Safety and Efficacy Study on Cenegermin (Oxervate®) vs Vehicle in Severe Sjogren's Dry Eye Disease (PROTEGO-1 Study)

A 4-week, Phase III, Multicenter, Double-masked, Vehicle-controlled Clinical Study to Evaluate Safety and Efficacy of Oxervate® (Cenegermin) 20 mcg/mL Ophthalmic Solution vs Vehicle in Severe Sjogren's Dry Eye Disease

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT05133180

Enrollment

104

Registered

2021-11-24

Start date

2022-01-19

Completion date

2022-12-19

Last updated

2024-06-07

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Dry Eye

Keywords

Sjorgen's dry eye

Brief summary

Primary objectives * To compare the efficacy of cenegermin vs vehicle in Schirmer I test (without anaesthesia) \>10mm/5min at Week 4 by testing the superiority. * To compare the efficacy of cenegermin vs vehicle in Symptom Assessment in Dry Eye questionnaire (SANDE) global score at Week 12 by testing the superiority. Secondary objectives * To compare the efficacy of cenegermin vs vehicle in Schirmer I test at Week 4, 8, 12 and 16 by testing the superiority. * To compare the efficacy of cenegermin vs vehicle in Cornea and conjunctiva vital staining with fluorescein (National Eye Institute \[NEI\] scales) at Week 4, 8, 12 and 16 by testing the superiority. * To compare the efficacy of cenegermin vs vehicle in Tear Film Break-Up Time (TFBUT) at Week 4, 8, 12 and 16 by testing the superiority. * To compare the efficacy of cenegermin vs vehicle in SANDE scores at Week 8, 12 and 16 by testing the superiority. * To compare the efficacy of cenegermin vs vehicle in worsening in symptom scores (SANDE) and/or NEI score at Week 4 by testing the superiority. * To compare the efficacy of cenegermin vs vehicle in impact of dry eye on everyday life (IDEEL) questionnaire at Week 4, 8, 12 and 16 by testing the superiority.

Detailed description

This is a 4 week phase III, multicenter, double-masked, vehicle-controlled study to evaluate safety and efficacy of cenegermin ophthalmic solution at 20 mcg/mL solution versus vehicle, in patients with severe Sjogren's dry eye disease. During the screening all procedures for inclusion and exclusion were performed. From the day of screening the patients stopped any kind of further treatment, except commercially available preservative free artificial tears provided by Sponsor. At the end of the wash out period, patients meeting the entry criteria for this study were randomized 1:1 and treated for 4 weeks with either cenegermin ophthalmic solution 20 mcg/mL TID or vehicle TID. During the 4 weeks of masked treatment only the administration of IMP was allowed. During the follow up period, the patient could administer additional artificial tear eye drops, provided by Sponsor, only if strictly needed, and should document in the patient's diary the number of additional drops administered for each eye. Patients were then followed up for efficacy and safety endpoints until week 16 and for safety endpoints until week 24. The total duration of the study was 25 weeks including 1 week of screening.

Interventions

DRUGOxervate

Oxervate®, an ophthalmic solution containing cenegermin 20 mcg/mL, which is a recombinant human Nerve Growth Factor (rhNGF); one drop of the test product will be instilled in both eyes three times daily (TID).

OTHERVehicle

Vehicle will be instilled with the same scheme of the test product

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

TRIPLE (Subject, Caregiver, Investigator)

Masking description

double-masked study

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

1. Male or female aged ≥ 18 years 2. Patients with a confirmed diagnosis of Sjögren's syndrome or other autoimmune disease known to induce Sjögren's Dry Eye Disease (DED). 3. Patients with severe Sjögren's dry eye disease characterized by the following clinical features: 1. Corneal and/or conjunctival staining with fluorescein using National Eye Institute (NEI) grading system ≥3 2. SANDE questionnaire \>25 mm 3. Schirmer test I (without anaesthesia) ≥2 ≤5mm/5min 4. The same eye (eligible eye) must fulfill all the above criteria 5. Patients diagnosed with severe Sjögren's dry eye disease at least 3 months before enrolment 6. Best corrected distance visual acuity (BCDVA) score of ≥ 0.1 decimal units (20/200 Snellen value) in each eye at the time of study enrolment 7. If a female of childbearing potential, have a negative urine pregnancy test and use a highly effective method to avoid pregnancy for the duration of the trial and 30 days after the study treatment period. Males of reproductive potential should use effective contraception during treatment and 30 days after the study treatment period. 8. Only patients who satisfy all Informed Consent requirements may be included in the study. The patient and/or his/her legal representative must read, sign and date the Informed Consent document before any study-related procedures are performed. The Informed Consent Form signed by patients and/or legal representative must have been approved by the IRB/IEC for the current study 9. Patients must have the ability and willingness to comply with study procedures.

Exclusion criteria

1. Inability to speak and understand the local language sufficiently to understand the nature of the study, to provide written informed consent, and to allow the completion of all study assessments 2. Evidence of an active ocular infection, in either eye 3. Presence of any other ocular disorder or condition requiring topical medication during the entire duration of study in either eye 4. History of severe systemic allergy or of ocular allergy (including seasonal conjunctivitis) or chronic conjunctivitis and/or keratitis other than dry eye 5. Intraocular inflammation defined as Tyndall score \>0 6. History of malignancy in the last 5 years 7. Systemic disease not stabilized within 1 month before Screening Visit (e.g. diabetes with glycemia out of range, thyroid malfunction) or judged by the investigator to be incompatible with the study (e.g. current systemic infections) or with a condition incompatible with the frequent assessment required by the study 8. Patient had a serious adverse reaction or significant hypersensitivity to any drug or chemically related compounds or had a clinically significant allergy to drugs, foods, amide local anesthetics or other materials including commercial artificial tears (in the opinion of the investigator). 9. Females of childbearing potential (those who are not surgically sterilized or post-menopausal for at least 1 year) are excluded from participation in the study if they meet any one of the following conditions: 1. are currently pregnant or, 2. have a positive result at the urine pregnancy test (Baseline/Day 1) or, 3. intend to become pregnant during the study treatment period or, 4. are breast-feeding or, 5. are not willing to use highly effective birth control measures During the entire course of and 30 days after the study treatment periods 10. Any concurrent medical condition, that in the judgment of the PI, might interfere with the conduct of the study, confound the interpretation of the study results, or endanger the patient's well-being 11. Use of topical cyclosporine, or topical ophthalmic treatments of the same class, within 14 days of screening visit (day -8) 12. Use of topical corticosteroids, lifitegrast, autologous serum tears in either eye during the study (previous use not an

