0 units on a scale Standard Deviation 0.0	-0.3 units on a scale Standard Deviation 0.8
Change From Baseline in Slit Lamp Examination Conjunctiva - Erythema, Day 1 vs Day -15	-0.2 units on a scale Standard Deviation 0.5	-0.3 units on a scale Standard Deviation 0.6
Change From Baseline in Slit Lamp Examination Conjunctiva - Erythema, Day 8 vs Day -15	-0.4 units on a scale Standard Deviation 0.7	-0.4 units on a scale Standard Deviation 0.7
Change From Baseline in Slit Lamp Examination Conjunctiva - Erythema, Day 29 vs Day -15	-0.5 units on a scale Standard Deviation 0.7	-0.4 units on a scale Standard Deviation 0.9
Change From Baseline in Slit Lamp Examination Conjunctiva - Erythema, Day 56 vs Day -15	-0.5 units on a scale Standard Deviation 0.9	-0.6 units on a scale Standard Deviation 1.0
Change From Baseline in Slit Lamp Examination Conjunctiva - Oedema, Day 1 vs Day -15	0.0 units on a scale Standard Deviation 0.6	-0.3 units on a scale Standard Deviation 0.6
Change From Baseline in Slit Lamp Examination Conjunctiva - Oedema, Day 8 vs Day -15	-0.4 units on a scale Standard Deviation 0.8	-0.4 units on a scale Standard Deviation 0.7
Change From Baseline in Slit Lamp Examination Conjunctiva - Oedema, Day 29 vs Day -15	-0.7 units on a scale Standard Deviation 0.9	-0.4 units on a scale Standard Deviation 0.9
Change From Baseline in Slit Lamp Examination Conjunctiva - Oedema, Day 56 vs Day -15	-0.3 units on a scale Standard Deviation 1.0	-0.6 units on a scale Standard Deviation 1.0
Change From Baseline in Slit Lamp Examination Lens, Day 1 vs Day -15	0.1 units on a scale Standard Deviation 0.2	0.0 units on a scale Standard Deviation 0.0
Change From Baseline in Slit Lamp Examination Lens, Day 8 vs Day -15	0.0 units on a scale Standard Deviation 0.3	0.0 units on a scale Standard Deviation 0.0
Change From Baseline in Slit Lamp Examination Lens, Day 29 vs Day -15	-0.1 units on a scale Standard Deviation 0.5	-0.1 units on a scale Standard Deviation 0.3
Change From Baseline in Slit Lamp Examination Lens, Day 56 vs Day -15	-0.1 units on a scale Standard Deviation 0.5	-0.1 units on a scale Standard Deviation 0.3
Change From Baseline in Slit Lamp Examination Iris, Day 1 vs Day -15	0.0 units on a scale Standard Deviation 0.0	0.0 units on a scale Standard Deviation 0.0
Change From Baseline in Slit Lamp Examination Iris, Day 8 vs Day -15	0.0 units on a scale Standard Deviation 0.0	0.0 units on a scale Standard Deviation 0.0
Change From Baseline in Slit Lamp Examination Iris, Day 29 vs Day -15	0.0 units on a scale Standard Deviation 0.0	0.0 units on a scale Standard Deviation 0.0
Change From Baseline in Slit Lamp Examination Iris, Day 56 vs Day -15	0.0 units on a scale Standard Deviation 0.0	0.0 units on a scale Standard Deviation 0.0
Change From Baseline in Slit Lamp Examination Anterior Chamber Inflammation, Day 1 vs Day -15	0.0 units on a scale Standard Deviation 0.0	0.0 units on a scale Standard Deviation 0.0
Change From Baseline in Slit Lamp Examination Anterior Chamber Inflammation, Day 8 vs Day -15	0.0 units on a scale Standard Deviation 0.0	0.0 units on a scale Standard Deviation 0.0
Change From Baseline in Slit Lamp Examination Anterior Chamber Inflammation, Day 29 vs Day -15	0.0 units on a scale Standard Deviation 0.0	0.0 units on a scale Standard Deviation 0.0
Change From Baseline in Slit Lamp Examination Anterior Chamber Inflammation, Day 56 vs Day -15	0.0 units on a scale Standard Deviation 0.0	0.0 units on a scale Standard Deviation 0.0

SECONDARY outcome

Timeframe: Baseline, Day 1, Day 8, Day 29 and Day 56

Population: FAS: all enrolled patients, who received at least one dose of the IMP. This analysis set was used for the efficacy analysis.

The Schirmer test type II (with anaesthesia) was performed to measure aqueous tear secretion following the instillation of a preservative-free anaesthetic eye drop (Oxybuprocaine Chlorhydrate 0.4%). The rounded tip of a standardized paper strip is inserted into the lower fornix of the eye, and the wetted length extending out from the lower lid is recorded after 5 min of eye closure. Both eyes could be tested at the same time. Changes from baseline in values of Schirmer's test type I are summarised by eye and evaluation visit and stratified by severity level. The longer the wetted length the healthier the status of the eye. Only study eye's results are reported hereunder.

Outcome measures

Outcome measures
Measure	SANDE Changes From Baseline With rhNGF 20 μg/mL n=20 Participants Mean (±SD) changes from baseline and the outcome of their comparison with baseline after treatment with rhNGF 20 μg/mL - Day 1, 8, 29, 56	SANDE Changes From Baseline With rhNGF 4 μg/mL n=20 Participants Mean (±SD) changes from baseline and the outcome of their comparison with baseline after treatment with rhNGF 4 μg/mL - Day 1, 8, 29, 56
Change From Baseline in Tear Wetting Distance as Determined by Schirmer Tear Test II - Study Eye Day 1 vs Day -15	-2.0 millimeters Standard Deviation 9.5	2.5 millimeters Standard Deviation 5.7
Change From Baseline in Tear Wetting Distance as Determined by Schirmer Tear Test II - Study Eye Day 8 vs Day -15	1.6 millimeters Standard Deviation 13.3	2.1 millimeters Standard Deviation 5.9
Change From Baseline in Tear Wetting Distance as Determined by Schirmer Tear Test II - Study Eye Day 29 vs Day -15	3.8 millimeters Standard Deviation 8.7	6.5 millimeters Standard Deviation 8.9
Change From Baseline in Tear Wetting Distance as Determined by Schirmer Tear Test II - Study Eye Day 56 vs Day -15	2.2 millimeters Standard Deviation 11.4	6.9 millimeters Standard Deviation 5.7

SECONDARY outcome

Timeframe: Baseline, Day 1, Day 8, Day 29 and Day 56

Population: FAS: all enrolled patients, who received at least one dose of the IMP. This analysis set was used for the efficacy analysis

TFBUT was measured by determining the time to tear break-up. The TFBUT was performed after instillation of 5 μl of 2% preservative-free sodium fluorescein solution into the inferior conjunctival cul-de-sac of each eye. With the aid of a slit lamp at 10X magnification using cobalt blue illumination, the examiner will monitor the integrity of the tear film, noting the time it takes to form lacunae (clear spaces in the tear film) from the time that the eye is opened after the last blink. The longer the time the better the integrity of the tear film. Only Study eye's results are reported hereunder.

