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Clinical Trial Results:
A 4-week, Phase III, multicentre, double-masked, vehicle-controlled 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 (PROTEGO-1 study)

Summary
EudraCT number	2021-003346-21
Trial protocol	IT
Global end of trial date	19 Dec 2022

Results information
Results version number	v1(current)
This version publication date	19 Jan 2024
First version publication date	19 Jan 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

NGF0121

ISRCTN number

US NCT number

NCT05133180

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

13 Dec 2023

Is this the analysis of the primary completion data?

Yes

Primary completion date

19 Dec 2022

Global end of trial reached?

Yes

Global end of trial date

19 Dec 2022

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).

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 thumbprint 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, administered additional drops and documented 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. 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 for 28 days (four weeks).

Actual start date of recruitment

19 Jan 2022

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Italy: 51

Country: Number of subjects enrolled

United States: 53

Worldwide total number of subjects

104

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 126 patients were assessed for eligibility. There were 22 screening failures. The remaining patients (n=104) were randomized 1:1 as follows: 52 to cenegermin and 52 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 study enrolment.

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.

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 52 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 51 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	52	51
Completed	50	49
Not completed	2	2
Consent withdrawn by subject	1	1
Disease progression	-	1
Lost to follow-up	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 104 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 103 patients: 52 patients in the cenegermin group and 51 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	52	51	103
Age categorical
Units: Subjects
In utero	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0
Newborns (0-27 days)	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0
Children (2-11 years)	0	0	0
Adolescents (12-17 years)	0	0	0
Adults (18-64 years)	39	34	73
From 65-84 years	13	16	29
85 years and over	0	1	1
Age continuous
Units: years
arithmetic mean (standard deviation)	55.3 ( 13.47 )	58.7 ( 14.10 )	-
Gender categorical
Units: Subjects
Female	50	47	97
Male	2	4	6
Geographic region
Units: Subjects
Europe	27	23	50
US	25	28	53
Site
Units: Subjects
Site #01	10	8	18
Site #02	4	3	7
Site #04	13	12	25
Site #05	7	8	15
Site #06	5	5	10
Site #07	6	8	14
Site #08	0	1	1
Site #09	2	0	2
Site #10	4	5	9
Site #12	1	1	2
Race
Units: Subjects
Asian	0	3	3
Black or African American	0	1	1
White	43	39	82
Other	2	0	2
Multiple	1	1	2
Missing	6	7	13
Ethnicity
Units: Subjects
Hispanic or Latino	7	5	12
Not Hispanic or Latino	41	39	80
Missing	3	5	8
Not reported	1	2	3

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	52	51
Units: Subjects	19	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 >10mm/5min 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

103

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

16.946

Confidence interval

level

95%

sides

2-sided

lower limit

3.412

upper limit

84.165

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	52	51
Units: Change from baseline in SANDE score
arithmetic mean (confidence interval 95%)	-29.528 (-42.126 to -16.930)	-24.967 (-37.009 to -12.926)

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 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

103

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.322 ^[1]

Method

ANCOVA

Parameter type

Adjusted means difference

Point estimate

-4.561

Confidence interval

level

95%

sides

2-sided

lower limit

-13.581

upper limit

4.459

Notes
[1] - Adjusted means difference [95% CI] between the two groups (-4.561 [-13.581; 4.459]) was not statistically significant (p-value=0.322).

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	52	51
Units: Subjects	18	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 >10mm/5min 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

103

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

15.95

Confidence interval

level

95%

sides

2-sided

lower limit

3.091

upper limit

82.31

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	52	51
Units: Change from Baseline in SANDE score
arithmetic mean (confidence interval 95%)	-31.445 (-43.795 to -19.095)	-26.713 (-38.538 to -14.887)

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

103

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.307 ^[2]

Method

ANCOVA

Parameter type

Adjusted means difference

Point estimate

-4.732

Confidence interval

level

95%

sides

2-sided

lower limit

-13.819

upper limit

4.354

Notes
[2] - Adjusted mean change from baseline in the cenegermin group was not statistically significantly superior to that in the vehicle group (p-value=0.307).

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	52	51
Units: Change from baseline in SANDE score
arithmetic mean (confidence interval 95%)	-24.546 (-38.261 to -10.831)	-21.793 (-34.944 to -8.643)

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

103

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.572 ^[3]

Method

ANCOVA

Parameter type

Adjusted means difference

Point estimate

-2.753

Confidence interval

level

95%

sides

2-sided

lower limit

-12.303

upper limit

6.798

Notes
[3] - The adjusted means difference between the two groups was not statistically significant (p-value=0.572).

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	52	51
Units: Changes from baseline in IDEEL modules
least squares mean (confidence interval 95%)
QoL (Daily activities) - Week 4	11.524 (5.207 to 17.842)	9.364 (3.354 to 15.374)
QoL (Daily activities) - Week 12	13.301 (6.267 to 20.335)	9.223 (2.437 to 16.008)
QoL (Feelings) - Week 4	14.385 (6.840 to 21.930)	11.955 (4.732 to 19.177)
QoL (Feelings) - Week 12	16.069 (7.476 to 24.661)	10.519 (2.185 to 18.853)
QoL (Work) - Week 4	17.591 (8.213 to 26.969)	14.291 (5.787 to 22.795)
QoL (Work) - Week 12	18.619 (9.309 to 27.928)	15.144 (6.371 to 23.916)
TS (Treatment - in general) - Week 4	9.505 (2.772 to 16.237)	8.432 (1.840 to 15.025)
TS (Treatment - in general) - Week 12	6.482 (-0.877 to 13.842)	4.239 (-2.942 to 11.420)
TS (Treatment - Eye drops) - Week 4	13.879 (2.071 to 25.686)	14.428 (3.246 to 25.609)
TS (Treatment - Eye drops) - Week 12	12.733 (1.180 to 24.285)	16.938 (5.033 to 28.844)
Symptom-Bother - Week 4	-10.241 (-16.924 to -3.557)	-9.435 (-15.876 to -2.995)
Symptom-Bother - Week 12	-16.323 (-23.582 to -9.064)	-7.533 (-14.574 to -0.493)

QoL (Daily activities) - Week 4

Statistical analysis description

Analysis is based on MMRM with Multiple Imputation (MI) under missing not at random (MNAR) 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

103

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.468 ^[4]

Method

Mixed Model for Repeated Measures

Parameter type

LS means difference

Point estimate

2.16

Confidence interval

level

95%

sides

2-sided

lower limit

-3.668

upper limit

7.988

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

103

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.268 ^[5]

Method

Mixed Model for Repeated Measures

Parameter type

LS means difference

Point estimate

4.078

Confidence interval

level

95%

sides

2-sided

lower limit

-3.142

upper limit

11.299

Notes
[5] - Not statistically significant result.

