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Clinical Trial Results:
An open-label study evaluating safety and efficacy of recombinant human nerve growth factor (rhNGF) eye drops at different doses in patients with Dry Eye

Summary
EudraCT number	2013-004271-12
Trial protocol	AT
Global end of trial date	30 Jan 2015

Results information
Results version number	v1(current)
This version publication date	02 Oct 2016
First version publication date	02 Oct 2016
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

NGF0213

ISRCTN number

US NCT number

NCT02101281

WHO universal trial number (UTN)

Sponsor organisation name

Dompé farmaceutici spa

Sponsor organisation address

Via Santa Lucia 6, Milano, Italy, 20122

Public contact

Medical Expert, Dompé farmaceutici spa, +39 02583831, flavio.mantelli@dompe.com

Scientific contact

Medical Expert, Dompé farmaceutici spa, +39 02583831, flavio.mantelli@dompe.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

02 Jul 2015

Is this the analysis of the primary completion data?

Yes

Primary completion date

30 Jan 2015

Global end of trial reached?

Yes

Global end of trial date

30 Jan 2015

Was the trial ended prematurely?

Main objective of the trial

The primary objective of this study is to assess the efficacy and safety of different doses of rhNGF when administered as eye drops to patients with Dry Eye. on the basis of the following assessments: - Symptom Assessment in Dry Eye (SANDE) - Ocular surface vital staining (National Eye Institute [NEI] scales) - Schirmer test type I (without anaesthesia) performed on days 1, 8±1, 29±1 and 56±4. Changes from baseline (screening visit) will be evaluated. - Treatment-emergent adverse events (TEAEs), assessed throughout the study

Protection of trial subjects

The study protocol final version 2.0, 10JAN14, the Investigator’s brochure and all other relevant documentation were reviewed and approved by an independent Ethics Committee (Ethik-Kommission der Medizinischen Fakultät der Universität Wien und des Allgemeines Krankenhauses der Stadt Wien AKH", Vienna; Appendix 16.1.3) on 20JAN14. Ref. nr. 2029/2013. The study was performed in accordance with the relevant guidelines and the Declaration of Helsinki. The present clinical trial was carried out according to the general principles of: “ICH Harmonised Tripartite Guidelines for Good Clinical Practice “ICH Topic E6, CPMP/ICH/135/95, July 1996 including post Step 4 errata, status September 1997 and post Step 5 errata (linguistic corrections), July 2002. Before being admitted to the clinical study, subjects expressed their consent to participate. The investigator explained the nature, scope and possible consequences of the clinical study in an understandable form. Information was provided to the subjects in both oral and written form. Each patient received a copy of the written informed consent form, signed by them and the investigator.

Background therapy

Required use of artificial tears for the treatment of dry eye within the 3 months prior to study enrolment. Current use or recommended use of artificial tears for the treatment of dry eye.

Evidence for comparator

N.A.

Actual start date of recruitment

24 Mar 2014

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Austria: 40

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

All patients have been recruited in Department of Clinical Pharmacology, Medical University and General Hospital of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria. The date of first enrolment was on 24 March 2014 and the last vol. completed on 30 January 2015.

Screening details

All patients are screened basing on the inclusion and exclusion criteria and than enrolled.

Number of subjects started

Number of subjects completed

Period 1 title

overall trial (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Group 1

Arm description

Group 1: rhNGF 20 μg/mL: 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. Batch: f14131; expiry: OCT14. At the end of the 1st study part (Group 1), the primary efficacy and safety parameters were analysed. Dose escalation proceeded with Group 2 since there were no safety findings that could pose unacceptable risks to patients. In detail, the study continued with the dose of 4 μg/mL since at least 2 out of the 3 primary efficacy parameters improved in Group 1.

Arm type

Experimental

Investigational medicinal product name

rhNGF 20 μg/mL

Investigational medicinal product code

Other name

Pharmaceutical forms

Eye drops, solution

Routes of administration

Ophthalmic use

Dosage and administration details

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.

Group 2

Arm description

Group 2: rhNGF 4 μg/mL: 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.

Arm type

Experimental

Investigational medicinal product name

rhNGF 4 μg/mL

Investigational medicinal product code

Other name

Pharmaceutical forms

Eye drops, solution

Routes of administration

Ophthalmic use

Dosage and administration details

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

Number of subjects in period 1	Group 1	Group 2
Started	20	20
Completed	20	20

Baseline characteristics

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Reporting group title

Group 1

Reporting group description

Reporting group title

Group 2

Reporting group description

Reporting group values	Group 1	Group 2	Total
Number of subjects	20	20	40
Age categorical
Units: Subjects
Adults (18-64 years)	18	14	32
From 65-84 years	2	6	8
85 years and over	0	0	0
Age continuous
Male and female patients ≥18 year old with dry eye syndrome. Patients with severe dry eye due to primary or secondary Sjogren`s syndrome (due to polyarthritis) or a graft versus host disease (GvHD) and diabetes etc. could be included in the study. For each treatment group not less than 6 subjects had a severe dry eye condition according to the Report of the International Dry Eye Workshop (DEWS), 2007 (2).
Units: years
arithmetic mean (standard deviation)	48.4 ± 12	55.9 ± 14.8	-
Gender categorical
Units: Subjects
Female	16	17	33
Male	4	3	7

Subject analysis set title

FAS (symptoms assessment in dry eye,gruppo 1)

Subject analysis set type

Full analysis

Subject analysis set description

Full Analysis Set (FAS): all enrolled patients who received at least one dose of the IMP L . This analysis set was used for the efficacy analysis. Group 1: rhNGF 20 μg/mL

Subject analysis set title

PP (Symptom assessment in dry eye gruppo 1)

Subject analysis set type

Per protocol

Subject analysis set description

Per Protocol set (PP): all enrolled patients who received at least one dose of the IMP fulfilled the study protocol requirements in terms of IMP intake and collection of primary efficacy data and with no major deviations that could affect study results. This analysis set was used for the efficacy analysis. Group 2 : rhNGF 20 μg/m

Subject analysis set title

FAS (Symptom assessment in dry eye gruppo 2)

Subject analysis set type

Full analysis

Subject analysis set description

Full Analysis Set (FAS): all enrolled patients who received at least one dose of the IMP. This analysis set was used for the efficacy analysis. Group 2 : rhNGF 4 μg/mL

Subject analysis set title

PP (Symptom assessment in dry eye gruppo2)

Subject analysis set type

Per protocol

Subject analysis set description

Per Protocol set (PP): all enrolled patients who fulfilled the study protocol requirements in terms of IMP intake and collection of primary efficacy data and with no major deviations that could affect study results. This analysis set was used for the efficacy analysis. Group 2 : rhNGF 4 μg/mL

Subject analysis sets values	FAS (symptoms assessment in dry eye,gruppo 1)	PP (Symptom assessment in dry eye gruppo 1)	FAS (Symptom assessment in dry eye gruppo 2)	PP (Symptom assessment in dry eye gruppo2)
Number of subjects	20	14	20	16
Age categorical
Units: Subjects
Adults (18-64 years)
From 65-84 years
85 years and over
Age continuous
Male and female patients ≥18 year old with dry eye syndrome. Patients with severe dry eye due to primary or secondary Sjogren`s syndrome (due to polyarthritis) or a graft versus host disease (GvHD) and diabetes etc. could be included in the study. For each treatment group not less than 6 subjects had a severe dry eye condition according to the Report of the International Dry Eye Workshop (DEWS), 2007 (2).
Units: years
arithmetic mean (standard deviation)	48.4 ± 12	46.9 ± 11.4	55.9 ± 14.8	56.3 ± 13.4
Gender categorical
Units: Subjects
Female	16	11	17	14
Male	4	3	3	2

End points

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Reporting group title

Group 1

Reporting group description

Reporting group title

Group 2

Reporting group description

Subject analysis set title

FAS (symptoms assessment in dry eye,gruppo 1)

Subject analysis set type

Full analysis

Subject analysis set description

Full Analysis Set (FAS): all enrolled patients who received at least one dose of the IMP L . This analysis set was used for the efficacy analysis. Group 1: rhNGF 20 μg/mL

Subject analysis set title

PP (Symptom assessment in dry eye gruppo 1)

Subject analysis set type

Per protocol

Subject analysis set description

Subject analysis set title

FAS (Symptom assessment in dry eye gruppo 2)

Subject analysis set type

Full analysis

Subject analysis set description

Full Analysis Set (FAS): all enrolled patients who received at least one dose of the IMP. This analysis set was used for the efficacy analysis. Group 2 : rhNGF 4 μg/mL

Subject analysis set title

PP (Symptom assessment in dry eye gruppo2)

Subject analysis set type

Per protocol

Subject analysis set description

Primary: Symptom assessment in dry eye (SANDE)

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End point title

Symptom assessment in dry eye (SANDE)

End point description

The SANDE questionnaire was a short questionnaire to evaluate both dry eye intensity and frequency by using a 100-mm VAS. The patient symptoms of ocular dryness and/or irritation were quantified on the scale based on two questions that inquired about both severity and frequency of symptoms. The patients evaluated their symptoms using the VAS giving the value they were feeling from none to an extreme value. Each VAS value was measured in millimetres from the left end of the line to each patient’s mark. The question about symptom severity and the question about symptom irritation were evaluated through 2 distinct 100-mm VAS. VAS values of SANDE and their changes from baseline are listed and summarised using descriptive statistics by dose group, disease severity at screening and evaluation visit. VAS values of SANDE were compared within dose group, disease severity and evaluation visit versus their baseline values by a two-sided Wilcoxon signed-rank test with a nominal α level of 0.05

End point type

Primary

End point timeframe

visit 1 (Screening day-15 up to day-1), visit 2 (day 1), visit 3(day 1 to day 7+-1), visit 6 (day 29+-1) and final visit(visit 7, day 54+-4 /EVT)

End point values	FAS (symptoms assessment in dry eye,gruppo 1)	PP (Symptom assessment in dry eye gruppo 1)	FAS (Symptom assessment in dry eye gruppo 2)	PP (Symptom assessment in dry eye gruppo2)
Number of subjects analysed	20	14	20	16
Units: 100 mm VAS
arithmetic mean (standard deviation)
overall visit 1-frequency	55.3 ± 27.3	56.6 ± 29.2	59.7 ± 29.2	50.6 ± 25.2
overall visit 2-frequency	47.3 ± 24.2	45.1 ± 24.8	49.7 ± 22.4	45.8 ± 21
overall visit 3-frequency	40.3 ± 23.1	39.4 ± 22.3	36.4 ± 23.8	32.3 ± 24.9
overall visit 6-frequency	28.4 ± 26.2	27.1 ± 25.3	33.5 ± 26.4	28.4 ± 23.1
overall final visit-frequency	25.2 ± 26.5	26.9 ± 26.8	31.7 ± 26.8	23.3 ± 22
overall visit 1-severity	52.8 ± 23.2	54.1 ± 23.3	60.1 ± 29.6	54.1 ± 28.7
overall visit 2-severity	45.3 ± 23.7	43.1 ± 23.8	50.3 ± 21.6	46.9 ± 21.9
overall visit 3-severity	41.1 ± 23.1	39.6 ± 22.2	39.1 ± 27	33.5 ± 26.6
overall visit 6-severity	25.9 ± 26.9	24.7 ± 25.7	31.5 ± 25.5	26.9 ± 21.7
overall final visit-severity	23.9 ± 28.1	25.8 ± 28.1	31.9 ± 27.9	22.4 ± 20.9

Attachments

End Point

Symptom assessment in dry eye-SANDE, Full analysis

Statistical analysis description

VAS values of symptom assessment in dry eye and their changes from baseline (screening visit assessment) will be listed and summarised using classic descriptive statistics (i.e. arithmetic mean, SD, CV (%), minimum, median and maximum values) by dose group, disease severity at screening and evaluation visit.

