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Clinical Trial Results:
A 4 week, Phase III, multicenter, double-masked, vehicle-controlled study to evaluate safety and efficacy of Cenegermin (Oxervate®) 20 mcg/mL ophthalmic solution versus vehicle, in patients with severe Sjogren’s dry eye disease under treatment with Cyclosporine A (PROTEGO-2 study)

Summary
EudraCT number	2021-003749-39
Trial protocol	IT
Global end of trial date	24 May 2023

Results information
Results version number	v1(current)
This version publication date	08 May 2024
First version publication date	08 May 2024
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

NGF0221

ISRCTN number

US NCT number

NCT05136170

WHO universal trial number (UTN)

Sponsor organisation name

Dompé farmaceutici S.p.A.

Sponsor organisation address

Via Santa Lucia, 6, Milano, Italy, 20122

Public contact

Flavio Mantelli, Dompé farmaceutici S.p.A., +39 08623381, flavio.mantelli@dompe.com

Scientific contact

Flavio Mantelli, Dompé farmaceutici S.p.A., +39 08623381, 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

21 Dec 2023

Is this the analysis of the primary completion data?

Yes

Primary completion date

24 May 2023

Global end of trial reached?

Yes

Global end of trial date

24 May 2023

Was the trial ended prematurely?

Main objective of the trial

The study objective was to assess the efficacy and safety of cenegermin (rhNGF) ophthalmic solution at 20 mcg/mL concentration administered three times daily (TID) for four weeks in patients with severe Sjogren’s dry eye disease (DED) who were under treatment with topical Cyclosporine A (CsA) or other drugs of the same class.

Protection of trial subjects

The study was conducted in full compliance with applicable legislation, Food and Drug Administration (FDA), European Medicine Agency (EMA) and International Conference on Harmonisation (ICH) guidelines for good clinical practice (GCP) and in accordance with the ethical principles that have their origins in the Declaration of Helsinki and 21 CFR Section 312.120. Eligible patients took part in the study after providing the written informed consent approved by the Independent Ethics Committee (IEC) or Institutional Review Board (IRB). Informed consent was obtained before starting any procedure pertaining to the study (i.e., all the procedures described in the protocol). A Patient Information Sheet and informed consent form (ICF), which met regulatory requirements and were appropriate for this study, were provided to the patient. Each patient read or was read (if he or she could not read or write), assent understanding of, and sign or thumb-printed an instrument of informed consent and after having had an opportunity to discuss them with the Principal Investigator (PI) before signing; each patient was made aware that he or she could withdraw from the study at any time. Patients could voluntarily discontinue treatment with the IMP(s) for any reason at any time. Patients could be withdrawn from treatment with the IMP and assessments at any time, if deemed necessary by the Investigator. The investigator advised patients that prematurely discontinued on any therapies or treatments for their condition and referred them for further treatment, as appropriate. Before the trial formally started, Dompé farmaceutici S.p.A. took out a study-specific insurance contract according to national laws for patients/Investigators/Institutions participating in the clinical trial.

Background therapy

If strictly needed, the patient could take preservative free artificial tears (provided by the Sponsor). One drop of Blink® Tears or equivalent was instilled in both eyes during the screening week, only if strictly needed by the patient. The patient documented in the patient’s Diary the number of additional drops administered for each eye. One drop of Blink® Tears or equivalent was instilled in both eyes during the four weeks of masked treatment, only if strictly needed by the patient. The patient documented in the patient’s Diary the number of additional drops administered for each eye. One drop of Blink® Tears or equivalent was instilled in both eye TID (morning, afternoon, and evening) during the initially eight weeks of follow-up. The patient, only if strictly needed, could administer additional drops and had to document in the patient’s Diary the number of additional drops administered for each eye.

Evidence for comparator

As part of the development plan, the present study was designed to evaluate the safety and efficacy of Oxervate® (cenegermin ophthalmic solution, rhNGF) vs vehicle in patients with severe Sjogren’s DED under treatment with Cyclosporine A. No particular safety risks are foreseen with respect to the safety profile of the marketed product Oxervate® (cenegermin 20 mcg/mL ophthalmic solution). The patients with severe Sjogren’s DED participating in this study could potentially benefit from the application of cenegermin.

Actual start date of recruitment

17 Mar 2022

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

United States: 42

Country: Number of subjects enrolled

Italy: 43

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

Three sites in Italy and 7 sites in US enrolled patients. A total of 97 patients were assessed for eligibility. There were 12 screening failures. The remaining patients (n=85) were randomized 1:1 as follows: 44 to cenegermin and 41 to vehicle. One patient in the vehicle group did not receive study medication and was excluded from the SAF and FAS.

Screening details

Adults (≥ 18 years) with a diagnosis of severe Sjögren's DED, characterized by: corneal and/or conjunctival staining with fluorescein using NEI grading system ≥3, SANDE questionnaire >25 mm, Schirmer test I (without anaesthesia) ≥2 ≤5mm/5min. BCDVA score ≥ 0.1 decimal units (20/200 Snellen value) in each eye at enrolment. Under treatment with CsA.

Period 1 title

Treatment period (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst, Carer, Assessor

Blinding implementation details

This was a double-blind study. Blinding was ensured as described in the Study Protocol: vials containing cenegermin or vehicle were identical in appearance, and the contents of the vials were indistinguishable. All staff directly involved in the analysis of study results remained masked to treatment assignments while the study was in progress. The blind was not broken for any patient during the study before the database lock.

Are arms mutually exclusive

Yes

Cenegermin

Arm description

Group 1: Cenegermin (rhNGF 20 mcg/mL)

Arm type

Experimental

Investigational medicinal product name

Cenegermin

Investigational medicinal product code

Other name

Oxervate®, rhNGF

Pharmaceutical forms

Eye drops, solution

Routes of administration

Ocular use

Dosage and administration details

One drop of cenegermin 20 mcg/mL was instilled in both eyes TID (every six hours, e.g., 7:00 am, 01:00 pm; 07:00 pm).

Vehicle

Arm description

Group 2: Placebo vehicle (Vehicle vials). Out of the 41 patients enrolled in the study and assigned to the vehicle treatment group, one patient did not receive any dose of study medication and was therefore excluded from the SAF and FAS populations. Thus, results are reported for the 40 patients in the vehicle group who received treatment.

Arm type

Placebo

Investigational medicinal product name

Vehicle

Investigational medicinal product code

Other name

Pharmaceutical forms

Eye drops, solution

Routes of administration

Ocular use

Dosage and administration details

One drop of vehicle ophthalmic solution was instilled in both eyes TID (every six hours, e.g., 7:00 am, 01:00 pm; 07:00 pm).

Number of subjects in period 1 ^[1]	Cenegermin	Vehicle
Started	44	40
Completed	41	39
Not completed	3	1
Consent withdrawn by subject	2	1
Can no longer make office visits	1	-

Notes
[1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: Out of the 85 patients enrolled in the study, one patient in the vehicle group was excluded from the SAF and FAS populations because this patient did not receive any dose of study medication. Therefore, both SAF and FAS populations consisted of 84 patients: 44 patients in the cenegermin group and 40 patients in the vehicle group.

Baseline characteristics

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Reporting group title

Cenegermin

Reporting group description

Group 1: Cenegermin (rhNGF 20 mcg/mL)

Reporting group title

Vehicle

Reporting group description

Reporting group values	Cenegermin	Vehicle	Total
Number of subjects	44	40	84
Age categorical
Units: Subjects
Adults (18-64 years)	35	27	62
From 65-84 years	9	13	22
Age continuous
Units: years
arithmetic mean (standard deviation)	55.0 ( 13.93 )	58.1 ( 12.84 )	-
Gender categorical
Units: Subjects
Female	38	35	73
Male	6	5	11
Geographic region
Units: Subjects
Europe	23	19	42
US	21	21	42
Site
Units: Subjects
Site #01	9	7	16
Site #02	4	3	7
Site #04	10	9	19
Site #05	4	5	9
Site #06	1	0	1
Site #07	2	1	3
Site #08	2	4	6
Site #09	3	3	6
Site #10	6	6	12
Site #12	3	2	5
Race
Units: Subjects
Asian	0	4	4
Unknown	0	1	1
Black or African American	4	4	8
White	37	30	67
Other	2	1	3
Missing	1	0	1
Ethnicity
Units: Subjects
Hispanic or Latino	3	2	5
Not Hispanic or Latino	41	38	79

End points

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Reporting group title

Cenegermin

Reporting group description

Group 1: Cenegermin (rhNGF 20 mcg/mL)

Reporting group title

Vehicle

Reporting group description

Primary: Schirmer I test (without anaesthesia) >10mm/5min at Week 4

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End point title

Schirmer I test (without anaesthesia) >10mm/5min at Week 4

End point description

Patients achieving Schirmer I test (without anaesthesia) value of >10mm/5min at Week 4

End point type

Primary

End point timeframe

Week 4

End point values	Cenegermin	Vehicle
Number of subjects analysed	44	40
Units: Subjects	19	4

Logistic Regression Model

Statistical analysis description

Analysis is based on logistic regression model with multiple imputation (MI) under a missing not at random (MNAR) mechanism using retrieve dropouts with proportion of patients reaching a value of Schirmer I test > 10 mm/5 min at Week 4 as dependent variable, treatment, gender, age class and baseline Schirmer I test value as qualitative independent variables. Site is considered as random effects that vary randomly among patients.

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.002

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

8.498

Confidence interval

level

95%

sides

2-sided

lower limit

2.165

upper limit

33.356

Primary: Change from Baseline in the Global SANDE Score at Week 12

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End point title

Change from Baseline in the Global SANDE Score at Week 12

End point description

Change from Baseline in the Global SANDE score at Week 12, analysis of covariance (ANCOVA). Results described below refer to the adjusted means from the ANCOVA model.

End point type

Primary

End point timeframe

Week 12

End point values	Cenegermin	Vehicle
Number of subjects analysed	44	40
Units: Change from baseline in SANDE score
arithmetic mean (confidence interval 95%)	-12.452 (-19.962 to -4.942)	-13.042 (-20.650 to -5.433)

ANCOVA

Statistical analysis description

Analysis is based on ANCOVA model with multiple imputation (MI) under a missing not at random (MNAR) mechanism using retrieve dropouts with change from baseline in the global SANDE score at Week 12 as dependent variable, treatment, gender, age class and baseline global SANDE score as qualitative independent variables. Site is considered as random effects that vary randomly among patients.

