Trial Outcomes & Findings for Efficacy and Safety of the Ophthalmic Solution PRO-087 Versus Systane ® Ultra and Ultra Preservative Free (087LATAMFIV) (NCT NCT03223909)

NCT ID: NCT03223909

Last Updated: 2019-10-31

Results Overview

Best-corrected visual acuity

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

326 participants

Primary outcome timeframe

Change from Baseline visual acuity at 90 days

Results posted on

2019-10-31

Participant Flow

Participant milestones

Participant milestones
Measure	PRO-087 PF Preservative free (PF) PRO-087 ophthalmic solution. Dropper bottle. Multidose 1 drop every 4 hours for 90 days. PRO-087: 0.1% sodium hyaluronate, free-preservative 0.18% chondroitin sulphate	Systane Ultra Systane Ultra ophthalmic solution, Dropper bottle, Multidose. 1 drop every 4 hours for 90 days. Systane Ultra: Is a sterile solution containing polyethylene glycol 400, propylene glycol, hydroxypropyl-guar, sorbitol, aminomethylpropanol, boric acid, potassium chloride, sodium chloride and POLYQUAD® (poly-hydronium chloride) 0.001% as preservative.	Systane Ultra PF Systane Ultra, preservative free ophthalmic solution, single-use vials. 1 drop every 4 hours for 90 days. Systane Ultra Preservative Free: Polyethylene Glycol 400 0.4%Lubricant, Propylene Glycol 0.3% Lubricant,
Overall Study STARTED	120	109	97
Overall Study COMPLETED	72	64	81
Overall Study NOT COMPLETED	48	45	16

Reasons for withdrawal

Reasons for withdrawal
Measure	PRO-087 PF Preservative free (PF) PRO-087 ophthalmic solution. Dropper bottle. Multidose 1 drop every 4 hours for 90 days. PRO-087: 0.1% sodium hyaluronate, free-preservative 0.18% chondroitin sulphate	Systane Ultra Systane Ultra ophthalmic solution, Dropper bottle, Multidose. 1 drop every 4 hours for 90 days. Systane Ultra: Is a sterile solution containing polyethylene glycol 400, propylene glycol, hydroxypropyl-guar, sorbitol, aminomethylpropanol, boric acid, potassium chloride, sodium chloride and POLYQUAD® (poly-hydronium chloride) 0.001% as preservative.	Systane Ultra PF Systane Ultra, preservative free ophthalmic solution, single-use vials. 1 drop every 4 hours for 90 days. Systane Ultra Preservative Free: Polyethylene Glycol 400 0.4%Lubricant, Propylene Glycol 0.3% Lubricant,
Overall Study Protocol Violation	48	45	16

Baseline Characteristics

Efficacy and Safety of the Ophthalmic Solution PRO-087 Versus Systane ® Ultra and Ultra Preservative Free (087LATAMFIV)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	PRO-087 PF n=72 Participants Preservative free (PF) PRO-087 ophthalmic solution. Dropper bottle. Multidose 1 drop every 4 hours for 90 days. PRO-087: 0.1% sodium hyaluronate, free-preservative 0.18% chondroitin sulphate	Systane Ultra n=64 Participants Systane Ultra ophthalmic solution, Dropper bottle, Multidose. 1 drop every 4 hours for 90 days. Systane Ultra: Is a sterile solution containing polyethylene glycol 400, propylene glycol, hydroxypropyl-guar, sorbitol, aminomethylpropanol, boric acid, potassium chloride, sodium chloride and POLYQUAD® (poly-hydronium chloride) 0.001% as preservative.	Systane Ultra PF n=81 Participants Systane Ultra, preservative free ophthalmic solution, single-use vials. 1 drop every 4 hours for 90 days. Systane Ultra Preservative Free: Polyethylene Glycol 400 0.4%Lubricant, Propylene Glycol 0.3% Lubricant,	Total n=217 Participants Total of all reporting groups
Age, Continuous	57.5 years STANDARD_DEVIATION 15.3 • n=5 Participants	55.0 years STANDARD_DEVIATION 17.6 • n=7 Participants	51.9 years STANDARD_DEVIATION 16.2 • n=5 Participants	54.2 years STANDARD_DEVIATION 16.5 • n=4 Participants
Sex: Female, Male Female	52 Participants n=5 Participants	46 Participants n=7 Participants	63 Participants n=5 Participants	161 Participants n=4 Participants
Sex: Female, Male Male	20 Participants n=5 Participants	18 Participants n=7 Participants	18 Participants n=5 Participants	56 Participants n=4 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) White	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) More than one race	72 Participants n=5 Participants	64 Participants n=7 Participants	81 Participants n=5 Participants	217 Participants n=4 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants

PRIMARY outcome

Timeframe: Change from Baseline visual acuity at 90 days

Population: the statistical analysis was carried out by intention to treat (ITT)

Best-corrected visual acuity

Outcome measures

Outcome measures
Measure	PRO-087 PF n=72 Participants Preservative free (PF) PRO-087 ophthalmic solution. Dropper bottle. Multidose 1 drop every 4 hours for 90 days. PRO-087: 0.1% sodium hyaluronate, free-preservative 0.18% chondroitin sulphate	Systane Ultra n=64 Participants Systane Ultra ophthalmic solution, Dropper bottle, Multidose. 1 drop every 4 hours for 90 days. Systane Ultra: Is a sterile solution containing polyethylene glycol 400, propylene glycol, hydroxypropyl-guar, sorbitol, aminomethylpropanol, boric acid, potassium chloride, sodium chloride and POLYQUAD® (poly-hydronium chloride) 0.001% as preservative.	Systane Ultra PF n=81 Participants Systane Ultra, preservative free ophthalmic solution, single-use vials. 1 drop every 4 hours for 90 days. Systane Ultra Preservative Free: Polyethylene Glycol 400 0.4%Lubricant, Propylene Glycol 0.3% Lubricant,
Visual Acuity Base Line	0.187 LogMAR Standard Deviation 0.25	0.215 LogMAR Standard Deviation 0.26	0.219 LogMAR Standard Deviation 0.23
Visual Acuity Final Visit	0.172 LogMAR Standard Deviation 0.24	0.187 LogMAR Standard Deviation 0.24	0.176 LogMAR Standard Deviation 0.21

SECONDARY outcome

Timeframe: Final Visit (day 90)

Population: the statistical analysis was carried out by intention to treat

Percentage of the damaged epithelium of the ocular surface, reduction of staining according to the oxford scale.

Outcome measures

Outcome measures
Measure	PRO-087 PF n=72 Participants Preservative free (PF) PRO-087 ophthalmic solution. Dropper bottle. Multidose 1 drop every 4 hours for 90 days. PRO-087: 0.1% sodium hyaluronate, free-preservative 0.18% chondroitin sulphate	Systane Ultra n=64 Participants Systane Ultra ophthalmic solution, Dropper bottle, Multidose. 1 drop every 4 hours for 90 days. Systane Ultra: Is a sterile solution containing polyethylene glycol 400, propylene glycol, hydroxypropyl-guar, sorbitol, aminomethylpropanol, boric acid, potassium chloride, sodium chloride and POLYQUAD® (poly-hydronium chloride) 0.001% as preservative.	Systane Ultra PF n=81 Participants Systane Ultra, preservative free ophthalmic solution, single-use vials. 1 drop every 4 hours for 90 days. Systane Ultra Preservative Free: Polyethylene Glycol 400 0.4%Lubricant, Propylene Glycol 0.3% Lubricant,
Corneal Epithelization Defects With Rose of Bengal Normal (0)	80.6 percentage of defects	73.4 percentage of defects	77.8 percentage of defects
Corneal Epithelization Defects With Rose of Bengal Very mild (1)	18.1 percentage of defects	25 percentage of defects	19.1 percentage of defects
Corneal Epithelization Defects With Rose of Bengal Mild (2)	1.4 percentage of defects	1.6 percentage of defects	3.1 percentage of defects
Corneal Epithelization Defects With Rose of Bengal Moderate (3)	0 percentage of defects	0 percentage of defects	0 percentage of defects
Corneal Epithelization Defects With Rose of Bengal Severe (4)	0 percentage of defects	0 percentage of defects	0 percentage of defects

SECONDARY outcome

Timeframe: Base line and Final Visit (day 90)

Tear breakup time (TBUT) is a clinical test used to assess for evaporative dry eye disease. To measure TBUT, fluorescein is instilled into the patient's tear film and the patient is asked not to blink while the tear film is observed under a broad beam of cobalt blue illumination. The TBUT is recorded as the number of seconds that elapse between the last blink and the appearance of the first dry spot in the tear film, as seen in this progression of these slit lamps photos over time. A TBUT under 10 seconds is considered abnormal