QoL (Feelings) - Week 4

Statistical analysis description

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

103

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.492 ^[6]

Method

Mixed Model for Repeated Measures

Parameter type

LS means difference

Point estimate

2.431

Confidence interval

level

95%

sides

2-sided

lower limit

-4.5

upper limit

9.362

Notes
[6] - Not statistically significant result.

QoL (Feelings) - Week 12

Statistical analysis description

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

103

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.227 ^[7]

Method

Mixed Model for Repeated Measures

Parameter type

LS means difference

Point estimate

5.55

Confidence interval

level

95%

sides

2-sided

lower limit

-3.462

upper limit

14.562

Notes
[7] - Not statistically significant result.

QoL (Work) - Week 4

Statistical analysis description

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

103

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.51 ^[8]

Method

Mixed Model for Repeated Measures

Parameter type

LS means difference

Point estimate

3.3

Confidence interval

level

95%

sides

2-sided

lower limit

-6.511

upper limit

13.111

Notes
[8] - Not statistically significant result.

QoL (Work) - Week 12

Statistical analysis description

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

103

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.501 ^[9]

Method

Mixed Model for Repeated Measures

Parameter type

LS means difference

Point estimate

3.475

Confidence interval

level

95%

sides

2-sided

lower limit

-6.651

upper limit

13.601

Notes
[9] - Not statistically significant result.

TS (Treatment - in general) - Week 4

Statistical analysis description

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

103

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.745 ^[10]

Method

Mixed Model for Repeated Measures

Parameter type

LS means difference

Point estimate

1.072

Confidence interval

level

95%

sides

2-sided

lower limit

-5.398

upper limit

7.542

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

103

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.564 ^[11]

Method

Mixed Model for Repeated Measures

Parameter type

LS means difference

Point estimate

2.244

Confidence interval

level

95%

sides

2-sided

lower limit

-5.387

upper limit

9.874

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

103

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.924 ^[12]

Method

Mixed Model for Repeated Measures

Parameter type

LS means difference

Point estimate

-0.549

Confidence interval

level

95%

sides

2-sided

lower limit

-11.82

upper limit

10.723

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

103

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.467 ^[13]

Method

Mixed Model for Repeated Measures

Parameter type

LS means difference

Point estimate

-4.206

Confidence interval

level

95%

sides

2-sided

lower limit

-15.53

upper limit

7.118

Notes
[13] - Not statistically significant result.

Symptom-Bother - Week 4

Statistical analysis description

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

103

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.802 ^[14]

Method

Mixed Model for Repeated Measures

Parameter type

LS means difference

Point estimate

-0.805

Confidence interval

level

95%

sides

2-sided

lower limit

-7.086

upper limit

5.476

Notes
[14] - Not statistically significant result.

Symptom-Bother - Week 12

Statistical analysis description

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

103

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.019

Method

Mixed Model for Repeated Measures

Parameter type

LS means difference

Point estimate

-8.789

Confidence interval

level

95%

sides

2-sided

lower limit

-16.16

upper limit

-1.418

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	52	51
Units: Change from baseline
least squares mean (confidence interval 95%)
Week 4	-4.107 (-5.723 to -2.490)	-2.588 (-4.118 to -1.059)
Week 8	-4.442 (-6.145 to -2.739)	-2.668 (-4.298 to -1.038)
Week 12	-3.714 (-5.522 to -1.905)	-2.490 (-4.222 to -0.758)

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. Subject will be considered as a random effect and the covariance matrix used will be unstructured.

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

103

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.045 ^[15]

Method

Mixed Model for Repeated Measures

Parameter type

LS means difference

Point estimate

-1.518

Confidence interval

level

95%

sides

2-sided

lower limit

-3.005

upper limit

-0.031

Notes
[15] - Not statistically significant at the 2.5% level of significance.

Week 8

Statistical analysis description

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

103

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.038 ^[16]

Method

Mixed Model for Repeated Measures

Parameter type

LS means difference

Point estimate

-1.773

Confidence interval

level

95%

sides

2-sided

lower limit

-3.446

upper limit

-0.101

Notes
[16] - Not statistically significant result.

Week 12

Statistical analysis description

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

103

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2 ^[17]

Method

Mixed Model for Repeated Measures

Parameter type

LS means difference

Point estimate

-1.224

Confidence interval

level

95%

sides

2-sided

lower limit

-3.096

upper limit

0.649

Notes
[17] - 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	52	51
Units: Change from baseline in TFBUT
least squares mean (confidence interval 95%)
Week 4	1.808 (0.437 to 3.178)	0.167 (-1.144 to 1.479)
Week 8	2.010 (0.579 to 3.441)	0.876 (-0.502 to 2.255)
Week 12	1.973 (0.588 to 3.358)	0.613 (-0.715 to 1.941)

Week 4

Statistical analysis description

Analysis is based on MMRM with Multiple Imputation (MI) under missing not at random (MNAR) 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

103

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.016

Method

Mixed Model for Repeated Measures

Parameter type

LS means difference

Point estimate

1.64

Confidence interval

level

95%

sides

2-sided

lower limit

0.3

upper limit

2.98

Week 8

Statistical analysis description

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

103

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.129 ^[18]

Method

Mixed Model for Repeated Measures

Parameter type

LS means difference

Point estimate

1.133

Confidence interval

level

95%

sides

2-sided

lower limit

-0.329

upper limit

2.596

Notes
[18] - Not statistically significant at the 2.5% level of significance.

Week 12

Statistical analysis description

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

103

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.05 ^[19]

Method

Mixed Model for Repeated Measures

Parameter type

LS means difference

Point estimate

1.36

Confidence interval

level

95%

sides

2-sided

lower limit

-0.002

upper limit

2.722

Notes
[19] - Not statistically significant at the 2.5% level of significance.