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.89 ^[1]

Method

ANCOVA

Parameter type

Adjusted means difference

Point estimate

0.59

Confidence interval

level

95%

sides

2-sided

lower limit

-7.801

upper limit

8.981

Notes
[1] - Adjusted means difference [95% CI] between the two groups (0.590 [-7.801; 8.981]) was not statistically significant (p-value = 0.890).

Secondary: Schirmer I test (without anaesthesia) >10mm/5min at Week 8

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End point title

Schirmer I test (without anaesthesia) >10mm/5min at Week 8

End point description

KEY SECONDARY ENDPOINT: Patients achieving Schirmer I test value of >10mm/5min at Week 8

End point type

Secondary

End point timeframe

Week 8

End point values	Cenegermin	Vehicle
Number of subjects analysed	44	40
Units: Subjects	11	2

Logistic Regression Model

Statistical analysis description

Analysis is based on logistic regression model with multiple imputation (MI) under missing not at random (MNAR) using retrieve dropouts with proportion of patients reaching a value of Schirmer I test > 10 mm/5 min at Week 8 as dependent variable, treatment, gender, age class and baseline Schirmer I test value as qualitative independent variables. Site is considered as random effects that vary randomly among patients.

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.022

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

6.648

Confidence interval

level

95%

sides

2-sided

lower limit

1.307

upper limit

33.808

Secondary: Change from Baseline in Symptoms Questionnaire (SANDE) Score for Severity at Week 12

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End point title

Change from Baseline in Symptoms Questionnaire (SANDE) Score for Severity at Week 12

End point description

KEY SECONDARY ENDPOINT: Change from Baseline in SANDE scores for Severity at Week 12, analysis of covariance (ANCOVA). Results described below refer to the adjusted means from the ANCOVA model.

End point type

Secondary

End point timeframe

Week 12

End point values	Cenegermin	Vehicle
Number of subjects analysed	44	40
Units: Change from Baseline in SANDE score
arithmetic mean (confidence interval 95%)	-11.851 (-19.824 to -3.878)	-12.072 (-20.188 to -3.957)

ANCOVA

Statistical analysis description

Analysis is based on ANCOVA model with multiple imputation (MI) under missing not at random (MNAR) using retrieve dropouts with change from baseline in the severity SANDE score at Week 12 as dependent variable, treatment, gender, age class and baseline severity SANDE score as qualitative independent variables. Site is considered as random effects that vary randomly among patients.

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.962 ^[2]

Method

ANCOVA

Parameter type

Adjusted means difference

Point estimate

0.221

Confidence interval

level

95%

sides

2-sided

lower limit

-8.934

upper limit

9.377

Notes
[2] - The adjusted mean change from baseline in the cenegermin group was not statistically significantly superior to that in the vehicle group (p-value = 0.962).

Secondary: Change from Baseline in Symptoms Questionnaire (SANDE) Score for Frequency at Week 12

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End point title

Change from Baseline in Symptoms Questionnaire (SANDE) Score for Frequency at Week 12

End point description

KEY SECONDARY ENDPOINT: Change from Baseline in SANDE scores for Frequency at Week 12 , analysis of covariance (ANCOVA). Results described below refer to the adjusted means from the ANCOVA model.

End point type

Secondary

End point timeframe

Week 12.

End point values	Cenegermin	Vehicle
Number of subjects analysed	44	40
Units: Change from baseline in SANDE score
arithmetic mean (confidence interval 95%)	-14.606 (-23.007 to -6.204)	-14.770 (-23.258 to -6.281)

ANCOVA

Statistical analysis description

Analysis is based on ANCOVA model with multiple imputation (MI) under missing not at random (MNAR) using retrieve dropouts with change from baseline in the frequency SANDE score at Week 12 as dependent variable, treatment, gender, age class and baseline frequency SANDE score as qualitative independent variables. Site is considered as random effects that vary randomly among patients.

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.973 ^[3]

Method

ANCOVA

Parameter type

Adjusted means difference

Point estimate

0.164

Confidence interval

level

95%

sides

2-sided

lower limit

-9.221

upper limit

9.549

Notes
[3] - The adjusted means difference between the two groups was not statistically significant (p-value = 0.973).

Secondary: Change from Baseline in IDEEL modules (Quality Of Life, Dry Eye Treatment Satisfaction & Bother and Dry Eye Symptom-Bother modules) at Week 12 and at Week 4

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End point title

Change from Baseline in IDEEL modules (Quality Of Life, Dry Eye Treatment Satisfaction & Bother and Dry Eye Symptom-Bother modules) at Week 12 and at Week 4

End point description

KEY SECONDARY ENDPOINT: Change from Baseline at Week 12 and at Week 4 in IDEEL modules, including Quality Of Life (QoL), Dry Eye Treatment Satisfaction & Bother (TS) and Dry Eye Symptom-Bother modules.

End point type

Secondary

End point timeframe

Week 12 and Week 4.

End point values	Cenegermin	Vehicle
Number of subjects analysed	44	40
Units: Changes from baseline in IDEEL modules
least squares mean (confidence interval 95%)
QoL (Daily activities) - Week 4	13.690 (8.034 to 19.346)	11.312 (5.393 to 17.231)
QoL (Daily activities) - Week 12	13.769 (7.711 to 19.827)	6.659 (0.549 to 12.769)
QoL (Feelings) - Week 4	8.811 (2.356 to 15.266)	12.977 (6.263 to 19.692)
QoL (Feelings) - Week 12	11.413 (5.058 to 17.767)	10.355 (3.923 to 16.787)
QoL (Work) - Week 4	10.689 (2.183 to 19.195)	14.596 (5.224 to 23.967)
QoL (Work) - Week 12	13.225 (5.547 to 20.903)	13.509 (5.084 to 21.934)
TS (Treatment - in general) - Week 4	8.708 (2.786 to 14.630)	8.757 (2.493 to 15.022)
TS (Treatment - in general) - Week 12	7.281 (1.570 to 12.992)	5.305 (-0.513 to 11.124)
TS (Treatment - Eye drops) - Week 4	11.368 (3.535 to 19.202)	8.598 (0.287 to 16.908)
TS (Treatment - Eye drops) - Week 12	11.447 (3.576 to 19.318)	6.193 (-1.781 to 14.167)
Symptom-Bother - Week 4	-8.030 (-13.302 to -2.758)	-13.262 (-18.758 to -7.766)
Symptom-Bother - Week 12	-10.814 (-16.220 to -5.407)	-10.657 (-16.102 to -5.212)

QoL (Daily activities) - Week 4

Statistical analysis description

Analysis is based on MMRM with multiple Imputation (MI) under missing not at random using (MNAR) retrieve dropouts with change from baseline in IDEEL Quality of life module at each timepoint adjusting by gender, age class, IDEEL scale baseline value, treatment, visit, and treatment by visit interaction. Patient was considered as a random effect and the covariance matrix used was unstructured.

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.52 ^[4]

Method

Mixed Model for Repeated Measures

Parameter type

LS means difference

Point estimate

2.378

Confidence interval

level

95%

sides

2-sided

lower limit

-4.869

upper limit

9.625

Notes
[4] - Not statistically significant result.

QoL (Daily activities) - Week 12

Statistical analysis description

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.073 ^[5]

Method

Mixed Model for Repeated Measures

Parameter type

LS means difference

Point estimate

7.11

Confidence interval

level

95%

sides

2-sided

lower limit

-0.653

upper limit

14.873

Notes
[5] - Not statistically significant result.

QoL (Feelings) - Week 4

Statistical analysis description

Analysis is based on MMRM with Multiple Imputation under missing not at random using retrieve dropouts with change from baseline in IDEEL Quality of life module at each timepoint adjusting by gender, age class, IDEEL scale baseline value, treatment, visit, and treatment by visit interaction. Patient was considered as a random effect and the covariance matrix used was unstructured.

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.317 ^[6]

Method

Mixed Model for Repeated Measures

Parameter type

LS means difference

Point estimate

-4.166

Confidence interval

level

95%

sides

2-sided

lower limit

-12.322

upper limit

3.989

Notes
[6] - Not statistically significant result.

QoL (Feelings) - Week 12

Statistical analysis description

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.792 ^[7]

Method

Mixed Model for Repeated Measures

Parameter type

LS means difference

Point estimate

1.058

Confidence interval

level

95%

sides

2-sided

lower limit

-6.786

upper limit

8.901

Notes
[7] - Not statistically significant result.

QoL (Work) - Week 4

Statistical analysis description

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.488 ^[8]

Method

Mixed Model for Repeated Measures

Parameter type

LS means difference

Point estimate

-3.907

Confidence interval

level

95%

sides

2-sided

lower limit

-14.948

upper limit

7.135

Notes
[8] - Not statistically significant result.

QoL (Work) - Week 12

Statistical analysis description

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.954 ^[9]

Method

Mixed Model for Repeated Measures

Parameter type

LS means difference

Point estimate

-0.284

Confidence interval

level

95%

sides

2-sided

lower limit

-9.998

upper limit

9.431

Notes
[9] - Not statistically significant result.

TS (Treatment - in general) - Week 4

Statistical analysis description

Analysis is based on MMRM with Multiple Imputation under missing not at random using retrieve dropouts with change from baseline in IDEEL Dry eye Treatment satisfaction & Bother module at each timepoint adjusting by gender, age class, IDEEL scale baseline value, treatment, visit, and treatment by visit interaction. Subject was considered as a random effect and the covariance matrix used was unstructured.

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.99 ^[10]

Method

Mixed Model for Repeated Measures

Parameter type

LS means difference

Point estimate

-0.049

Confidence interval

level

95%

sides

2-sided

lower limit

-7.658

upper limit

7.559

Notes
[10] - Not statistically significant result.

TS (Treatment - in general) - Week 12

Statistical analysis description

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.582 ^[11]

Method

Mixed Model for Repeated Measures

Parameter type

LS means difference

Point estimate

1.976

Confidence interval

level

95%

sides

2-sided

lower limit

-5.065

upper limit

9.017

Notes
[11] - Not statistically significant result.

TS (Treatment - Eye drops) - Week 4

Statistical analysis description

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.586 ^[12]

Method

Mixed Model for Repeated Measures

Parameter type

LS means difference

Point estimate

2.771

Confidence interval

level

95%

sides

2-sided

lower limit

-7.213

upper limit

12.754

Notes
[12] - Not statistically significant result.

TS (Treatment - Eye drops) - Week 12

Statistical analysis description

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.29 ^[13]

Method

Mixed Model for Repeated Measures

Parameter type

LS means difference

Point estimate

5.254

Confidence interval

level

95%

sides

2-sided

lower limit

-4.488

upper limit

14.996

Notes
[13] - Not statistically significant result.