Comparison groups

FAS (symptoms assessment in dry eye,gruppo 1) v PP (Symptom assessment in dry eye gruppo 1) v FAS (Symptom assessment in dry eye gruppo 2) v PP (Symptom assessment in dry eye gruppo2)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

equivalence

P-value

< 0.05

Method

Wilcoxon (Mann-Whitney)

Parameter type

Mean difference (net)

Point estimate

0.1

Confidence interval

level

80%

sides

2-sided

lower limit

upper limit

Variability estimate

Standard deviation

Dispersion value

26.5

Primary: Ocular surface vital staining with lissamine green (LG) (National Eye Institute [NEI] scales)

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End point title

Ocular surface vital staining with lissamine green (LG) (National Eye Institute [NEI] scales)

End point description

LG impregnated paper strips (EasyOpht, Italy) containing 1.5 mg of the dye were used to detect conjunctival and corneal epithelial defects. As grading scale of the corneal and conjunctival damage, the NEI/Industry Workshop guideline was used. 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. Both nasally and temporally, the conjunctiva was 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. Before placing the strip in the lower fornix of the eye, a drop of sterile saline was added to the strip.

End point type

Primary

End point timeframe

visit 1 (Screening day-15 up to day-1), visit 2 (day 1), visit 3(day 1 to day 7+-1), visit 6 (day 29+-1) and final visit(visit 7, day 54+-4 /EVT)

End point values	FAS (symptoms assessment in dry eye,gruppo 1)	PP (Symptom assessment in dry eye gruppo 1)	FAS (Symptom assessment in dry eye gruppo 2)	PP (Symptom assessment in dry eye gruppo2)
Number of subjects analysed	20	20	20	20
Units: millimeter(s)
arithmetic mean (standard deviation)
overall visit 2-study eye	11.8 ± 3.5	11.9 ± 3.6	12.9 ± 5.4	12 ± 4
overall visit 3-study eye	7.4 ± 2.8	7.6 ± 3.1	10.4 ± 5.5	9.2 ± 4.4
overall visit 6-study eye	3.8 ± 3.1	3.9 ± 3.3	7.5 ± 4.8	7.2 ± 4.6
overall final visit -study eye	5.5 ± 3.2	6.1 ± 3.5	7.7 ± 5.3	7.1 ± 5.3
overall visit 2- non study eye	10.3 ± 4.1	9.9 ± 4.4	9.1 ± 6.1	8.1 ± 4
overall visit 3- non study eye	7.3 ± 3.9	7.4 ± 3.3	9.3 ± 6.1	8.1 ± 5.2
overall visit 6- non study eye	4.1 ± 3.6	4.2 ± 3.3	7.6 ± 5.7	7.1 ± 5.6
overall final visit - non study eye	5 ± 4.4	5.2 ± 4.7	7.3 ± 5.5	6.9 ± 5.7

Attachments

End Point

Ocular surface staining with Lissamine green [NEI]

Statistical analysis description

Ocular surface staining with Lissamine green scores, total corneal staining score, total conjunctival staining score and total staining score and their changes from baseline (screening visit assessment) will be listed and summarised using classic descriptive statistics (i.e. arithmetic mean, SD, CV (%), minimum, median and maximum values) by dose group, disease severity at screening, eye (study eye and non study eye) and evaluation visit.

Comparison groups

FAS (symptoms assessment in dry eye,gruppo 1) v PP (Symptom assessment in dry eye gruppo 1) v FAS (Symptom assessment in dry eye gruppo 2) v PP (Symptom assessment in dry eye gruppo2)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

equivalence

P-value

< 0.05

Method

Wilcoxon (Mann-Whitney)

Parameter type

Mean difference (net)

Point estimate

0.1

Confidence interval

level

80%

sides

2-sided

lower limit

upper limit

Variability estimate

Standard deviation

Dispersion value

1.6

Primary: Schirmer test type I (without anaesthesia)

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End point title

Schirmer test type I (without anaesthesia)

End point description

Schirmer plus® strips (Gecis, France) were used. This test was performed to measure aqueous tear secretion prior to the instillation of any dilating or anaesthetic eye drops. Both eyes could be tested at the same time. While the patient was looking upwards, the lower lid was drawn gently downwards and temporarily. The rounded bent end of a sterile strip was inserted into the lower conjunctival sac over the temporal one-third of the lower eyelid margin, without touching directly the Schirmer test strip with the fingers.After 5 min, the Schirmer test strip was removed and the length of the tear absorption on the strip was measured (millimeters/5 min). The wetting distance at 5 min for each eye was recorded. Values of Schirmer's test type I (i.e. tear wetting distance at 5 min) 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.

End point type

Primary

End point timeframe

visit 1(screening day -15 up to day -1), visit 2 (day 1), visit 3 (day 8+-1), visit 6 (day 29+-1), final visit( visit 7, day 56+-4/ETV)

End point values	FAS (symptoms assessment in dry eye,gruppo 1)	PP (Symptom assessment in dry eye gruppo 1)	FAS (Symptom assessment in dry eye gruppo 2)	PP (Symptom assessment in dry eye gruppo2)
Number of subjects analysed	20	14	20	16
Units: mm/ 5minuti
arithmetic mean (standard deviation)
overall Visit 2 - Study Eye	5.4 ± 5.7	5.4 ± 5.7	6.5 ± 6.7	7.3 ± 7.2
overall Visit 3 - Study Eye	8.6 ± 9	5.9 ± 6.8	5.9 ± 6.8	6.6 ± 7.3
overall Visit 6 - Study Eye	9.4 ± 7.8	8.4 ± 8.1	8.2 ± 6.8	8.8 ± 6.9
overall Final Visit - Study Eye	8.7 ± 10.2	7.7 ± 9.6	9.8 ± 8.8	10.8 ± 8.9
overall Visit 2 - Non Study Eye	10.1 ± 8.1	9.4 ± 6.2	8.6 ± 8.7	10.2 ± 9.1
overall Visit 3- Non Study Eye	7.4 ± 9.4	4.6 ± 5.5	7.5 ± 8.1	8.9 ± 8.5
overall Visit 6 - Non Study Eye	11.4 ± 10.7	10.8 ± 11.2	9.4 ± 8.4	10.8 ± 8.3
overall Final Visit - Non Study Eye	8.8 ± 8.8	7.6 ± 8.4	9.6 ± 9.5	11.3 ± 9.9

Attachments

End Point

Schirmer's test type I (without anaesthesia)

Statistical analysis description

Values of Schirmer's test type I (i.e. tear wetting distance at 5 minutes) and their changes from baseline (screening visit assessment) will be listed and summarised using classic descriptive statistics (i.e. arithmetic mean, SD, CV (%), minimum, median and maximum values) by dose group, disease severity at screening, eye (study eye and non study eye) and evaluation visit.

Comparison groups

FAS (symptoms assessment in dry eye,gruppo 1) v PP (Symptom assessment in dry eye gruppo 1) v FAS (Symptom assessment in dry eye gruppo 2) v PP (Symptom assessment in dry eye gruppo2)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

equivalence

P-value

< 0.05

Method

Wilcoxon (Mann-Whitney)

Parameter type

Mean difference (net)

Point estimate

0.1

Confidence interval

level

80%

sides

2-sided

lower limit

upper limit

Variability estimate

Standard deviation

Dispersion value

10.2

Primary: Treatment-emergent adverse events (TEAEs)

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End point title

Treatment-emergent adverse events (TEAEs)

End point description

AEs were coded by SOC and Preferred Term (PT), using the MedDRA.AEs were classified as pre-treatment AEs (PTAEs) and TEAEs according to the period of occurrence.TEAEs are summarised by dose and overall. The n° and % of patients with any TEAE and the n° of TEAEs are tabulated by SOC and PT, seriousness, relationship to treatment and severity. TEAEs are summarised in tables of frequency. The n° and % of patients with any TEAE, the n° of TEAEs, the n° and % of patients with any TEAE by severity, the n° of TEAEs by severity, the n° and % of patients with any TEAE related to study drug, the n° of TEAEs related to study drug are presented.Serious TEAEs are summarised by dose.The n° and % of patients with any serious TEAE, the n° of serious TEAEs, the n° and % of patients with any serious TEAE,n° of serious TEAEs,n° and % of patients with any serious TEAE related to study drug and n° of serious TEAEs related to study drug are presented.

End point type

Primary

End point timeframe

after the first dose of IMP.

End point values	Group 1	Group 2
Number of subjects analysed	20	20
Units: number of TEAEs
n° of TEAEs	36	65
n° of related TEAEs	11	4
n° of patients with TEAEs	14	15
n° of patients with related TEAEs	8	3

TEAEs

Statistical analysis description

due to the low number patients it was possible to perform only a descriptive analisys calculation of the percentage of unrilated, related and overall TEAEs occured

Comparison groups

Group 2 v Group 1

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0 ^[1]

Method

not provided

Parameter type

not provided

Point estimate

Confidence interval

level

sides

2-sided

lower limit

upper limit

Variability estimate

Standard deviation

Dispersion value

Notes
[1] - not provided

Secondary: Visual analogue scale (VAS) for ocular tolerability (foreign body sensation, burning/stinging, itching, pain, stick feeling, blurred vision and photophobia)

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End point title

Visual analogue scale (VAS) for ocular tolerability (foreign body sensation, burning/stinging, itching, pain, stick feeling, blurred vision and photophobia)

End point description

A global ocular tolerability score was determined using a 100 mm VAS on which 0 meant no symptoms and 100 meant the worst possible discomfort. This evaluation was to be performed before any ophthalmic assessment at each scheduled visit. Specific ocular symptoms to be measured with the VAS included:  foreign body sensation,  burning/stinging,  itching,  pain,  sticky feeling  blurred vision  photophobia The patients evaluated their symptoms using the VAS giving the value they were feeling from none to an extreme value. The patients were expected to complete the evaluation in about 5 min.