Outcome measures

Outcome measures
Measure	PRO-087 PF n=72 Participants Preservative free (PF) PRO-087 ophthalmic solution. Dropper bottle. Multidose 1 drop every 4 hours for 90 days. PRO-087: 0.1% sodium hyaluronate, free-preservative 0.18% chondroitin sulphate	Systane Ultra n=64 Participants Systane Ultra ophthalmic solution, Dropper bottle, Multidose. 1 drop every 4 hours for 90 days. Systane Ultra: Is a sterile solution containing polyethylene glycol 400, propylene glycol, hydroxypropyl-guar, sorbitol, aminomethylpropanol, boric acid, potassium chloride, sodium chloride and POLYQUAD® (poly-hydronium chloride) 0.001% as preservative.	Systane Ultra PF n=81 Participants Systane Ultra, preservative free ophthalmic solution, single-use vials. 1 drop every 4 hours for 90 days. Systane Ultra Preservative Free: Polyethylene Glycol 400 0.4%Lubricant, Propylene Glycol 0.3% Lubricant,
Tear Film Break-up Time (TBUT) Base Line	7.08 seconds Standard Deviation 1.01	7.10 seconds Standard Deviation 1.01	7.10 seconds Standard Deviation 1.01
Tear Film Break-up Time (TBUT) Final visit	8.28 seconds Standard Deviation 2.3	8.46 seconds Standard Deviation 2.6	8.52 seconds Standard Deviation 2.2

SECONDARY outcome

Timeframe: Base line and Final Visit (day 90)

Schirmer's test determines whether the eye produces enough tears to keep it moist. This test is used when a person experiences very dry eyes or excessive watering of the eyes. It poses no risk to the subject. A negative (more than 10 mm of moisture on the filter paper in 5 minutes) test result is normal. Both eyes normally secrete the same amount of tears.

Outcome measures

Outcome measures
Measure	PRO-087 PF n=72 Participants Preservative free (PF) PRO-087 ophthalmic solution. Dropper bottle. Multidose 1 drop every 4 hours for 90 days. PRO-087: 0.1% sodium hyaluronate, free-preservative 0.18% chondroitin sulphate	Systane Ultra n=64 Participants Systane Ultra ophthalmic solution, Dropper bottle, Multidose. 1 drop every 4 hours for 90 days. Systane Ultra: Is a sterile solution containing polyethylene glycol 400, propylene glycol, hydroxypropyl-guar, sorbitol, aminomethylpropanol, boric acid, potassium chloride, sodium chloride and POLYQUAD® (poly-hydronium chloride) 0.001% as preservative.	Systane Ultra PF n=81 Participants Systane Ultra, preservative free ophthalmic solution, single-use vials. 1 drop every 4 hours for 90 days. Systane Ultra Preservative Free: Polyethylene Glycol 400 0.4%Lubricant, Propylene Glycol 0.3% Lubricant,
Schirmer Test basal visit (day 1)	9.48 mm Standard Deviation 2.5	9.05 mm Standard Deviation 2.7	9.25 mm Standard Deviation 2.7
Schirmer Test Final Visit	10.19 mm Standard Deviation 4.2	12.21 mm Standard Deviation 4.5	12.16 mm Standard Deviation 5.6

SECONDARY outcome

Timeframe: 90 days

Population: Statistical analysis was performed by protocol (PP)

Presence of adverse events modifying some of the abovementioned criteria or others, evaluated as serious.

Outcome measures

Outcome measures
Measure	PRO-087 PF n=120 Participants Preservative free (PF) PRO-087 ophthalmic solution. Dropper bottle. Multidose 1 drop every 4 hours for 90 days. PRO-087: 0.1% sodium hyaluronate, free-preservative 0.18% chondroitin sulphate	Systane Ultra n=109 Participants Systane Ultra ophthalmic solution, Dropper bottle, Multidose. 1 drop every 4 hours for 90 days. Systane Ultra: Is a sterile solution containing polyethylene glycol 400, propylene glycol, hydroxypropyl-guar, sorbitol, aminomethylpropanol, boric acid, potassium chloride, sodium chloride and POLYQUAD® (poly-hydronium chloride) 0.001% as preservative.	Systane Ultra PF n=97 Participants Systane Ultra, preservative free ophthalmic solution, single-use vials. 1 drop every 4 hours for 90 days. Systane Ultra Preservative Free: Polyethylene Glycol 400 0.4%Lubricant, Propylene Glycol 0.3% Lubricant,
Adverse Events	19.2 percentage of adverse events	21.1 percentage of adverse events	20.6 percentage of adverse events