Symptom-Bother - Week 4

Statistical analysis description

Analysis is based on MMRM with Multiple Imputation under missing not at random using retrieve dropouts with change from baseline in IDEEL Dry eye Symptom bother module at each timepoint adjusting by gender, age class, IDEEL scale baseline value, treatment, visit, and treatment by visit interaction. Subject was considered as a random effect and the covariance matrix used was unstructured.

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.125 ^[14]

Method

Mixed Model for Repeated Measures

Parameter type

LS means difference

Point estimate

5.232

Confidence interval

level

95%

sides

2-sided

lower limit

-1.457

upper limit

11.922

Notes
[14] - Not statistically significant result.

Symptom-Bother - Week 12

Statistical analysis description

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.964 ^[15]

Method

Mixed Model for Repeated Measures

Parameter type

LS means difference

Point estimate

-0.156

Confidence interval

level

95%

sides

2-sided

lower limit

-6.912

upper limit

6.6

Notes
[15] - Not statistically significant result.

Secondary: Change from Baseline in Cornea and Conjunctiva Vital Staining with Fluorescein (National Eye Institute [NEI] scales) at Week 4, Week 8 and Week 12

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End point title

Change from Baseline in Cornea and Conjunctiva Vital Staining with Fluorescein (National Eye Institute [NEI] scales) at Week 4, Week 8 and Week 12

End point description

KEY SECONDARY ENDPOINT: Change from Baseline in Cornea and Conjunctiva Vital Staining with Fluorescein NEI scale up to Week 12, MMRM.

End point type

Secondary

End point timeframe

Week 4, Week 8 and Week 12.

End point values	Cenegermin	Vehicle
Number of subjects analysed	44	40
Units: Change from baseline
least squares mean (confidence interval 95%)
Week 4	-3.331 (-4.725 to -1.938)	-2.354 (-3.889 to -0.819)
Week 8	-3.102 (-4.439 to -1.765)	-2.445 (-3.897 to -0.993)
Week 12	-3.595 (-4.987 to -2.203)	-3.571 (-5.048 to -2.094)

Week 4

Statistical analysis description

Analysis is based on MMRM with Multiple Imputation under missing not at random using retrieve dropouts with change from baseline in Cornea and conjunctiva vital staining with fluorescein NEI scale at each timepoint adjusting by gender, age class, NEI scale baseline value, treatment, visit, and treatment by visit interaction. Patient was considered as a random effect and the covariance matrix used was unstructured.

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.28 ^[16]

Method

Mixed Model for Repeated Measures

Parameter type

LS means difference

Point estimate

-0.977

Confidence interval

level

95%

sides

2-sided

lower limit

-2.749

upper limit

0.795

Notes
[16] - Not statistically significant result.

Week 8

Statistical analysis description

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.44 ^[17]

Method

Mixed Model for Repeated Measures

Parameter type

LS means difference

Point estimate

-0.657

Confidence interval

level

95%

sides

2-sided

lower limit

-2.324

upper limit

1.01

Notes
[17] - Not statistically significant result.

Week 12

Statistical analysis description

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.978 ^[18]

Method

Mixed Model for Repeated Measures

Parameter type

LS means difference

Point estimate

-0.024

Confidence interval

level

95%

sides

2-sided

lower limit

-1.743

upper limit

1.694

Notes
[18] - Not statistically significant result.

Secondary: Change from Baseline in Tear Film Break-Up Time (TFBUT) at Week 4, Week 8 and Week 12

Top of page

End point title

Change from Baseline in Tear Film Break-Up Time (TFBUT) at Week 4, Week 8 and Week 12

End point description

KEY SECONDARY ENDPOINT: Change from Baseline in TFBUT up to Week 12, MMRM.

End point type

Secondary

End point timeframe

Week 4, Week 8 and Week 12.

End point values	Cenegermin	Vehicle
Number of subjects analysed	44	40
Units: Change from baseline in TFBUT
least squares mean (confidence interval 95%)
Week 4	1.020 (0.253 to 1.787)	0.225 (-0.586 to 1.036)
Week 8	0.899 (0.074 to 1.725)	0.951 (0.088 to 1.813)
Week 12	0.917 (0.123 to 1.711)	0.782 (-0.040 to 1.603)

Week 4

Statistical analysis description

Analysis is based on MMRM with Multiple Imputation under missing not at random using retrieve dropouts with change from baseline in TFBUT at each timepoint adjusting by gender, age class, TFBUT scale baseline value, treatment, visit, and treatment by visit interaction. Patient was considered as a random effect and the covariance matrix used was unstructured

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.102 ^[19]

Method

Mixed Model for Repeated Measures

Parameter type

LS means difference

Point estimate

0.795

Confidence interval

level

95%

sides

2-sided

lower limit

-0.157

upper limit

1.748

Notes
[19] - Not statistically significant result.

Week 8

Statistical analysis description

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.923 ^[20]

Method

Mixed Model for Repeated Measures

Parameter type

LS means difference

Point estimate

-0.051

Confidence interval

level

95%

sides

2-sided

lower limit

-1.094

upper limit

0.991

Notes
[20] - Not statistically significant result.

Week 12

Statistical analysis description

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.787 ^[21]

Method

Mixed Model for Repeated Measures

Parameter type

LS means difference

Point estimate

0.136

Confidence interval

level

95%

sides

2-sided

lower limit

-0.849

upper limit

1.12

Notes
[21] - Not statistically significant result.

Secondary: Change from Baseline in Schirmer I Test (without anaesthesia) at Week 4, Week 8, Week 12, and Week 16

Top of page

End point title

Change from Baseline in Schirmer I Test (without anaesthesia) at Week 4, Week 8, Week 12, and Week 16

End point description

Change from Baseline in Schirmer I Test at each Timepoint.

End point type

Secondary

End point timeframe

Week 4, Week 8, Week 12 and Week 16.

End point values	Cenegermin	Vehicle
Number of subjects analysed	44 ^[22]	40 ^[23]
Units: Change from baseline in Schirmer I Test
arithmetic mean (standard deviation)
Week 4	5.4 ( 5.2 )	1.7 ( 3.2 )
Week 8	4.9 ( 4.5 )	1.5 ( 3.0 )
Week 12	4.1 ( 4.7 )	3.1 ( 6.3 )
Week 16	3.4 ( 4.0 )	2.4 ( 4.9 )

Notes
[22] - Week 4, n=43; Week 8, n=40; Week 12, n=40; Week 16, n=41.
[23] - Week 4, n=39; Week 8, n=38; Week 12, n=39; Week 16, n=38.

Week 4

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[24]

P-value

< 0.001 ^[25]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[24] - 84 subjects are included in the FAS, however only 82 subjects are analyzed in this table due to the presence of missing values.
[25] - p-value corresponds to a non-parametric Mann–Whitney–Wilcoxon (Wilcoxon rank sum) test of the comparisons between Cenegermin and Vehicle in all patients.

Week 8

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[26]

P-value

< 0.001 ^[27]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[26] - 84 subjects are included in the FAS, however only 78 subjects are analyzed in this table due to the presence of missing values.
[27] - p-value corresponds to a non-parametric Mann–Whitney–Wilcoxon (Wilcoxon rank sum) test of the comparisons between Cenegermin and Vehicle in all patients.

Week 12

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[28]

P-value

= 0.014 ^[29]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[28] - 84 subjects are included in the FAS, however only 79 subjects are analyzed in this table due to the presence of missing values.
[29] - p-value corresponds to a non-parametric Mann–Whitney–Wilcoxon (Wilcoxon rank sum) test of the comparisons between Cenegermin and Vehicle in all patients.

Week 16

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[30]

P-value

= 0.095 ^[31]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[30] - 84 subjects are included in the FAS, however only 79 subjects are analyzed in this table due to the presence of missing values.
[31] - Not statistically significant result. p-value corresponds to a non-parametric Mann–Whitney–Wilcoxon (Wilcoxon rank sum) test of the comparisons between Cenegermin and Vehicle in all patients.

Secondary: Change from Baseline in Cornea and Conjunctiva Vital Staining with Fluorescein (National Eye Institute [NEI] scales) at Week 4, Week 8, Week 12 and Week 16

Top of page

End point title

Change from Baseline in Cornea and Conjunctiva Vital Staining with Fluorescein (National Eye Institute [NEI] scales) at Week 4, Week 8, Week 12 and Week 16

End point description

Change from baseline in Cornea and Conjunctiva Vital Staining with Fluorescein (NEI scale) at each Timepoint

End point type

Secondary

End point timeframe

Week 4, Week 8, Week 12 and Week 16

End point values	Cenegermin	Vehicle
Number of subjects analysed	44 ^[32]	40 ^[33]
Units: Change from baseline in NEI scale
arithmetic mean (standard deviation)
Week 4	-3.6 ( 4.6 )	-2.4 ( 4.7 )
Week 8	-3.1 ( 3.8 )	-2.9 ( 3.9 )
Week 12	-3.4 ( 4.6 )	-3.0 ( 3.8 )
Week 16	-2.0 ( 6.9 )	-2.3 ( 4.2 )

Notes
[32] - Week 4, n=42; Week 8, n=39; Week 12, n=39; Week 16, n=40.
[33] - Week 4, n=37; Week 8, n=36; Week 12, n=37; Week 16, n=36.

Week 4

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[34]

P-value

= 0.02 ^[35]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[34] - 84 subjects are included in the FAS, however only 79 subjects are analyzed in this table due to the presence of missing values.
[35] - p-value corresponds to a non-parametric Mann–Whitney–Wilcoxon (Wilcoxon rank sum) test of the comparisons between Cenegermin and Vehicle in all patients.

Week 8

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[36]

P-value

= 0.328 ^[37]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[36] - 84 subjects are included in the FAS, however only 75 subjects are analyzed in this table due to the presence of missing values.
[37] - Not statistically significant result. p-value corresponds to a non-parametric Mann–Whitney–Wilcoxon (Wilcoxon rank sum) test of the comparisons between Cenegermin and Vehicle in all patients.

Week 12

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[38]

P-value

= 0.287 ^[39]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[38] - 84 subjects are included in the FAS, however only 76 subjects are analyzed in this table due to the presence of missing values.
[39] - Not statistically significant result. p-value corresponds to a non-parametric Mann–Whitney–Wilcoxon (Wilcoxon rank sum) test of the comparisons between Cenegermin and Vehicle in all patients.