End point type

Secondary

End point timeframe

visit 1, visit 2, visit 3, visit 6 and final visit

End point values	FAS (symptoms assessment in dry eye,gruppo 1)	PP (Symptom assessment in dry eye gruppo 1)	FAS (Symptom assessment in dry eye gruppo 2)	PP (Symptom assessment in dry eye gruppo2)
Number of subjects analysed	20	14	20	16
Units: 100 mm VAS
arithmetic mean (standard deviation)
overall visit 2 Foreign B.S. Study Eye	29.6 ± 26.5	27.8 ± 27.1	47.1 ± 28.6	43.3 ± 24.1
overall visit 3 Foreign B.S. Study Eye	22.8 ± 25.3	18.5 ± 25.3	28.4 ± 27.4	27.7 ± 26.3
overall visit 6 Foreign B.S. Study Eye	16.6 ± 24.7	15.5 ± 24.8	18.7 ± 19.5	18.3 ± 20
overall final visit Foreign B.S. Study Eye	17.4 ± 25.8	16.1 ± 25.4	18.4 ± 25.9	12.8 ± 15
overall visit 2 Foreign B.S. Non Study Eye	23 ± 23.3	20.2 ± 21.5	43.4 ± 28.7	40.6 ± 25
overall visit 3 Foreign B.S. Non Study Eye	19.5 ± 23.4	13.7 ± 20.9	34.5 ± 31.2	33.2 ± 31.5
overall visit 6 Foreign B.S. Non Study Eye	14.8 ± 21.1	12.2 ± 17.4	20 ± 23.1	18 ± 20
overall final visit Foreign B.S. Non Study Eye	14.5 ± 21.4	12.7 ± 18.2	20.4 ± 26.5	15.9 ± 19.7
overall visit 2 Burning/Stinging Study Eye	26.9 ± 24.8	22.9 ± 25	39.4 ± 28.6	35.8 ± 25.8
overall visit 3 Burning/Stinging Study Eye	22.4 ± 24.2	17.9 ± 23.7	33.1 ± 28.6	27.6 ± 27.8
overall visit 6 Burning/Stinging Study Eye	15.5 ± 24.7	15.1 ± 24.3	21.2 ± 23.4	19.6 ± 22
overall final visit Burning/Stinging Study Eye	18 ± 25.7	17.2 ± 25.2	16.9 ± 23.6	10.6 ± 11.6
overall visit 2 Burning/Stinging Non Study Eye	23.5 ± 21.6	17.7 ± 18.6	41.4 ± 29.7	37.3 ± 26.6
overall visit 3 Burning/Stinging Non Study Eye	20 ± 22.9	13.5 ± 18.2	27.5 ± 27.7	24.9 ± 27.5
overall visit 6 Burning/Stinging Non Study Eye	12.4 ± 19.1	10.6 ± 16.7	22.6 ± 24.3	20.6 ± 22.3
overall final visit Burning/Stinging Non Study Eye	15.2 ± 21.4	14.1 ± 18.3	20.7 ± 26.7	13.5 ± 17.6
overall visit 2 Itching Study Eye	28.7 ± 26.2	23 ± 27.1	40 ± 30	36.6 ± 26.9
overall visit 3 Itching Study Eye	19.6 ± 18.1	15.6 ± 20.4	29.9 ± 29.9	26.8 ± 30
overall visit 6 Itching Study Eye	12.7 ± 21	14.4 ± 23.7	19.1 ± 22.4	18.8 ± 23.6
overall final visit Itching Study Eye	17.4 ± 26.4	17.5 ± 25.7	18.8 ± 21.9	11.1 ± 12.3
overall visit 2 Itching Non Study Eye	20.5 ± 17.9	16.3 ± 18.6	39 ± 30.9	35.7 ± 28.2
overall visit 3 Itching Non Study Eye	21.1 ± 22.1	13.9 ± 19	29.8 ± 29.8	25.5 ± 31.3
overall visit 6 Itching Non Study Eye	9.5 ± 13.4	10.6 ± 15.8	18.2 ± 22.1	15.9 ± 20.1
overall final visit Itching Non Study Eye	14.7 ± 23.1	14.5 ± 20.2	19.4 ± 23.4	13 ± 15.6
overall visit 2 Pain Study Eye	21.5 ± 24.6	20.3 ± 25.6	27 ± 25	23.4 ± 17.5
overall visit 3 Pain Study Eye	25.3 ± 34.2	24.4 ± 34.6	25.4 ± 27.8	22.9 ± 23.6
overall visit 6 Pain Study Eye	16.3 ± 28.2	15.7 ± 27.4	16.1 ± 24.9	14.3 ± 23.3
overall final visit Pain Study Eye	15.8 ± 27	16 ± 26.5	12.6 ± 20.3	7.6 ± 9.9
overall visit 2 Pain Non Study Eye	13.3 ± 14.5	11.1 ± 16.2	27.3 ± 24.3	23.2 ± 15.9
overall visit 3 Pain Non Study Eye	21.1 ± 30.4	18.7 ± 28.7	29.9 ± 28.2	26.9 ± 26.4
overall visit 6 Pain Non Study Eye	9.6 ± 17.4	7.6 ± 13.8	17.9 ± 24.1	16.6 ± 22.7
overall final visit Pain Non Study Eye	12.7 ± 22.3	11.9 ± 18.6	14.4 ± 23.5	9.2 ± 15.1
overall visit 2 Sticky Feeling Study Eye	21 ± 22	26 ± 24.3	37.4 ± 30.9	34.3 ± 29.5
overall visit 3 Sticky Feeling Study Eye	18.5 ± 21.9	19.3 ± 25.1	21.9 ± 27.3	22.3 ± 27.5
overall visit 6 Sticky Feeling Study Eye	17.5 ± 28.9	16.5 ± 25.7	16.6 ± 26.4	14.6 ± 24.5
overall final visit Sticky Feeling Study Eye	17.1 ± 30.1	17.1 ± 29.7	16.2 ± 23.6	11.2 ± 17.8
overall visit 2 Sticky Feeling Non Study Eye	19.5 ± 21.7	20.2 ± 20.8	31.5 ± 30.5	27.9 ± 28.4
overall visit 3 Sticky Feeling Non Study Eye	16.5 ± 19.9	13.9 ± 16.9	22 ± 27.6	22.1 ± 27.1
overall visit 6 Sticky Feeling Non Study Eye	12.4 ± 23	9.2 ± 13.6	17.7 ± 26.9	15.6 ± 25
overall final visit Sticky Feeling Non Study Eye	15.8 ± 27.6	14.9 ± 24.8	16.4 ± 24.1	11 ± 18.1
overall visit 2 Blurred Vision Study Eye	34.7 ± 25.6	32.7 ± 26.7	47.5 ± 31.7	45.1 ± 28.4
overall visit 3 Blurred Vision Study Eye	28.8 ± 28.5	24.3 ± 29.3	37.3 ± 32.5	34.8 ± 30.4
overall visit 6 Blurred Vision Study Eye	17.7 ± 26.5	16.4 ± 26.2	25.7 ± 28	19.9 ± 21
overall final visit Blurred Vision Study Eye	19.3 ± 27.6	19.6 ± 28.3	26.1 ± 27.9	20.5 ± 21.3
overall visit 2 Blurred Vision Non Study Eye	30.3 ± 21.5	26.9 ± 22.2	43.5 ± 33.5	40.3 ± 30.6
overall visit 3 Blurred Vision Non Study Eye	25.9 ± 25.9	22 ± 25.5	34.5 ± 32.7	30.9 ± 29.5
overall visit 6 Blurred Vision Non Study Eye	16 ± 20.7	14.6 ± 18.1	27.3 ± 28.8	22.3 ± 23.9
overall final visit Blurred Vision Non Study Eye	17 ± 24.9	16.9 ± 23.9	24 ± 28.1	18.4 ± 21.7
overall visit 2 Photophobia Study Eye	38.9 ± 30.6	40.1 ± 30.1	53.1 ± 32.5	56.4 ± 29.7
overall visit 3 Photophobia Study Eye	32.9 ± 30.5	31.9 ± 30.6	37.3 ± 31.7	37.4 ± 33.4
overall visit 6 Photophobia Study Eye	28.4 ± 31.2	30.6 ± 30.3	29.8 ± 34.8	23.8 ± 31.3
overall final visit Photophobia Study Eye	27.7 ± 32.3	29.9 ± 31.5	25.1 ± 26.8	23.7 ± 27.9
overall visit 2 Photophobia Non Study Eye	37 ± 28.2	35.1 ± 27.7	50.1 ± 30.2	52.8 ± 26.7
overall visit 3 Photophobia Non Study Eye	30.3 ± 28	29.4 ± 27	32.2 ± 29.7	31.4 ± 30.8
overall visit 6 Photophobia Non Study Eye	21.9 ± 27.8	21.9 ± 25.8	31 ± 35.5	25.8 ± 33
overall final visit Photophobia Non Study Eye	24.2 ± 29.1	25.7 ± 26.6	24.1 ± 24.4	22.1 ± 24.7

Attachments

End Point

Visual analogue scale (VAS)for ocular tolerability

Statistical analysis description

VAS values for ocular tolerability symptoms and their changes from baseline (screening visit assessment) will be listed and summarised using classic descriptive statistics (i.e. arithmetic mean, SD, CV (%), minimum, median and maximum values) by dose group, disease severity at screening, eye (study eye and non study eye) and evaluation visit.

Comparison groups

FAS (symptoms assessment in dry eye,gruppo 1) v PP (Symptom assessment in dry eye gruppo 1) v FAS (Symptom assessment in dry eye gruppo 2) v PP (Symptom assessment in dry eye gruppo2)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

equivalence

P-value

< 0.05

Method

Wilcoxon (Mann-Whitney)

Parameter type

Mean difference (final values)

Point estimate

17.4

Confidence interval

level

80%

sides

2-sided

lower limit

upper limit

Variability estimate

Standard deviation

Dispersion value

25.8

Secondary: Slit lamp examination (Eyelid - meibomian glands, eyelid – erythema, eyelid - oedema lashes, conjunctiva erythema, lens, iris, anterior chamber)

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End point title

Slit lamp examination (Eyelid - meibomian glands, eyelid – erythema, eyelid - oedema lashes, conjunctiva erythema, lens, iris, anterior chamber)

End point description

The slit lamp examination was performed before the instillation of any dilating or anaesthetic eye drops or the fluorescein agent (Fluorescein Minims, Fluorescein sodium 2%). The patient was sitting at the slit lamp while being examined. Grading of the eyelids, lashes, conjunctiva, cornea, lens, iris and anterior chamber.