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	52 ^[20]	51 ^[21]
Units: Change from baseline in Schirmer I Test
arithmetic mean (standard deviation)
Week 4	5.4 ( 6.6 )	0.8 ( 2.7 )
Week 8	4.9 ( 6.6 )	1.4 ( 2.9 )
Week 12	3.8 ( 5.2 )	1.4 ( 4.1 )
Week 16	3.6 ( 5.1 )	1.7 ( 4.8 )

Notes
[20] - Week 4, n=51; Week 8, n=49; Week 12, n=49; Week 16, n=50.
[21] - Week 4, n=50; Week 8, n=49; Week 12, n=49; Week 16, n=49.

Week 4

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

103

Analysis specification

Pre-specified

Analysis type

superiority ^[22]

P-value

< 0.001 ^[23]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[22] - 103 subjects are included in the FAS, however only 101 subjects are analyzed in this table due to the presence of missing values.
[23] - 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

103

Analysis specification

Pre-specified

Analysis type

superiority ^[24]

P-value

= 0.009 ^[25]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[24] - 103 subjects are included in the FAS, however only 98 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 12

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

103

Analysis specification

Pre-specified

Analysis type

superiority ^[26]

P-value

= 0.02 ^[27]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[26] - 103 subjects are included in the FAS, however only 98 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 16

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

103

Analysis specification

Pre-specified

Analysis type

superiority ^[28]

P-value

= 0.022 ^[29]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[28] - 103 subjects are included in the FAS, however only 99 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

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	52 ^[30]	51 ^[31]
Units: Change from baseline in NEI scale
arithmetic mean (standard deviation)
Week 4	-3.1 ( 5.0 )	-2.0 ( 2.8 )
Week 8	-3.5 ( 5.0 )	-2.1 ( 3.8 )
Week 12	-2.7 ( 5.6 )	-2.0 ( 4.0 )
Week 16	-3.3 ( 4.6 )	-2.7 ( 5.8 )

Notes
[30] - Week 4, n=51; Week 8, n=49; Week 12, n=49; Week 16, n=50.
[31] - Week 4, n=50; Week 8, n=49; Week 12, n=49; Week 16, n=49.

Week 4

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

103

Analysis specification

Pre-specified

Analysis type

superiority ^[32]

P-value

= 0.117 ^[33]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[32] - 103 subjects are included in the FAS, however only 101 subjects are analyzed in this table due to the presence of missing values.
[33] - 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 8

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

103

Analysis specification

Pre-specified

Analysis type

superiority ^[34]

P-value

= 0.095 ^[35]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[34] - 103 subjects are included in the FAS, however only 98 subjects are analyzed in this table due to the presence of missing values.
[35] - 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

103

Analysis specification

Pre-specified

Analysis type

superiority ^[36]

P-value

= 0.217 ^[37]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[36] - 103 subjects are included in the FAS, however only 98 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 16

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

103

Analysis specification

Pre-specified

Analysis type

superiority ^[38]

P-value

= 0.065 ^[39]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[38] - 103 subjects are included in the FAS, however only 99 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.

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	52 ^[40]	51 ^[41]
Units: Change from baseline in TFBUT
arithmetic mean (standard deviation)
Week 4	1.7 ( 4.2 )	0.1 ( 2.6 )
Week 8	2.0 ( 4.4 )	0.8 ( 3.1 )
Week 12	1.9 ( 4.1 )	0.6 ( 2.9 )
Week 16	1.3 ( 3.1 )	0.4 ( 2.8 )

Notes
[40] - Week 4, n=51; Week 8, n=49; Week 12, n=49; Week 16, n=50.
[41] - Week 4, n=50; Week 8, n=49; Week 12, n=49; Week 16, n=49.

Week 4

Comparison groups

Vehicle v Cenegermin

Number of subjects included in analysis

103

Analysis specification

Pre-specified

Analysis type

superiority ^[42]

P-value

= 0.031 ^[43]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[42] - 103 subjects are included in the FAS, however only 101 subjects are analyzed in this table due to the presence of missing values.
[43] - 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

103

Analysis specification

Pre-specified

Analysis type

superiority ^[44]

P-value

= 0.273 ^[45]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[44] - 103 subjects are included in the FAS, however only 98 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 Vehicle in all patients.

Week 12

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

103

Analysis specification

Pre-specified

Analysis type

superiority ^[46]

P-value

= 0.072 ^[47]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[46] - 103 subjects are included in the FAS, however only 98 subjects are analyzed in this table due to the presence of missing values.
[47] - 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

103

Analysis specification

Pre-specified

Analysis type

superiority ^[48]

P-value

= 0.125 ^[49]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[48] - 103 subjects are included in the FAS, however only 99 subjects are analyzed in this table due to the presence of missing values.
[49] - 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 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	52 ^[50]	51 ^[51]
Units: Change from baseline in SANDE scores
arithmetic mean (standard deviation)
Global Score - Week 8	-26.0 ( 20.1 )	-15.2 ( 22.1 )
Global Score - Week 12	-20.4 ( 22.0 )	-15.7 ( 26.7 )
Global Score - Week 16	-15.2 ( 20.5 )	-16.0 ( 25.2 )
Severity - Week 8	-23.7 ( 20.8 )	-14.4 ( 21.6 )
Severity - Week 12	-21.2 ( 23.5 )	-15.7 ( 26.5 )
Severity - Week 16	-16.6 ( 23.6 )	-16.1 ( 25.9 )
Frequency - Week 8	-27.1 ( 22.5 )	-15.9 ( 24.4 )
Frequency - Week 12	-17.9 ( 23.4 )	-15.7 ( 28.2 )
Frequency - Week 16	-12.5 ( 21.2 )	-16.1 ( 25.6 )

Notes
[50] - Week 8, n=49; Week 12, n=49; Week 16, n=50.
[51] - Week 8, n=49; Week 12, n=49; Week 16, n=49.

Global Score - Week 8

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

103

Analysis specification

Pre-specified

Analysis type

superiority ^[52]

P-value

= 0.005 ^[53]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[52] - 103 subjects are included in the FAS, however only 98 subjects are analyzed in this table due to the presence of missing values.
[53] - 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 - Week 12

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

103

Analysis specification

Pre-specified

Analysis type

superiority ^[54]

P-value

= 0.116 ^[55]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[54] - 103 subjects are included in the FAS, however only 98 subjects are analyzed in this table due to the presence of missing values.
[55] - 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.