Week 16

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[40]

P-value

= 0.777 ^[41]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[40] - 84 subjects are included in the FAS, however only 76 subjects are analyzed in this table due to the presence of missing values.
[41] - Not statistically significant result. p-value corresponds to a non-parametric Mann–Whitney–Wilcoxon (Wilcoxon rank sum) test of the comparisons between Cenegermin and Vehicle in all patients.

Secondary: Change from Baseline in Tear Film Break-Up Time (TFBUT) at Week 4, Week 8, Week 12 and Week 16

Top of page

End point title

Change from Baseline in Tear Film Break-Up Time (TFBUT) at Week 4, Week 8, Week 12 and Week 16

End point description

Change from baseline in TFBUT at each Timepoint.

End point type

Secondary

End point timeframe

Week 4, Week 8, Week 12 and Week 16.

End point values	Cenegermin	Vehicle
Number of subjects analysed	44 ^[42]	40 ^[43]
Units: Change from baseline in TFBUT
arithmetic mean (standard deviation)
Week 4	1.1 ( 2.4 )	0.2 ( 2.2 )
Week 8	0.9 ( 2.5 )	0.9 ( 2.3 )
Week 12	1.0 ( 2.6 )	0.7 ( 1.8 )
Week 16	1.3 ( 2.8 )	1.1 ( 2.5 )

Notes
[42] - Week 4, n=43; Week 8, n=40; Week 12, n=40; Week 16, n=41.
[43] - Week 4, n=39; Week 8, n=38; Week 12, n=39; Week 16, n=38.

Week 4

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[44]

P-value

= 0.126 ^[45]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[44] - 84 subjects are included in the FAS, however only 82 subjects are analyzed in this table due to the presence of missing values.
[45] - Not statistically significant result. p-value corresponds to a non-parametric Mann–Whitney–Wilcoxon (Wilcoxon rank sum) test of the comparisons between Cenegermin and and Vehicle in all patients.

Week 8

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[46]

P-value

= 0.968 ^[47]

Method

t-test, 2-sided

Confidence interval

Notes
[46] - 84 subjects are included in the FAS, however only 78 subjects are analyzed in this table due to the presence of missing values.
[47] - Not statistically significant result. p-value corresponds to a two sample (independent group) t-test of the comparisons between Cenegermin and and Vehicle in all patients.

Week 12

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[48]

P-value

= 0.613 ^[49]

Method

t-test, 2-sided

Confidence interval

Notes
[48] - 84 subjects are included in the FAS, however only 79 subjects are analyzed in this table due to the presence of missing values.
[49] - Not statistically significant result. p-value corresponds to a two sample (independent group) t-test of the comparisons between Cenegermin and and Vehicle in all patients.

Week 16

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[50]

P-value

= 0.805 ^[51]

Method

t-test, 2-sided

Confidence interval

Notes
[50] - 84 subjects are included in the FAS, however only 79 subjects are analyzed in this table due to the presence of missing values.
[51] - Not statistically significant result. p-value corresponds to a two sample (independent group) t-test of the comparisons between Cenegermin and and Vehicle in all patients.

Secondary: Change from Baseline in Symptoms Questionnaire (SANDE) Global Scores, and for Severity and Frequency at Week 8, Week 12, and Week 16

Top of page

End point title

Change from Baseline in Symptoms Questionnaire (SANDE) Global Scores, and for Severity and Frequency at Week 8, Week 12, and Week 16

End point description

Change from baseline in SANDE Global scores, SANDE Severity scores and SANDE Frequency scores at each Timepoint.

End point type

Secondary

End point timeframe

Week 8, Week 12, and Week 16

End point values	Cenegermin	Vehicle
Number of subjects analysed	44 ^[52]	40 ^[53]
Units: Change from baseline in SANDE scores
arithmetic mean (standard deviation)
Global Score - Week 8	-12.9 ( 19.0 )	-10.3 ( 19.2 )
Global Score - Week 12	-9.5 ( 17.0 )	-11.3 ( 22.5 )
Global Score - Week 16	-9.0 ( 22.3 )	-11.1 ( 19.0 )
Severity - Week 8	-10.7 ( 19.6 )	-9.9 ( 20.9 )
Severity - Week 12	-8.6 ( 19.6 )	-10.2 ( 25.1 )
Severity - Week 16	-7.9 ( 22.9 )	-10.2 ( 20.2 )
Frequency - Week 8	-16.4 ( 23.2 )	-10.9 ( 21.2 )
Frequency - Week 12	-10.3 ( 23.6 )	-12.3 ( 23.5 )
Frequency - Week 16	-10.5 ( 24.2 )	-12.2 ( 18.6 )

Notes
[52] - Week 8, n=40; Week 12, n=40; Week 16, n=41.
[53] - Week 8, n=38; Week 12, n=39; Week 16, n=38.

Global Score - Week 8

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[54]

P-value

= 0.543 ^[55]

Method

t-test, 2-sided

Confidence interval

Notes
[54] - 84 subjects are included in the FAS, however only 78 subjects are analyzed in this table due to the presence of missing values.
[55] - Not statistically significant result. p-value corresponds to two sample (independent group) t-test of the comparisons between Cenegermin and Vehicle in all patients.

Global Score - Week 12

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[56]

P-value

= 0.677 ^[57]

Method

t-test, 2-sided

Confidence interval

Notes
[56] - 84 subjects are included in the FAS, however only 79 subjects are analyzed in this table due to the presence of missing values.
[57] - Not statistically significant result. p-value corresponds to two sample (independent group) t-test of the comparisons between Cenegermin and Vehicle in all patients.

Global Score - Week 16

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[58]

P-value

= 0.914 ^[59]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[58] - 84 subjects are included in the FAS, however only 79 subjects are analyzed in this table due to the presence of missing values.
[59] - Not statistically significant result. p-value corresponds to a non-parametric Mann–Whitney–Wilcoxon (Wilcoxon rank sum) test of the comparisons between Cenegermin and Vehicle in all patients.

Severity - Week 8

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[60]

P-value

= 0.874 ^[61]

Method

t-test, 2-sided

Confidence interval

Notes
[60] - 84 subjects are included in the FAS, however only 78 subjects are analyzed in this table due to the presence of missing values.
[61] - Not statistically significant result. p-value corresponds to two sample (independent group) t-test of the comparisons between Cenegermin and Vehicle in all patients.

Severity - Week 12

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[62]

P-value

= 0.945 ^[63]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[62] - 84 subjects are included in the FAS, however only 79 subjects are analyzed in this table due to the presence of missing values.
[63] - Not statistically significant result. p-value corresponds to a non-parametric Mann–Whitney–Wilcoxon (Wilcoxon rank sum) test of the comparisons between Cenegermin and Vehicle in all patients.

Severity - Week 16

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[64]

P-value

= 0.727 ^[65]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[64] - 84 subjects are included in the FAS, however only 79 subjects are analyzed in this table due to the presence of missing values.
[65] - Not statistically significant result. p-value corresponds to a non-parametric Mann–Whitney–Wilcoxon (Wilcoxon rank sum) test of the comparisons between Cenegermin and Vehicle in all patients.

Frequency - Week 8

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[66]

P-value

= 0.342 ^[67]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[66] - 84 subjects are included in the FAS, however only 78 subjects are analyzed in this table due to the presence of missing values.
[67] - Not statistically significant result. p-value corresponds to a non-parametric Mann–Whitney–Wilcoxon (Wilcoxon rank sum) test of the comparisons between Cenegermin and Vehicle in all patients.

Frequency - Week 12

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[68]

P-value

= 0.821 ^[69]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[68] - 84 subjects are included in the FAS, however only 79 subjects are analyzed in this table due to the presence of missing values.
[69] - Not statistically significant result. p-value corresponds to a non-parametric Mann–Whitney–Wilcoxon (Wilcoxon rank sum) test of the comparisons between Cenegermin and Vehicle in all patients.

Frequency - Week 16

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[70]

P-value

= 0.926 ^[71]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[70] - 84 subjects are included in the FAS, however only 79 subjects are analyzed in this table due to the presence of missing values.
[71] - Not statistically significant result. p-value corresponds to a non-parametric Mann–Whitney–Wilcoxon (Wilcoxon rank sum) test of the comparisons between Cenegermin and Vehicle in all patients.

Secondary: Number of Patients experienced a Worsening in Symptom Scores (SANDE Global Scores) and/or NEI Score ≥ 50% at Week 4

Top of page

End point title

Number of Patients experienced a Worsening in Symptom Scores (SANDE Global Scores) and/or NEI Score ≥ 50% at Week 4

End point description

Number of Patients experienced a Worsening in Symptom Scores (SANDE Global Score) and/or NEI Score ≥50% at Week 4.

End point type

Secondary

End point timeframe

Week 4

End point values	Cenegermin	Vehicle
Number of subjects analysed	44 ^[72]	40 ^[73]
Units: Subjects
Worsening in symptom scores (SANDE global score)	14	5
NEI score >= 50%	1	1
Worsening in symptom scores and/or NEI score >= 50	15	5

Notes
[72] - Wors. Symptom scores, n=43; NEI score ≥50%, n=42; Wors. symptom scores and/or NEI score ≥50%, n=42.
[73] - Wors. Symptom scores, n=39; NEI score ≥50%, n=37; Wors. symptom scores and/or NEI score ≥50%, n=37.

Worsening in symptom scores (SANDE global score)

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[74]

P-value

= 0.0344 ^[75]

Method

Chi-squared

Confidence interval

Notes
[74] - 84 subjects are included in the FAS, however only 82 subjects are analyzed in this table due to the presence of missing values.
[75] - p-value corresponds to Chi-square test of the comparisons between Cenegermin and Vehicle in all patients.

NEI score >= 50%

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[76]

P-value

= 1 ^[77]

Method

Fisher exact

Confidence interval

Notes
[76] - 84 subjects are included in the FAS, however only 79 subjects are analyzed in this table due to the presence of missing values.
[77] - Not statistically significant result. p-value corresponds to a Fisher`s exact test of the comparisons between Cenegermin and Vehicle in all patients.

Worsening in symptom scores and/or NEI score >= 50

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[78]

P-value

= 0.0235 ^[79]

Method

Chi-squared

Confidence interval

Notes
[78] - 84 subjects are included in the FAS, however only 79 subjects are analyzed in this table due to the presence of missing values.
[79] - p-value corresponds to Chi-square test of the comparisons between Cenegermin and Vehicle in all patients.

Secondary: IDEEL Questionnaire at Week 4, Week, 8, Week 12, and Week 16

Top of page

End point title

IDEEL Questionnaire at Week 4, Week, 8, Week 12, and Week 16

End point description

Change from baseline in IDEEL Quality of Life (QoL) module, Treatment Satisfaction (TS) module, and Symptom-Bother module at each Timepoint.