End point type

Secondary

End point timeframe

visit 1, visit 2, visit 3, visit 6 and final visit

End point values	FAS (symptoms assessment in dry eye,gruppo 1)	PP (Symptom assessment in dry eye gruppo 1)	FAS (Symptom assessment in dry eye gruppo 2)	PP (Symptom assessment in dry eye gruppo2)
Number of subjects analysed	20	14	20	16
Units: SLE (Slit lamp examination scale)
arithmetic mean (standard deviation)
overall-Eyelid-Meibomian glands-visit 2 Study Eye	1.3 ± 0.8	1.1 ± 0.8	0.5 ± 0.6	0.4 ± 0.5
overall-Eyelid-Meibomian glands-visit 3 Study Eye	1.1 ± 0.7	0.9 ± 0.5	0.3 ± 0.6	0.3 ± 0.4
overall-Eyelid-Meibomian glands-visit 6 Study Eye	0.6 ± 0.8	0.4 ± 0.5	0.4 ± 0.5	0.4 ± 0.5
overall-Eyelid-Meibomian glands-final v-Study Eye	0.8 ± 0.6	0.8 ± 0.6	0.4 ± 0.5	0.4 ± 0.5
overall-Eyelid - Erythema - visit 2 - Study Eye	0.8 ± 0.8	0.8 ± 0.7	0.3 ± 0.7	0.3 ± 0.6
overall-Eyelid - Erythema - visit 3 - Study Eye	0.6 ± 0.6	0.5 ± 0.5	0.4 ± 0.7	0.3 ± 0.7
overall-Eyelid - Erythema - visit 6 - Study Eye	0.2 ± 0.4	0.1 ± 0.3	0.4 ± 0.7	0.4 ± 0.6
overall-Eyelid - Erythema - final visit -Study Eye	0.2 ± 0.4	0.1 ± 0.3	0.3 ± 0.4	0.3 ± 0.4
overall-Eyelid Oedema - visit 2 - Study Eye	0.6 ± 0.6	0.6 ± 0.6	0.3 ± 0.6	0.3 ± 0.6
overall-Eyelid Oedema - visit 3 - Study Eye	0.2 ± 0.4	0.2 ± 0.4	0.4 ± 0.7	0.4 ± 0.7
overall-Eyelid Oedema - visit 6 - Study Eye	0.1 ± 0.2	0.1 ± 0.3	0.4 ± 0.7	0.4 ± 0.6
overall-Eyelid Oedema - final visit - Study Eye	0.1 ± 0.2	0.1 ± 0.3	0.3 ± 0.6	0.3 ± 0.6
overall - Lashes - visit 2- Study Eye	0 ± 0	0 ± 0	0 ± 0	0 ± 0
overall - Lashes - visit 3 - Study Eye	0 ± 0	0 ± 0	0 ± 0	0 ± 0
overall - Lashes - visit 6 - Study Eye	0 ± 0	0 ± 0	0 ± 0	0 ± 0
overall - Lashes - final visit - Study Eye	0 ± 0	0 ± 0	0 ± 0	0 ± 0
overall- Conju.Erythema- visit 2 - Study Eye	1.4 ± 0.5	1.1 ± 0.4	1.3 ± 0.6	1.3 ± 0.6
overall- Conju.Erythema- visit 3 - Study Eye	1.2 ± 0.6	1.1 ± 0.7	1 ± 0.3	1 ± 0.4
overall- Conju.Erythema- visit 6 - Study Eye	1.1 ± 0.5	1 ± 0.4	1 ± 0.6	1 ± 0.5
overall- Conju.Erythema- final visit - Study Eye	1.1 ± 0.6	1.1 ± 0.5	1 ± 0.5	0.9 ± 0.4
overall-Conju.Oedema- visit 2 - Study Eye	1.1 ± 0.9	0.7 ± 0.5	0.6 ± 0.7	0.6 ± 0.6
overall-Conju.Oedema- visit 3 - Study Eye	0.8 ± 0.6	0.8 ± 0.6	0.5 ± 0.5	0.6 ± 0.5
overall-Conju.Oedema- visit 6 - Study Eye	0.5 ± 0.5	0.5 ± 0.5	0.5 ± 0.7	0.5 ± 0.7
overall-Conju.Oedema- final visit - Study Eye	0.9 ± 0.6	0.7 ± 0.5	0.3 ± 0.7	0.3 ± 0.7
overall- Lens - visit 2- Study Eye	0.4 ± 0.5	0.3 ± 0.5	0.4 ± 0.6	0.4 ± 0.7
overall- Lens - visit 3 - Study Eye	0.4 ± 0.5	0.2 ± 0.4	0.4 ± 0.6	0.4 ± 0.7
overall- Lens - visit 6 - Study Eye	0.3 ± 0.5	0.2 ± 0.4	0.3 ± 0.5	0.3 ± 0.5
overall- Lens - final visit - Study Eye	0.3 ± 0.5	0.2 ± 0.4	0.3 ± 0.5	0.3 ± 0.5
overall- Iris - visit 2- Study Eye	0 ± 0	0 ± 0	0 ± 0	0 ± 0
overall- Iris - visit 3- Study Eye	0 ± 0	0 ± 0	0 ± 0	0 ± 0
overall- Iris - visit 6- Study Eye	0 ± 0	0 ± 0	0 ± 0	0 ± 0
overall- Iris - final visit - Study Eye	0 ± 0	0 ± 0	0 ± 0	0 ± 0
overall- Ant.Cham.Infl.- visit 2- Study Eye	0 ± 0	0 ± 0	0 ± 0	0 ± 0
overall- Ant.Cham.Infl.- visit 3 - Study Eye	0 ± 0	0 ± 0	0 ± 0	0 ± 0
overall- Ant.Cham.Infl.- visit 6 - Study Eye	0 ± 0	0 ± 0	0 ± 0	0 ± 0
overall- Ant.Cham.Infl.- final visit - Study Eye	0 ± 0	0 ± 0	0 ± 0	0 ± 0
overall-Eyelid-Meib. glands-visit 2-Non Study Eye	1.1 ± 0.7	0.9 ± 0.6	0.5 ± 0.7	0.5 ± 0.6
overall-Eyelid-Meib. glands-visit 3-Non Study Eye	1 ± 0.7	0.8 ± 0.6	0.5 ± 0.7	0.5 ± 0.6
overall-Eyelid-Meib. glands-visit 6-Non Study Eye	0.7 ± 0.7	0.6 ± 0.5	0.3 ± 0.5	0.3 ± 0.5
overall-EyelidMeibglands-final visit Non Study Eye	0.7 ± 0.7	0.6 ± 0.6	0.4 ± 0.5	0.4 ± 0.5
overall-Eyelid-Erythema- visit 2-Non Study Eye	0.8 ± 0.7	0.7 ± 0.6	0.4 ± 0.8	0.3 ± 0.8
overall-Eyelid-Erythema- visit 3-Non Study Eye	0.6 ± 0.6	0.5 ± 0.5	0.4 ± 0.8	0.3 ± 0.8
overall-Eyelid-Erythema- visit 6-Non Study Eye	0.2 ± 0.4	0.1 ± 0.3	0.3 ± 0.6	0.3 ± 0.4
overall-Eyelid-Erythema-final visit-Non Study Eye	0.2 ± 0.4	0.1 ± 0.3	0.2 ± 0.4	0.2 ± 0.4
overall-Eyelid Oedema-visit 2-Non Study Eye	0.5 ± 0.5	0.5 ± 0.5	0.3 ± 0.6	0.3 ± 0.6
overall-Eyelid Oedema-visit 3-Non Study Eye	0.2 ± 0.4	0.1 ± 0.4	0.4 ± 0.8	0.4 ± 0.9
overall-Eyelid Oedema-visit 6-Non Study Eye	0.1 ± 0.2	0.1 ± 0.3	0.4 ± 0.7	0.3 ± 0.6
overall-Eyelid Oedema-final visit-Non Study Eye	0.1 ± 0.2	0.1 ± 0.3	0.2 ± 0.5	0.2 ± 0.5
overall - Lashes - visit 2- Non Study Eye	0 ± 0	0 ± 0	0 ± 0	0 ± 0
overall - Lashes - visit 3 - Non Study Eye	0 ± 0	0 ± 0	0 ± 0	0 ± 0
overall - Lashes - visit 6 - Non Study Eye	0 ± 0	0 ± 0	0 ± 0	0 ± 0
overall - Lashes -final visit- Non Study Eye	0 ± 0	0 ± 0	0 ± 0	0 ± 0
overall- Conju.Erythe.- visit 2-Non Study Eye	1.4 ± 0.5	1.2 ± 0.4	1.2 ± 0.5	1.2 ± 0.5
overall- Conju.Erythe.- visit 3 -Non Study Eye	1.1 ± 0.6	1 ± 0.6	1.1 ± 0.4	1.1 ± 0.5
overall- Conju.Erythe.- visit 6 -Non Study Eye	1 ± 0.5	1 ± 0.4	0.9 ± 0.6	0.9 ± 0.5
overall- Conju.Erythe.- final visit-Non Study Eye	0.9 ± 0.6	1 ± 0.4	1 ± 0.5	0.9 ± 0.4
overall-Conju.Oedema-visit 2-Non Study Eye	1.1 ± 0.8	0.7 ± 0.5	0.7 ± 0.7	0.7 ± 0.6
overall-Conju.Oedema-visit 3 -Non Study Eye	0.8 ± 0.4	0.8 ± 0.4	0.6 ± 0.6	0.6 ± 0.6
overall-Conju.Oedema-visit 6 -Non Study Eye	0.4 ± 0.5	0.4 ± 0.5	0.5 ± 0.7	0.5 ± 0.7
overall-Conju.Oedema-final visit-Non Study Eye	0.7 ± 0.6	0.6 ± 0.5	0.3 ± 0.7	0.3 ± 0.7
overall- Lens - visit 2- Non Study Eye	0.4 ± 0.5	0.3 ± 0.5	0.3 ± 0.5	0.3 ± 0.5
overall- Lens - visit 3- Non Study Eye	0.4 ± 0.5	0.2 ± 0.4	0.3 ± 0.5	0.3 ± 0.5
overall- Lens - visit 6 - Non Study Eye	0.3 ± 0.5	0.2 ± 0.4	0.3 ± 0.5	0.3 ± 0.5
overall- Lens - final visit - Non Study Eye	0.3 ± 0.5	0.2 ± 0.4	0.3 ± 0.5	0.3 ± 0.5
overall- Iris - visit 2- Non Study Eye	0 ± 0	0 ± 0	0 ± 0	0 ± 0
overall- Iris - visit 3 - Non Study Eye	0 ± 0	0 ± 0	0 ± 0	0 ± 0
overall- Iris - visit 6 - Non Study Eye	0 ± 0	0 ± 0	0 ± 0	0 ± 0
overall- Iris - final visit - Non Study Eye	0 ± 0	0 ± 0	0 ± 0	0 ± 0
overall- Ant.Cham.Infl.- visit 2- Non Study Eye	0 ± 0	0 ± 0	0 ± 0	0 ± 0
overall- Ant.Cham.Infl.- visit 3 - Non Study Eye	0 ± 0	0 ± 0	0 ± 0	0 ± 0
overall- Ant.Cham.Infl.- visit 6 - Non Study Eye	0 ± 0	0 ± 0	0 ± 0	0 ± 0
overall- Ant.Cham.Infl.-final visit -Non Study Eye	0 ± 0	0 ± 0	0 ± 0	0 ± 0

Attachments

End Point

Slit lamp examination

Statistical analysis description

Slit lamp examination scores and their changes from baseline (screening visit assessment) will be listed and summarised using classic descriptive statistics (i.e. arithmetic mean, SD, CV (%), minimum, median and maximum values) by dose group, disease severity at screening, eye (study eye and non study eye) and evaluation visit.

Comparison groups

FAS (symptoms assessment in dry eye,gruppo 1) v PP (Symptom assessment in dry eye gruppo 1) v FAS (Symptom assessment in dry eye gruppo 2) v PP (Symptom assessment in dry eye gruppo2)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

equivalence

P-value

< 0.05

Method

Wilcoxon (Mann-Whitney)

Parameter type

Mean difference (net)

Point estimate

0.1

Confidence interval

level

80%

sides

2-sided

lower limit

upper limit

Variability estimate

Standard deviation

Dispersion value

0.6

Secondary: Schirmer test type II (with anaesthesia)

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End point title

Schirmer test type II (with anaesthesia)

End point description

This test was performed to measure basal aqueous tear secretion following the instillation of a preservative-free anaesthetic eye drop (Oxybuprocaine Chlorhydrate 0.4%). Both eyes could be tested at the same time. Schirmer plus® strips (Gecis, France) were used. This test was conducted in a dimly lit room. While the patient looked upwards, the lower lid was drawn gently downwards and temporarily. The rounded bent end of a sterile strip was inserted into the lower conjunctival sac over the temporal one-third of the lower eyelid margin. The test was done without touching directly the Schirmer test strip with the fingers to avoid contamination of skin oils. The patients were instructed to close their eyes gently. After 5 minutes, the Schirmer test strip was removed and the length of the tear absorption on the strip was measured (mm/5 min).