Global Score - Week 16

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

103

Analysis specification

Pre-specified

Analysis type

superiority ^[56]

P-value

= 0.864 ^[57]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[56] - 103 subjects are included in the FAS, however only 99 subjects are analyzed in this table due to the presence of missing values.
[57] - 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

103

Analysis specification

Pre-specified

Analysis type

superiority ^[58]

P-value

= 0.016 ^[59]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[58] - 103 subjects are included in the FAS, however only 98 subjects are analyzed in this table due to the presence of missing values.
[59] - 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 12

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

103

Analysis specification

Pre-specified

Analysis type

superiority ^[60]

P-value

= 0.16 ^[61]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[60] - 103 subjects are included in the FAS, however only 98 subjects are analyzed in this table due to the presence of missing values.
[61] - 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

103

Analysis specification

Pre-specified

Analysis type

superiority ^[62]

P-value

= 0.839 ^[63]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[62] - 103 subjects are included in the FAS, however only 99 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.

Frequency - Week 8

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

103

Analysis specification

Pre-specified

Analysis type

superiority ^[64]

P-value

= 0.011 ^[65]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[64] - 103 subjects are included in the FAS, however only 98 subjects are analyzed in this table due to the presence of missing values.
[65] - 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

103

Analysis specification

Pre-specified

Analysis type

superiority ^[66]

P-value

= 0.316 ^[67]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[66] - 103 subjects are included in the FAS, however only 98 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 16

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

103

Analysis specification

Pre-specified

Analysis type

superiority ^[68]

P-value

= 0.685 ^[69]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[68] - 103 subjects are included in the FAS, however only 99 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.

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	52 ^[70]	51 ^[71]
Units: Subjects
Worsening in symptom scores (SANDE global score)	4	11
NEI score >= 50%	1	0
Worsening in symptom scores and/or NEI score >= 50	4	11

Notes
[70] - Week 4, n=51
[71] - Week 4, n=50

Worsening in symptom scores (SANDE global score)

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

103

Analysis specification

Pre-specified

Analysis type

superiority ^[72]

P-value

= 0.0455 ^[73]

Method

Chi-squared

Confidence interval

Notes
[72] - 103 subjects are included in the FAS, however only 101 subjects are analyzed in this table due to the presence of missing values.
[73] - 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

103

Analysis specification

Pre-specified

Analysis type

superiority ^[74]

P-value

= 1 ^[75]

Method

Fisher exact

Confidence interval

Notes
[74] - 103 subjects are included in the FAS, however only 101 subjects are analyzed in this table due to the presence of missing values.
[75] - Not statistically significant result. p-value corresponds to 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

103

Analysis specification

Pre-specified

Analysis type

superiority ^[76]

P-value

= 0.0455 ^[77]

Method

Chi-squared

Confidence interval

Notes
[76] - 103 subjects are included in the FAS, however only 101 subjects are analyzed in this table due to the presence of missing values.
[77] - 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	52	51
Units: Change from baseline in IDEEL score
arithmetic mean (standard deviation)
QoL (Impact on Daily Activities) - Week 4	12.1 ( 18.5 )	7.8 ( 18.4 )
QoL (Impact on Daily Activities) - Week 8	14.6 ( 18.8 )	6.5 ( 23.2 )
QoL (Impact on Daily Activities) - Week 12	14.7 ( 19.2 )	7.2 ( 22.8 )
QoL (Impact on Daily Activities) - Week 16	15.1 ( 20.8 )	9.7 ( 21.1 )
QoL (Emotional Impact due to Dry Eye) - Week 4	15.6 ( 22.6 )	10.7 ( 16.9 )
QoL (Emotional Impact due to Dry Eye) - Week 8	18.4 ( 21.9 )	10.3 ( 22.9 )
QoL (Emotional Impact due to Dry Eye) - Week 12	17.9 ( 24.5 )	8.9 ( 24.4 )
QoL (Emotional Impact due to Dry Eye) - Week 16	19.0 ( 23.1 )	11.5 ( 23.3 )
QoL (Impact on Work due to Dry Eye) - Week 4	18.8 ( 22.8 )	8.0 ( 19.8 )
QoL (Impact on Work due to Dry Eye) - Week 8	17.7 ( 25.7 )	9.5 ( 25.9 )
QoL (Impact on Work due to Dry Eye) - Week 12	19.1 ( 21.1 )	8.2 ( 21.2 )
QoL (Impact on Work due to Dry Eye) - Week 16	20.9 ( 24.2 )	9.3 ( 26.7 )
TS (Satisfaction with Effectiveness) - Week 4	17.8 ( 35.4 )	3.4 ( 36.5 )
TS (Satisfaction with Effectiveness) - Week 8	17.7 ( 31.0 )	7.7 ( 36.4 )
TS (Satisfaction with Effectiveness) - Week 12	15.2 ( 28.4 )	7.2 ( 36.7 )
TS (Satisfaction with Effectiveness) - Week 16	13.4 ( 28.7 )	1.2 ( 35.9 )
TS (Treatment Bother/Inconvenience) - Week 4	16.3 ( 22.2 )	4.9 ( 25.6 )
TS (Treatment Bother/Inconvenience) - Week 8	16.6 ( 21.1 )	2.7 ( 28.1 )
TS (Treatment Bother/Inconvenience) - Week 12	13.6 ( 25.0 )	3.2 ( 28.0 )
TS (Treatment Bother/Inconvenience) - Week 16	13.3 ( 23.6 )	5.3 ( 27.3 )
Symptom-Bother - Week 4	-13.9 ( 18.9 )	-10.3 ( 19.3 )
Symptom-Bother - Week 8	-19.5 ( 20.3 )	-6.9 ( 19.2 )
Symptom-Bother - Week 12	-20.7 ( 20.1 )	-8.3 ( 22.2 )
Symptom-Bother - Week 16	-18.6 ( 19.4 )	-11.1 ( 22.3 )

QoL (Impact on Daily Activities) - Week 4

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

103

Analysis specification

Pre-specified

Analysis type

superiority ^[78]

P-value

= 0.202 ^[79]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[78] - 103 subjects are included in the FAS, however only 101 subjects (Cenegermin, n=51; Vehicle, n=50) are analyzed in this table due to the presence of missing values.
[79] - 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 8

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

103

Analysis specification

Pre-specified

Analysis type

superiority ^[80]

P-value

= 0.06 ^[81]

Method

t-test, 2-sided

Confidence interval

Notes
[80] - 103 subjects are included in the FAS, however only 98 (Cenegermin, n=49; Vehicle, n=49) subjects are analyzed in this table due to the presence of missing values.
[81] - Not statistically significant result. p-value corresponds to 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