Outcome measures

Outcome measures
Measure	SANDE Changes From Baseline With rhNGF 20 μg/mL n=20 Participants Mean (±SD) changes from baseline and the outcome of their comparison with baseline after treatment with rhNGF 20 μg/mL - Day 1, 8, 29, 56	SANDE Changes From Baseline With rhNGF 4 μg/mL n=20 Participants Mean (±SD) changes from baseline and the outcome of their comparison with baseline after treatment with rhNGF 4 μg/mL - Day 1, 8, 29, 56
Change From Baseline in Tear Film Break-Up Time (TFBUT) Average Tear Film Break-Up Time, Day 1 vs Day -15	0.6 seconds Standard Deviation 2.1	-0.7 seconds Standard Deviation 1.7
Change From Baseline in Tear Film Break-Up Time (TFBUT) Average Tear Film Break-Up Time, Day 8 vs Day -15	1.5 seconds Standard Deviation 2.6	-0.3 seconds Standard Deviation 2.1
Change From Baseline in Tear Film Break-Up Time (TFBUT) Average Tear Film Break-Up Time, Day 29 vs Day -15	2.6 seconds Standard Deviation 2.9	-0.6 seconds Standard Deviation 2.2
Change From Baseline in Tear Film Break-Up Time (TFBUT) Average Tear Film Break-Up Time, Day 56 vs Day -15	2.2 seconds Standard Deviation 2.8	-0.3 seconds Standard Deviation 2.8

SECONDARY outcome

Timeframe: Baseline, Day 1, Day 8, Day 29 and Day 56

Population: FAS: all enrolled patients, who received at least one dose of the IMP. This analysis set was used for the efficacy analysis.

Fluorescein staining of the cornea is a methodology to visualize corneal epithelial defects under slit lamp microscopy in patients with suspicious or known Dry Eye Disease (DED). Fluorescein dyed - impregnated paper strips were used. Before placing the strip in the lower fornix of the eye, a drop of sterile saline was added to the strip. The cornea was divided into five sectors (central, superior, inferior, nasal and temporal), each of which was scored on a scale of 0-3, with a maximal global score of 15. For a better reading under the slit lamp, no intense illumination beam was used, since it could reduce the contrast and lead to an underestimation of grading. The lower the score the lower the corneal damage.

Outcome measures

Outcome measures
Measure	SANDE Changes From Baseline With rhNGF 20 μg/mL n=20 Participants Mean (±SD) changes from baseline and the outcome of their comparison with baseline after treatment with rhNGF 20 μg/mL - Day 1, 8, 29, 56	SANDE Changes From Baseline With rhNGF 4 μg/mL n=20 Participants Mean (±SD) changes from baseline and the outcome of their comparison with baseline after treatment with rhNGF 4 μg/mL - Day 1, 8, 29, 56
Change From Baseline in Corneal Fluorescein Staining Central cornea, Day 1 vs Day -15	-0.1 units on a scale Standard Deviation 0.5	0.1 units on a scale Standard Deviation 0.3
Change From Baseline in Corneal Fluorescein Staining Central cornea, Day 8 vs Day -15	-0.3 units on a scale Standard Deviation 0.9	-0.2 units on a scale Standard Deviation 0.5
Change From Baseline in Corneal Fluorescein Staining Central cornea, Day 29 vs Day -15	-0.5 units on a scale Standard Deviation 0.8	-0.2 units on a scale Standard Deviation 0.7
Change From Baseline in Corneal Fluorescein Staining Central cornea, Day 56 vs Day -15	-0.5 units on a scale Standard Deviation 0.7	-0.1 units on a scale Standard Deviation 0.9
Change From Baseline in Corneal Fluorescein Staining Superior cornea, Day 1 vs Day -15	0.1 units on a scale Standard Deviation 0.9	0.1 units on a scale Standard Deviation 0.5
Change From Baseline in Corneal Fluorescein Staining Superior cornea, Day 8 vs Day -15	-0.4 units on a scale Standard Deviation 0.8	-0.1 units on a scale Standard Deviation 0.7
Change From Baseline in Corneal Fluorescein Staining Superior cornea, Day 29 vs Day -15	-0.4 units on a scale Standard Deviation 0.8	-0.1 units on a scale Standard Deviation 0.9
Change From Baseline in Corneal Fluorescein Staining Superior cornea, Day 56 vs Day -15	-0.1 units on a scale Standard Deviation 0.8	-0.4 units on a scale Standard Deviation 0.8
Change From Baseline in Corneal Fluorescein Staining Inferior cornea, Day 1 vs Day -15	-0.1 units on a scale Standard Deviation 0.6	0.1 units on a scale Standard Deviation 0.4
Change From Baseline in Corneal Fluorescein Staining Inferior cornea, Day 8 vs Day -15	-0.4 units on a scale Standard Deviation 0.8	-0.1 units on a scale Standard Deviation 0.6
Change From Baseline in Corneal Fluorescein Staining Inferior cornea, Day 29 vs Day -15	-0.8 units on a scale Standard Deviation 0.9	-0.3 units on a scale Standard Deviation 1.0
Change From Baseline in Corneal Fluorescein Staining Inferior cornea, Day 56 vs Day -15n	-0.8 units on a scale Standard Deviation 1.0	-0.3 units on a scale Standard Deviation 0.9
Change From Baseline in Corneal Fluorescein Staining Nasal cornea, Day 1 vs Day -15	-0.2 units on a scale Standard Deviation 0.6	0.1 units on a scale Standard Deviation 0.7
Change From Baseline in Corneal Fluorescein Staining Nasal cornea, Day 8 vs Day -15	-0.5 units on a scale Standard Deviation 0.8	0.0 units on a scale Standard Deviation 0.8
Change From Baseline in Corneal Fluorescein Staining Nasal cornea, Day 29 vs Day -15	-0.9 units on a scale Standard Deviation 0.9	-0.3 units on a scale Standard Deviation 0.9
Change From Baseline in Corneal Fluorescein Staining Nasal cornea, Day 56 vs Day -15	-0.8 units on a scale Standard Deviation 0.8	-0.2 units on a scale Standard Deviation 0.5
Change From Baseline in Corneal Fluorescein Staining Temporal cornea, Day 1 vs Day -15	0.0 units on a scale Standard Deviation 0.6	0.1 units on a scale Standard Deviation 0.6
Change From Baseline in Corneal Fluorescein Staining Temporal cornea, Day 8 vs Day -15	-0.4 units on a scale Standard Deviation 0.8	-0.1 units on a scale Standard Deviation 0.8
Change From Baseline in Corneal Fluorescein Staining temporal cornea, Day 29 vs Day -15	-0.6 units on a scale Standard Deviation 0.7	-0.4 units on a scale Standard Deviation 0.8
Change From Baseline in Corneal Fluorescein Staining Temporal cornea, Day 56 vs Day -15	-0.8 units on a scale Standard Deviation 0.7	-0.3 units on a scale Standard Deviation 0.8
Change From Baseline in Corneal Fluorescein Staining Total score cornea, Day 1 vs Day -15	-0.3 units on a scale Standard Deviation 2.6	0.4 units on a scale Standard Deviation 1.4
Change From Baseline in Corneal Fluorescein Staining Total score cornea, Day 8 vs Day -15	-1.9 units on a scale Standard Deviation 3.0	-0.4 units on a scale Standard Deviation 2.2
Change From Baseline in Corneal Fluorescein Staining Total score cornea, Day 29 vs Day -15	-3.1 units on a scale Standard Deviation 2.7	-1.2 units on a scale Standard Deviation 2.9
Change From Baseline in Corneal Fluorescein Staining Total score cornea, Day 56 vs Day -15	-2.9 units on a scale Standard Deviation 2.7	-1.2 units on a scale Standard Deviation 2.8