End point type

Secondary

End point timeframe

visit 1, visit 2, visit 3, visit 6 and final visit

End point values	FAS (symptoms assessment in dry eye,gruppo 1)	PP (Symptom assessment in dry eye gruppo 1)	FAS (Symptom assessment in dry eye gruppo 2)	PP (Symptom assessment in dry eye gruppo2)
Number of subjects analysed	20	14	20	16
Units: 0 mm/5 minutes
arithmetic mean (standard deviation)
overall visit 2 Study Eye	11.3 ± 8.7	10.6 ± 7.5	9.3 ± 7.6	10.1 ± 8.1
overall visit 3 Study Eye	14.9 ± 10.6	15 ± 10.5	8.9 ± 6.9	10.1 ± 7.2
overall visit 6 Study Eye	17 ± 9.2	15.8 ± 8.9	13.2 ± 11	15 ± 11
overall final visit Study Eye	15.4 ± 9.6	14.5 ± 8.7	13.7 ± 8.5	15.1 ± 8.7
overall visit 2 Non Study Eye	13.5 ± 8.7	13.8 ± 7.6	9.4 ± 7.1	10.6 ± 7.5
overall visit 3 Non Study Eye	14 ± 10.4	14.7 ± 11	10.3 ± 6.1	11.6 ± 6.2
overall visit 6 Non Study Eye	18.1 ± 9.4	16.6 ± 9.77	13.5 ± 10.4	15.6 ± 9.9
overall final visit Non Study Eye	15 ± 8.2	14.2 ± 7	12.5 ± 9.3	14.8 ± 8.9

Attachments

End Point

Schirmer test type II (with anaesthesia)

Statistical analysis description

Values of Schirmer's test type II (i.e. tear wetting distance at 5 minutes) and their changes from baseline (screening visit assessment) will be listed and summarised using classic descriptive statistics (i.e. arithmetic mean, SD, CV (%), minimum, median and maximum values) by dose group, disease severity at screening, eye (study eye and non study eye) and evaluation visit.

Comparison groups

FAS (symptoms assessment in dry eye,gruppo 1) v PP (Symptom assessment in dry eye gruppo 1) v FAS (Symptom assessment in dry eye gruppo 2) v PP (Symptom assessment in dry eye gruppo2)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

equivalence

P-value

< 0.05

Method

Wilcoxon (Mann-Whitney)

Parameter type

Mean difference (final values)

Point estimate

8.7

Confidence interval

level

80%

sides

2-sided

lower limit

upper limit

Variability estimate

Standard deviation

Dispersion value

9.6

Secondary: Tear film break-up time (TFBUT)

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End point title

Tear film break-up time (TFBUT)

End point description

Patients with a TFBUT test ≤10 in the worse eye (study eye) at the screening visit were eligible for enrolment. 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 (using Fluorescein Minims, Fluorescein sodium 2% Chauvin Pharmaceuticals Ltd,106 London Road, Kingston-upon-Thames; Surrey KT2 6TN, UK, with UK marketing authorization PL 0033/5008R) into the inferior conjunctival cul-de-sac of each eye. The patient was instructed to blink several times to thoroughly mix the fluorescein with the tear film. In order to achieve maximum fluorescence, the examiner waited approximately 30 seconds after instillation before evaluating TFBUT.

End point type

Secondary

End point timeframe

visit 1, visit 2, visit 3, visit 6 and final visit

End point values	FAS (symptoms assessment in dry eye,gruppo 1)	PP (Symptom assessment in dry eye gruppo 1)	FAS (Symptom assessment in dry eye gruppo 2)	PP (Symptom assessment in dry eye gruppo2)
Number of subjects analysed	20	14	13	16
Units: second
arithmetic mean (standard deviation)
overall visit 2 Study Eye	4 ± 1.8	4.1 ± 2	2.3 ± 2.1	2.6 ± 2.2
overall visit 3 Study Eye	4.9 ± 2.2	5.1 ± 2.2	2.7 ± 1.7	2.7 ± 1.7
overall visit 6 Study Eye	6 ± 2.5	5.9 ± 2.4	2.5 ± 1.3	2.6 ± 1.3
overall final visit Study Eye	5.6 ± 2.4	5.3 ± 1.9	2.7 ± 2.1	2.9 ± 2.1
overall visit 2 Non Study Eye	4.5 ± 2.2	4.4 ± 2.4	2.9 ± 1.9	2.9 ± 1.8
overall visit 3 Non Study Eye	5.2 ± 2.4	5.6 ± 2.2	3 ± 1.6	3.1 ± 1.7
overall visit 6 Non Study Eye	6 ± 2.6	6 ± 2.9	2.6 ± 1.2	2.8 ± 1.1
overall final visit Non Study Eye	5.7 ± 2.5	5.9 ± 3	2.6 ± 1.6	2.8 ± 1.6

Attachments

End Point

Tear film break-up time (TFBUT)

Statistical analysis description

Values of tear film break-up time and their changes from baseline (screening visit assessment) will be listed and summarised using classic descriptive statistics (i.e. arithmetic mean, SD, CV (%), minimum, median and maximum values) by dose group, disease severity at screening, eye (study eye and non study eye) and evaluation visit.

Comparison groups

FAS (symptoms assessment in dry eye,gruppo 1) v PP (Symptom assessment in dry eye gruppo 1) v FAS (Symptom assessment in dry eye gruppo 2) v PP (Symptom assessment in dry eye gruppo2)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

equivalence

P-value

< 0.05

Method

Wilcoxon (Mann-Whitney)

Parameter type

Mean difference (final values)

Point estimate

5.6

Confidence interval

level

80%

sides

2-sided

lower limit

upper limit

Variability estimate

Standard deviation

Dispersion value

2.4

Secondary: Corneal fluorescein staining

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End point title

Corneal fluorescein staining

End point description

Corneal fluorescein staining scores, total corneal staining scores and their changes from baseline (screening visit assessment) are listed and summarised using classic descriptive statistics by dose group, disease severity at screening, eye (study eye and non study eye) and evaluation visit. Corneal fluorescein staining scores and total corneal staining scores were compared within each dose group, disease severity at screening, evaluation visit and eye (study eye and non study eye) versus their baseline values by a two-sided Wilcoxon signed-rank test with a nominal α level of 0.05.

End point type

Secondary

End point timeframe

visit 1, visit 2, visit 3, visit 6 and final visit

End point values	FAS (symptoms assessment in dry eye,gruppo 1)	PP (Symptom assessment in dry eye gruppo 1)	FAS (Symptom assessment in dry eye gruppo 2)	PP (Symptom assessment in dry eye gruppo2)
Number of subjects analysed	20	14	20	16
Units: ranking test
arithmetic mean (standard deviation)
overall visit 2 Study Eye	4.9 ± 2.8	4.6 ± 3.1	5.6 ± 3.7	5.1 ± 3.2
overall visit 3 Study Eye	3.3 ± 2.6	3.1 ± 2.9	4.8 ± 3.8	4.2 ± 3.3
overall visit 6 Study Eye	2.1 ± 2.2	1.8 ± 2.2	4.1 ± 3.6	3.8 ± 3.4
overall final visit Study Eye	2.4 ± 2.2	2.6 ± 2.5	4 ± 3	3.7 ± 2.8
overall visit 2 Non Study Eye	4.4 ± 3.1	3.7 ± 3.2	4.5 ± 3.1	3.9 ± 2
overall visit 3 Non Study Eye	3.1 ± 2.3	2.7 ± 2.4	4.1 ± 3.8	3.4 ± 3.1
overall visit 6 Non Study Eye	1.9 ± 2.4	1.7 ± 2.3	3.7 ± 3.3	3.1 ± 2.3
overall final visit Non Study Eye	2.2 ± 1.9	2.1 ± 2	3.8 ± 2.9	3.5 ± 2.8

Corneal fluorescein staining

Statistical analysis description

Corneal fluorescein staining scores, total corneal staining score and their changes from baseline (screening visit assessment) will be listed and summarised using classic descriptive statistics (i.e. arithmetic mean, SD, CV (%), minimum, median and maximum values) by dose group, disease severity at screening, eye (study eye and non study eye) and evaluation visit.

Comparison groups

FAS (symptoms assessment in dry eye,gruppo 1) v PP (Symptom assessment in dry eye gruppo 1) v FAS (Symptom assessment in dry eye gruppo 2) v PP (Symptom assessment in dry eye gruppo2)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

equivalence

P-value

< 0.05

Method

Wilcoxon (Mann-Whitney)

Parameter type

Median difference (net)

Point estimate

0.1

Confidence interval

level

80%

sides

2-sided

lower limit

upper limit

Variability estimate

Standard deviation

Dispersion value

2.2

Secondary: Corneal sensitivity (Cochet-Bonnet aesthesiometry)

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End point title

Corneal sensitivity (Cochet-Bonnet aesthesiometry)

End point description

For the assessment of corneal sensation the Luneau Cochet-Bonnet aesthesiometer (Western Ophthalmics Corporation©) was used. Corneal sensation was measured in both eyes in each of the four quadrants of the cornea using the Cochet Bonnet aesthesiometer before the instillation of any dilating or anesthetic eye drops.

End point type

Secondary

End point timeframe

visit 1, visit 2, visit 3, visit 6 and final visit

End point values	FAS (symptoms assessment in dry eye,gruppo 1)	PP (Symptom assessment in dry eye gruppo 1)	FAS (Symptom assessment in dry eye gruppo 2)	PP (Symptom assessment in dry eye gruppo2)
Number of subjects analysed	20	14	20	16
Units: cm
arithmetic mean (standard deviation)
overall visit 2 Study Eye	5.65 ± 0.54	5.64 ± 0.6	5.63 ± 0.99	5.91 ± 0.27
overall visit 3 Study Eye	5.63 ± 0.72	5.57 ± 0.83	5.8 ± 0.44	5.91 ± 0.38
overall visit 6 Study Eye	5.93 ± 0.18	5.89 ± 0.21	5.79 ± 0.61	5.75 ± 0.66
overall final visit Study Eye	5.88 ± 0.39	5.82 ± 0.46	5.93 ± 0.18	5.91 ± 0.2
overall visit 2 Non Study Eye	5.85 ± 0.37	5.86 ± 0.36	5.73 ± 0.7	5.94 ± 0.17
overall visit 3 Non Study Eye	5.83 ± 0.34	5.79 ± 0.38	5.9 ± 0.31	6 ± 0
overall visit 6 Non Study Eye	5.93 ± 0.18	5.89 ± 0.21	5.89 ± 0.21	5.91 ± 0.2
overall final visit Non Study Eye	5.9 ± 0.31	5.86 ± 0.36	5.85 ± 0.29	5.91 ± 0.2

Corneal sensitivity (Cochet-Bonnet aesthesiometry)

Statistical analysis description

Values of corneal sensitivity (i.e. the length of the filament in cm at which the patient corneal sensation was observed) and their changes from baseline (screening visit assessment) will be listed and summarised using classic descriptive statistics (i.e. arithmetic mean, SD, CV (%), minimum, median and maximum values) by dose group, disease severity at screening, eye (study eye and non study eye) and evaluation visit

Comparison groups

FAS (symptoms assessment in dry eye,gruppo 1) v PP (Symptom assessment in dry eye gruppo 1) v FAS (Symptom assessment in dry eye gruppo 2) v PP (Symptom assessment in dry eye gruppo2)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

equivalence

P-value

< 0.05

Method

Wilcoxon (Mann-Whitney)

Parameter type

Mean difference (final values)

Point estimate

5.88

Confidence interval

level

80%

sides

2-sided

lower limit

4.5

upper limit

Variability estimate

Standard deviation

Dispersion value

0.39

Secondary: Intraocular pressure (IOP)

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End point title

Intraocular pressure (IOP)

End point description

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. The patient’s position was adjusted until the patient’s head was firmly positioned on the chin rest and against the forehead rest without leaning forward or straining. Both eyes were tested, with the right eye preceding the left eye. The same equipment was used throughout the study. IOP for each eye in mmHg was recorded in the CRF.