103

Analysis specification

Pre-specified

Analysis type

superiority ^[82]

P-value

= 0.082 ^[83]

Method

t-test, 2-sided

Confidence interval

Notes
[82] - 103 subjects are included in the FAS, however only 98 (Cenegermin, n=49; Vehicle, n=49) subjects are analyzed in this table due to the presence of missing values.
[83] - Not statistically significant result. p-value corresponds to two sample (independent group) t-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

103

Analysis specification

Pre-specified

Analysis type

superiority ^[84]

P-value

= 0.203 ^[85]

Method

t-test, 2-sided

Confidence interval

Notes
[84] - 103 subjects are included in the FAS, however only 99 (Cenegermin, n=50; Vehicle, n=49) subjects are analyzed in this table due to the presence of missing values.
[85] - Not statistically significant result. p-value corresponds to two sample (independent group) t-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

103

Analysis specification

Pre-specified

Analysis type

superiority ^[86]

P-value

= 0.219 ^[87]

Method

t-test, 2-sided

Confidence interval

Notes
[86] - 103 subjects are included in the FAS, however only 101 (Cenegermin, n=51; Vehicle, n=50) subjects are analyzed in this table due to the presence of missing values.
[87] - Not statistically significant result. p-value corresponds to 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

103

Analysis specification

Pre-specified

Analysis type

superiority ^[88]

P-value

= 0.079 ^[89]

Method

t-test, 2-sided

Confidence interval

Notes
[88] - 103 subjects are included in the FAS, however only 98 (Cenegermin, n=49; Vehicle, n=49) subjects are analyzed in this table due to the presence of missing values.
[89] - Not statistically significant result. p-value corresponds to 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

103

Analysis specification

Pre-specified

Analysis type

superiority ^[90]

P-value

= 0.07 ^[91]

Method

t-test, 2-sided

Confidence interval

Notes
[90] - 103 subjects are included in the FAS, however only 98 (Cenegermin, n=49; Vehicle, n=49) subjects are analyzed in this table due to the presence of missing values.
[91] - Not statistically significant result. p-value corresponds to two sample (independent group) t-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

103

Analysis specification

Pre-specified

Analysis type

superiority ^[92]

P-value

= 0.114 ^[93]

Method

t-test, 2-sided

Confidence interval

Notes
[92] - 103 subjects are included in the FAS, however only 99 (Cenegermin, n=50; Vehicle, n=49) subjects are analyzed in this table due to the presence of missing values.
[93] - Not statistically significant result. p-value corresponds to 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

103

Analysis specification

Pre-specified

Analysis type

superiority ^[94]

P-value

= 0.069 ^[95]

Method

t-test, 2-sided

Confidence interval

Notes
[94] - 103 subjects are included in the FAS, however only 54 (Cenegermin, n=24; Vehicle, n=30) subjects are analyzed in this table due to the presence of missing values.
[95] - Not statistically significant result. p-value corresponds to 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 8

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

103

Analysis specification

Pre-specified

Analysis type

superiority ^[96]

P-value

= 0.251 ^[97]

Method

t-test, 2-sided

Confidence interval

Notes
[96] - 103 subjects are included in the FAS, however only 54 (Cenegermin, n=24; Vehicle, n=30) subjects are analyzed in this table due to the presence of missing values.
[97] - Not statistically significant result. p-value corresponds to 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 12

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

103

Analysis specification

Pre-specified

Analysis type

superiority ^[98]

P-value

= 0.073 ^[99]

Method

t-test, 2-sided

Confidence interval

Notes
[98] - 103 subjects are included in the FAS, however only 51 (Cenegermin, n=23; Vehicle, n=28) subjects are analyzed in this table due to the presence of missing values.
[99] - Not statistically significant result. p-value corresponds to 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 16

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

103

Analysis specification

Pre-specified

Analysis type

superiority ^[100]

P-value

= 0.112 ^[101]

Method

t-test, 2-sided

Confidence interval

Notes
[100] - 103 subjects are included in the FAS, however only 52 (Cenegermin, n=23; Vehicle, n=29) subjects are analyzed in this table due to the presence of missing values.
[101] - Not statistically significant result. p-value corresponds to two sample (independent group) t-test of the comparisons between Cenegermin and Vehicle in all patients.

TS (Satisfaction with Effectiveness) - Week 4

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

103

Analysis specification

Pre-specified

Analysis type

superiority ^[102]

P-value

= 0.058 ^[103]

Method

t-test, 2-sided

Confidence interval

Notes
[102] - 103 subjects are included in the FAS, however only 92 (Cenegermin, n=48; Vehicle, n=44) subjects are analyzed in this table due to the presence of missing values.
[103] - Not statistically significant result. p-value corresponds to 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

103

Analysis specification

Pre-specified

Analysis type

superiority ^[104]

P-value

= 0.16 ^[105]

Method

t-test, 2-sided

Confidence interval

Notes
[104] - 103 subjects are included in the FAS, however only 91 (Cenegermin, n=47; Vehicle, n=44) subjects are analyzed in this table due to the presence of missing values.
[105] - Not statistically significant result. p-value corresponds to 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

103

Analysis specification

Pre-specified

Analysis type

superiority ^[106]

P-value

= 0.243 ^[107]

Method

t-test, 2-sided

Confidence interval

Notes
[106] - 103 subjects are included in the FAS, however only 92 (Cenegermin, n=48; Vehicle, n=44) subjects are analyzed in this table due to the presence of missing values.
[107] - Not statistically significant result. p-value corresponds to 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

103

Analysis specification

Pre-specified

Analysis type

superiority ^[108]

P-value

= 0.076 ^[109]

Method

t-test, 2-sided

Confidence interval

Notes
[108] - 103 subjects are included in the FAS, however only 90 (Cenegermin, n=48; Vehicle, n=42) subjects are analyzed in this table due to the presence of missing values.
[109] - Not statistically significant result. p-value corresponds to 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

103

Analysis specification

Pre-specified

Analysis type

superiority ^[110]

P-value

= 0.025 ^[111]

Method

t-test, 2-sided

Confidence interval

Notes
[110] - 103 subjects are included in the FAS, however only 92 (Cenegermin, n=48; Vehicle, n=44) subjects are analyzed in this table due to the presence of missing values.
[111] - p-value corresponds to two sample (independent group) t-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

103

Analysis specification

Pre-specified

Analysis type

superiority ^[112]