SECONDARY outcome

Timeframe: Change from Baseline OSDI at 90 days

Population: The statistical analysis was carried out by intention to treat

The OSDI, which was created to order to quickly assess the symptoms of ocular irritation in dry eye disease and how they affect functioning related to vision. This 12-item questionnaire assesses dry eye symptoms and the effects it has on vision-related function in the past of the patient's life. The questionnaire has 3 subscales: ocular symptoms, vision-related function, and environmental triggers. Patients rate their responses on a 0 to 4 scale with 0 corresponding to "none of the time" and 4 corresponding to "all of the time." A final score is calculated which ranges from 0 to 100 with scores 0 to 12 representing normal, 13 to 22 representing mild dry eye disease, 23 to 32 representing moderate dry eye disease, and greater than 33 representing severe dry eye disease.

Outcome measures

Outcome measures
Measure	PRO-087 PF n=72 Participants Preservative free (PF) PRO-087 ophthalmic solution. Dropper bottle. Multidose 1 drop every 4 hours for 90 days. PRO-087: 0.1% sodium hyaluronate, free-preservative 0.18% chondroitin sulphate	Systane Ultra n=64 Participants Systane Ultra ophthalmic solution, Dropper bottle, Multidose. 1 drop every 4 hours for 90 days. Systane Ultra: Is a sterile solution containing polyethylene glycol 400, propylene glycol, hydroxypropyl-guar, sorbitol, aminomethylpropanol, boric acid, potassium chloride, sodium chloride and POLYQUAD® (poly-hydronium chloride) 0.001% as preservative.	Systane Ultra PF n=81 Participants Systane Ultra, preservative free ophthalmic solution, single-use vials. 1 drop every 4 hours for 90 days. Systane Ultra Preservative Free: Polyethylene Glycol 400 0.4%Lubricant, Propylene Glycol 0.3% Lubricant,
Ocular Surface Disease Index (OSDI) Base Line	16.59 score on a scale Standard Deviation 7.3	15.74 score on a scale Standard Deviation 7.0	16.31 score on a scale Standard Deviation 7.7
Ocular Surface Disease Index (OSDI) Final Visit	5.99 score on a scale Standard Deviation 8.2	7.47 score on a scale Standard Deviation 8.8	6.32 score on a scale Standard Deviation 7.7

SECONDARY outcome

Timeframe: Change from Baseline Goblet cells population at 90 days

Population: the statistical analysis was carried out by intention to treat

Increase of 20% from baseline

Outcome measures

Outcome measures
Measure	PRO-087 PF n=72 Participants Preservative free (PF) PRO-087 ophthalmic solution. Dropper bottle. Multidose 1 drop every 4 hours for 90 days. PRO-087: 0.1% sodium hyaluronate, free-preservative 0.18% chondroitin sulphate	Systane Ultra n=64 Participants Systane Ultra ophthalmic solution, Dropper bottle, Multidose. 1 drop every 4 hours for 90 days. Systane Ultra: Is a sterile solution containing polyethylene glycol 400, propylene glycol, hydroxypropyl-guar, sorbitol, aminomethylpropanol, boric acid, potassium chloride, sodium chloride and POLYQUAD® (poly-hydronium chloride) 0.001% as preservative.	Systane Ultra PF n=81 Participants Systane Ultra, preservative free ophthalmic solution, single-use vials. 1 drop every 4 hours for 90 days. Systane Ultra Preservative Free: Polyethylene Glycol 400 0.4%Lubricant, Propylene Glycol 0.3% Lubricant,
Goblet Cells Population Base Line	341.2 cells/mm^2 Standard Deviation 136.9	338.5 cells/mm^2 Standard Deviation 150.6	327.4 cells/mm^2 Standard Deviation 146.8
Goblet Cells Population Final Visit	447.3 cells/mm^2 Standard Deviation 173.4	413.5 cells/mm^2 Standard Deviation 157.7	442.6 cells/mm^2 Standard Deviation 147.2

SECONDARY outcome

Timeframe: Final Visit (day 90)

Population: the statistical analysis was carried out by intention to treat

Percentage of the damaged epithelium of the ocular surface, reduction of staining according to the oxford scale.