SECONDARY outcome

Timeframe: Baseline, Day 1, Day 8, Day 29 and Day 56

Population: FAS: all enrolled patients, who received at least one dose of the IMP. This analysis set was used for the efficacy analysis.

Corneal sensitivity was measured in cm through the Luneau-Cochet-Bonnet aesthesiometer. This contains a thin, retractable, nylon monofilament that extends up to 6 cm in length. Variable pressure can be applied to the cornea by adjusting the monofilament length. The monofilament length ranges from 6 to 0.5 cm. As the monofilament length is decreased the pressure increases from 11 mm/g to 200 mm/g. The filament is retracted incrementally in 0.5 cm until the patient gives a positive reaction indicating that the contact of the monofilament on the cornea has been sensed. The shorter filament lengths indicate decreased corneal sensation. The length of the filament (in cm) at which the patient sensed the contact with the cornea is recorded. Only study eye's results are reported hereunder.

Outcome measures

Outcome measures
Measure	SANDE Changes From Baseline With rhNGF 20 μg/mL n=20 Participants Mean (±SD) changes from baseline and the outcome of their comparison with baseline after treatment with rhNGF 20 μg/mL - Day 1, 8, 29, 56	SANDE Changes From Baseline With rhNGF 4 μg/mL n=20 Participants Mean (±SD) changes from baseline and the outcome of their comparison with baseline after treatment with rhNGF 4 μg/mL - Day 1, 8, 29, 56
Change From Baseline in Corneal Sensitivity to Contact (Cochet-Bonnet Aesthesiometry) Filament Length of Contact Sensation,Day1vsDay-15	0.05 cm Standard Deviation 0.58	0.20 cm Standard Deviation 0.41
Change From Baseline in Corneal Sensitivity to Contact (Cochet-Bonnet Aesthesiometry) Filament Length of Contact Sensation,Day8vsDay-15	0.03 cm Standard Deviation 0.41	0.38 cm Standard Deviation 0.94
Change From Baseline in Corneal Sensitivity to Contact (Cochet-Bonnet Aesthesiometry) Filament Length of Contact Sensation,Day29vsDay-15	0.33 cm Standard Deviation 0.82	0.39 cm Standard Deviation 1.25
Change From Baseline in Corneal Sensitivity to Contact (Cochet-Bonnet Aesthesiometry) Filament Length of Contact Sensation,Day56vsDay-15	0.28 cm Standard Deviation 0.60	0.50 cm Standard Deviation 1.19

SECONDARY outcome

Timeframe: Baseline, Day 1, Day 8, Day 29 and Day 56

Population: FAS: all enrolled patients, who received at least one dose of the IMP. This analysis set was used for the efficacy analysis.

IOP was performed using either Goldmann applanation tonometry or a handheld applanation tonometer (e.g. Tonopen) after the instillation of a topical anaesthetic. IOP was measured in both eyes after completion of all other slit lamp examinations to avoid potential interference with the other evaluations. Only study eye's results are reported hereunder.

Outcome measures

Outcome measures
Measure	SANDE Changes From Baseline With rhNGF 20 μg/mL n=20 Participants Mean (±SD) changes from baseline and the outcome of their comparison with baseline after treatment with rhNGF 20 μg/mL - Day 1, 8, 29, 56	SANDE Changes From Baseline With rhNGF 4 μg/mL n=20 Participants Mean (±SD) changes from baseline and the outcome of their comparison with baseline after treatment with rhNGF 4 μg/mL - Day 1, 8, 29, 56
Change From Baseline in Intraocular Pressure (IOP) Day 1 vs Day -15	-0.9 mmHg Standard Deviation 1.6	0.2 mmHg Standard Deviation 2.3
Change From Baseline in Intraocular Pressure (IOP) Day 8 vs Day -15	-1.9 mmHg Standard Deviation 2.2	0.5 mmHg Standard Deviation 3.2
Change From Baseline in Intraocular Pressure (IOP) Day 29 vs Day -15	-1.6 mmHg Standard Deviation 2.6	1.3 mmHg Standard Deviation 3.1
Change From Baseline in Intraocular Pressure (IOP) Day 56 vs Day -15	-1.7 mmHg Standard Deviation 3.0	0.9 mmHg Standard Deviation 2.9

SECONDARY outcome

Timeframe: Baseline, Day 1, Day 8, Day 29 and Day 56

Population: FAS: all enrolled patients, who received at least one dose of the IMP. This analysis set was used for the efficacy analysis.