Design outcomes

Primary

Measure	Time frame	Description
Change From Baseline in Symptoms Questionnaire (SANDE) Global Score at Week 12	at week 12	The SANDE questionnaire is comprised of two questions: 1) How often do your eyes feel dry and/or irritated? And 2) How severe you feel your symptoms of dryness and/or irritation are? The SANDE questionnaire uses a 100 mm horizontal line for each question to assess the extent of patients' symptoms. In this questionnaire, frequency of symptoms ranges from rarely (0) to all of the time (100) and the severity of symptoms ranges from very mild (0) to very severe (100). At each visit, patients were asked to place a mark on the two given lines based on the extent of their symptoms. The locations of the marks made by the patients on the 100 mm horizontal lines were measured in mm from left to right. The global SANDE score is calculated by multiplying the frequency score by the severity score and obtaining the square root. Both for total score and for frequency or severity scores, 0 is the best condition, 100 the worst condition. Please note that adjusted means are reported.
Number of Patients Reaching a Value of Schirmer I Test (Without Anaesthesia) >10mm/5min at Week 4	at week 4	The Schirmer test type I (without anaesthesia) was performed to measure aqueous tear secretion. The rounded bend end of a sterile strip was inserted into the lower conjunctival sac over the temporal one-third of the lower eyelid margin. After 5 minutes had elapsed, the Schirmer's test strip was removed and the length of the tear absorption on the strip was measured (millimeters/5 minutes). The longer the wetted length, the healthier the status of the eye.