End point type

Secondary

End point timeframe

Week 4, Week, 8, Week 12, and Week 16.

End point values	Cenegermin	Vehicle
Number of subjects analysed	44	40
Units: Change from baseline in IDEEL score
arithmetic mean (standard deviation)
QoL (Impact on Daily Activities) - Week 4	10.9 ( 20.7 )	10.3 ( 16.4 )
QoL (Impact on Daily Activities) - Week 8	9.2 ( 20.6 )	7.2 ( 17.0 )
QoL (Impact on Daily Activities) - Week 12	11.9 ( 20.8 )	5.6 ( 19.3 )
QoL (Impact on Daily Activities) - Week 16	10.8 ( 19.6 )	8.1 ( 16.2 )
QoL (Emotional Impact due to Dry Eye) - Week 4	4.3 ( 21.6 )	10.1 ( 17.5 )
QoL (Emotional Impact due to Dry Eye) - Week 8	6.1 ( 20.0 )	8.5 ( 16.0 )
QoL (Emotional Impact due to Dry Eye) - Week 12	7.4 ( 21.8 )	7.4 ( 16.6 )
QoL (Emotional Impact due to Dry Eye) - Week 16	6.7 ( 25.0 )	7.6 ( 16.1 )
QoL (Impact on Work due to Dry Eye) - Week 4	9.8 ( 24.7 )	13.4 ( 16.1 )
QoL (Impact on Work due to Dry Eye) - Week 8	9.5 ( 21.7 )	8.1 ( 14.3 )
QoL (Impact on Work due to Dry Eye) - Week 12	10.4 ( 19.9 )	11.8 ( 20.0 )
QoL (Impact on Work due to Dry Eye) - Week 16	13.6 ( 21.3 )	8.9 ( 15.1 )
TS (Satisfaction with Effectiveness) - Week 4	11.3 ( 30.4 )	10.1 ( 25.1 )
TS (Satisfaction with Effectiveness) - Week 8	12.0 ( 25.5 )	5.2 ( 25.2 )
TS (Satisfaction with Effectiveness) - Week 12	13.1 ( 26.8 )	7.4 ( 25.7 )
TS (Satisfaction with Effectiveness) - Week 16	13.1 ( 29.0 )	7.9 ( 26.1 )
TS (Treatment Bother/Inconvenience) - Week 4	5.5 ( 21.7 )	6.2 ( 12.7 )
TS (Treatment Bother/Inconvenience) - Week 8	3.3 ( 18.9 )	5.0 ( 14.8 )
TS (Treatment Bother/Inconvenience) - Week 12	4.5 ( 19.8 )	4.2 ( 12.4 )
TS (Treatment Bother/Inconvenience) - Week 16	5.4 ( 18.5 )	3.3 ( 11.3 )
Symptom-Bother - Week 4	-5.8 ( 18.7 )	-11.9 ( 12.5 )
Symptom-Bother - Week 8	-7.2 ( 16.4 )	-7.9 ( 12.9 )
Symptom-Bother - Week 12	-8.6 ( 15.5 )	-9.5 ( 17.7 )
Symptom-Bother - Week 16	-8.0 ( 17.0 )	-9.2 ( 13.9 )

QoL (Impact on Daily Activities) - Week 4

Comparison groups

Vehicle v Cenegermin

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[80]

P-value

= 0.888 ^[81]

Method

t-test, 2-sided

Confidence interval

Notes
[80] - 84 subjects are included in the FAS, however only 81 subjects (Cenegermin, n=43; Vehicle, n=38) are analyzed in this table due to the presence of missing values.
[81] - Not statistically significant result. p-value corresponds to a two sample (independent group) t-test of the comparisons between Cenegermin and Vehicle in all patients.

QoL (Impact on Daily Activities) - Week 8

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[82]

P-value

= 0.651 ^[83]

Method

t-test, 2-sided

Confidence interval

Notes
[82] - 84 subjects are included in the FAS, however only 77 subjects (Cenegermin, n=40; Vehicle, n=37) are analyzed in this table due to the presence of missing values.
[83] - Not statistically significant result. p-value corresponds to a two sample (independent group) t-test of the comparisons between Cenegermin and Vehicle in all patients.

QoL (Impact on Daily Activities) - Week 12

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[84]

P-value

= 0.267 ^[85]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[84] - 84 subjects are included in the FAS, however only 78 subjects (Cenegermin, n=40; Vehicle, n=38) are analyzed in this table due to the presence of missing values.
[85] - Not statistically significant result. p-value corresponds to a non-parametric Mann–Whitney–Wilcoxon (Wilcoxon rank sum) test of the comparisons between Cenegermin and Vehicle in all patients.

QoL (Impact on Daily Activities) - Week 16

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[86]

P-value

= 0.459 ^[87]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[86] - 84 subjects are included in the FAS, however only 78 subjects (Cenegermin, n=41; Vehicle, n=37) are analyzed in this table due to the presence of missing values.
[87] - Not statistically significant result. p-value corresponds to a non-parametric Mann–Whitney–Wilcoxon (Wilcoxon rank sum) test of the comparisons between Cenegermin and Vehicle in all patients.

QoL (Emotional Impact due to Dry Eye) - Week 4

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[88]

P-value

= 0.192 ^[89]

Method

t-test, 2-sided

Confidence interval

Notes
[88] - 84 subjects are included in the FAS, however only 82 subjects (Cenegermin, n=43; Vehicle, n=39) are analyzed in this table due to the presence of missing values.
[89] - Not statistically significant result. p-value corresponds to a two sample (independent group) t-test of the comparisons between Cenegermin and Vehicle in all patients.

QoL (Emotional Impact due to Dry Eye) - Week 8

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[90]

P-value

= 0.568 ^[91]

Method

t-test, 2-sided

Confidence interval

Notes
[90] - 84 subjects are included in the FAS, however only 78 subjects (Cenegermin, n=40; Vehicle, n=38) are analyzed in this table due to the presence of missing values.
[91] - Not statistically significant result. p-value corresponds to a two sample (independent group) t-test of the comparisons between Cenegermin and Vehicle in all patients.

QoL (Emotional Impact due to Dry Eye) - Week 12

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[92]

P-value

= 0.871 ^[93]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[92] - 84 subjects are included in the FAS, however only 79 subjects (Cenegermin, n=40; Vehicle, n=39) are analyzed in this table due to the presence of missing values.
[93] - Not statistically significant result. p-value corresponds to a non-parametric Mann–Whitney–Wilcoxon (Wilcoxon rank sum) test of the comparisons between Cenegermin and Vehicle in all patients.

QoL (Emotional Impact due to Dry Eye) - Week 16

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[94]

P-value

= 0.85 ^[95]

Method

t-test, 2-sided

Confidence interval

Notes
[94] - 84 subjects are included in the FAS, however only 79 subjects (Cenegermin, n=41; Vehicle, n=38) are analyzed in this table due to the presence of missing values.
[95] - Not statistically significant result. p-value corresponds to a two sample (independent group) t-test of the comparisons between Cenegermin and Vehicle in all patients.

QoL (Impact on Work due to Dry Eye) - Week 4

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[96]

P-value

= 0.364 ^[97]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[96] - 84 subjects are included in the FAS, however only 49 subjects (Cenegermin, n=27; Vehicle, n=22) are analyzed in this table due to the presence of missing values.
[97] - Not statistically significant result. p-value corresponds to a non-parametric Mann–Whitney–Wilcoxon (Wilcoxon rank sum) test of the comparisons between Cenegermin and Vehicle in all patients.

QoL (Impact on Work due to Dry Eye) - Week 8

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[98]

P-value

= 0.646 ^[99]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[98] - 84 subjects are included in the FAS, however only 49 subjects (Cenegermin, n=28; Vehicle, n=21) are analyzed in this table due to the presence of missing values.
[99] - Not statistically significant result. p-value corresponds to a non-parametric Mann–Whitney–Wilcoxon (Wilcoxon rank sum) test of the comparisons between Cenegermin and Vehicle in all patients.

QoL (Impact on Work due to Dry Eye) - Week 12

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[100]

P-value

= 0.739 ^[101]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[100] - 84 subjects are included in the FAS, however only 49 subjects (Cenegermin, n=27; Vehicle, n=22) are analyzed in this table due to the presence of missing values.
[101] - Not statistically significant result. p-value corresponds to a non-parametric Mann–Whitney–Wilcoxon (Wilcoxon rank sum) test of the comparisons between Cenegermin and Vehicle in all patients.

QoL (Impact on Work due to Dry Eye) - Week 16

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[102]

P-value

= 0.664 ^[103]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[102] - 84 subjects are included in the FAS, however only 50 subjects (Cenegermin, n=28; Vehicle, n=22) are analyzed in this table due to the presence of missing values.
[103] - Not statistically significant result. p-value corresponds to a non-parametric Mann–Whitney–Wilcoxon (Wilcoxon rank sum) test of the comparisons between Cenegermin and Vehicle in all patients.

TS (Satisfaction with Effectiveness) - Week 4

Comparison groups

Vehicle v Cenegermin

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[104]

P-value

= 0.846 ^[105]

Method

t-test, 2-sided

Confidence interval

Notes
[104] - 84 subjects are included in the FAS, however only 78 subjects (Cenegermin, n=42; Vehicle, n=36) are analyzed in this table due to the presence of missing values.
[105] - Not statistically significant result. p-value corresponds to a two sample (independent group) t-test of the comparisons between Cenegermin and Vehicle in all patients.

TS (Satisfaction with Effectiveness) - Week 8

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[106]

P-value

= 0.248 ^[107]

Method

t-test, 2-sided

Confidence interval

Notes
[106] - 84 subjects are included in the FAS, however only 76 subjects (Cenegermin, n=39; Vehicle, n=37) are analyzed in this table due to the presence of missing values.
[107] - Not statistically significant result. p-value corresponds to a two sample (independent group) t-test of the comparisons between Cenegermin and Vehicle in all patients.

TS (Satisfaction with Effectiveness) - Week 12

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[108]

P-value

= 0.341 ^[109]

Method

t-test, 2-sided

Confidence interval

Notes
[108] - 84 subjects are included in the FAS, however only 77 subjects (Cenegermin, n=39; Vehicle, n=38) are analyzed in this table due to the presence of missing values.
[109] - Not statistically significant result. p-value corresponds to a two sample (independent group) t-test of the comparisons between Cenegermin and Vehicle in all patients.