The OSDI is based on a 12-item questionnaire designed to provide a rapid assessment of the symptoms of ocular irritation consistent with dry eye disease and their impact on vision-related functioning. The 12 items of the OSDI questionnaire are graded on a 0-4 scale as follows: Grade 0 = none Grade 1 = some Grade 2 = half Grade 3 = most Grade 4 = all The total OSDI score was then calculated on the basis of the following formula: OSDI=\[(sum of scores for all questions answered) × 100\]/\[(total number of questions answered) × 4\]. Thus, the OSDI total score scales from 0 to 100, with higher scores representing greater disability.

Outcome measures

Outcome measures
Measure	SANDE Changes From Baseline With rhNGF 20 μg/mL n=20 Participants Mean (±SD) changes from baseline and the outcome of their comparison with baseline after treatment with rhNGF 20 μg/mL - Day 1, 8, 29, 56	SANDE Changes From Baseline With rhNGF 4 μg/mL n=20 Participants Mean (±SD) changes from baseline and the outcome of their comparison with baseline after treatment with rhNGF 4 μg/mL - Day 1, 8, 29, 56
Change From Baseline in Ocular Surface Disease Index (OSDI) Day 56 vs Day -15	-23.47 score on a scale Standard Deviation 22.72	-14.76 score on a scale Standard Deviation 17.91
Change From Baseline in Ocular Surface Disease Index (OSDI) Day 1 vs Day -15	-5.37 score on a scale Standard Deviation 9.38	-0.22 score on a scale Standard Deviation 12.90
Change From Baseline in Ocular Surface Disease Index (OSDI) Day 8 vs Day -15	-14.33 score on a scale Standard Deviation 13.03	-10.39 score on a scale Standard Deviation 16.88
Change From Baseline in Ocular Surface Disease Index (OSDI) Day 29 vs Day -15	-22.92 score on a scale Standard Deviation 18.73	-18.75 score on a scale Standard Deviation 24.78

SECONDARY outcome

Timeframe: Baseline, Day 1, Day 8, Day 29 and Day 56

Population: FAS: all enrolled patients, who received at least one dose of the IMP. This analysis set was used for the efficacy analysis.

Values of Best-Corrected Distance Visual Acuity (BCDVA) scores were measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) score. The ETDRS charts use letters, or a geometric progression in letter size from line to line, under standardized lighting conditions. The patient starts at the top of the chart, or on the last row where he or she can read all of the letters, and reads down the chart until he or she reaches a row where a minimum of three letters on a line cannot be read. The patient is scored by how many letters could be correctly identified. Therefore, the higher the number of letters the higher the visual acuity. Changes in the ETDRS score from baseline (screening visit) are summarised by eye (study eye and non study eye) and evaluation visit, and stratified by severity level. Only study eye's results are reported hereunder.

Outcome measures

Outcome measures
Measure	SANDE Changes From Baseline With rhNGF 20 μg/mL n=20 Participants Mean (±SD) changes from baseline and the outcome of their comparison with baseline after treatment with rhNGF 20 μg/mL - Day 1, 8, 29, 56	SANDE Changes From Baseline With rhNGF 4 μg/mL n=20 Participants Mean (±SD) changes from baseline and the outcome of their comparison with baseline after treatment with rhNGF 4 μg/mL - Day 1, 8, 29, 56
Change From Baseline in Visual Acuity (BCDVA) Day 1 vs Day -15	0.7 letters Standard Deviation 2.9	1.6 letters Standard Deviation 5.8
Change From Baseline in Visual Acuity (BCDVA) Day 8 vs Day -15	0.5 letters Standard Deviation 2.9	3.4 letters Standard Deviation 6.3
Change From Baseline in Visual Acuity (BCDVA) Day 29 vs Day -15	1.3 letters Standard Deviation 3.8	5.1 letters Standard Deviation 11.7
Change From Baseline in Visual Acuity (BCDVA) Day 56 vs Day -15	1.2 letters Standard Deviation 3.8	6.7 letters Standard Deviation 10.6

SECONDARY outcome

Timeframe: Baseline, Day 1, Day 8, Day 29 and Day 56

Population: FAS: all enrolled patients, who received at least one dose of the IMP. This analysis set was used for the efficacy analysis.

This test allows seeing inside the fundus of the eye and other structures using an ophthalmoscope. The fundus examination included assessments of vitreous, macula, retina and optic nerve head for both eyes. Only the results concerning the study eye are reported hereunder. These structures will be assessed according to the criteria outlined below. Vitreous The examiner will judge the appearance of the vitreous in the visual axis. Normal: Absence of any opacity Abnormal: Presence of opacity Macula, (Peripheral) Retina and Optic Nerve Head The examiner will provide a separate assessment of the macular, choroid and peripheral retina Normal: Absence of any structural or vascular change, inflammation, oedema or haemorrhage. Abnormal: Evidence of any ongoing or previous structural/vascular change, inflammation, oedema or haemorrhage.

Outcome measures

Outcome measures
Measure	SANDE Changes From Baseline With rhNGF 20 μg/mL n=20 Participants Mean (±SD) changes from baseline and the outcome of their comparison with baseline after treatment with rhNGF 20 μg/mL - Day 1, 8, 29, 56	SANDE Changes From Baseline With rhNGF 4 μg/mL n=20 Participants Mean (±SD) changes from baseline and the outcome of their comparison with baseline after treatment with rhNGF 4 μg/mL - Day 1, 8, 29, 56
Number of Participants With a Change in Fundus Ophthalmoscopy Vitreous, Day 1 vs Day -15	0 Participants	0 Participants
Number of Participants With a Change in Fundus Ophthalmoscopy Vitreous, Day 8 vs Day -15	0 Participants	0 Participants
Number of Participants With a Change in Fundus Ophthalmoscopy Vitreous, Day 29 vs Day -15	0 Participants	0 Participants
Number of Participants With a Change in Fundus Ophthalmoscopy Vitreous, Day 56 vs Day -15	0 Participants	0 Participants
Number of Participants With a Change in Fundus Ophthalmoscopy Macula, Retina and Optic Nerve Head - Day 1	0 Participants	0 Participants
Number of Participants With a Change in Fundus Ophthalmoscopy Macula, Retina and Optic Nerve Head - Day 8	0 Participants	0 Participants
Number of Participants With a Change in Fundus Ophthalmoscopy Macula, Retina and Optic Nerve Head - Day 29	0 Participants	0 Participants
Number of Participants With a Change in Fundus Ophthalmoscopy Macula, Retina and Optic Nerve Head - Day 56	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Changes from baseline up to day 56±4

Population: FAS: all enrolled patients, who received at least one dose of the IMP. This analysis set was used for the efficacy analysis.