P-value

= 0.009 ^[113]

Method

t-test, 2-sided

Confidence interval

Notes
[112] - 103 subjects are included in the FAS, however only 92 (Cenegermin, n=46; Vehicle, n=46) subjects are analyzed in this table due to the presence of missing values.
[113] - p-value corresponds to two sample (independent group) t-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

103

Analysis specification

Pre-specified

Analysis type

superiority ^[114]

P-value

= 0.063 ^[115]

Method

t-test, 2-sided

Confidence interval

Notes
[114] - 103 subjects are included in the FAS, however only 93 (Cenegermin, n=47; Vehicle, n=46) subjects are analyzed in this table due to the presence of missing values.
[115] - Not statistically significant result. p-value corresponds to two sample (independent group) t-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

103

Analysis specification

Pre-specified

Analysis type

superiority ^[116]

P-value

= 0.128 ^[117]

Method

t-test, 2-sided

Confidence interval

Notes
[116] - 103 subjects are included in the FAS, however only 94 (Cenegermin, n=48; Vehicle, n=46) subjects are analyzed in this table due to the presence of missing values.
[117] - Not statistically significant result. p-value corresponds to two sample (independent group) t-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

103

Analysis specification

Pre-specified

Analysis type

superiority ^[118]

P-value

= 0.349 ^[119]

Method

t-test, 2-sided

Confidence interval

Notes
[118] - 103 subjects are included in the FAS, however only 101 (Cenegermin, n=51; Vehicle, n=50) subjects are analyzed in this table due to the presence of missing values.
[119] - Not statistically significant result. p-value corresponds to 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

103

Analysis specification

Pre-specified

Analysis type

superiority ^[120]

P-value

= 0.002 ^[121]

Method

t-test, 2-sided

Confidence interval

Notes
[120] - 103 subjects are included in the FAS, however only 98 (Cenegermin, n=49; Vehicle, n=49) subjects are analyzed in this table due to the presence of missing values.
[121] - p-value corresponds to 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

103

Analysis specification

Pre-specified

Analysis type

superiority ^[122]

P-value

= 0.005 ^[123]

Method

t-test, 2-sided

Confidence interval

Notes
[122] - 103 subjects are included in the FAS, however only 98 (Cenegermin, n=49; Vehicle, n=49) subjects are analyzed in this table due to the presence of missing values.
[123] - p-value corresponds to 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

103

Analysis specification

Pre-specified

Analysis type

superiority ^[124]

P-value

= 0.076 ^[125]

Method

t-test, 2-sided

Confidence interval

Notes
[124] - 103 subjects are included in the FAS, however only 99 (Cenegermin, n=50; Vehicle, n=49) subjects are analyzed in this table due to the presence of missing values.
[125] - Not statistically significant result. p-value corresponds to two sample (independent group) t-test of the comparisons between Cenegermin and Vehicle in all patients.

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

Top of page

End point title

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

End point description

Use of Preservative Free Artificial Tears by Study Period

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	52 ^[126]	51 ^[127]
Units: Preservative Free Artificial Tears
arithmetic mean (standard deviation)
Treatment Period	298.6 ( 443.5 )	195.0 ( 174.8 )
Follow-up Period	364.5 ( 366.6 )	284.8 ( 187.9 )
Overall	331.9 ( 405.6 )	242.5 ( 186.3 )

Notes
[126] - Treatment period, n=46; Follow-up period, n=47; Overall, n=49
[127] - Treatment period, n=40; Follow-up period, n=45; Overall, n=49

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

End point type

Other pre-specified

End point timeframe

Week 2

End point values	Cenegermin	Vehicle
Number of subjects analysed	52 ^[128]	51 ^[129]
Units: Change from baseline to Week 2
arithmetic mean (standard deviation)	4.1 ( 5.6 )	0.8 ( 3.4 )

Notes
[128] - N=50
[129] - N=51

Change from baseline to Week 2

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

103

Analysis specification

Pre-specified

Analysis type

superiority ^[130]

P-value

< 0.001 ^[131]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[130] - 103 subjects are included in the FAS, however only 101 subjects are analyzed in this table due to the presence of missing values.
[131] - 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

End point type

Other pre-specified

End point timeframe

Week 2

End point values	Cenegermin	Vehicle
Number of subjects analysed	52 ^[132]	51 ^[133]
Units: Change from baseline to Week 2
arithmetic mean (standard deviation)	-2.7 ( 4.2 )	-1.6 ( 3.4 )

Notes
[132] - N=50
[133] - N=51

Change from baseline to Week 2

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

103

Analysis specification

Pre-specified

Analysis type

superiority ^[134]

P-value

= 0.038 ^[135]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[134] - 103 subjects are included in the FAS, however only 101 subjects are analyzed in this table due to the presence of missing values.
[135] - 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 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

End point type

Other pre-specified

End point timeframe

Week 2

End point values	Cenegermin	Vehicle
Number of subjects analysed	52 ^[136]	51 ^[137]
Units: Change from baseline to Week 2
arithmetic mean (standard deviation)	1.2 ( 3.4 )	0.1 ( 2.4 )

Notes
[136] - N=50
[137] - N=51

Change from baseline to Week 2

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

103

Analysis specification

Pre-specified

Analysis type

superiority ^[138]

P-value

= 0.023 ^[139]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[138] - 103 subjects are included in the FAS, however only 101 subjects are analyzed in this table due to the presence of missing values.
[139] - 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 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

End point type

Other pre-specified

End point timeframe

Week 2 and Week 4

End point values	Cenegermin	Vehicle
Number of subjects analysed	52 ^[140]	51 ^[141]
Units: Change from baseline
arithmetic mean (standard deviation)
Global Score - Change from baseline to Week 2	-13.9 ( 19.9 )	-14.7 ( 21.7 )
Global Score - Change from baseline to Week 4	-18.8 ( 20.9 )	-17.4 ( 22.8 )
Severity - Change from baseline to Week 2	-13.3 ( 21.9 )	-13.9 ( 21.2 )
Severity - Change from baseline to Week 4	-17.8 ( 23.0 )	-16.6 ( 23.1 )
Frequency - Change from baseline to Week 2	-13.8 ( 21.2 )	-15.4 ( 23.8 )
Frequency - Change from baseline to Week 4	-19.3 ( 22.3 )	-18.0 ( 24.6 )

Notes
[140] - Week 2, n=50; Week 4, n=51.
[141] - Week 2, n=51; Week 4, n=50.