End point type

Secondary

End point timeframe

visit 1, visit 2, visit 3, visit 6 and final visit

End point values	FAS (symptoms assessment in dry eye,gruppo 1)	PP (Symptom assessment in dry eye gruppo 1)	FAS (Symptom assessment in dry eye gruppo 2)	PP (Symptom assessment in dry eye gruppo2)
Number of subjects analysed	20	14	20	16
Units: mmHg
arithmetic mean (standard deviation)
overall visit 2 Study Eye	15 ± 1.6	14.7 ± 1.4	12.9 ± 2.4	12.9 ± 2.3
overall visit 3 Study Eye	14.1 ± 1.6	14 ± 1.6	13.2 ± 2.9	12.4 ± 2.4
overall visit 6 Study Eye	14.4 ± 1.9	14.4 ± 1.7	14.1 ± 2.4	13.8 ± 2.2
overall final visit Study Eye	14.2 ± 2.7	14.4 ± 3.1	13.6 ± 2.5	13.6 ± 2.2
overall visit 2 Non Study Eye	14.9 ± 1.6	14.5 ± 1.4	13.2 ± 2.2	12.9 ± 2.3
overall visit 3 Non Study Eye	13.9 ± 2	13.8 ± 1.9	12.8 ± 2.4	12.5 ± 1.8
overall visit 6 Non Study Eye	13.9 ± 2	13.6 ± 1.9	13.9 ± 1.8	13.6 ± 1.6
overall final visit Non Study Eye	14 ± 2.7	14.1 ± 2.6	13.7 ± 2.4	13.7 ± 2.2

Intraocular pressure (IOP)

Statistical analysis description

Values of intraocular pressure and their changes from baseline (screening visit assessment) will be listed and summarised using classic descriptive statistics (i.e. arithmetic mean, SD, CV (%), minimum, median and maximum values) by dose group, disease severity at screening, eye (study eye and non study eye) and evaluation visit.

Comparison groups

FAS (symptoms assessment in dry eye,gruppo 1) v PP (Symptom assessment in dry eye gruppo 1) v FAS (Symptom assessment in dry eye gruppo 2) v PP (Symptom assessment in dry eye gruppo2)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

equivalence

P-value

< 0.05

Method

Wilcoxon (Mann-Whitney)

Parameter type

Mean difference (final values)

Point estimate

14.2

Confidence interval

level

80%

sides

2-sided

lower limit

upper limit

Variability estimate

Standard deviation

Dispersion value

2.7

Secondary: Visual acuity (early treatment diabetic retinopathy study [ETDRS] chart)

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End point title

Visual acuity (early treatment diabetic retinopathy study [ETDRS] chart)

End point description

Refraction and visual acuity measurements were performed for all patients by trained vision examiners only. The name and certification number of the vision examiner were documented in the patient’s visual acuity (VA) worksheet (provided by the Sponsor) at each visit. Refraction was measured prior to visual acuity testing to obtain best-corrected vision as described below. Best-corrected visual acuity was measured at all visits using standard charts, lighting, and procedures. Best correction was determined by careful refraction at that visit according to the standard protocol for refraction as described below. The refraction equipment required included:  Retroilluminated Light box and ETDRS 4 meter distance acuity chart set  Trial lens frames  Trial lens set with plus or minus cylinder lenses  Jackson cross-cylinders of 0.25, 0.50, and 1.00 diopters  Pinhole occluder  Tissues or eye pads and tape  A 1 meter rigid measuring stick Visual acuity chart 1 was used for test

End point type

Secondary

End point timeframe

visit 1, visit 2, visit 3, visit 6 and final

End point values	FAS (symptoms assessment in dry eye,gruppo 1)	PP (Symptom assessment in dry eye gruppo 1)	FAS (Symptom assessment in dry eye gruppo 2)	PP (Symptom assessment in dry eye gruppo2)
Number of subjects analysed	20	14	20	16
Units: cm
arithmetic mean (standard deviation)
overall visit 2 Study Eye	86.1 ± 5.1	86.6 ± 5.9	76.2 ± 20.9	78.5 ± 13.5
overall visit 3 Study Eye	85.9 ± 5.1	85.8 ± 6.1	78 ± 19.4	80 ± 14.4
overall visit 6 Study Eye	86.7 ± 4.4	87.3 ± 5.1	78.9 ± 15.4	79.9 ± 14.5
overall final visit Study Eye	86.6 ± 3.7	87 ± 4.2	81.3 ± 13.3	82.8 ± 11.2
overall visit 2 Non Study Eye	87.3 ± 3.9	87.9 ± 4.3	80.9 ± 10.7	81.9 ± 9.8
overall visit 3 Non Study Eye	87.1 ± 4.1	86.8 ± 4.6	81.2 ± 11.6	81.7 ± 10.3
overall visit 6 Non Study Eye	87 ± 4.8	87.4 ± 5.5	81 ± 11.5	82.2 ± 10
overall final visit Non Study Eye	87 ± 4	87.1 ± 4.4	82.3 ± 10.4	81.9 ± 1.3

Attachments

End Point

Visual acuity (early treatment diabetic retinopath

Statistical analysis description

Values of visual acuity and their changes from baseline (screening visit assessment) will be listed and summarised using classic descriptive statistics (i.e. arithmetic mean, SD, CV (%), minimum, median and maximum values) by dose group, disease severity at screening, eye (study eye and non study eye) and evaluation visit.

Comparison groups

FAS (symptoms assessment in dry eye,gruppo 1) v PP (Symptom assessment in dry eye gruppo 1) v FAS (Symptom assessment in dry eye gruppo 2) v PP (Symptom assessment in dry eye gruppo2)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

equivalence

P-value

< 0.05

Method

Wilcoxon (Mann-Whitney)

Parameter type

Mean difference (final values)

Point estimate

86.6

Confidence interval

level

80%

sides

2-sided

lower limit

upper limit

Variability estimate

Standard deviation

Dispersion value

3.7

Secondary: Fundus ophthalmoscopy

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End point title

Fundus ophthalmoscopy

End point description

The fundus examination included ophthalmoscopic assessments of vitreous, macula, retina and optic nerve head for both eyes. For the screening examination of the fundus oculi, the pupils were dilated. For examination of the fundus oculi, dilation was only required in the event of an assessment of an AE.

End point type

Secondary

End point timeframe

visit 1, visit 2, visit 3, visit 6 and final visit

End point values	FAS (symptoms assessment in dry eye,gruppo 1)	PP (Symptom assessment in dry eye gruppo 1)	FAS (Symptom assessment in dry eye gruppo 2)	PP (Symptom assessment in dry eye gruppo2)
Number of subjects analysed	20	14	20	16
Units: grades
arithmetic mean (standard deviation)
overall Vitreous - visit 2 Study Eye	0.1 ± 0.2	0 ± 0	0 ± 0	0 ± 0
overall Vitreous - visit 3 Study Eye	0.1 ± 0.2	0 ± 0	0 ± 0	0 ± 0
overall Vitreous - visit 6 Study Eye	0.1 ± 0.2	0 ± 0	0 ± 0	0 ± 0
overall Vitreous - final visit Study Eye	0.1 ± 0.2	0 ± 0	0 ± 0	0 ± 0
overall Vitreous - visit 2 Non Study Eye	0.1 ± 0.2	0 ± 0	0 ± 0	0 ± 0
overall Vitreous - visit 3 Non Study Eye	0.1 ± 0.2	0 ± 0	0 ± 0	0 ± 0
overall Vitreous - visit 6 Non Study Eye	0.1 ± 0.2	0 ± 0	0 ± 0	0 ± 0
overall Vitreous - final visit Non Study Eye	0.1 ± 0.2	0 ± 0	0 ± 0	0 ± 0
overall M.R. and O.N.H. - visit 2 Study Eye	0 ± 0	0 ± 0	0 ± 0	0 ± 0
overall M.R. and O.N.H. - visit 3 Study Eye	0 ± 0	0 ± 0	0 ± 0	0 ± 0
overall M.R. and O.N.H. - visit 6 Study Eye	0 ± 0	0 ± 0	0 ± 0	0 ± 0
overall M.R. and O.N.H. - final visit Study Eye	0 ± 0	0 ± 0	0 ± 0	0 ± 0
overall M.R. and O.N.H. - visit 2 Non Study Eye	0 ± 0	0 ± 0	0 ± 0	0 ± 0
overall M.R. and O.N.H. - visit 3 Non Study Eye	0 ± 0	0 ± 0	0 ± 0	0 ± 0
overall M.R. and O.N.H. - visit 6 Non Study Eye	0 ± 0	0 ± 0	0 ± 0	0 ± 0
overall M.R. and O.N.H. -final visit Non Study Eye	0 ± 0	0 ± 0	0 ± 0	0 ± 0

Attachments

End Point

Fundus ophthalmoscopy

Statistical analysis description

Fundus ophthalmoscopy scores and their changes from baseline (screening visit assessment) will be listed and summarised using classic descriptive statistics (i.e. arithmetic mean, SD, CV (%), minimum, median and maximum values) by dose group, disease severity at screening, eye (study eye and non study eye) and evaluation visit.

Comparison groups

FAS (symptoms assessment in dry eye,gruppo 1) v PP (Symptom assessment in dry eye gruppo 1) v FAS (Symptom assessment in dry eye gruppo 2) v PP (Symptom assessment in dry eye gruppo2)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

equivalence

P-value

< 0.05

Method

Wilcoxon (Mann-Whitney)

Parameter type

Median difference (net)

Point estimate

0.1

Confidence interval

level

80%

sides

2-sided

lower limit

upper limit

Variability estimate

Standard deviation

Dispersion value

0.2

Secondary: Tear film osmolarity

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End point title

Tear film osmolarity

End point description

Tear film osmolarity as a marker of tear film solute content was performed with a TearLab Osmolarity System.The concentration of the tears was assessed in both eyes before the instillation of any dilating or anesthetic drops.To perform the test, the patient was sitting with head tilted back and eyes looking upward towards the ceiling. One hand was placed on the patient’s face for stabilisation.The eyelid was not moved away from the eye as pulling the eyelid down would have broken the tear lake and hindered the tear film collection.The handheld TearLab Osmolarity Pen was placed close to the eye just above the outer 1/3 of the lower eyelid and gently lower allowing the bottom of the tip to come into contact with the lower eyelid and the line of moisture along the inner eyelid margin.While avoiding contact with the bulbar conjunctiva, the Pen tip was pressed down lightly on the eyelid to collect the tears.