Values of tear film osmolarity and their changes from baseline (screening visit) are summarised by eye (study eye and non study eye) and evaluation visit and stratified by severity level. Only study eye's results are reported hereunder.

Outcome measures

Outcome measures
Measure	SANDE Changes From Baseline With rhNGF 20 μg/mL n=20 Participants Mean (±SD) changes from baseline and the outcome of their comparison with baseline after treatment with rhNGF 20 μg/mL - Day 1, 8, 29, 56	SANDE Changes From Baseline With rhNGF 4 μg/mL n=20 Participants Mean (±SD) changes from baseline and the outcome of their comparison with baseline after treatment with rhNGF 4 μg/mL - Day 1, 8, 29, 56
Change From Baseline in Tear Film Osmolarity Day 29 vs Day -15	-5.5 mOsm/L Standard Deviation 10.8	-1.4 mOsm/L Standard Deviation 19.0
Change From Baseline in Tear Film Osmolarity Day 56 vs Day -15	-4.8 mOsm/L Standard Deviation 14.2	4.1 mOsm/L Standard Deviation 19.8
Change From Baseline in Tear Film Osmolarity Day 1 vs Day -15	-9.1 mOsm/L Standard Deviation 13.1	-0.8 mOsm/L Standard Deviation 18.3
Change From Baseline in Tear Film Osmolarity Day 8 vs Day -15	-4.1 mOsm/L Standard Deviation 16.2	0.5 mOsm/L Standard Deviation 15.0

SECONDARY outcome

Timeframe: Baseline, Day 1, Day 8, Day 29 and Day 56

Population: FAS: all enrolled patients, who received at least one dose of the IMP. This analysis set was used for the efficacy analysis.

Four conjunctival impression cytology samples (temporal, nasal, inferior and superior bulbar conjunctiva) for conjunctival goblet cell counts were performed in the worse eye (study eye). Conjunctival epithelium samples are obtained following the instillation of a preservative-free anaesthetic eye drop by slightly pressing on the bulbar conjunctiva a 0.1 μm cellulose acetate filter. When the disc is removed the apical layers of conjunctival epithelium remain "impressed" on it. Cells on the filter are fixed and stained. The final results will be expressed as mean ± SD of 3 consecutive optic fields for each sample. A higher number of goblet cells indicates a healthier eye.

Outcome measures

Outcome measures
Measure	SANDE Changes From Baseline With rhNGF 20 μg/mL n=20 Participants Mean (±SD) changes from baseline and the outcome of their comparison with baseline after treatment with rhNGF 20 μg/mL - Day 1, 8, 29, 56	SANDE Changes From Baseline With rhNGF 4 μg/mL n=20 Participants Mean (±SD) changes from baseline and the outcome of their comparison with baseline after treatment with rhNGF 4 μg/mL - Day 1, 8, 29, 56
Change From Baseline in Conjunctival Impression Cytology for Goblet Cells' Count Temporal Bulbar Conjunctiva, Day 1 vs Day -15	-2.04 cell counts Standard Deviation 7.66	-0.19 cell counts Standard Deviation 3.40
Change From Baseline in Conjunctival Impression Cytology for Goblet Cells' Count Temporal Bulbar Conjunctiva, Day 8 vs Day -15	-2.25 cell counts Standard Deviation 6.73	0.16 cell counts Standard Deviation 2.19
Change From Baseline in Conjunctival Impression Cytology for Goblet Cells' Count Temporal Bulbar Conjunctiva, Day 29 vs Day -15	0.03 cell counts Standard Deviation 11.18	0.83 cell counts Standard Deviation 2.72
Change From Baseline in Conjunctival Impression Cytology for Goblet Cells' Count Temporal Bulbar Conjunctiva, Day 56 vs Day -15	-2.47 cell counts Standard Deviation 7.86	0.00 cell counts Standard Deviation 2.76
Change From Baseline in Conjunctival Impression Cytology for Goblet Cells' Count Nasal Bulbar Conjunctiva, Day 1 vs Day -15	-0.84 cell counts Standard Deviation 8.55	-0.52 cell counts Standard Deviation 2.50
Change From Baseline in Conjunctival Impression Cytology for Goblet Cells' Count Nasal Bulbar Conjunctiva, Day 8 vs Day -15	0.98 cell counts Standard Deviation 14.02	1.24 cell counts Standard Deviation 4.06
Change From Baseline in Conjunctival Impression Cytology for Goblet Cells' Count Nasal Bulbar Conjunctiva, Day 29 vs Day -15	0.96 cell counts Standard Deviation 9.14	-0.06 cell counts Standard Deviation 2.98
Change From Baseline in Conjunctival Impression Cytology for Goblet Cells' Count Nasal Bulbar Conjunctiva, Day 56 vs Day -15	0.99 cell counts Standard Deviation 12.81	1.19 cell counts Standard Deviation 3.89
Change From Baseline in Conjunctival Impression Cytology for Goblet Cells' Count Inferior Bulbar Conjunctiva, Day 1 vs Day -15	-2.77 cell counts Standard Deviation 7.49	-2.17 cell counts Standard Deviation 4.65
Change From Baseline in Conjunctival Impression Cytology for Goblet Cells' Count Inferior Bulbar Conjunctiva, Day 8 vs Day -15	-1.11 cell counts Standard Deviation 11.30	-1.33 cell counts Standard Deviation 3.41
Change From Baseline in Conjunctival Impression Cytology for Goblet Cells' Count Inferior Bulbar Conjunctiva, Day 29 vs Day -15	-3.79 cell counts Standard Deviation 7.30	-1.60 cell counts Standard Deviation 3.11
Change From Baseline in Conjunctival Impression Cytology for Goblet Cells' Count Inferior Bulbar Conjunctiva, Day 56 vs Day -15	-1.60 cell counts Standard Deviation 8.94	-1.07 cell counts Standard Deviation 4.46
Change From Baseline in Conjunctival Impression Cytology for Goblet Cells' Count Superior Bulbar Conjunctiva, Day 1 vs Day -15	-2.28 cell counts Standard Deviation 9.87	0.73 cell counts Standard Deviation 2.23
Change From Baseline in Conjunctival Impression Cytology for Goblet Cells' Count Superior Bulbar Conjunctiva, Day 8 vs Day -15	-2.48 cell counts Standard Deviation 12.53	0.33 cell counts Standard Deviation 2.35
Change From Baseline in Conjunctival Impression Cytology for Goblet Cells' Count Superior Bulbar Conjunctiva, Day 29 vs Day -15	-4.44 cell counts Standard Deviation 10.16	0.44 cell counts Standard Deviation 1.93
Change From Baseline in Conjunctival Impression Cytology for Goblet Cells' Count Superior Bulbar Conjunctiva, Day 56 vs Day -15	-1.09 cell counts Standard Deviation 10.45	1.07 cell counts Standard Deviation 1.99