TS (Satisfaction with Effectiveness) - Week 16

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[110]

P-value

= 0.413 ^[111]

Method

t-test, 2-sided

Confidence interval

Notes
[110] - 84 subjects are included in the FAS, however only 77 subjects (Cenegermin, n=40; Vehicle, n=37) are analyzed in this table due to the presence of missing values.
[111] - Not statistically significant result. p-value corresponds to a two sample (independent group) t-test of the comparisons between Cenegermin and Vehicle in all patients.

TS (Treatment Bother/Inconvenience) - Week 4

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[112]

P-value

= 0.927 ^[113]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[112] - 84 subjects are included in the FAS, however only 78 subjects (Cenegermin, n=43; Vehicle, n=35) are analyzed in this table due to the presence of missing values.
[113] - Not statistically significant result. p-value corresponds to a non-parametric Mann–Whitney–Wilcoxon (Wilcoxon rank sum) test of the comparisons between Cenegermin and Vehicle in all patients.

TS (Treatment Bother/Inconvenience) - Week 8

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[114]

P-value

= 0.914 ^[115]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[114] - 84 subjects are included in the FAS, however only 75 subjects (Cenegermin, n=39; Vehicle, n=36) are analyzed in this table due to the presence of missing values.
[115] - Not statistically significant result. p-value corresponds to a non-parametric Mann–Whitney–Wilcoxon (Wilcoxon rank sum) test of the comparisons between Cenegermin and Vehicle in all patients.

TS (Treatment Bother/Inconvenience) - Week 12

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[116]

P-value

= 0.564 ^[117]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[116] - 84 subjects are included in the FAS, however only 76 subjects (Cenegermin, n=39; Vehicle, n=37) are analyzed in this table due to the presence of missing values.
[117] - Not statistically significant result. p-value corresponds to a non-parametric Mann–Whitney–Wilcoxon (Wilcoxon rank sum) test of the comparisons between Cenegermin and Vehicle in all patients.

TS (Treatment Bother/Inconvenience) - Week 16

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[118]

P-value

= 0.489 ^[119]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[118] - 84 subjects are included in the FAS, however only 75 subjects (Cenegermin, n=39; Vehicle, n=36) are analyzed in this table due to the presence of missing values.
[119] - Not statistically significant result. p-value corresponds to a non-parametric Mann–Whitney–Wilcoxon (Wilcoxon rank sum) test of the comparisons between Cenegermin and Vehicle in all patients.

Symptom-Bother - Week 4

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[120]

P-value

= 0.082 ^[121]

Method

t-test, 2-sided

Confidence interval

Notes
[120] - 84 subjects are included in the FAS, however only 82 subjects (Cenegermin, n=43; Vehicle, n=39) are analyzed in this table due to the presence of missing values.
[121] - Not statistically significant result. p-value corresponds to a two sample (independent group) t-test of the comparisons between Cenegermin and Vehicle in all patients.

Symptom-Bother - Week 8

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[122]

P-value

= 0.848 ^[123]

Method

t-test, 2-sided

Confidence interval

Notes
[122] - 84 subjects are included in the FAS, however only 78 subjects (Cenegermin, n=40; Vehicle, n=38) are analyzed in this table due to the presence of missing values.
[123] - Not statistically significant result. p-value corresponds to a two sample (independent group) t-test of the comparisons between Cenegermin and Vehicle in all patients.

Symptom-Bother - Week 12

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[124]

P-value

= 0.805 ^[125]

Method

t-test, 2-sided

Confidence interval

Notes
[124] - 84 subjects are included in the FAS, however only 79 subjects (Cenegermin, n=40; Vehicle, n=39) are analyzed in this table due to the presence of missing values.
[125] - Not statistically significant result. p-value corresponds to a two sample (independent group) t-test of the comparisons between Cenegermin and Vehicle in all patients.

Symptom-Bother - Week 16

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[126]

P-value

= 0.833 ^[127]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[126] - 84 subjects are included in the FAS, however only 79 subjects (Cenegermin, n=41; Vehicle, n=38) are analyzed in this table due to the presence of missing values.
[127] - Not statistically significant result. p-value corresponds to a non-parametric Mann–Whitney–Wilcoxon (Wilcoxon rank sum) test of the comparisons between Cenegermin and Vehicle in all patients.

Other pre-specified: Proportion and Frequency of Preservative Free Artificial Tears Use (number of drops/day)

Top of page

End point title

Proportion and Frequency of Preservative Free Artificial Tears Use (number of drops/day)

End point description

Use of Preservative Free Artificial Tears by Study Period is calculated as: total number of drops of the preservative free artificial tears during the X period/ total number of days of the X period * 100.

End point type

Other pre-specified

End point timeframe

Treatment Period, Follow-up Period and Overall

End point values	Cenegermin	Vehicle
Number of subjects analysed	44 ^[128]	40 ^[129]
Units: Preservative Free Artificial Tears
arithmetic mean (standard deviation)
Treatment Period	261.2 ( 220.2 )	215.7 ( 184.7 )
Follow-up Period	330.0 ( 178.1 )	317.6 ( 168.3 )
Overall	294.7 ( 202.5 )	268.1 ( 182.6 )

Notes
[128] - Treatment period, n=40; Follow-up period, n=38; Overall, n=41.
[129] - Treatment period, n=35; Follow-up period, n=37; Overall, n=38.

No statistical analyses for this end point

Other pre-specified: Change from Baseline in Schirmer I Test (without anaesthesia) at Week 2

Top of page

End point title

Change from Baseline in Schirmer I Test (without anaesthesia) at Week 2

End point description

Change from Baseline in Schirmer I Test (without anaesthesia) at Week 2

End point type

Other pre-specified

End point timeframe

Week 2

End point values	Cenegermin	Vehicle
Number of subjects analysed	44 ^[130]	40 ^[131]
Units: Change from baseline to Week 2
arithmetic mean (standard deviation)	4.4 ( 5.0 )	1.0 ( 2.4 )

Notes
[130] - N=43
[131] - N=39

Change from baseline to Week 2

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[132]

P-value

< 0.001 ^[133]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[132] - 84 subjects are included in the FAS, however only 82 subjects are analyzed in this table due to the presence of missing values.
[133] - p-value corresponds to a non-parametric Mann–Whitney–Wilcoxon (Wilcoxon rank sum) test of the comparisons between Cenegermin and Vehicle in all patients.

Other pre-specified: Change from Baseline in Cornea and Conjunctiva Vital Staining with Fluorescein (National Eye Institute [NEI] scales) at Week 2

Top of page

End point title

Change from Baseline in Cornea and Conjunctiva Vital Staining with Fluorescein (National Eye Institute [NEI] scales) at Week 2

End point description

Change from Baseline in Cornea and Conjunctiva Vital Staining with Fluorescein (National Eye Institute [NEI] scales) at Week 2.

End point type

Other pre-specified

End point timeframe

Week 2.

End point values	Cenegermin	Vehicle
Number of subjects analysed	44 ^[134]	40 ^[135]
Units: Change from baseline to Week 2
arithmetic mean (standard deviation)	-2.6 ( 4.8 )	-2.0 ( 5.2 )

Notes
[134] - N=42.
[135] - N=37.

Change from baseline to Week 2

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[136]

P-value

= 0.046 ^[137]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[136] - 84 subjects are included in the FAS, however only 79 subjects are analyzed in this table due to the presence of missing values.
[137] - p-value corresponds to a non-parametric Mann–Whitney–Wilcoxon (Wilcoxon rank sum) test of the comparisons between Cenegermin and Vehicle in all patients.

Other pre-specified: Change from Baseline in Tear Film Break-Up Time (TFBUT) at Week 2

Top of page

End point title

Change from Baseline in Tear Film Break-Up Time (TFBUT) at Week 2

End point description

Change from Baseline in Tear Film Break-Up Time (TFBUT) at Week 2.

End point type

Other pre-specified

End point timeframe

Week 2.

End point values	Cenegermin	Vehicle
Number of subjects analysed	44 ^[138]	40 ^[139]
Units: Change from baseline to Week 2
arithmetic mean (standard deviation)	0.7 ( 2.1 )	0.2 ( 2.0 )

Notes
[138] - N=43.
[139] - N=39.

Change from baseline to Week 2

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[140]

P-value

= 0.34 ^[141]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[140] - 84 subjects are included in the FAS, however only 82 subjects are analyzed in this table due to the presence of missing values.
[141] - Not statistically significant result. p-value corresponds to a non-parametric Mann–Whitney–Wilcoxon (Wilcoxon rank sum) test of the comparisons between Cenegermin and Vehicle in all patients.

Other pre-specified: Change from Baseline in Symptoms Questionnaire (SANDE) Global Scores, and for Severity and Frequency at Week 2, and Week 4

Top of page

End point title

Change from Baseline in Symptoms Questionnaire (SANDE) Global Scores, and for Severity and Frequency at Week 2, and Week 4

End point description

Change from Baseline in Symptoms Questionnaire (SANDE) Global Scores, and for Severity and Frequency at Week 2, and Week 4.

End point type

Other pre-specified

End point timeframe

Week 2 and Week 4.

End point values	Cenegermin	Vehicle
Number of subjects analysed	44 ^[142]	40 ^[143]
Units: Change from baseline
arithmetic mean (standard deviation)
Global Score - Change from baseline to Week 2	-2.1 ( 18.0 )	-12.3 ( 13.7 )
Global Score - Change from baseline to Week 4	-11.5 ( 17.4 )	-15.0 ( 18.0 )
Severity - Change from baseline to Week 2	-0.5 ( 20.1 )	-12.3 ( 14.9 )
Severity - Change from baseline to Week 4	-9.2 ( 19.7 )	-13.6 ( 17.2 )
Frequency - Change from baseline to Week 2	-3.8 ( 18.9 )	-12.0 ( 14.7 )
Frequency - Change from baseline to Week 4	-14.5 ( 18.8 )	-16.9 ( 22.2 )

Notes
[142] - Week 2, n=43; Week 4, n=43.
[143] - Week 2, n=39; Week 4, n=39.

Global Score - Change from baseline to Week 2

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[144]

P-value

= 0.017 ^[145]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[144] - 84 subjects are included in the FAS, however only 82 subjects are analyzed in this table due to the presence of missing values.
[145] - p-value corresponds to a non-parametric Mann–Whitney–Wilcoxon (Wilcoxon rank sum) test of the comparisons between Cenegermin and Vehicle in all patients.