End point type

Secondary

End point timeframe

visit 1, visit 2, visit 3, visit 6 and final visit

End point values	FAS (symptoms assessment in dry eye,gruppo 1)	PP (Symptom assessment in dry eye gruppo 1)	FAS (Symptom assessment in dry eye gruppo 2)	PP (Symptom assessment in dry eye gruppo2)
Number of subjects analysed	20	14	20	16
Units: mOsm/L
arithmetic mean (standard deviation)
overall visit 2 Study Eye	304.6 ± 9.1	303.4 ± 9.5	313.2 ± 16.8	314.6 ± 18.2
overall visit 3 Study Eye	309.6 ± 11.9	308.3 ± 13.4	314.4 ± 19.2	313.2 ± 21
overall visit 6 Study Eye	308.2 ± 12.3	305.9 ± 12	312.5 ± 12.3	313.6 ± 13.1
overall final visit Study Eye	308.8 ± 9.8	308.1 ± 11.1	318 ± 18.3	315.3 ± 17.9
overall visit 2 Non Study Eye	307.1 ± 20.5	302.9 ± 14	319.9 ± 20.9	321.3 ± 22.3
overall visit 3 Non Study Eye	304.4 ± 11.3	303 ± 12.1	314.1 ± 19	314.6 ± 21.5
overall visit 6 Non Study Eye	307 ± 12.9	303.7 ± 8	307.6 ± 12.7	307.8 ± 8.2
overall final visit Non Study Eye	311.7 ± 10.1	311.3 ± 11.4	313.7 ± 20.3	314 ± 22.6

Attachments

End Point

Tear film osmolarity

Statistical analysis description

Values of tear film osmolarity and their changes from baseline (screening visit assessment) will be listed and summarised using classic descriptive statistics (i.e. arithmetic mean, SD, CV (%), minimum, median and maximum values) by dose group, disease severity at screening, eye (study eye and non study eye) and evaluation visit.

Comparison groups

FAS (symptoms assessment in dry eye,gruppo 1) v PP (Symptom assessment in dry eye gruppo 1) v FAS (Symptom assessment in dry eye gruppo 2) v PP (Symptom assessment in dry eye gruppo2)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

equivalence

P-value

< 0.05

Method

Wilcoxon (Mann-Whitney)

Parameter type

Mean difference (final values)

Point estimate

308.8

Confidence interval

level

80%

sides

2-sided

lower limit

291

upper limit

326

Variability estimate

Standard deviation

Dispersion value

9.8

Secondary: Conjunctival impression cytology for goblet cells' count

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End point title

Conjunctival impression cytology for goblet cells' count

End point description

Values of conjunctival impression cytology for goblet cells' count and their changes from baseline (screening visit assessment), mean±SD of 3 consecutive optic fields and mean±SD of changes from baseline of 3 consecutive optic fields for each impression cytology sample are listed. Mean of 3 consecutive optic fields and mean of changes from baseline of 3 consecutive optic fields for each impression cytology sample are summarised using classic descriptive statistics by dose group, disease severity at ascreening and evaluation visit. Values of conjunctival impression cytology for goblet cells' count were compared within each dose group, disease severity at screening and evaluation visit versus their baseline values by a two-sided Wilcoxon signed-rank test with a nominal α level of 0.05.

End point type

Secondary

End point timeframe

visit 1, visit 2, visit 3, visit 6 and final visit

End point values	FAS (symptoms assessment in dry eye,gruppo 1)	PP (Symptom assessment in dry eye gruppo 1)	FAS (Symptom assessment in dry eye gruppo 2)	PP (Symptom assessment in dry eye gruppo2)
Number of subjects analysed	20	14	20	16
Units: α level
arithmetic mean (standard deviation)
overall visit 2 Temporal B.C.	5.04 ± 5.63	5.43 ± 5.99	1.62 ± 1.64	1.69 ± 1.76
overall visit 3 Temporal B.C.	4.17 ± 4.59	4.05 ± 5.1	1.47 ± 1.86	1.71 ± 1.94
overall visit 6 Temporal B.C.	6.35 ± 10.57	4.94 ± 7.71	2.15 ± 3.05	2.51 ± 3.22
overall final visit Temporal B.C.	3.9 ± 4.95	2.75 ± 4.03	1.82 ± 2.42	1.9 ± 2.41
overall visit 2 Nasal B.C.	3.92 ± 3.44	3.39 ± 3.44	1.5 ± 2.1	1.81 ± 2.24
overall visit 3 Nasal B.C.	5.82 ± 11.04	2.33 ± 3.67	2.93 ± 4.36	3.47 ± 4.61
overall visit 6 Nasal B.C.	5.18 ± 4.84	5.09 ± 5.08	1.53 ± 1.81	1.67 ± 1.89
overall final visit Nasal B.C.	5.97 ± 9.49	4.9 ± 8.18	2.82 ± 3.17	3.33 ± 3.27
overall visit 2 Inferior B.C.	3.61 ± 3.89	4.44 ± 4.37	1.23 ± 1.49	1.4 ± 1.61
overall visit 3 Inferior B.C.	5.63 ± 8.38	2.33 ± 3.41	1.32 ± 2.34	1.54 ± 2.49
overall visit 6 Inferior B.C.	2.88 ± 3.46	2.15 ± 1.64	1.05 ± 1.48	1.23 ± 1.55
overall final visit Inferior B.C.	5.26 ± 5.88	4.72 ± 7.61	2.33 ± 2.45	2.6 ± 2.64
overall visit 2 Superior B.C.	5.77 ± 9.97	7.52 ± 11.17	1.88 ± 2.58	2.13 ± 2.81
overall visit 3 Superior B.C.	5.7 ± 7.62	4.19 ± 7.15	1.58 ± 2.17	1.96 ± 2.31
overall visit 6 Superior B.C.	3.96 ± 4.87	2.77 ± 3.83	1.57 ± 1.87	1.6 ± 1.93
overall final visit Superior B.C.	5.98 ± 9.67	4.81 ± 6.75	2.2 ± 1.95	2.56 ± 1.93

Attachments

End Point

Conjunctival impression cytology for goblet cells'

Statistical analysis description

Values of conjunctival impression cytology for goblet cells' count, their changes from baseline screening visit assessment),mean ±SD of 3 consecutive optic fields and mean ±SD of changes from baseline of 3 consecutive optic fields for each impression cytology sample will be listed.Mean of 3 consecutive optic fields and mean of changes from baseline of 3 consecutive optic fields for each impression cytology sample will be summarised using classic descriptive statistics (i.e.arithmetic mean,SD)

Comparison groups

FAS (symptoms assessment in dry eye,gruppo 1) v PP (Symptom assessment in dry eye gruppo 1) v FAS (Symptom assessment in dry eye gruppo 2) v PP (Symptom assessment in dry eye gruppo2)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

equivalence

P-value

< 0.05

Method

Wilcoxon (Mann-Whitney)

Parameter type

Mean difference (net)

Point estimate

0.1

Confidence interval

level

80%

sides

2-sided

lower limit

upper limit

14.3

Variability estimate

Standard deviation

Dispersion value

4.95

Secondary: Frequency of artificial tears use

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End point title

Frequency of artificial tears use

End point description

Frequencies of artificial tears use and their changes from baseline (screening visit assessment) are listed and summarised using classic descriptive statistics by dose group, disease severity at screening and evaluation visit. Artificial tears accountability is listed. The average frequency of artificial tear use during the study in the intervals Day 1 - Day 8, Day 9 - Day 29 and Day 30 - Day 56 is listed and summarised using classic descriptive statistics by dose group. The average use for each subject was calculated as the total number of drops used in each period divided by the actual period duration. Data were stratified according to the illness severity level.

End point type

Secondary

End point timeframe

visit 1, visit 2, visit 3, visit 6 and final visit

End point values	FAS (symptoms assessment in dry eye,gruppo 1)	PP (Symptom assessment in dry eye gruppo 1)	FAS (Symptom assessment in dry eye gruppo 2)	PP (Symptom assessment in dry eye gruppo2)
Number of subjects analysed	20	14	20	16
Units: number of drops per day period
Day 1 (00:00) - Day 8 (23:59)	10	7	12	9
Day 9 (00:00) - Day 29 (23:59)	10	8	13	9
Day 30 (00:00) - Day 56 (23:59)	11	9	12	9

Attachments

End Point

Frequency of artificial tears use during the study

Statistical analysis description

Frequencies of artificial tears use during the study and their changes from baseline (screening visit assessment) will be listed and summarised using classic descriptive statistics (i.e. arithmetic mean, SD, CV (%), minimum, median and maximum values) by dose group, disease severity at screening and evaluation visit.

Comparison groups

FAS (symptoms assessment in dry eye,gruppo 1) v PP (Symptom assessment in dry eye gruppo 1) v FAS (Symptom assessment in dry eye gruppo 2) v PP (Symptom assessment in dry eye gruppo2)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

equivalence

P-value

< 0.05

Method

Wilcoxon (Mann-Whitney)

Parameter type

Median difference (net)

Point estimate

0.1

Confidence interval

level

80%

sides

2-sided

lower limit

0.04

upper limit

7.85

Variability estimate

Standard deviation

Dispersion value

2.961

Secondary: Vital signs (blood pressure; BP, pulse rate; PR), body weight (BW), physical examinations.

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End point title

Vital signs (blood pressure; BP, pulse rate; PR), body weight (BW), physical examinations.

End point description

Values of vital signs, their changes from baseline (screening visit assessment) and, only for visits 2 and 3 post-dose assessments, their changes from pre-dose are listed. A table of all abnormal values of vital signs is presented and values of vital signs, their changes from baseline and, only for visits 2 and 3 post-dose assessments, their changes from pre-dose are summarised using classic descriptive statistics by dose group, evaluation visit and evaluation time point.