Global Score - Change from baseline to Week 2

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

103

Analysis specification

Pre-specified

Analysis type

superiority ^[142]

P-value

= 0.954 ^[143]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[142] - 103 subjects are included in the FAS, however only 101 subjects are analyzed in this table due to the presence of missing values.
[143] - 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 participants

Global Score - Change from baseline to Week 4

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

103

Analysis specification

Pre-specified

Analysis type

superiority ^[144]

P-value

= 0.752 ^[145]

Method

t-test, 2-sided

Confidence interval

Notes
[144] - 103 subjects are included in the FAS, however only 101 subjects are analyzed in this table due to the presence of missing values.
[145] - Not statistically significant result. p-value corresponds to a two sample (independent group) t-test of the comparisons between Cenegermin and Vehicle in all participants

Severity - Change from baseline to Week 2

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

103

Analysis specification

Pre-specified

Analysis type

superiority ^[146]

P-value

= 0.817 ^[147]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[146] - 103 subjects are included in the FAS, however only 101 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 participants

Severity - Change from baseline to Week 4

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

103

Analysis specification

Pre-specified

Analysis type

superiority ^[148]

P-value

= 0.552 ^[149]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[148] - 103 subjects are included in the FAS, however only 101 subjects are analyzed in this table due to the presence of missing values.
[149] - 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 participants

Frequency - Change from baseline to Week 2

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

103

Analysis specification

Pre-specified

Analysis type

superiority ^[150]

P-value

= 0.651 ^[151]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[150] - 103 subjects are included in the FAS, however only 101 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 participants

Frequency - Change from baseline to Week 4

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

103

Analysis specification

Pre-specified

Analysis type

superiority ^[152]

P-value

= 0.521 ^[153]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[152] - 103 subjects are included in the FAS, however only 101 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 participants

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

End point type

Other pre-specified

End point timeframe

Week 2

End point values	Cenegermin	Vehicle
Number of subjects analysed	52 ^[154]	51 ^[155]
Units: Subjects
Worsening in symptom scores (SANDE global score)	12	11
NEI score >= 50%	1	0
Worsening in symptom scores and/or NEI score >= 50	12	11

Notes
[154] - Week 2, n=50
[155] - Week 2, n=51

Worsening in symptom scores (SANDE global score)

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

103

Analysis specification

Pre-specified

Analysis type

superiority ^[156]

P-value

= 0.7708 ^[157]

Method

Chi-squared

Confidence interval

Notes
[156] - 103 subjects are included in the FAS, however only 101 subjects are analyzed in this table due to the presence of missing values.
[157] - Not statistically significant result. 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

103

Analysis specification

Pre-specified

Analysis type

superiority ^[158]

P-value

= 0.495 ^[159]

Method

Fisher exact

Confidence interval

Notes
[158] - 103 subjects are included in the FAS, however only 101 subjects are analyzed in this table due to the presence of missing values.
[159] - Not statistically significant result. p-value corresponds to 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

103

Analysis specification

Pre-specified

Analysis type

superiority ^[160]

P-value

= 0.7708 ^[161]

Method

Chi-squared

Confidence interval

Notes
[160] - 103 subjects are included in the FAS, however only 101 subjects are analyzed in this table due to the presence of missing values.
[161] - Not statistically significant result. 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	52 ^[162]	51 ^[163]
Units: Change from baseline in Schirmer II test
arithmetic mean (standard deviation)	3.7 ( 6.2 )	0.6 ( 4.6 )

Notes
[162] - N=51
[163] - N=48

Change from baseline to Week 4

Comparison groups

Cenegermin v Vehicle

Number of subjects included in analysis

103

Analysis specification

Pre-specified

Analysis type

superiority ^[164]

P-value

= 0.002 ^[165]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[164] - 103 subjects are included in the FAS, however only 99 subjects are analyzed in this table due to the presence of missing values.
[165] - 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)

Top of page

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	52	51
Units: Subjects
CFB to Week 2 - No change	37	32
CFB to Week 2 - 20/125 to 20/160	1	0
CFB to Week 2 - 20/50 to 20/40	1	1
CFB to Week 2 - 20/40 to 20/32	0	1
CFB to Week 2 - 20/32 to 20/20	0	1
CFB to Week 2 - 20/32 to 20/25	4	4
CFB to Week 2 - 20/25 to 20/16	0	1
CFB to Week 2 - 20/25 to 20/20	3	1
CFB to Week 2 - 20/25 to 20/40	0	2
CFB to Week 2 - 20/20 to 20/16	0	3
CFB to Week 2 - 20/20 to 20/25	0	3
CFB to Week 2 - 20/20 to 20/32	1	1
CFB to Week 2 - 20/16 to 20/20	3	1
CFB to Week 4 - No change	36	37
CFB to Week 4 - 20/125 to 20/160	1	0
CFB to Week 4 - 20/50 to 20/40	1	1
CFB to Week 4 - 20/40 to 20/32	1	0
CFB to Week 4 - 20/32 to 20/20	1	2
CFB to Week 4 - 20/32 to 20/25	1	1
CFB to Week 4 - 20/32 to 20/40	0	1
CFB to Week 4 - 20/25 to 20/20	4	4
CFB to Week 4 - 20/25 to 20/32	1	1
CFB to Week 4 - 20/20 to 20/25	1	1
CFB to Week 4 - 20/20 to 20/32	0	1
CFB to Week 4 - 20/20 to 20/40	1	0
CFB to Week 4 - 20/16 to 20/20	3	1
CFB to Week 8 - No change	35	27
CFB to Week 8 - 20/125 to 20/200	1	0
CFB to Week 8 - 20/50 to 20/32	1	0
CFB to Week 8 - 20/50 to 20/40	0	1
CFB to Week 8 - 20/40 to 20/32	1	0
CFB to Week 8 - 20/32 to 20/25	3	3
CFB to Week 8 - 20/25 to 20/16	1	1
CFB to Week 8 - 20/25 to 20/20	3	4
CFB to Week 8 - 20/25 to 20/32	0	2
CFB to Week 8 - 20/20 to 20/16	0	4
CFB to Week 8 - 20/20 to 20/25	0	5
CFB to Week 8 - 20/20 to 20/32	2	0
CFB to Week 8 - 20/16 to 20/20	2	2
CFB to Week 12 - No change	38	29
CFB to Week 12 - 20/125 to 20/320	1	0
CFB to Week 12 - 20/50 to 20/40	1	1
CFB to Week 12 - 20/32 to 20/20	0	3
CFB to Week 12 - 20/32 to 20/25	3	2
CFB to Week 12 - 20/25 to 20/16	1	0
CFB to Week 12 - 20/25 to 20/20	2	2
CFB to Week 12 - 20/25 to 20/32	1	2
CFB to Week 12 - 20/20 to 20/16	0	3
CFB to Week 12 - 20/20 to 20/25	0	4
CFB to Week 12 - 20/20 to 20/32	1	1
CFB to Week 12 - 20/16 to 20/20	0	1
CFB to Week 12 - 20/16 to 20/25	1	1
CFB to Week 16 - No change	36	33
CFB to Week 16 - 20/125 to 20/250	1	0
CFB to Week 16 - 20/80 to 20/63	1	0
CFB to Week 16 - 20/50 to 20/40	1	1
CFB to Week 16 - 20/40 to 20/32	1	0
CFB to Week 16 - 20/32 to 20/20	1	2
CFB to Week 16 - 20/32 to 20/25	1	2
CFB to Week 16 - 20/25 to 20/16	0	1
CFB to Week 16 - 20/25 to 20/20	4	2
CFB to Week 16 - 20/20 to 20/16	0	2
CFB to Week 16 - 20/20 to 20/25	1	4
CFB to Week 16 - 20/20 to 20/32	1	1
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 has 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