Global Score - Change from baseline to Week 4

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[146]

P-value

= 0.339 ^[147]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[146] - 84 subjects are included in the FAS, however only 82 subjects are analyzed in this table due to the presence of missing values.
[147] - Not statistically significant result. p-value corresponds to a non-parametric Mann–Whitney–Wilcoxon (Wilcoxon rank sum) test of the comparisons between Cenegermin and Vehicle in all patients.

Severity - Change from baseline to Week 2

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[148]

P-value

= 0.004 ^[149]

Method

t-test, 2-sided

Confidence interval

Notes
[148] - 84 subjects are included in the FAS, however only 82 subjects are analyzed in this table due to the presence of missing values.
[149] - p-value corresponds to a two sample (independent group) t-test of the comparisons between Cenegermin and Vehicle in all patients.

Severity - Change from baseline to Week 4

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[150]

P-value

= 0.292 ^[151]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[150] - 84 subjects are included in the FAS, however only 82 subjects are analyzed in this table due to the presence of missing values.
[151] - Not statistically significant result. p-value corresponds to a non-parametric Mann–Whitney–Wilcoxon (Wilcoxon rank sum) test of the comparisons between Cenegermin and Vehicle in all patients.

Frequency - Change from baseline to Week 2

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[152]

P-value

= 0.09 ^[153]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[152] - 84 subjects are included in the FAS, however only 82 subjects are analyzed in this table due to the presence of missing values.
[153] - Not statistically significant result. p-value corresponds to a non-parametric Mann–Whitney–Wilcoxon (Wilcoxon rank sum) test of the comparisons between Cenegermin and Vehicle in all patients.

Frequency - Change from baseline to Week 4

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[154]

P-value

= 0.54 ^[155]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[154] - 84 subjects are included in the FAS, however only 82 subjects are analyzed in this table due to the presence of missing values.
[155] - Not statistically significant result. p-value corresponds to a non-parametric Mann–Whitney–Wilcoxon (Wilcoxon rank sum) test of the comparisons between Cenegermin and Vehicle in all patients.

Other pre-specified: Number of Patients experienced a Worsening in Symptom Scores (SANDE Global Score) and/or NEI Score ≥ 50% assessed at Week 2

Top of page

End point title

Number of Patients experienced a Worsening in Symptom Scores (SANDE Global Score) and/or NEI Score ≥ 50% assessed at Week 2

End point description

Number of Patients experienced a Worsening in Symptom Scores (SANDE Global Score) and/or NEI Score ≥ 50% assessed at Week 2

End point type

Other pre-specified

End point timeframe

Week 2.

End point values	Cenegermin	Vehicle
Number of subjects analysed	44 ^[156]	40 ^[157]
Units: Subjects
Worsening in symptom scores (SANDE global score)	17	5
NEI score >= 50%	1	0
Worsening in symptom scores and/or NEI score >= 50	18	5

Notes
[156] - Wors. Symptom scores, n=43; NEI score ≥50%, n=42; Wors. symptom scores and/or NEI score ≥50%, n=42.
[157] - Wors. Symptom scores, n=39; NEI score ≥50%, n=37; Wors. symptom scores and/or NEI score ≥50%, n=38.

Worsening in symptom scores (SANDE global score)

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[158]

P-value

= 0.0064 ^[159]

Method

Chi-squared

Confidence interval

Notes
[158] - 84 subjects are included in the FAS, however only 82 subjects are analyzed in this table due to the presence of missing values.
[159] - p-value corresponds to Chi-square test of the comparisons between Cenegermin and Vehicle in all patients.

NEI score >= 50%

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[160]

P-value

= 1 ^[161]

Method

Fisher exact

Confidence interval

Notes
[160] - 84 subjects are included in the FAS, however only 79 subjects are analyzed in this table due to the presence of missing values.
[161] - Not statistically significant result. p-value corresponds to a Fisher`s exact test of the comparisons between Cenegermin and Vehicle in all patients.

Worsening in symptom scores and/or NEI score >= 50

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[162]

P-value

= 0.0034 ^[163]

Method

Chi-squared

Confidence interval

Notes
[162] - 84 subjects are included in the FAS, however only 80 subjects are analyzed in this table due to the presence of missing values.
[163] - p-value corresponds to Chi-square test of the comparisons between Cenegermin and Vehicle in all patients.

Other pre-specified: Change from Baseline in Schirmer Test II (with topical Anaesthesia) at Week 4

Top of page

End point title

Change from Baseline in Schirmer Test II (with topical Anaesthesia) at Week 4

End point description

Change from Baseline in Schirmer Test II (with topical Anaesthesia) at Week 4.

End point type

Other pre-specified

End point timeframe

Week 4.

End point values	Cenegermin	Vehicle
Number of subjects analysed	44 ^[164]	40 ^[165]
Units: Change from baseline in Schirmer II test
arithmetic mean (standard deviation)	4.3 ( 4.2 )	1.4 ( 3.7 )

Notes
[164] - N=42.
[165] - N=38.

Change from baseline to Week 4

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[166]

P-value

< 0.001 ^[167]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[166] - 84 subjects are included in the FAS, however only 80 subjects are analyzed in this table due to the presence of missing values.
[167] - p-value corresponds to a non-parametric Mann–Whitney–Wilcoxon (Wilcoxon rank sum) test of the comparisons between Cenegermin and Vehicle in all participants.

Other pre-specified: Change from Baseline in Best corrected distance visual acuity (BCDVA)

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End point title

Change from Baseline in Best corrected distance visual acuity (BCDVA)

End point description

Change from baseline (CFB) in BCDVA at each timepoint.

End point type

Other pre-specified

End point timeframe

Week 2, Week 4, Week 8, Week 12 and Week 16.

End point values	Cenegermin	Vehicle
Number of subjects analysed	44	40
Units: Subjects
CFB to Week 2 - No change	32	29
CFB to Week 2 - 20/63 to 20/40	0	1
CFB to Week 2 - 20/50 to 20/40	0	1
CFB to Week 2 - 20/40 to 20/25	1	1
CFB to Week 2 - 20/32 to 20/20	1	0
CFB to Week 2 - 20/32 to 20/25	1	1
CFB to Week 2 - 20/25 to 20/20	3	2
CFB to Week 2 - 20/20 to 20/16	2	0
CFB to Week 2 - 20/20 to 20/25	1	2
CFB to Week 2 - 20/16 to 20/12.5	0	1
CFB to Week 2 - 20/16 to 20/20	1	0
CFB to Week 2 - 20/16 to 20/25	1	0
CFB to Week 2 - 20/16 to 20/32	0	1
CFB to Week 4 - No change	31	33
CFB to Week 4 - 20/63 to 20/40	0	1
CFB to Week 4 - 20/40 to 20/25	1	1
CFB to Week 4 - 20/40 to 20/32	1	0
CFB to Week 4 - 20/32 to 20/20	0	1
CFB to Week 4 - 20/32 to 20/25	1	0
CFB to Week 4 - 20/25 to 20/20	3	2
CFB to Week 4 - 20/20 to 20/25	3	0
CFB to Week 4 - 20/20 to 20/32	1	0
CFB to Week 4 - 20/16 to 20/20	2	0
CFB to Week 4 - 20/16 to 20/32	0	1
CFB to Week 8 - No change	26	29
CFB to Week 8 - 20/63 to 20/40	0	1
CFB to Week 8 - 20/50 to 20/40	0	1
CFB to Week 8 - 20/40 to 20/20	0	1
CFB to Week 8 - 20/40 to 20/25	1	0
CFB to Week 8 - 20/40 to 20/32	1	0
CFB to Week 8 - 20/40 to 20/50	1	0
CFB to Week 8 - 20/32 to 20/20	1	0
CFB to Week 8 - 20/32 to 20/25	1	1
CFB to Week 8 - 20/25 to 20/20	2	1
CFB to Week 8 - 20/25 to 20/32	1	0
CFB to Week 8 - 20/20 to 20/16	2	1
CFB to Week 8 - 20/20 to 20/25	2	2
CFB to Week 8 - 20/16 to 20/20	2	0
CFB to Week 8 - 20/16 to 20/32	0	1
CFB to Week 12 - No change	29	30
CFB to Week 12 - 20/63 to 20/80	0	1
CFB to Week 12 - 20/50 to 20/63	0	1
CFB to Week 12 - 20/40 to 20/20	0	1
CFB to Week 12 - 20/40 to 20/32	1	0
CFB to Week 12 - 20/32 to 20/20	1	0
CFB to Week 12 - 20/32 to 20/25	1	1
CFB to Week 12 - 20/25 to 20/20	3	1
CFB to Week 12 - 20/25 to 20/32	1	0
CFB to Week 12 - 20/20 to 20/16	0	1
CFB to Week 12 - 20/20 to 20/25	1	2
CFB to Week 12 - 20/20 to 20/32	1	0
CFB to Week 12 - 20/16 to 20/20	1	0
CFB to Week 12 - 20/16 to 20/50	0	1
CFB to Week 12 - 20/12.5 to 20/16	1	0
CFB to Week 16 - No change	25	27
CFB to Week 16 - 20/63 to 20/50	0	1
CFB to Week 16 - 20/50 to 20/40	0	1
CFB to Week 16 - 20/40 to 20/20	0	1
CFB to Week 16 - 20/40 to 20/25	1	0
CFB to Week 16 - 20/40 to 20/32	1	0
CFB to Week 16 - 20/40 to 20/50	1	0
CFB to Week 16 - 20/32 to 20/25	2	2
CFB to Week 16 - 20/25 to 20/16	0	1
CFB to Week 16 - 20/25 to 20/20	4	0
CFB to Week 16 - 20/25 to 20/32	0	2
CFB to Week 16 - 20/20 to 20/16	3	0
CFB to Week 16 - 20/20 to 20/25	2	2
CFB to Week 16 - 20/16 to 20/20	2	1

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Following study ICF signature, at each visit, after the patient had the opportunity to spontaneously mention any problems, the Investigator or appropriate designee inquired about AEs.

Adverse event reporting additional description

All AEs were followed-up to determine outcome of the reaction. All ADRs and SAEs ongoing at the time the patient’s study participation ended were evaluated within 10 days after the final visit. After this period, all unresolved ADRs and SAEs were reported as “ongoing” in the eCRF.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

24.1

Reporting group title

Cenegermin

Reporting group description

Cenegermin (rhNGF 20 mcg/mL)

Reporting group title

Vehicle

Reporting group description

Placebo vehicle (Vehicle vials). Out of the 41 patients enrolled in the study and assigned to the vehicle treatment group, one patient did not receive any dose of study medication and was therefore excluded from the SAF and FAS populations. Thus, results are reported for the 40 patients in the vehicle group who received treatment.