Secondary

Measure	Time frame	Description
Key Secondary Outcome: Change From Baseline in Symptoms Assessment in Dry Eye (SANDE) Score for Frequency at Week 12	At week 12	The SANDE questionnaire is comprised of two questions: 1) How often do your eyes feel dry and/or irritated? And 2) How severe you feel your symptoms of dryness and/or irritation are? This questionnaire uses a 100 mm horizontal line for each question to assess ocular discomfort and/or dryness experienced by the patients. In the SANDE questionnaire, frequency of symptoms ranges from rarely (0) to all of the time (100) and the severity of symptoms ranges from very mild (0) to very severe (100). At each visit, patients were asked to place a mark on the two given lines based on the extent of their symptoms. The locations of the marks made by the patients on the 100 mm horizontal lines were measured in mm from left to right and recorded. 0 was the best condition and 100 marked the worst condition. Global score from the SANDE questionnaire was calculated by multiplying the frequency score by the severity score and obtaining the square root. Means are adjusted means.
Key Secondary Outcome: Change From Baseline in Symptoms Assessment in Dry Eye (SANDE) Score for Severity at Week 12	at Week 12	The SANDE questionnaire is comprised of two questions: 1) How often do your eyes feel dry and/or irritated? And 2) How severe you feel your symptoms of dryness and/or irritation are? This questionnaire uses a 100 mm horizontal line for each question to assess ocular discomfort and/or dryness experienced by the patients. In the SANDE questionnaire, frequency of symptoms ranges from rarely (0) to all of the time (100) and the severity of symptoms ranges from very mild (0) to very severe (100). At each visit, patients were asked to place a mark on the two given lines based on the extent of their symptoms. The locations of the marks made by the patients on the 100 mm horizontal lines were measured in mm from left to right and recorded. 0 was the best condition and 100 marked the worst condition. Global score from the SANDE questionnaire was calculated by multiplying the frequency score by the severity score and obtaining the square root. Means are adjusted means.
Key Secondary Outcome: Change From Baseline in Quality of Life Module Measured by Impact of Dry Eye on Everyday Life [IDEEL] Questionnaire at Week 12 and at Week 4	At Weeks 12 and 4	IDEEL is a 57-item questionnaire that assesses the impact of dry eye symptoms on everyday life. It is composed of 3 modules (Dry eye Quality of Life, Dry eye Treatment satisfaction & Bother, Dry eye Symptom Bother). This outcome is about the first module: Quality of Life module (27 items) is composed by 3 dimensions: Dimension 1 - Impact on Daily Activities, calculated by mean of the non-missing item scores 1-6 multiplied by 20. (range 0-100) Dim. 2 - Emotional Impact: calculated by mean of the non-missing item scores 10-20 multiplied by 25. (range 0-100) Dim. 3 - Impact on Work: calculated by mean of the non-missing item scores 23-27 multiplied by 25. (range 0-100) Scores for each dimension of this module ranged from 0 to 100, where higher scores indicated less impact on daily activities, on work and on emotions. No combination of dimensions scores is done.
Key Secondary Outcome: Change From Baseline in Treatment Satisfaction & Bother Module Measured by Impact of Dry Eye on Everyday Life [IDEEL] Questionnaire at Weeks 12 and 4	at Weeks 12 and 4	IDEEL is a 57-item questionnaire that assesses the impact of dry eye symptoms on everyday life. It is composed of 3 modules (Quality of Life, Treatment satisfaction & Bother, Symptom Bother). This outcome is about the second module: Treatment Satisfaction & Bother (8 items). This is composed by 2 dimensions: Dim. 1 - Satisfaction with Treatment Effectiveness, calculated by mean of the non-missing item scores 2-5 multiplied by 25. (range 0-100) Dim. 2 - Treatment-Related Bother / Inconvenience calculated as the mean of the non-missing item scores 6, 8-10 multiplied by 25. (range 0-100) Scores for each dimension of this module range from 0 to 100, where higher scores indicate a greater satisfaction in treatment effectiveness and less treatment-related bother. No combination of dimension scores is done.
Key Secondary Outcome: Change From Baseline in Symptom Bother Module Measured by Impact of Dry Eye on Everyday Life [IDEEL] Questionnaire at Weeks 12 and 4	at Weeks 12 and 4	IDEEL is a 57-item questionnaire that assesses the impact of dry eye symptoms on everyday life. It is composed of 3 modules (Quality of Life, Treatment Satisfaction & Bother, Symptom Bother). This outcome is about the third module: Symptom Bother (20 items). This is composed by 1 dimension: Dry Eye Symptom-Bother (range 0-100) The Symptom Bother score is calculated if at least 50% (10 items) of the 20 items within the dimension are completed, and non-missing; otherwise the score is set to missing. The Symptom Bother score is calculated as the mean of the non-missing item scores 1-20 multiplied by 25. The higher the score the greater the symptom bother.
Key Secondary Outcome: Change From Baseline in Cornea and Conjunctiva Vital Staining With Fluorescein (National Eye Institute [NEI] Scales) at Weeks 4, 8, 12	At weeks 4, 8, 12	The examiner compared the overall appearance of the patient's corneal staining with a reference figure, simulating the pattern of staining encountered in dry eye disease. non attempt was made to count the dots or to assess the position or confluence of the dots. The examiner selected the appropriate grade that best represented the state of corneal staining intuitionally. The grading system recommended by NEI divides the cornea into five zones (central, superior, temporal, nasal, and inferior) and for each zone, the severity of the corneal staining is graded on a scale from 0 to 3 based on a reference figure. Therefore the maximum score (worst outcome) was 15, and the minimum (best outcome) was 0.
Key Secondary Outcome: Change From Baseline in Tear Film Break-Up Time (TFBUT) at Week 4, Week 8, Week 12	At weeks 4, 8, 12	TFBUT was measured by determining the time to tear break-up.The TFBUT test was performed after instillation of 5 μl of 2% preservative free sodium fluorescein solution into the lower conjunctival sac of each eye. This measurement was performed within 10 seconds maximum. The TFBUT was measured twice during the first minute of instillation of the fluorescein. If the 2 readings differed by more than 2 sec., a third reading was taken. The TFBUT value was the average of the 2 or 3 measurements. Generally, a TFBUT value of 10-35 sec was considered normal. A value of less than 10 seconds may indicate tear film instability.
Change From Baseline in Schirmer I Test (Without Anaesthesia) [Time Frame: Week 4, 8, 12 and 16].	Week 4, 8, 12 and 16	The Schirmer test type I (without anaesthesia) was performed to measure aqueous tear secretion. The rounded bend end of a sterile strip was inserted into the lower conjunctival sac over the temporal one-third of the lower eyelid margin. After 5 minutes had elapsed, the Schirmer's test strip was removed and the length of the tear absorption on the strip was measured (millimeters/5 minutes). The longer, the wetted length, the healthier the status of the eye.
Change From Baseline in Tear Film Break-Up Time (TFBUT) at Week 16	at week 16	TFBUT was measured by determining the time to tear break-up.The TFBUT test was performed after instillation of 5 μl of 2% preservative free sodium fluorescein solution into the lower conjunctival sac of each eye. This measurement was performed within 10 seconds maximum. The TFBUT was measured twice during the first minute of instillation of the fluorescein. If the 2 readings differed by more than 2 sec., a third reading was taken. The TFBUT value was the average of the 2 or 3 measurements. Generally, a TFBUT value of 10-35 sec was considered normal. A value of less than 10 seconds may indicate tear film instability.
Change From Baseline in Symptoms Questionnaire (SANDE) Global Score at Week 8, Week 12, Week 16	at Week 8, Week 12, Week 16	The SANDE questionnaire is comprised of two questions: 1) How often do your eyes feel dry and/or irritated? And 2) How severe you feel your symptoms of dryness and/or irritation are? This questionnaire uses a 100 mm horizontal line for each question to assess ocular discomfort and/or dryness experienced by the patients. In the SANDE questionnaire, frequency of symptoms ranges from rarely (0) to all of the time (100) and the severity of symptoms ranges from very mild (0) to very severe (100). At each visit, patients were asked to place a mark on the two given lines based on the extent of their symptoms. The locations of the marks made by the patients on the 100 mm horizontal lines were measured in mm from left to right and recorded. 0 was the best condition and 100 marked the worst condition. Global score from the SANDE questionnaire was calculated by multiplying the frequency score by the severity score and obtaining the square root.
Change From Baseline in Symptoms Questionnaire (SANDE) Score for Frequency at Week 8, Week 12, Week 16	at Week 8, Week 12, Week 16	The SANDE questionnaire is comprised of two questions: 1) How often do your eyes feel dry and/or irritated? And 2) How severe you feel your symptoms of dryness and/or irritation are? This questionnaire uses a 100 mm horizontal line for each question to assess ocular discomfort and/or dryness experienced by the patients. In the SANDE questionnaire, frequency of symptoms ranges from rarely (0) to all of the time (100) and the severity of symptoms ranges from very mild (0) to very severe (100). At each visit, patients were asked to place a mark on the two given lines based on the extent of their symptoms. The locations of the marks made by the patients on the 100 mm horizontal lines were measured in mm from left to right and recorded. 0 was the best condition and 100 marked the worst condition. Global score from the SANDE questionnaire was calculated by multiplying the frequency score by the severity score and obtaining the square root.
Change From Baseline in Symptoms Assessment in Dry Eye (SANDE) Score for Severity at Week 8, Week 12 and Week 16	at Week 8, week 12 and week 16	The SANDE questionnaire is comprised of two questions: 1) How often do your eyes feel dry and/or irritated? And 2) How severe you feel your symptoms of dryness and/or irritation are? This questionnaire uses a 100 mm horizontal line for each question to assess ocular discomfort and/or dryness experienced by the patients. In the SANDE questionnaire, frequency of symptoms ranges from rarely (0) to all of the time (100) and the severity of symptoms ranges from very mild (0) to very severe (100). At each visit, patients were asked to place a mark on the two given lines based on the extent of their symptoms. The locations of the marks made by the patients on the 100 mm horizontal lines were measured in mm from left to right and recorded. 0 was the best condition and 100 marked the worst condition. Global score from the SANDE questionnaire was calculated by multiplying the frequency score by the severity score and obtaining the square root.
Number of Patients Who Experienced a Worsening in Symptoms Scores (SANDE) and/or NEI Score > = 50% at Week 4	at week 4	Symptoms Scores (SANDE) and/or NEI Score were punctually described in the previous outcome descriptions. For Sande score, the scale ranges from 0 to 100 for both severity and frequency, where 0 was the best condition and 100 marked the worst condition. Hence the higher the score, the worse the outcome. For NEI score, the maximum score (worst outcome) was 15, and the minimum (best outcome) was 0; hence the higher the score, the worse the outcome.
Change From Baseline in Quality of Life Module Measured by Impact of Dry Eye on Everyday Life [IDEEL] Questionnaire at Weeks 8 and 16	At weeks 8 and 16	IDEEL is a 57-item questionnaire that assesses the impact of dry eye symptoms on everyday life. It is composed of 3 modules (Dry eye Quality of Life, Dry eye Treatment satisfaction & Bother, Dry eye Symptom Bother). This outcome is about the first module: Quality of Life module (27 items) is composed by 3 dimensions: Dimension 1 - Impact on Daily Activities, calculated by mean of the non-missing item scores 1-6 multiplied by 20. (range 0-100) Dim. 2 - Emotional Impact: calculated by mean of the non-missing item scores 10-20 multiplied by 25. (range 0-100) Dim. 3 - Impact on Work: calculated by mean of the non-missing item scores 23-27 multiplied by 25. (range 0-100) Scores for each dimension of this module ranged from 0 to 100, where higher scores indicated less impact on daily activities, on work and on emotions. No combination of dimensions scores is done.
Change From Baseline in Symptom Bother Module Measured by Impact of Dry Eye on Everyday Life [IDEEL] Questionnaire at Week 8 and Week 16	at Week 8 and Week 16	IDEEL is a 57-item questionnaire that assesses the impact of dry eye symptoms on everyday life. It is composed of 3 modules (Quality of Life, Treatment Satisfaction & Bother, Symptom Bother). This outcome is about the third module: Symptom Bother (20 items). This is composed by 1 dimension: Dry Eye Symptom-Bother (range 0-100) The Symptom Bother score is calculated if at least 50% (10 items) of the 20 items within the dimension are completed, and non-missing; otherwise the score is set to missing. The Symptom Bother score is calculated as the mean of the non-missing item scores 1-20 multiplied by 25. The higher the score the greater the symptom bother.
Change From Baseline in Treatment Satisfaction & Bother Module Measured by Impact of Dry Eye on Everyday Life [IDEEL] Questionnaire at Week 8 and Week 16	at Week 8 and Week 16	IDEEL is a 57-item questionnaire that assesses the impact of dry eye symptoms on everyday life. It is composed of 3 modules (Quality of Life, Treatment satisfaction & Bother, Symptom Bother). This outcome is about the second module: Treatment Satisfaction & Bother (8 items). This is composed by 2 dimensions: Dim. 1 - Satisfaction with Treatment Effectiveness, calculated by mean of the non-missing item scores 2-5 multiplied by 25. (range 0-100) Dim. 2 - Treatment-Related Bother / Inconvenience calculated as the mean of the non-missing item scores 6, 8-10 multiplied by 25. (range 0-100) Scores for each dimension of this module range from 0 to 100, where higher scores indicate a greater satisfaction in treatment effectiveness and less treatment-related bother. No combination of dimension scores is done.
Change From Baseline in Cornea and Conjunctiva Vital Staining With Fluorescein (National Eye Institute [NEI] Scales) at Week 16	at Week 16	The examiner compared the overall appearance of the patient's corneal staining with a reference figure, simulating the pattern of staining encountered in dry eye disease. non attempt was made to count the dots or to assess the position or confluence of the dots. The examiner selected the appropriate grade that best represented the state of corneal staining intuitionally. The grading system recommended by NEI divides the cornea into five zones (central, superior, temporal, nasal, and inferior) and for each zone, the severity of the corneal staining is graded on a scale from 0 to 3 based on a reference figure. Therefore the maximum score (worst outcome) was 15, and the minimum (best outcome) was 0.
Key Secondary Outcome: Number of Patients Reaching a Value of Schirmer I Test (Without Anaesthesia) > 10mm/5min at Week 8	at Week 8	The Schirmer test type I (without anaesthesia) was performed to measure aqueous tear secretion. The rounded bend end of a sterile strip was inserted into the lower conjunctival sac over the temporal one-third of the lower eyelid margin. After 5 minutes had elapsed, the Schirmer's test strip was removed and the length of the tear absorption on the strip was measured (millimeters/5 minutes). The longer and the wetted length, the healthier the status of the eye.