SECONDARY outcome

Timeframe: Day 1-Day 8, Day 9-Day 29, Day 30-Day 56 intervals

Population: FAS: all enrolled patients, who received at least one dose of the IMP. This analysis set was used for the efficacy analysis.

During the treatment with rhNGF at both doses (from day 1 to day 29), and in the follow-up period (from day 29 to day 56) the mean frequency of daily use of artificial tears was measured.

Outcome measures

Outcome measures
Measure	SANDE Changes From Baseline With rhNGF 20 μg/mL n=20 Participants Mean (±SD) changes from baseline and the outcome of their comparison with baseline after treatment with rhNGF 20 μg/mL - Day 1, 8, 29, 56	SANDE Changes From Baseline With rhNGF 4 μg/mL n=20 Participants Mean (±SD) changes from baseline and the outcome of their comparison with baseline after treatment with rhNGF 4 μg/mL - Day 1, 8, 29, 56
Mean Frequency of Artificial Tears Use Day 1-Day 8	1.813 uses per day Standard Deviation 1.894	1.083 uses per day Standard Deviation 1.541
Mean Frequency of Artificial Tears Use Day 9-Day 29	2.133 uses per day Standard Deviation 2.814	1.271 uses per day Standard Deviation 1.334
Mean Frequency of Artificial Tears Use Day 30-Day 56	2.869 uses per day Standard Deviation 2.961	2.460 uses per day Standard Deviation 2.860

Adverse Events

Group 1 - rhNGF 20 μg/mL

Serious events: 0 serious events

Other events: 14 other events

Deaths: 0 deaths

Group 2 - rhNGF 4 μg/mL

Serious events: 1 serious events

Other events: 15 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Group 1 - rhNGF 20 μg/mL n=20 participants at risk (first planned dose): one drop (35 μL) corresponding to 0.70 μg of rhNGF was instilled into each eye twice a day (b.i.d.) every 12±2 h for a total daily dose of 2.8 μg (both eyes), for 28 consecutive days. Total dose was 78.4 μg/28 days. rhNGF 20 µg/mL: 1 drop for each eye, twice daily for 28 day	Group 2 - rhNGF 4 μg/mL n=20 participants at risk after completion of Group 1 treatment, one drop (35 μL) corresponding to 0.14 μg of rhNGF was instilled into each eye b.i.d. every 12±2 h for a total daily dose of 0.56 μg, for 28 consecutive days. Total dose was 15.68 μg/28 days. rhNGF 4 µg/mL: 1 drop each eye, twice daily for 28 day
Injury, poisoning and procedural complications Fall	0.00% 0/20 • From screening throughout the study until the final visit, up to 56 days More specifically, adverse events are assessed at screening (visit 1), at visits 2-6 and at visit 7 (final visit, Day 56)	5.0% 1/20 • Number of events 1 • From screening throughout the study until the final visit, up to 56 days More specifically, adverse events are assessed at screening (visit 1), at visits 2-6 and at visit 7 (final visit, Day 56)