24.0

Reporting group title

Cenegermin

Reporting group description

Group 1: Cenegermin (rhNGF 20 mcg/mL)

Reporting group title

Vehicle

Reporting group description

Group 2: Placebo vehicle (Vehicle vials)

Serious adverse events	Cenegermin	Vehicle
Total subjects affected by serious adverse events
subjects affected / exposed	2 / 52 (3.85%)	1 / 51 (1.96%)
number of deaths (all causes)	0	0
number of deaths resulting from adverse events	0	0
Eye disorders
Visual acuity reduced
subjects affected / exposed	1 / 52 (1.92%)	0 / 51 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Pancreatitis acute
subjects affected / exposed	1 / 52 (1.92%)	0 / 51 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
Hypertransaminasaemia
subjects affected / exposed	1 / 52 (1.92%)	0 / 51 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthropathy
subjects affected / exposed	0 / 52 (0.00%)	1 / 51 (1.96%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Bacteraemia
subjects affected / exposed	1 / 52 (1.92%)	0 / 51 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Cenegermin	Vehicle
Total subjects affected by non serious adverse events
subjects affected / exposed	37 / 52 (71.15%)	15 / 51 (29.41%)
Nervous system disorders
Headache
subjects affected / exposed	3 / 52 (5.77%)	2 / 51 (3.92%)
occurrences all number	3	3
Eye disorders
Dry eye
subjects affected / exposed	3 / 52 (5.77%)	1 / 51 (1.96%)
occurrences all number	4	2
Eye discharge
subjects affected / exposed	2 / 52 (3.85%)	2 / 51 (3.92%)
occurrences all number	2	2
Eye irritation
subjects affected / exposed	1 / 52 (1.92%)	3 / 51 (5.88%)
occurrences all number	4	4
Eye pain
subjects affected / exposed	25 / 52 (48.08%)	5 / 51 (9.80%)
occurrences all number	31	5
Eye pruritus
subjects affected / exposed	1 / 52 (1.92%)	5 / 51 (9.80%)
occurrences all number	1	7
Eyelid pain
subjects affected / exposed	11 / 52 (21.15%)	0 / 51 (0.00%)
occurrences all number	16	0
Foreign body sensation in eyes
subjects affected / exposed	2 / 52 (3.85%)	4 / 51 (7.84%)
occurrences all number	2	4
Ocular hyperaemia
subjects affected / exposed	1 / 52 (1.92%)	2 / 51 (3.92%)
occurrences all number	1	2
Photophobia
subjects affected / exposed	4 / 52 (7.69%)	3 / 51 (5.88%)
occurrences all number	4	3
Vision blurred
subjects affected / exposed	4 / 52 (7.69%)	2 / 51 (3.92%)
occurrences all number	4	2
Infections and infestations
COVID-19
subjects affected / exposed	2 / 52 (3.85%)	1 / 51 (1.96%)
occurrences all number	2	1

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

06 Sep 2021

This document amended the Protocol version 2.0 and was included in the Protocol version 4.0. The purpose of this amendment was to fulfil the requests reported in the FDA’s “Review Comments” letter dated August 17th, 2021. Furthermore, the amendment included changes in order to align the protocol to the version submitted in Italy.

12 Nov 2021

This document amended the Protocol version 3.0 and was included in the Protocol version 4.0_Italy specific. The purpose of this amendment was to fulfil the requests reported in the Agenzia Italiana del Farmaco (AIFA)’s “Review Comments” letter dated November 12th, 2021.

18 Nov 2021

This document amended the Protocol version 4.0_Italy Specific and was included in the Protocol 5.0_Italy Specific. The purpose of this amendment was to fulfil the requests reported in the AIFA’s “Review Comments” dated November 18th, 2021.

26 Jan 2022

This document amended the Protocol version 4.0 and was included in the Protocol Version 6.0. The purpose of this amendment was to align version numbers as Protocol NGF0121 EU (Version 5.0 Italy specific) and US (version 4.0 US specific) and to add the study name (PROTEGO-1). 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.

05 Feb 2022

This document amended the Protocol Version 5.0_Italy Specific and was included in Protocol Version 6.0. The purpose of this amendment was to align version numbers as Protocol NGF0121 EU (Version 5.0 Italy specific) and US (version 4.0 US specific) and to add the study name (PROTEGO-1). Some changes were implemented after specific requests from FDA. Furthermore, minor changes to better explain the study design and to correct some typos 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 high inflammation level, and cenegermin is not an anti-inflammatory drug. Vehicle response could be due to a beneficial effect of vehicle. The short treatment duration could explain not observed superiority of cenegermin.

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Clinical trials

Clinical Trial Results: A 4-week, Phase III, multicentre, double-masked, vehicle-controlled 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 (PROTEGO-1 study)

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 (n° drops/day)

Other pre-specified: Proportion and Frequency of Preservative Free Artificial Tears Use (n° 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

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A 4-week, Phase III, multicentre, double-masked, vehicle-controlled 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 (PROTEGO-1 study)