Other

Measure	Time frame	Description
Incidence and Frequency of TEAEs, Assessed Throughout the Study.	From Screening to Visit 7 (follow-up, week 24)	TEAE=any AE started on or after the date of the first dose of study medication or started prior to first dose and worsened in severity after the first dose.

Countries

Italy, United States

Participant flow

Recruitment details

A total of 126 patients ≥ 18 years with severe Sjögren's DE were assessed for eligibility. The enrolled patients (n=104) were randomized 1:1 in the study as follows: 52 patients to cenegermin and 52 to vehicle. A total of 5 patients discontinued the study prematurely: 2 patients from cenegermin group and 3 from vehicle. Regarding treatment discontinuation, a total of 5 patients discontinued the treatment prematurely: 3 patients from cenegermin and 2 from vehicle.

Participants by arm

Arm	Count
Oxervate (FAS) One drop of cenegermin 20 mcg/mL (rhNGF 20 mcg/mL) in the pharmaceutical form of ophthalmic sterile solution was instilled in both eyes three times daily (TID), every six hours. Oxervate: Oxervate®, an ophthalmic solution containing cenegermin 20 mcg/mL, which is a recombinant human Nerve Growth Factor (rhNGF); one drop of the test product will be instilled in both eyes three times daily (TID).	52
Vehicle (FAS) One drop of vehicle ophthalmic solution was instilled in both eyes TID (every six hours). Vehicle: Vehicle will be instilled with the same scheme of the test product	51
Total	103

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Documented disease progression	0	1
Overall Study	Lost to Follow-up	1	1
Overall Study	Withdrawal of consent	1	1

Baseline characteristics

Characteristic	Total	Oxervate (FAS)	Vehicle (FAS)
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	30 Participants	13 Participants	17 Participants
Age, Categorical Between 18 and 65 years	73 Participants	39 Participants	34 Participants
Age, Continuous	57.0 years STANDARD_DEVIATION 13.83	55.3 years STANDARD_DEVIATION 13.47	58.7 years STANDARD_DEVIATION 14.1
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	3 Participants	0 Participants	3 Participants
Race (NIH/OMB) Black or African American	1 Participants	0 Participants	1 Participants
Race (NIH/OMB) More than one race	2 Participants	1 Participants	1 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	15 Participants	8 Participants	7 Participants
Race (NIH/OMB) White	82 Participants	43 Participants	39 Participants
Region of Enrollment Italy	50 participants	27 participants	23 participants
Region of Enrollment United States	53 participants	25 participants	28 participants
Sex: Female, Male Female	97 Participants	50 Participants	47 Participants
Sex: Female, Male Male	6 Participants	2 Participants	4 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 52	0 / 51
other Total, other adverse events	37 / 52	15 / 51
serious Total, serious adverse events	2 / 52	1 / 51

Outcome results

Primary

Change From Baseline in Symptoms Questionnaire (SANDE) Global Score at Week 12

The SANDE questionnaire is comprised of two questions: 1) How often do your eyes feel dry and/or irritated? And 2) How severe you feel your symptoms of dryness and/or irritation are? The SANDE questionnaire uses a 100 mm horizontal line for each question to assess the extent of patients' symptoms. In this questionnaire, frequency of symptoms ranges from rarely (0) to all of the time (100) and the severity of symptoms ranges from very mild (0) to very severe (100). At each visit, patients were asked to place a mark on the two given lines based on the extent of their symptoms. The locations of the marks made by the patients on the 100 mm horizontal lines were measured in mm from left to right. The global SANDE score is calculated by multiplying the frequency score by the severity score and obtaining the square root. Both for total score and for frequency or severity scores, 0 is the best condition, 100 the worst condition. Please note that adjusted means are reported.

Time frame: at week 12

Population: The Full Analysis Set (FAS) population consisted of all patients who were randomized and received at least one dose of the investigational product.~Please note that adjusted means are reported.

Arm	Measure	Value (MEAN)
Oxervate (FAS)	Change From Baseline in Symptoms Questionnaire (SANDE) Global Score at Week 12	-29.5 score on a scale
Vehicle (FAS)	Change From Baseline in Symptoms Questionnaire (SANDE) Global Score at Week 12	-25 score on a scale

Comparison: This endpoint was analyzed by means of an Analysis of Covariance with change from baseline in global SANDE Score at Week 12 as dependent variable, treatment, gender, age class, baseline global SANDE score as fixed effects and site as random effect. For missing data, Multiple Imputation approach is adopted by performing a regression model with the baseline global SANDE score, gender, age class, and intermediate global SANDE scores up to week 12 as explanatory variables and generating 200 datasetsp-value: 0.32295% CI: [-13.581, 4.459]ANCOVA

Primary

Number of Patients Reaching a Value of Schirmer I Test (Without Anaesthesia) >10mm/5min at Week 4

The Schirmer test type I (without anaesthesia) was performed to measure aqueous tear secretion. The rounded bend end of a sterile strip was inserted into the lower conjunctival sac over the temporal one-third of the lower eyelid margin. After 5 minutes had elapsed, the Schirmer's test strip was removed and the length of the tear absorption on the strip was measured (millimeters/5 minutes). The longer the wetted length, the healthier the status of the eye.