Other adverse events

Additional Information

Flavio Mantelli, MD, PhD

Dompé

Phone: +39 513138

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Group 1 - rhNGF 20 μg/mL n=20 participants at risk (first planned dose): one drop (35 μL) corresponding to 0.70 μg of rhNGF was instilled into each eye twice a day (b.i.d.) every 12±2 h for a total daily dose of 2.8 μg (both eyes), for 28 consecutive days. Total dose was 78.4 μg/28 days. rhNGF 20 µg/mL: 1 drop for each eye, twice daily for 28 day	Group 2 - rhNGF 4 μg/mL n=20 participants at risk after completion of Group 1 treatment, one drop (35 μL) corresponding to 0.14 μg of rhNGF was instilled into each eye b.i.d. every 12±2 h for a total daily dose of 0.56 μg, for 28 consecutive days. Total dose was 15.68 μg/28 days. rhNGF 4 µg/mL: 1 drop each eye, twice daily for 28 day
Eye disorders Abnormal sensation in eye	20.0% 4/20 • Number of events 4 • From screening throughout the study until the final visit, up to 56 days More specifically, adverse events are assessed at screening (visit 1), at visits 2-6 and at visit 7 (final visit, Day 56)	40.0% 8/20 • Number of events 9 • From screening throughout the study until the final visit, up to 56 days More specifically, adverse events are assessed at screening (visit 1), at visits 2-6 and at visit 7 (final visit, Day 56)
Eye disorders Eye pain	25.0% 5/20 • Number of events 7 • From screening throughout the study until the final visit, up to 56 days More specifically, adverse events are assessed at screening (visit 1), at visits 2-6 and at visit 7 (final visit, Day 56)	30.0% 6/20 • Number of events 7 • From screening throughout the study until the final visit, up to 56 days More specifically, adverse events are assessed at screening (visit 1), at visits 2-6 and at visit 7 (final visit, Day 56)
Eye disorders Eye irritation	15.0% 3/20 • Number of events 6 • From screening throughout the study until the final visit, up to 56 days More specifically, adverse events are assessed at screening (visit 1), at visits 2-6 and at visit 7 (final visit, Day 56)	35.0% 7/20 • Number of events 7 • From screening throughout the study until the final visit, up to 56 days More specifically, adverse events are assessed at screening (visit 1), at visits 2-6 and at visit 7 (final visit, Day 56)
Eye disorders Eye pruritus	10.0% 2/20 • Number of events 4 • From screening throughout the study until the final visit, up to 56 days More specifically, adverse events are assessed at screening (visit 1), at visits 2-6 and at visit 7 (final visit, Day 56)	25.0% 5/20 • Number of events 5 • From screening throughout the study until the final visit, up to 56 days More specifically, adverse events are assessed at screening (visit 1), at visits 2-6 and at visit 7 (final visit, Day 56)
Eye disorders Vision blurred	15.0% 3/20 • Number of events 4 • From screening throughout the study until the final visit, up to 56 days More specifically, adverse events are assessed at screening (visit 1), at visits 2-6 and at visit 7 (final visit, Day 56)	10.0% 2/20 • Number of events 2 • From screening throughout the study until the final visit, up to 56 days More specifically, adverse events are assessed at screening (visit 1), at visits 2-6 and at visit 7 (final visit, Day 56)
Eye disorders Foreign body sensation in eyes	0.00% 0/20 • From screening throughout the study until the final visit, up to 56 days More specifically, adverse events are assessed at screening (visit 1), at visits 2-6 and at visit 7 (final visit, Day 56)	20.0% 4/20 • Number of events 4 • From screening throughout the study until the final visit, up to 56 days More specifically, adverse events are assessed at screening (visit 1), at visits 2-6 and at visit 7 (final visit, Day 56)
Eye disorders Photophobia	5.0% 1/20 • Number of events 2 • From screening throughout the study until the final visit, up to 56 days More specifically, adverse events are assessed at screening (visit 1), at visits 2-6 and at visit 7 (final visit, Day 56)	15.0% 3/20 • Number of events 3 • From screening throughout the study until the final visit, up to 56 days More specifically, adverse events are assessed at screening (visit 1), at visits 2-6 and at visit 7 (final visit, Day 56)
Eye disorders Lacrimation increased	0.00% 0/20 • From screening throughout the study until the final visit, up to 56 days More specifically, adverse events are assessed at screening (visit 1), at visits 2-6 and at visit 7 (final visit, Day 56)	15.0% 3/20 • Number of events 3 • From screening throughout the study until the final visit, up to 56 days More specifically, adverse events are assessed at screening (visit 1), at visits 2-6 and at visit 7 (final visit, Day 56)
Eye disorders Visual impairment	5.0% 1/20 • Number of events 1 • From screening throughout the study until the final visit, up to 56 days More specifically, adverse events are assessed at screening (visit 1), at visits 2-6 and at visit 7 (final visit, Day 56)	5.0% 1/20 • Number of events 1 • From screening throughout the study until the final visit, up to 56 days More specifically, adverse events are assessed at screening (visit 1), at visits 2-6 and at visit 7 (final visit, Day 56)
Eye disorders Asthenopia	5.0% 1/20 • Number of events 1 • From screening throughout the study until the final visit, up to 56 days More specifically, adverse events are assessed at screening (visit 1), at visits 2-6 and at visit 7 (final visit, Day 56)	0.00% 0/20 • From screening throughout the study until the final visit, up to 56 days More specifically, adverse events are assessed at screening (visit 1), at visits 2-6 and at visit 7 (final visit, Day 56)
Eye disorders Erythema of eyelid	0.00% 0/20 • From screening throughout the study until the final visit, up to 56 days More specifically, adverse events are assessed at screening (visit 1), at visits 2-6 and at visit 7 (final visit, Day 56)	5.0% 1/20 • Number of events 1 • From screening throughout the study until the final visit, up to 56 days More specifically, adverse events are assessed at screening (visit 1), at visits 2-6 and at visit 7 (final visit, Day 56)
Eye disorders Eye discharge	5.0% 1/20 • Number of events 1 • From screening throughout the study until the final visit, up to 56 days More specifically, adverse events are assessed at screening (visit 1), at visits 2-6 and at visit 7 (final visit, Day 56)	0.00% 0/20 • From screening throughout the study until the final visit, up to 56 days More specifically, adverse events are assessed at screening (visit 1), at visits 2-6 and at visit 7 (final visit, Day 56)
Eye disorders Eye disorder	0.00% 0/20 • From screening throughout the study until the final visit, up to 56 days More specifically, adverse events are assessed at screening (visit 1), at visits 2-6 and at visit 7 (final visit, Day 56)	5.0% 1/20 • Number of events 1 • From screening throughout the study until the final visit, up to 56 days More specifically, adverse events are assessed at screening (visit 1), at visits 2-6 and at visit 7 (final visit, Day 56)
Eye disorders Eyelid pain	5.0% 1/20 • Number of events 1 • From screening throughout the study until the final visit, up to 56 days More specifically, adverse events are assessed at screening (visit 1), at visits 2-6 and at visit 7 (final visit, Day 56)	0.00% 0/20 • From screening throughout the study until the final visit, up to 56 days More specifically, adverse events are assessed at screening (visit 1), at visits 2-6 and at visit 7 (final visit, Day 56)
Eye disorders Eyelid sensory disorder	0.00% 0/20 • From screening throughout the study until the final visit, up to 56 days More specifically, adverse events are assessed at screening (visit 1), at visits 2-6 and at visit 7 (final visit, Day 56)	5.0% 1/20 • Number of events 1 • From screening throughout the study until the final visit, up to 56 days More specifically, adverse events are assessed at screening (visit 1), at visits 2-6 and at visit 7 (final visit, Day 56)