Serious adverse events	Cenegermin	Vehicle
Total subjects affected by serious adverse events
subjects affected / exposed	0 / 44 (0.00%)	0 / 40 (0.00%)
number of deaths (all causes)	0	0
number of deaths resulting from adverse events	0	0

Frequency threshold for reporting non-serious adverse events: 4.5%

Non-serious adverse events	Cenegermin	Vehicle
Total subjects affected by non serious adverse events
subjects affected / exposed	27 / 44 (61.36%)	18 / 40 (45.00%)
Investigations
SARS-CoV-2 test positive
subjects affected / exposed	2 / 44 (4.55%)	1 / 40 (2.50%)
occurrences all number	2	1
Injury, poisoning and procedural complications
Rib fracture
subjects affected / exposed	2 / 44 (4.55%)	0 / 40 (0.00%)
occurrences all number	2	0
Nervous system disorders
Headache
subjects affected / exposed	3 / 44 (6.82%)	4 / 40 (10.00%)
occurrences all number	3	4
Eye disorders
Eye discharge
subjects affected / exposed	2 / 44 (4.55%)	2 / 40 (5.00%)
occurrences all number	2	3
Eye pain
subjects affected / exposed	21 / 44 (47.73%)	4 / 40 (10.00%)
occurrences all number	23	4
Eyelid pain
subjects affected / exposed	7 / 44 (15.91%)	0 / 40 (0.00%)
occurrences all number	9	0
Foreign body sensation in eyes
subjects affected / exposed	0 / 44 (0.00%)	2 / 40 (5.00%)
occurrences all number	0	2
Vision blurred
subjects affected / exposed	1 / 44 (2.27%)	2 / 40 (5.00%)
occurrences all number	1	2
Dry eye
subjects affected / exposed	0 / 44 (0.00%)	3 / 40 (7.50%)
occurrences all number	0	3
Conjunctival hyperaemia
subjects affected / exposed	2 / 44 (4.55%)	1 / 40 (2.50%)
occurrences all number	2	1
Eye irritation
subjects affected / exposed	2 / 44 (4.55%)	1 / 40 (2.50%)
occurrences all number	2	1
Photophobia
subjects affected / exposed	2 / 44 (4.55%)	0 / 40 (0.00%)
occurrences all number	2	0
Swelling of eyelid
subjects affected / exposed	2 / 44 (4.55%)	1 / 40 (2.50%)
occurrences all number	2	1

More information

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Were there any global substantial amendments to the protocol? Yes

15 Oct 2021

Amendment 1 (US specific): The purpose of this amendment was to include changes in order to align the Protocol to the version submitted in Italy. Furthermore, minor changes to correct some typos were made.

10 Dec 2021

Amendment 1 (Italy specific): The purpose of this amendment was to fulfil the requests reported in the AIFA’s ‘Review Comments’ letter dated December 10, 2021.

02 Feb 2022

Amendment 2: The ‘track changes’ version highlights the differences from Protocol version 2.0 US Specific to Protocol version 4.0. The purpose of this amendment was to align version numbers as Protocol NGF0221 EU (Version 3.0 Italy specific) and Protocol NGF0221 US (version 2.0 US specific) and to add the study name (PROTEGO-2). Some changes were implemented after specific requests from the Italian Health authorities. Furthermore, minor changes to better explain the study design and to correct some typos were made.

08 Feb 2022

Amendment 3: The ‘track changes’ version highlights the differences from Protocol Version No. 3 Italy Specific to Protocol version 4.0. The purpose of this amendment was to align version numbers as Protocol NGF0221 EU (Version 3.0 Italy specific) and Protocol NGF0221 US (version 2.0 US specific) and to add the study name (PROTEGO-2). Furthermore, minor changes to better explain the study design and to correct some typos were made.

16 Jun 2022

Amendment 4: The purpose of this amendment was to update protocol NGF0221 to shift the key secondary endpoint of SANDE global score to the co-primary endpoint to satisfy the FDA’s request. The proposed change aligned with one of the other Phase 3 studies, NGF0121 (PROTEGO-1) – “A 4- week, Phase 3, multicenter, double-masked, vehicle-controlled clinical study to evaluate safety and efficacy of Oxervate (cenegermin) 20 mcg/mL ophthalmic solution versus vehicle, in patients with severe Sjogren's dry eye disease”. NGF0121 and NGF0221 were already approved by AIFA and EC/IRB and were then ongoing. Below is the list of substantial revisions made in the Protocol: • Added co-primary efficacy endpoint: change from baseline in SANDE global score at Week 12. (Shifted from secondary to co-primary endpoint) Consequently, • An increase in the sample size from 48 to 80 enrolled patients with a 10% dropout rate resulted in an increase in eligible patients from 42 to 72 patients. •Update to statistical methods to incorporate the above-listed modification. Furthermore, minor changes to correct some typographical errors were made.

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.

Patients had severe DED and persistent symptoms despite receiving topical CsA. The vehicle response could be due to a lubricating vehicle's effect or a variable response in patients with episodic flare-ups. Also, the treatment duration was short.

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Schirmer I test (without anaesthesia) >10mm/5min at Week 4

Primary: Schirmer I test (without anaesthesia) >10mm/5min at Week 4

Primary: Change from Baseline in the Global SANDE Score at Week 12

Primary: Change from Baseline in the Global SANDE Score at Week 12

Secondary: Schirmer I test (without anaesthesia) >10mm/5min at Week 8

Secondary: Schirmer I test (without anaesthesia) >10mm/5min at Week 8

Secondary: Change from Baseline in Symptoms Questionnaire (SANDE) Score for Severity at Week 12

Secondary: Change from Baseline in Symptoms Questionnaire (SANDE) Score for Severity at Week 12

Secondary: Change from Baseline in Symptoms Questionnaire (SANDE) Score for Frequency at Week 12

Secondary: Change from Baseline in Symptoms Questionnaire (SANDE) Score for Frequency at Week 12

Secondary: Change from Baseline in IDEEL modules (Quality Of Life, Dry Eye Treatment Satisfaction & Bother and Dry Eye Symptom-Bother modules) at Week 12 and at Week 4

Secondary: Change from Baseline in IDEEL modules (Quality Of Life, Dry Eye Treatment Satisfaction & Bother and Dry Eye Symptom-Bother modules) at Week 12 and at Week 4

Secondary: Change from Baseline in Cornea and Conjunctiva Vital Staining with Fluorescein (National Eye Institute [NEI] scales) at Week 4, Week 8 and Week 12

Secondary: Change from Baseline in Cornea and Conjunctiva Vital Staining with Fluorescein (National Eye Institute [NEI] scales) at Week 4, Week 8 and Week 12

Secondary: Change from Baseline in Tear Film Break-Up Time (TFBUT) at Week 4, Week 8 and Week 12

Secondary: Change from Baseline in Tear Film Break-Up Time (TFBUT) at Week 4, Week 8 and Week 12

Secondary: Change from Baseline in Schirmer I Test (without anaesthesia) at Week 4, Week 8, Week 12, and Week 16

Secondary: Change from Baseline in Schirmer I Test (without anaesthesia) at Week 4, Week 8, Week 12, and Week 16

Secondary: Change from Baseline in Cornea and Conjunctiva Vital Staining with Fluorescein (National Eye Institute [NEI] scales) at Week 4, Week 8, Week 12 and Week 16

Secondary: Change from Baseline in Cornea and Conjunctiva Vital Staining with Fluorescein (National Eye Institute [NEI] scales) at Week 4, Week 8, Week 12 and Week 16

Secondary: Change from Baseline in Tear Film Break-Up Time (TFBUT) at Week 4, Week 8, Week 12 and Week 16

Secondary: Change from Baseline in Tear Film Break-Up Time (TFBUT) at Week 4, Week 8, Week 12 and Week 16

Secondary: Change from Baseline in Symptoms Questionnaire (SANDE) Global Scores, and for Severity and Frequency at Week 8, Week 12, and Week 16

Secondary: Change from Baseline in Symptoms Questionnaire (SANDE) Global Scores, and for Severity and Frequency at Week 8, Week 12, and Week 16

Secondary: Number of Patients experienced a Worsening in Symptom Scores (SANDE Global Scores) and/or NEI Score ≥ 50% at Week 4

Secondary: Number of Patients experienced a Worsening in Symptom Scores (SANDE Global Scores) and/or NEI Score ≥ 50% at Week 4

Secondary: IDEEL Questionnaire at Week 4, Week, 8, Week 12, and Week 16

Secondary: IDEEL Questionnaire at Week 4, Week, 8, Week 12, and Week 16

Other pre-specified: Proportion and Frequency of Preservative Free Artificial Tears Use (number of drops/day)

Other pre-specified: Proportion and Frequency of Preservative Free Artificial Tears Use (number of drops/day)

Other pre-specified: Change from Baseline in Schirmer I Test (without anaesthesia) at Week 2

Other pre-specified: Change from Baseline in Schirmer I Test (without anaesthesia) at Week 2

Other pre-specified: Change from Baseline in Cornea and Conjunctiva Vital Staining with Fluorescein (National Eye Institute [NEI] scales) at Week 2

Other pre-specified: Change from Baseline in Cornea and Conjunctiva Vital Staining with Fluorescein (National Eye Institute [NEI] scales) at Week 2

Other pre-specified: Change from Baseline in Tear Film Break-Up Time (TFBUT) at Week 2

Other pre-specified: Change from Baseline in Tear Film Break-Up Time (TFBUT) at Week 2

Other pre-specified: Change from Baseline in Symptoms Questionnaire (SANDE) Global Scores, and for Severity and Frequency at Week 2, and Week 4

Other pre-specified: Change from Baseline in Symptoms Questionnaire (SANDE) Global Scores, and for Severity and Frequency at Week 2, and Week 4

Other pre-specified: Number of Patients experienced a Worsening in Symptom Scores (SANDE Global Score) and/or NEI Score ≥ 50% assessed at Week 2

Other pre-specified: Number of Patients experienced a Worsening in Symptom Scores (SANDE Global Score) and/or NEI Score ≥ 50% assessed at Week 2

Other pre-specified: Change from Baseline in Schirmer Test II (with topical Anaesthesia) at Week 4

Other pre-specified: Change from Baseline in Schirmer Test II (with topical Anaesthesia) at Week 4

Other pre-specified: Change from Baseline in Best corrected distance visual acuity (BCDVA)

Other pre-specified: Change from Baseline in Best corrected distance visual acuity (BCDVA)

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information