Time frame: at week 4

Population: The Full Analysis Set (FAS) population consisted of all patients who were randomized and received at least one dose of the investigational product. The number of participants effectively analyzed was 51 in Cenegermin group and 50 in the Vehicle group. In fact 1 patient in Cenegermin group and 1 patient in vehicle group had imputed values of missing data.

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Oxervate (FAS)	Number of Patients Reaching a Value of Schirmer I Test (Without Anaesthesia) >10mm/5min at Week 4	19 Participants
Vehicle (FAS)	Number of Patients Reaching a Value of Schirmer I Test (Without Anaesthesia) >10mm/5min at Week 4	2 Participants

Comparison: It was analyzed by means of a logistic regression model adjusting by pre-defined baseline factors (treatment, gender, age class, baseline Schirmer I test value as fixed effects and site as random effect). For the imputation of missing data at week 4, a Multiple Imputation approach is adopted by performing a regression model with the baseline Schirmer I test value, gender, age class, and Schirmer I test at week 2 as explanatory variables and generating 200 datasets.p-value: <0.00195% CI: [3.412, 84.165]Regression, Logistic

Secondary

Change From Baseline in Cornea and Conjunctiva Vital Staining With Fluorescein (National Eye Institute [NEI] Scales) at Week 16

The examiner compared the overall appearance of the patient's corneal staining with a reference figure, simulating the pattern of staining encountered in dry eye disease. non attempt was made to count the dots or to assess the position or confluence of the dots. The examiner selected the appropriate grade that best represented the state of corneal staining intuitionally. The grading system recommended by NEI divides the cornea into five zones (central, superior, temporal, nasal, and inferior) and for each zone, the severity of the corneal staining is graded on a scale from 0 to 3 based on a reference figure. Therefore the maximum score (worst outcome) was 15, and the minimum (best outcome) was 0.

Time frame: at Week 16

Population: The Full Analysis Set (FAS) population consisted of all patients who were randomized and received at least one dose of the investigational product. The number of participants effectively analyzed at weeks 8 and 12 was 49 in Cenegermin group and 49 in the Vehicle group. At week 4 the participants analyzed were 51 in Cenegermin and 50 in Vehicle group. At week 16, the number of participants analyzed were 50 in Cenegermin and 49 in Vehicle group.

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Oxervate (FAS)	Change From Baseline in Cornea and Conjunctiva Vital Staining With Fluorescein (National Eye Institute [NEI] Scales) at Week 16	-3.3 score on a scale	Standard Deviation 4.6
Vehicle (FAS)	Change From Baseline in Cornea and Conjunctiva Vital Staining With Fluorescein (National Eye Institute [NEI] Scales) at Week 16	-2.7 score on a scale	Standard Deviation 5.8

Comparison: Herein Week 16 was considered. Change from baseline between the two treatment groups was compared using a two-sample t-test or a Mann-Whitney-Wilcoxon (Wilson rank sum) test if normality assumption not met.p-value: 0.065Wilcoxon (Mann-Whitney)

Secondary

Change From Baseline in Quality of Life Module Measured by Impact of Dry Eye on Everyday Life [IDEEL] Questionnaire at Weeks 8 and 16

IDEEL is a 57-item questionnaire that assesses the impact of dry eye symptoms on everyday life. It is composed of 3 modules (Dry eye Quality of Life, Dry eye Treatment satisfaction & Bother, Dry eye Symptom Bother). This outcome is about the first module: Quality of Life module (27 items) is composed by 3 dimensions: Dimension 1 - Impact on Daily Activities, calculated by mean of the non-missing item scores 1-6 multiplied by 20. (range 0-100) Dim. 2 - Emotional Impact: calculated by mean of the non-missing item scores 10-20 multiplied by 25. (range 0-100) Dim. 3 - Impact on Work: calculated by mean of the non-missing item scores 23-27 multiplied by 25. (range 0-100) Scores for each dimension of this module ranged from 0 to 100, where higher scores indicated less impact on daily activities, on work and on emotions. No combination of dimensions scores is done.

Time frame: At weeks 8 and 16

Population: The Full Analysis Set (FAS) consisted of all patients randomized and dosed with at least one dose of the IP. The # of pts actually analyzed for Impact on Daily Activities and Emotional Impact due to Dry Eye was:~Week 4:~n=51 Cenegermin (C) n=50 Vehicle (V);~Weeks 8 and 12:~n=49 in both groups~Week 16:~n=50 C n=49 V.~For Impact on work due to dry eye the No of pts actually analyzed was:~Weeks 4 and 8 n= 24 C n= 30 V Week 12 n=23 C n=28 V~Week 16:~n= 23 C n=29 V

Arm	Measure	Group	Value (MEAN)	Dispersion
Oxervate (FAS)	Change From Baseline in Quality of Life Module Measured by Impact of Dry Eye on Everyday Life [IDEEL] Questionnaire at Weeks 8 and 16	Impact on Daily Activities - week 8	14.6 score on a scale	Standard Deviation 18.8
Oxervate (FAS)	Change From Baseline in Quality of Life Module Measured by Impact of Dry Eye on Everyday Life [IDEEL] Questionnaire at Weeks 8 and 16	Emotional Impact due to Dry Eye - week 8	18.4 score on a scale	Standard Deviation 21.9
Oxervate (FAS)	Change From Baseline in Quality of Life Module Measured by Impact of Dry Eye on Everyday Life [IDEEL] Questionnaire at Weeks 8 and 16	Impact on Work due to Dry Eye - week 8	17.7 score on a scale	Standard Deviation 25.7
Oxervate (FAS)	Change From Baseline in Quality of Life Module Measured by Impact of Dry Eye on Everyday Life [IDEEL] Questionnaire at Weeks 8 and 16	Impact on Daily Activities - week 16	15.1 score on a scale	Standard Deviation 20.8
Oxervate (FAS)	Change From Baseline in Quality of Life Module Measured by Impact of Dry Eye on Everyday Life [IDEEL] Questionnaire at Weeks 8 and 16	Emotional Impact due to Dry Eye - week 16	19.0 score on a scale	Standard Deviation 23.1
Oxervate (FAS)	Change From Baseline in Quality of Life Module Measured by Impact of Dry Eye on Everyday Life [IDEEL] Questionnaire at Weeks 8 and 16	Impact on Work due to Dry Eye - week 16	20.9 score on a scale	Standard Deviation 24.2
Vehicle (FAS)	Change From Baseline in Quality of Life Module Measured by Impact of Dry Eye on Everyday Life [IDEEL] Questionnaire at Weeks 8 and 16	Emotional Impact due to Dry Eye - week 16	11.5 score on a scale	Standard Deviation 23.3
Vehicle (FAS)	Change From Baseline in Quality of Life Module Measured by Impact of Dry Eye on Everyday Life [IDEEL] Questionnaire at Weeks 8 and 16	Impact on Daily Activities - week 8	6.5 score on a scale	Standard Deviation 23.2
Vehicle (FAS)	Change From Baseline in Quality of Life Module Measured by Impact of Dry Eye on Everyday Life [IDEEL] Questionnaire at Weeks 8 and 16	Impact on Daily Activities - week 16	9.7 score on a scale	Standard Deviation 21.1
Vehicle (FAS)	Change From Baseline in Quality of Life Module Measured by Impact of Dry Eye on Everyday Life [IDEEL] Questionnaire at Weeks 8 and 16	Emotional Impact due to Dry Eye - week 8	10.3 score on a scale	Standard Deviation 22.9
Vehicle (FAS)	Change From Baseline in Quality of Life Module Measured by Impact of Dry Eye on Everyday Life [IDEEL] Questionnaire at Weeks 8 and 16	Impact on Work due to Dry Eye - week 16	9.3 score on a scale	Standard Deviation 26.7
Vehicle (FAS)	Change From Baseline in Quality of Life Module Measured by Impact of Dry Eye on Everyday Life [IDEEL] Questionnaire at Weeks 8 and 16	Impact on Work due to Dry Eye - week 8	9.5 score on a scale	Standard Deviation 25.9