End point type

Secondary

End point timeframe

Visit 1, Visit 2, visit 3, visit 6 and final dose

End point values	Group 1	Group 2
Number of subjects analysed	20	20
Units: mmHg
arithmetic mean (standard deviation)
Systolic B. P. - Screening - Day -15/1	126.2 ± 15.1	123.1 ± 18
Systolic B. P. - Visit 2 - Day 1 - Pre-dose	125.3 ± 11.9	126.5 ± 13.3
Systolic B. P. - Visit 2 - Day 1 - Post-dose	118.4 ± 12.5	123.3 ± 15.3
Systolic B. P. - Visit 3 - Day 8±1 - Pre-dose	123.6 ± 12	120.1 ± 14.4
Systolic B. P. - Visit 3 - Day 8±1 - Post-dose	122 ± 13.6	123.9 ± 14.6
Systolic B. P. - Visit 6 - Day 29±1	124.5 ± 14.4	120.1 ± 10.6
Systolic B. P. - Final Visit - Day 56±4/ETV	122 ± 12	125 ± 15.3
Diastolic B. P. - Screening - Day -15/-1	78.5 ± 8.5	75.7 ± 10
Diastolic B. P. - Visit 2 - Day 1 - Pre-dose	76.9 ± 9.4	77.5 ± 10.4
Diastolic B. P. - Visit 2 - Day 1 - Post-dose	75.6 ± 8.4	76 ± 10.8
Diastolic B. P. - Visit 3 - Day 8±1 - Pre-dose	76.6 ± 11.8	74 ± 9.8
Diastolic B. P. - Visit 3 - Day 8±1 - Post-dose	74.9 ± 9.9	76.1 ± 9.8
Diastolic B. P. - Visit 6 - Day 29±1	75.1 ± 8.8	74.3 ± 10.1
Diastolic B. P. - Final Visit - Day 56±4/ETV	76.7 ± 7.4	75.8 ± 10.9

Attachments

End Point

Vital signs (blood pressure)

Comparison groups

Group 1 v Group 2

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

equivalence

P-value

< 0.05

Method

Wilcoxon (Mann-Whitney)

Parameter type

Mean difference (final values)

Point estimate

122

Confidence interval

level

80%

sides

2-sided

lower limit

100

upper limit

141

Variability estimate

Standard deviation

Dispersion value

Secondary: Vital signs (pulse rate)

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End point title

Vital signs (pulse rate)

End point description

End point type

Secondary

End point timeframe

Vital signs (pulse rate)

End point values	Group 1	Group 2
Number of subjects analysed	20	20
Units: beats/min
arithmetic mean (standard deviation)
Pulse Rate - Screening - Day -15/-1	71.5 ± 7.4	76.1 ± 11
Pulse Rate - Visit 2 - Day 1 - Pre-dose	75.3 ± 11	74.5 ± 10.4
Pulse Rate - Visit 2 - Day 1 - Post-dose	66.7 ± 7.7	66.6 ± 9.5
Pulse Rate - Visit 3 - Day 8±1 - Pre-dose	77.9 ± 10.7	76.1 ± 10.4
Pulse Rate - Visit 3 - Day 8±1 - Post-dose	68.5 ± 8.6	65.4 ± 9
Pulse Rate - Visit 6 - Day 29±1	73.3 ± 10.4	70.7 ± 12.2
Pulse Rate - Final Visit - Day 56±4/ETV	75 ± 8.6	3.6 ± 11.8

Attachments

End Point

Vital signs (pulse rate)

Comparison groups

Group 1 v Group 2

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

equivalence

P-value

< 0.05

Method

Wilcoxon (Mann-Whitney)

Parameter type

Mean difference (final values)

Point estimate

Confidence interval

level

80%

sides

2-sided

lower limit

upper limit

Variability estimate

Standard deviation

Dispersion value

8.6

Secondary: Vital signs (Body weight)

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End point title

Vital signs (Body weight)

End point description

End point type

Secondary

End point timeframe

Vital signs (Body weight)

End point values	Group 1	Group 2
Number of subjects analysed	20	20
Units: kg
arithmetic mean (standard deviation)
Body Weight - Screening - Day -15/-1	70.72 ± 8.71	73.23 ± 18.34
Body Weight - Final Visit - Day 56±4/ETV	70.21 ± 8.88	73.78 ± 18.13

Attachments

End Point

Vital signs (Body weight)

Comparison groups

Group 1 v Group 2

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

equivalence

P-value

< 0.05

Method

Wilcoxon (Mann-Whitney)

Parameter type

Mean difference (final values)

Point estimate

70.21

Confidence interval

level

80%

sides

2-sided

lower limit

upper limit

Variability estimate

Standard deviation

Dispersion value

8.88

Adverse events

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Timeframe for reporting adverse events

Visit 2 (Day 1 pre-dose); At home(Days 1 evening – 7±1 evening); Visit 3 (Day 8±1 pre-dose); At home(Days 8±1 -14±1); Visit 4; At home(Days 15±1-21±1); Visit 5, At home (Days 22±1 - 28±1); Visit 6 and Final Visit.

Adverse event reporting additional description

AEs assessed at home are monitored through a diary.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

17.0

Reporting group title

Group 1

Reporting group description

Reporting group title

Group 2

Reporting group description

Serious adverse events	Group 1	Group 2
Total subjects affected by serious adverse events
subjects affected / exposed	0 / 20 (0.00%)	1 / 20 (5.00%)
number of deaths (all causes)	0	0
number of deaths resulting from adverse events	0	0
Musculoskeletal and connective tissue disorders
Fall
Additional description: The fall was associated with the concussion and headache: these were reported as 3 distinct TEAEs of moderate intensity, of which only the fall was classified as a SAE. The investigator judged that all 3 TEAEs were unrelated to the IMP.
subjects affected / exposed	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 0%

Non-serious adverse events	Group 1	Group 2
Total subjects affected by non serious adverse events
subjects affected / exposed	14 / 20 (70.00%)	15 / 20 (75.00%)
Injury, poisoning and procedural complications
Concussion
Additional description: intensity: moderate
subjects affected / exposed	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0
Nervous system disorders
Headache
Additional description: intensity: moderate only for 1 patients of group 2
subjects affected / exposed	0 / 20 (0.00%)	5 / 20 (25.00%)
occurrences all number	0	0
Migraine
subjects affected / exposed	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	0	0
Ear and labyrinth disorders
Tinnitus
subjects affected / exposed	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	0	0
Eye disorders
Abnormal sensation in eye
Additional description: The abnormal sensation in eye, was not identified as ocular pain by any of the study subjects.
subjects affected / exposed	4 / 20 (20.00%)	8 / 20 (40.00%)
occurrences all number	0	0
Eye pain
Additional description: The most frequent related TEAE was eye pain, with an overall frequency of 10%.
subjects affected / exposed	5 / 20 (25.00%)	6 / 20 (30.00%)
occurrences all number	0	0
Eye irritation
Additional description: An intermittent eye irritation, mild in intensity.
subjects affected / exposed	3 / 20 (15.00%)	7 / 20 (35.00%)
occurrences all number	0	0
Eye pruritus
Additional description: The patient reported an intermittent eye pruritus of mild intensity.
subjects affected / exposed	2 / 20 (10.00%)	5 / 20 (25.00%)
occurrences all number	0	0
Vision blurred
subjects affected / exposed	3 / 20 (15.00%)	2 / 20 (10.00%)
occurrences all number	0	0
Foreign body sensation in eyes
subjects affected / exposed	0 / 20 (0.00%)	4 / 20 (20.00%)
occurrences all number	0	0
Photophobia
Additional description: The patient started to report photophobia of mild intensity which persisted during the study and was still ongoing at the end of the study.
subjects affected / exposed	1 / 20 (5.00%)	3 / 20 (15.00%)
occurrences all number	0	0
Lacrimation increased
subjects affected / exposed	0 / 20 (0.00%)	3 / 20 (15.00%)
occurrences all number	0	0
Visual impairment
Additional description: intensity: moderate for patient of group 2 intensityt: mild for patients of group 1
subjects affected / exposed	1 / 20 (5.00%)	1 / 20 (5.00%)
occurrences all number	0	0
Asthenopia
subjects affected / exposed	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	0	0
Erythema of eyelid
subjects affected / exposed	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0
Eye discharge
subjects affected / exposed	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	0	0
Eye disorder
subjects affected / exposed	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0
Eyelid pain
subjects affected / exposed	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	0	0
Eyelid sensory disorder
subjects affected / exposed	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0
Ocular discomfort
subjects affected / exposed	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0
Ocular hyperaemia
subjects affected / exposed	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0
Vitreous detachment
subjects affected / exposed	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	0	0
Gastrointestinal disorders
Flatulence
subjects affected / exposed	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0
Neck pain
subjects affected / exposed	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0
Infections and infestations
Conjunctivitis bacterial
Additional description: The patient experienced a bacterial conjunctivitis of mild intensity that was resolved.The bacterial infection was not related to the treatment.This AE led the pt to discontinue the study treatment and he brought back to the clinic the unused IMP.
subjects affected / exposed	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0
Rhinitis
subjects affected / exposed	0 / 20 (0.00%)	2 / 20 (10.00%)
occurrences all number	0	0
Herpes simplex
subjects affected / exposed	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	0	0
Nasopharyngitis
subjects affected / exposed	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	0	0
Sinusitis
subjects affected / exposed	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0
Urinary tract infection
subjects affected / exposed	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0

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Were there any global substantial amendments to the protocol? No

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results: An open-label study evaluating safety and efficacy of recombinant human nerve growth factor (rhNGF) eye drops at different doses in patients with Dry Eye

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Symptom assessment in dry eye (SANDE)

Primary: Symptom assessment in dry eye (SANDE)

Primary: Ocular surface vital staining with lissamine green (LG) (National Eye Institute [NEI] scales)

Primary: Ocular surface vital staining with lissamine green (LG) (National Eye Institute [NEI] scales)

Primary: Schirmer test type I (without anaesthesia)

Primary: Schirmer test type I (without anaesthesia)

Primary: Treatment-emergent adverse events (TEAEs)

Primary: Treatment-emergent adverse events (TEAEs)

Secondary: Visual analogue scale (VAS) for ocular tolerability (foreign body sensation, burning/stinging, itching, pain, stick feeling, blurred vision and photophobia)

Secondary: Visual analogue scale (VAS) for ocular tolerability (foreign body sensation, burning/stinging, itching, pain, stick feeling, blurred vision and photophobia)

Secondary: Slit lamp examination (Eyelid - meibomian glands, eyelid – erythema, eyelid - oedema lashes, conjunctiva erythema, lens, iris, anterior chamber)

Secondary: Slit lamp examination (Eyelid - meibomian glands, eyelid – erythema, eyelid - oedema lashes, conjunctiva erythema, lens, iris, anterior chamber)

Secondary: Schirmer test type II (with anaesthesia)

Secondary: Schirmer test type II (with anaesthesia)

Secondary: Tear film break-up time (TFBUT)

Secondary: Tear film break-up time (TFBUT)

Secondary: Corneal fluorescein staining

Secondary: Corneal fluorescein staining

Secondary: Corneal sensitivity (Cochet-Bonnet aesthesiometry)

Secondary: Corneal sensitivity (Cochet-Bonnet aesthesiometry)

Secondary: Intraocular pressure (IOP)

Secondary: Intraocular pressure (IOP)

Secondary: Visual acuity (early treatment diabetic retinopathy study [ETDRS] chart)

Secondary: Visual acuity (early treatment diabetic retinopathy study [ETDRS] chart)

Secondary: Fundus ophthalmoscopy

Secondary: Fundus ophthalmoscopy

Secondary: Tear film osmolarity

Secondary: Tear film osmolarity

Secondary: Conjunctival impression cytology for goblet cells' count

Secondary: Conjunctival impression cytology for goblet cells' count

Secondary: Frequency of artificial tears use

Secondary: Frequency of artificial tears use

Secondary: Vital signs (blood pressure; BP, pulse rate; PR), body weight (BW), physical examinations.

Secondary: Vital signs (blood pressure; BP, pulse rate; PR), body weight (BW), physical examinations.

Secondary: Vital signs (pulse rate)

Secondary: Vital signs (pulse rate)

Secondary: Vital signs (Body weight)

Secondary: Vital signs (Body weight)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
An open-label study evaluating safety and efficacy of recombinant human nerve growth factor (rhNGF) eye drops at different doses in patients with Dry Eye