Outcome measures

Outcome measures
Measure	PRO-087 PF n=72 Participants Preservative free (PF) PRO-087 ophthalmic solution. Dropper bottle. Multidose 1 drop every 4 hours for 90 days. PRO-087: 0.1% sodium hyaluronate, free-preservative 0.18% chondroitin sulphate	Systane Ultra n=64 Participants Systane Ultra ophthalmic solution, Dropper bottle, Multidose. 1 drop every 4 hours for 90 days. Systane Ultra: Is a sterile solution containing polyethylene glycol 400, propylene glycol, hydroxypropyl-guar, sorbitol, aminomethylpropanol, boric acid, potassium chloride, sodium chloride and POLYQUAD® (poly-hydronium chloride) 0.001% as preservative.	Systane Ultra PF n=81 Participants Systane Ultra, preservative free ophthalmic solution, single-use vials. 1 drop every 4 hours for 90 days. Systane Ultra Preservative Free: Polyethylene Glycol 400 0.4%Lubricant, Propylene Glycol 0.3% Lubricant,
Corneal Epithelization Defects With Fluorescein Severe (4)	0 percentage of defects	0.8 percentage of defects	0 percentage of defects
Corneal Epithelization Defects With Fluorescein Normal (0)	52.8 percentage of defects	53.1 percentage of defects	53.7 percentage of defects
Corneal Epithelization Defects With Fluorescein Very mild (1)	36.8 percentage of defects	36.7 percentage of defects	10.4 percentage of defects
Corneal Epithelization Defects With Fluorescein Mild (2)	10.4 percentage of defects	9.4 percentage of defects	15.4 percentage of defects
Corneal Epithelization Defects With Fluorescein Moderate (3)	0 percentage of defects	0 percentage of defects	2.5 percentage of defects

Adverse Events

PRO-087 PF

Serious events: 0 serious events

Other events: 24 other events

Deaths: 0 deaths

Systane Ultra

Serious events: 0 serious events

Other events: 29 other events

Deaths: 0 deaths

Systane Ultra PF

Serious events: 0 serious events

Other events: 19 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Additional Information

Ricardo Alonso Llamas Velázquez (clinical safety pharmacologist)

Laboratorios Sophia

Phone: +52 (33) 3001 4200

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee IPs may not share, disclose or partially or completely publish the information of this research in order to request and receive written approval from the sponsor.
Publication restrictions are in place