Comparison: Quality of life - Impact on daily activities - Week 8p-value: 0.06t-test, 2 sided

Comparison: Quality of life - Emotional impact due to Dry eye - Week 8p-value: 0.079t-test, 2 sided

Comparison: Quality of life - Impact on work due to Dry Eye - Week 8p-value: 0.251t-test, 2 sided

Comparison: Quality of life - Impact on daily activities - Week 16p-value: 0.203t-test, 2 sided

Comparison: Quality of life - Emotional impact due to Dry eye - Week 16p-value: 0.114t-test, 2 sided

Comparison: Quality of life - Impact on work due to Dry Eye - Week 16p-value: 0.112t-test, 2 sided

Secondary

Change From Baseline in Schirmer I Test (Without Anaesthesia) [Time Frame: Week 4, 8, 12 and 16].

The Schirmer test type I (without anaesthesia) was performed to measure aqueous tear secretion. The rounded bend end of a sterile strip was inserted into the lower conjunctival sac over the temporal one-third of the lower eyelid margin. After 5 minutes had elapsed, the Schirmer's test strip was removed and the length of the tear absorption on the strip was measured (millimeters/5 minutes). The longer, the wetted length, the healthier the status of the eye.

Time frame: Week 4, 8, 12 and 16

Population: The Full Analysis Set (FAS) population consisted of all patients who were randomized and received at least one dose of the investigational product. The actual number of participants effectively analyzed was 51 in the IMP group and 50 in the vehicle group at Week 4, 49 in both IMP and vehicle group at Week 8 and at Week 12, and 50 in the IMP group and 49 in the vehicle group at Week 16.

Arm	Measure	Group	Value (LEAST_SQUARES_MEAN)	Dispersion
Oxervate (FAS)	Change From Baseline in Schirmer I Test (Without Anaesthesia) [Time Frame: Week 4, 8, 12 and 16].	week 4	5.4 millimeters	Standard Deviation 6.6
Oxervate (FAS)	Change From Baseline in Schirmer I Test (Without Anaesthesia) [Time Frame: Week 4, 8, 12 and 16].	week 8	4.9 millimeters	Standard Deviation 6.6
Oxervate (FAS)	Change From Baseline in Schirmer I Test (Without Anaesthesia) [Time Frame: Week 4, 8, 12 and 16].	week 12	3.8 millimeters	Standard Deviation 5.2
Oxervate (FAS)	Change From Baseline in Schirmer I Test (Without Anaesthesia) [Time Frame: Week 4, 8, 12 and 16].	week 16	3.6 millimeters	Standard Deviation 5.1
Vehicle (FAS)	Change From Baseline in Schirmer I Test (Without Anaesthesia) [Time Frame: Week 4, 8, 12 and 16].	week 16	1.7 millimeters	Standard Deviation 4.8
Vehicle (FAS)	Change From Baseline in Schirmer I Test (Without Anaesthesia) [Time Frame: Week 4, 8, 12 and 16].	week 4	0.8 millimeters	Standard Deviation 2.7
Vehicle (FAS)	Change From Baseline in Schirmer I Test (Without Anaesthesia) [Time Frame: Week 4, 8, 12 and 16].	week 12	1.4 millimeters	Standard Deviation 4.1
Vehicle (FAS)	Change From Baseline in Schirmer I Test (Without Anaesthesia) [Time Frame: Week 4, 8, 12 and 16].	week 8	1.4 millimeters	Standard Deviation 2.9

Comparison: Herein Week 4 was considered. Change from baseline between the two treatment groups was compared using a two-sample t-test or a Mann-Whitney-Wilcoxon (Wilson rank sum) test if normality assumption not met.p-value: <0.001Wilcoxon (Mann-Whitney)

Comparison: Herein Week 8 was considered. Change from baseline between the two treatment groups was compared using a two-sample t-test or a Mann-Whitney-Wilcoxon (Wilson rank sum) test if normality assumption not met.p-value: 0.009Wilcoxon (Mann-Whitney)

Comparison: Herein Week 12 was considered. Change from baseline between the two treatment groups was compared using a two-sample t-test or a Mann-Whitney-Wilcoxon (Wilson rank sum) test if normality assumption not met.p-value: 0.02Wilcoxon (Mann-Whitney)

Secondary

Change From Baseline in Symptom Bother Module Measured by Impact of Dry Eye on Everyday Life [IDEEL] Questionnaire at Week 8 and Week 16

IDEEL is a 57-item questionnaire that assesses the impact of dry eye symptoms on everyday life. It is composed of 3 modules (Quality of Life, Treatment Satisfaction & Bother, Symptom Bother). This outcome is about the third module: Symptom Bother (20 items). This is composed by 1 dimension: Dry Eye Symptom-Bother (range 0-100) The Symptom Bother score is calculated if at least 50% (10 items) of the 20 items within the dimension are completed, and non-missing; otherwise the score is set to missing. The Symptom Bother score is calculated as the mean of the non-missing item scores 1-20 multiplied by 25. The higher the score the greater the symptom bother.

Time frame: at Week 8 and Week 16

Population: The Full Analysis Set (FAS) population consisted of all patients who were randomized and received at least one dose of the investigational product. The number of participants effectively analyzed was 51 in Cenegermin group and 50 in the Vehicle group at Week 4, 49 in both treatment groups at Week 8 and Week 12, 50 in Cenegermin group and 49 in Vehicle group at Week 16.