Eye disorders Ocular discomfort	0.00% 0/20 • From screening throughout the study until the final visit, up to 56 days More specifically, adverse events are assessed at screening (visit 1), at visits 2-6 and at visit 7 (final visit, Day 56)	5.0% 1/20 • Number of events 1 • From screening throughout the study until the final visit, up to 56 days More specifically, adverse events are assessed at screening (visit 1), at visits 2-6 and at visit 7 (final visit, Day 56)
Eye disorders Ocular hyperaemia	0.00% 0/20 • From screening throughout the study until the final visit, up to 56 days More specifically, adverse events are assessed at screening (visit 1), at visits 2-6 and at visit 7 (final visit, Day 56)	5.0% 1/20 • Number of events 1 • From screening throughout the study until the final visit, up to 56 days More specifically, adverse events are assessed at screening (visit 1), at visits 2-6 and at visit 7 (final visit, Day 56)
Eye disorders Vitrous detachment	5.0% 1/20 • Number of events 1 • From screening throughout the study until the final visit, up to 56 days More specifically, adverse events are assessed at screening (visit 1), at visits 2-6 and at visit 7 (final visit, Day 56)	0.00% 0/20 • From screening throughout the study until the final visit, up to 56 days More specifically, adverse events are assessed at screening (visit 1), at visits 2-6 and at visit 7 (final visit, Day 56)
Infections and infestations Rhinitis allergic	0.00% 0/20 • From screening throughout the study until the final visit, up to 56 days More specifically, adverse events are assessed at screening (visit 1), at visits 2-6 and at visit 7 (final visit, Day 56)	10.0% 2/20 • Number of events 2 • From screening throughout the study until the final visit, up to 56 days More specifically, adverse events are assessed at screening (visit 1), at visits 2-6 and at visit 7 (final visit, Day 56)
Infections and infestations Conjunctivitis bacterial	0.00% 0/20 • From screening throughout the study until the final visit, up to 56 days More specifically, adverse events are assessed at screening (visit 1), at visits 2-6 and at visit 7 (final visit, Day 56)	5.0% 1/20 • Number of events 1 • From screening throughout the study until the final visit, up to 56 days More specifically, adverse events are assessed at screening (visit 1), at visits 2-6 and at visit 7 (final visit, Day 56)
Infections and infestations Herpes simplex	5.0% 1/20 • Number of events 1 • From screening throughout the study until the final visit, up to 56 days More specifically, adverse events are assessed at screening (visit 1), at visits 2-6 and at visit 7 (final visit, Day 56)	0.00% 0/20 • From screening throughout the study until the final visit, up to 56 days More specifically, adverse events are assessed at screening (visit 1), at visits 2-6 and at visit 7 (final visit, Day 56)
Infections and infestations Nasopharyngitis	5.0% 1/20 • Number of events 1 • From screening throughout the study until the final visit, up to 56 days More specifically, adverse events are assessed at screening (visit 1), at visits 2-6 and at visit 7 (final visit, Day 56)	0.00% 0/20 • From screening throughout the study until the final visit, up to 56 days More specifically, adverse events are assessed at screening (visit 1), at visits 2-6 and at visit 7 (final visit, Day 56)
Infections and infestations Sinusitis	0.00% 0/20 • From screening throughout the study until the final visit, up to 56 days More specifically, adverse events are assessed at screening (visit 1), at visits 2-6 and at visit 7 (final visit, Day 56)	5.0% 1/20 • Number of events 1 • From screening throughout the study until the final visit, up to 56 days More specifically, adverse events are assessed at screening (visit 1), at visits 2-6 and at visit 7 (final visit, Day 56)
Infections and infestations Urinary tract infection	0.00% 0/20 • From screening throughout the study until the final visit, up to 56 days More specifically, adverse events are assessed at screening (visit 1), at visits 2-6 and at visit 7 (final visit, Day 56)	5.0% 1/20 • Number of events 1 • From screening throughout the study until the final visit, up to 56 days More specifically, adverse events are assessed at screening (visit 1), at visits 2-6 and at visit 7 (final visit, Day 56)
Nervous system disorders Headache	0.00% 0/20 • From screening throughout the study until the final visit, up to 56 days More specifically, adverse events are assessed at screening (visit 1), at visits 2-6 and at visit 7 (final visit, Day 56)	5.0% 1/20 • Number of events 1 • From screening throughout the study until the final visit, up to 56 days More specifically, adverse events are assessed at screening (visit 1), at visits 2-6 and at visit 7 (final visit, Day 56)
Nervous system disorders Migraine	0.00% 0/20 • From screening throughout the study until the final visit, up to 56 days More specifically, adverse events are assessed at screening (visit 1), at visits 2-6 and at visit 7 (final visit, Day 56)	25.0% 5/20 • Number of events 9 • From screening throughout the study until the final visit, up to 56 days More specifically, adverse events are assessed at screening (visit 1), at visits 2-6 and at visit 7 (final visit, Day 56)
Musculoskeletal and connective tissue disorders Back pain	0.00% 0/20 • From screening throughout the study until the final visit, up to 56 days More specifically, adverse events are assessed at screening (visit 1), at visits 2-6 and at visit 7 (final visit, Day 56)	5.0% 1/20 • Number of events 1 • From screening throughout the study until the final visit, up to 56 days More specifically, adverse events are assessed at screening (visit 1), at visits 2-6 and at visit 7 (final visit, Day 56)
Musculoskeletal and connective tissue disorders Neck pain	0.00% 0/20 • From screening throughout the study until the final visit, up to 56 days More specifically, adverse events are assessed at screening (visit 1), at visits 2-6 and at visit 7 (final visit, Day 56)	5.0% 1/20 • Number of events 1 • From screening throughout the study until the final visit, up to 56 days More specifically, adverse events are assessed at screening (visit 1), at visits 2-6 and at visit 7 (final visit, Day 56)
Ear and labyrinth disorders Tinnitus	5.0% 1/20 • Number of events 1 • From screening throughout the study until the final visit, up to 56 days More specifically, adverse events are assessed at screening (visit 1), at visits 2-6 and at visit 7 (final visit, Day 56)	0.00% 0/20 • From screening throughout the study until the final visit, up to 56 days More specifically, adverse events are assessed at screening (visit 1), at visits 2-6 and at visit 7 (final visit, Day 56)
Gastrointestinal disorders Flatulence	0.00% 0/20 • From screening throughout the study until the final visit, up to 56 days More specifically, adverse events are assessed at screening (visit 1), at visits 2-6 and at visit 7 (final visit, Day 56)	5.0% 1/20 • Number of events 1 • From screening throughout the study until the final visit, up to 56 days More specifically, adverse events are assessed at screening (visit 1), at visits 2-6 and at visit 7 (final visit, Day 56)
Injury, poisoning and procedural complications Concussion	0.00% 0/20 • From screening throughout the study until the final visit, up to 56 days More specifically, adverse events are assessed at screening (visit 1), at visits 2-6 and at visit 7 (final visit, Day 56)	5.0% 1/20 • Number of events 1 • From screening throughout the study until the final visit, up to 56 days More specifically, adverse events are assessed at screening (visit 1), at visits 2-6 and at visit 7 (final visit, Day 56)