Restriction type: OTHER

Measure	PRO-087 PF n=120 participants at risk Preservative free (PF) PRO-087 ophthalmic solution. Dropper bottle. Multidose 1 drop every 4 hours for 90 days. PRO-087: 0.1% sodium hyaluronate, free-preservative 0.18% chondroitin sulphate	Systane Ultra n=109 participants at risk Systane Ultra ophthalmic solution, Dropper bottle, Multidose. 1 drop every 4 hours for 90 days. Systane Ultra: Is a sterile solution containing polyethylene glycol 400, propylene glycol, hydroxypropyl-guar, sorbitol, aminomethylpropanol, boric acid, potassium chloride, sodium chloride and POLYQUAD® (poly-hydronium chloride) 0.001% as preservative.	Systane Ultra PF n=97 participants at risk Systane Ultra, preservative free ophthalmic solution, single-use vials. 1 drop every 4 hours for 90 days. Systane Ultra Preservative Free: Polyethylene Glycol 400 0.4%Lubricant, Propylene Glycol 0.3% Lubricant,
Eye disorders bacterial conjunctivitis	2.5% 3/120 • Number of events 3 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.	0.00% 0/109 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.	0.00% 0/97 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.
Eye disorders blepharitis	0.00% 0/120 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.	0.92% 1/109 • Number of events 1 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.	0.00% 0/97 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.
Gastrointestinal disorders enteroviric gastroenteritis	0.00% 0/120 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.	1.8% 2/109 • Number of events 2 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.	0.00% 0/97 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.
Eye disorders Defect of the corneal epithelium	5.0% 6/120 • Number of events 6 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.	5.5% 6/109 • Number of events 6 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.	4.1% 4/97 • Number of events 4 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.
Renal and urinary disorders Bacterial urinary infection	0.00% 0/120 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.	0.00% 0/109 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.	1.0% 1/97 • Number of events 1 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.
Gastrointestinal disorders Episodes of aggravated nausea	0.00% 0/120 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.	0.92% 1/109 • Number of events 1 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.	0.00% 0/97 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.
Respiratory, thoracic and mediastinal disorders Faringoamigdalitis	0.00% 0/120 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.	1.8% 2/109 • Number of events 2 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.	1.0% 1/97 • Number of events 1 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.
Renal and urinary disorders Urethritis	1.7% 2/120 • Number of events 2 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.	0.00% 0/109 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.	0.00% 0/97 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.
Nervous system disorders Headache	0.83% 1/120 • Number of events 1 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.	0.92% 1/109 • Number of events 1 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.	3.1% 3/97 • Number of events 3 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.
Gastrointestinal disorders Bacterial gastroenteritis	0.00% 0/120 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.	0.00% 0/109 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.	1.0% 1/97 • Number of events 1 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.
General disorders Anxiety	0.00% 0/120 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.	0.92% 1/109 • Number of events 1 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.	0.00% 0/97 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.
Eye disorders Allergic conjunctivitis	0.83% 1/120 • Number of events 1 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.	3.7% 4/109 • Number of events 4 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.	1.0% 1/97 • Number of events 1 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.
Respiratory, thoracic and mediastinal disorders cough	0.83% 1/120 • Number of events 1 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.	0.00% 0/109 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.	0.00% 0/97 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.
Eye disorders Eyelid spasm	0.00% 0/120 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.	0.92% 1/109 • Number of events 1 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.	0.00% 0/97 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.
General disorders Nuisance in the area of application	0.83% 1/120 • Number of events 1 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.	0.00% 0/109 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.	0.00% 0/97 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.
Skin and subcutaneous tissue disorders Contact dermatitis	0.83% 1/120 • Number of events 1 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.	0.00% 0/109 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.	1.0% 1/97 • Number of events 1 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.
Musculoskeletal and connective tissue disorders Flexo-extension injury	0.83% 1/120 • Number of events 1 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.	0.00% 0/109 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.	0.00% 0/97 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.
Respiratory, thoracic and mediastinal disorders flu	1.7% 2/120 • Number of events 2 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.	0.00% 0/109 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.	1.0% 1/97 • Number of events 1 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.
Eye disorders Feeling of burning	1.7% 2/120 • Number of events 2 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.	0.92% 1/109 • Number of events 1 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.	2.1% 2/97 • Number of events 2 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.
Eye disorders Blurry vision	0.00% 0/120 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.	1.8% 2/109 • Number of events 2 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.	0.00% 0/97 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.
Eye disorders Red eye	0.83% 1/120 • Number of events 1 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.	0.92% 1/109 • Number of events 1 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.	3.1% 3/97 • Number of events 3 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.
Eye disorders Prurito en el ojo	2.5% 3/120 • Number of events 3 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.	2.8% 3/109 • Number of events 3 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.	2.1% 2/97 • Number of events 2 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.
General disorders Light fever	0.00% 0/120 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.	0.00% 0/109 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.	1.0% 1/97 • Number of events 1 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.
Ear and labyrinth disorders Ringing in ears	0.00% 0/120 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.	0.92% 1/109 • Number of events 1 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.	0.00% 0/97 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.
Eye disorders Tearing	3.3% 4/120 • Number of events 4 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.	0.00% 0/109 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.	2.1% 2/97 • Number of events 2 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.
Gastrointestinal disorders Food poisoning	0.00% 0/120 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.	0.00% 0/109 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.	1.0% 1/97 • Number of events 1 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.
Skin and subcutaneous tissue disorders Cellulitis of the finger	0.83% 1/120 • Number of events 1 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.	0.00% 0/109 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.	0.00% 0/97 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.
Eye disorders Foreign body sensation in the eyes	0.83% 1/120 • Number of events 1 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.	1.8% 2/109 • Number of events 2 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.	1.0% 1/97 • Number of events 1 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.
Eye disorders Eye pain	0.00% 0/120 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.	0.92% 1/109 • Number of events 1 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.	0.00% 0/97 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.
Skin and subcutaneous tissue disorders Allergy	0.00% 0/120 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.	0.92% 1/109 • Number of events 1 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.	0.00% 0/97 • Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.