Arm	Measure	Group	Value (MEAN)	Dispersion
Oxervate (FAS)	Change From Baseline in Symptom Bother Module Measured by Impact of Dry Eye on Everyday Life [IDEEL] Questionnaire at Week 8 and Week 16	week 8	-19.5 score on a scale	Standard Deviation 20.3
Oxervate (FAS)	Change From Baseline in Symptom Bother Module Measured by Impact of Dry Eye on Everyday Life [IDEEL] Questionnaire at Week 8 and Week 16	week 16	-18.6 score on a scale	Standard Deviation 19.4
Vehicle (FAS)	Change From Baseline in Symptom Bother Module Measured by Impact of Dry Eye on Everyday Life [IDEEL] Questionnaire at Week 8 and Week 16	week 8	-6.9 score on a scale	Standard Deviation 19.2
Vehicle (FAS)	Change From Baseline in Symptom Bother Module Measured by Impact of Dry Eye on Everyday Life [IDEEL] Questionnaire at Week 8 and Week 16	week 16	-11.1 score on a scale	Standard Deviation 22.3

Comparison: Symptom bother module - Week 8p-value: 0.002t-test, 2 sided

Comparison: Symptom bother module - Week 16p-value: 0.076t-test, 2 sided

Secondary

Change From Baseline in Symptoms Assessment in Dry Eye (SANDE) Score for Severity at Week 8, Week 12 and Week 16

The SANDE questionnaire is comprised of two questions: 1) How often do your eyes feel dry and/or irritated? And 2) How severe you feel your symptoms of dryness and/or irritation are? This questionnaire uses a 100 mm horizontal line for each question to assess ocular discomfort and/or dryness experienced by the patients. In the SANDE questionnaire, frequency of symptoms ranges from rarely (0) to all of the time (100) and the severity of symptoms ranges from very mild (0) to very severe (100). At each visit, patients were asked to place a mark on the two given lines based on the extent of their symptoms. The locations of the marks made by the patients on the 100 mm horizontal lines were measured in mm from left to right and recorded. 0 was the best condition and 100 marked the worst condition. Global score from the SANDE questionnaire was calculated by multiplying the frequency score by the severity score and obtaining the square root.

Time frame: at Week 8, week 12 and week 16

Population: The Full Analysis Set (FAS) population consisted of all patients who were randomized and received at least one dose of the investigational product. The number of participants effectively analyzed was 49 in Cenegermin group and 49 in the Vehicle group at Week 8 and Week 12, and 50 in Cenegermin group and 49 in Vehicle group at Week 16

Arm	Measure	Group	Value (LEAST_SQUARES_MEAN)	Dispersion
Oxervate (FAS)	Change From Baseline in Symptoms Assessment in Dry Eye (SANDE) Score for Severity at Week 8, Week 12 and Week 16	week 8	-23.7 score on a scale	Standard Deviation 20.8
Oxervate (FAS)	Change From Baseline in Symptoms Assessment in Dry Eye (SANDE) Score for Severity at Week 8, Week 12 and Week 16	week 12	-21.2 score on a scale	Standard Deviation 23.5
Oxervate (FAS)	Change From Baseline in Symptoms Assessment in Dry Eye (SANDE) Score for Severity at Week 8, Week 12 and Week 16	week 16	-16.6 score on a scale	Standard Deviation 23.6
Vehicle (FAS)	Change From Baseline in Symptoms Assessment in Dry Eye (SANDE) Score for Severity at Week 8, Week 12 and Week 16	week 8	-14.4 score on a scale	Standard Deviation 21.6
Vehicle (FAS)	Change From Baseline in Symptoms Assessment in Dry Eye (SANDE) Score for Severity at Week 8, Week 12 and Week 16	week 12	-15.7 score on a scale	Standard Deviation 26.5
Vehicle (FAS)	Change From Baseline in Symptoms Assessment in Dry Eye (SANDE) Score for Severity at Week 8, Week 12 and Week 16	week 16	-16.1 score on a scale	Standard Deviation 25.9

Secondary

Change From Baseline in Symptoms Questionnaire (SANDE) Global Score at Week 8, Week 12, Week 16

The SANDE questionnaire is comprised of two questions: 1) How often do your eyes feel dry and/or irritated? And 2) How severe you feel your symptoms of dryness and/or irritation are? This questionnaire uses a 100 mm horizontal line for each question to assess ocular discomfort and/or dryness experienced by the patients. In the SANDE questionnaire, frequency of symptoms ranges from rarely (0) to all of the time (100) and the severity of symptoms ranges from very mild (0) to very severe (100). At each visit, patients were asked to place a mark on the two given lines based on the extent of their symptoms. The locations of the marks made by the patients on the 100 mm horizontal lines were measured in mm from left to right and recorded. 0 was the best condition and 100 marked the worst condition. Global score from the SANDE questionnaire was calculated by multiplying the frequency score by the severity score and obtaining the square root.

Time frame: at Week 8, Week 12, Week 16

Population: The Full Analysis Set (FAS) population consisted of all patients who were randomized and received at least one dose of the investigational product. The number of participants effectively analyzed was 49 in Cenegermin group and 49 in the Vehicle group at Week 8 and Week 12, and 50 in Cenegermin group and 49 in Vehicle group at Week 16.

Arm	Measure	Group	Value (LEAST_SQUARES_MEAN)	Dispersion
Oxervate (FAS)	Change From Baseline in Symptoms Questionnaire (SANDE) Global Score at Week 8, Week 12, Week 16	week 8	-26.0 score on a scale	Standard Deviation 20.1
Oxervate (FAS)	Change From Baseline in Symptoms Questionnaire (SANDE) Global Score at Week 8, Week 12, Week 16	week 12	-20.4 score on a scale	Standard Deviation 22
Oxervate (FAS)	Change From Baseline in Symptoms Questionnaire (SANDE) Global Score at Week 8, Week 12, Week 16	week 16	-15.2 score on a scale	Standard Deviation 20.5
Vehicle (FAS)	Change From Baseline in Symptoms Questionnaire (SANDE) Global Score at Week 8, Week 12, Week 16	week 8	-15.2 score on a scale	Standard Deviation 22.1
Vehicle (FAS)	Change From Baseline in Symptoms Questionnaire (SANDE) Global Score at Week 8, Week 12, Week 16	week 12	-15.7 score on a scale	Standard Deviation 26.7
Vehicle (FAS)	Change From Baseline in Symptoms Questionnaire (SANDE) Global Score at Week 8, Week 12, Week 16	week 16	-16.0 score on a scale	Standard Deviation 25.2

Secondary

Change From Baseline in Symptoms Questionnaire (SANDE) Score for Frequency at Week 8, Week 12, Week 16

The SANDE questionnaire is comprised of two questions: 1) How often do your eyes feel dry and/or irritated? And 2) How severe you feel your symptoms of dryness and/or irritation are? This questionnaire uses a 100 mm horizontal line for each question to assess ocular discomfort and/or dryness experienced by the patients. In the SANDE questionnaire, frequency of symptoms ranges from rarely (0) to all of the time (100) and the severity of symptoms ranges from very mild (0) to very severe (100). At each visit, patients were asked to place a mark on the two given lines based on the extent of their symptoms. The locations of the marks made by the patients on the 100 mm horizontal lines were measured in mm from left to right and recorded. 0 was the best condition and 100 marked the worst condition. Global score from the SANDE questionnaire was calculated by multiplying the frequency score by the severity score and obtaining the square root.

Time frame: at Week 8, Week 12, Week 16

Population: The Full Analysis Set (FAS) population consisted of all patients who were randomized and received at least one dose of the investigational product. The number of participants effectively analyzed was 49 in Cenegermin group and 49 in the Vehicle group at Week 8 and Week 12, and 50 in Cenegermin group and 49 in Vehicle group at Week 16

Arm	Measure	Group	Value (LEAST_SQUARES_MEAN)	Dispersion
Oxervate (FAS)	Change From Baseline in Symptoms Questionnaire (SANDE) Score for Frequency at Week 8, Week 12, Week 16	week 8	-27.1 score on a scale	Standard Deviation 22.5
Oxervate (FAS)	Change From Baseline in Symptoms Questionnaire (SANDE) Score for Frequency at Week 8, Week 12, Week 16	week 12	-17.9 score on a scale	Standard Deviation 23.4
Oxervate (FAS)	Change From Baseline in Symptoms Questionnaire (SANDE) Score for Frequency at Week 8, Week 12, Week 16	week 16	-12.5 score on a scale	Standard Deviation 21.2
Vehicle (FAS)	Change From Baseline in Symptoms Questionnaire (SANDE) Score for Frequency at Week 8, Week 12, Week 16	week 8	-15.9 score on a scale	Standard Deviation 24.4
Vehicle (FAS)	Change From Baseline in Symptoms Questionnaire (SANDE) Score for Frequency at Week 8, Week 12, Week 16	week 12	-15.7 score on a scale	Standard Deviation 28.2
Vehicle (FAS)	Change From Baseline in Symptoms Questionnaire (SANDE) Score for Frequency at Week 8, Week 12, Week 16	week 16	-16.1 score on a scale	Standard Deviation 25.6

Secondary

Change From Baseline in Tear Film Break-Up Time (TFBUT) at Week 16

TFBUT was measured by determining the time to tear break-up.The TFBUT test was performed after instillation of 5 μl of 2% preservative free sodium fluorescein solution into the lower conjunctival sac of each eye. This measurement was performed within 10 seconds maximum. The TFBUT was measured twice during the first minute of instillation of the fluorescein. If the 2 readings differed by more than 2 sec., a third reading was taken. The TFBUT value was the average of the 2 or 3 measurements. Generally, a TFBUT value of 10-35 sec was considered normal. A value of less than 10 seconds may indicate tear film instability.

Time frame: at week 16

Population: The Full Analysis Set (FAS) population consisted of all patients who were randomized and received at least one dose of the investigational product. he number of participants effectively analyzed at weeks 8 and 12 was 49 in Cenegermin group and 49 at the Vehicle group. At week 4 the participants analyzed were 51 in Cenegermin and 50 in Vehicle group. At week 16, the number of participants analyzed were 50 in Cenegermin group and 49 in the Vehicle group.

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Oxervate (FAS)	Change From Baseline in Tear Film Break-Up Time (TFBUT) at Week 16	1.3 seconds	Standard Deviation 3.1
Vehicle (FAS)	Change From Baseline in Tear Film Break-Up Time (TFBUT) at Week 16	0.4 seconds	Standard Deviation 2.8

Comparison: Herein week 16 was considered. Change from baseline between the two treatment groups was compared using a two-sample t-test or a Mann-Whitney-Wilcoxon (Wilson rank sum) test if normality assumption not met.p-value: 0.125Wilcoxon (Mann-Whitney)

Secondary

Change From Baseline in Treatment Satisfaction & Bother Module Measured by Impact of Dry Eye on Everyday Life [IDEEL] Questionnaire at Week 8 and Week 16

IDEEL is a 57-item questionnaire that assesses the impact of dry eye symptoms on everyday life. It is composed of 3 modules (Quality of Life, Treatment satisfaction & Bother, Symptom Bother). This outcome is about the second module: Treatment Satisfaction & Bother (8 items). This is composed by 2 dimensions: Dim. 1 - Satisfaction with Treatment Effectiveness, calculated by mean of the non-missing item scores 2-5 multiplied by 25. (range 0-100) Dim. 2 - Treatment-Related Bother / Inconvenience calculated as the mean of the non-missing item scores 6, 8-10 multiplied by 25. (range 0-100) Scores for each dimension of this module range from 0 to 100, where higher scores indicate a greater satisfaction in treatment effectiveness and less treatment-related bother. No combination of dimension scores is done.

Time frame: at Week 8 and Week 16

Population: The FAS consisted of all patients randomized and dosed with at least one dose of the IP. The # of pts effectively analyzed for Impact on Daily Activities and Emotional Impact due to Dry Eye was:~for Satisfaction with Treatment Effectiveness section:~Wk 4:~n=48 C n=44 V;~Wk 8:~n=47 C n=44 V Wk 12 n=48 C n=44 V~Wk 16:~n=48 C n=42 V.~For T-Related Bother / Inconvenience section:~Wk 4 n= 48 C n= 44 V~Wk 8:~n=46 both groups Wk 12 n=47 C n=46 V~Wk 16:~n= 48 C n=46 V

Arm	Measure	Group	Value (MEAN)	Dispersion
Oxervate (FAS)	Change From Baseline in Treatment Satisfaction & Bother Module Measured by Impact of Dry Eye on Everyday Life [IDEEL] Questionnaire at Week 8 and Week 16	Satisfaction with Treatment Effectiveness - week 8	17.7 score on a scale	Standard Deviation 31
Oxervate (FAS)	Change From Baseline in Treatment Satisfaction & Bother Module Measured by Impact of Dry Eye on Everyday Life [IDEEL] Questionnaire at Week 8 and Week 16	Treatment- Related Bother / Inconvenience - week 8	16.6 score on a scale	Standard Deviation 21.1
Oxervate (FAS)	Change From Baseline in Treatment Satisfaction & Bother Module Measured by Impact of Dry Eye on Everyday Life [IDEEL] Questionnaire at Week 8 and Week 16	Satisfaction with Treatment Effectiveness - week 16	13.4 score on a scale	Standard Deviation 28.7
Oxervate (FAS)	Change From Baseline in Treatment Satisfaction & Bother Module Measured by Impact of Dry Eye on Everyday Life [IDEEL] Questionnaire at Week 8 and Week 16	Treatment- Related Bother / Inconvenience - week 16	13.3 score on a scale	Standard Deviation 23.6
Vehicle (FAS)	Change From Baseline in Treatment Satisfaction & Bother Module Measured by Impact of Dry Eye on Everyday Life [IDEEL] Questionnaire at Week 8 and Week 16	Treatment- Related Bother / Inconvenience - week 16	5.3 score on a scale	Standard Deviation 27.3
Vehicle (FAS)	Change From Baseline in Treatment Satisfaction & Bother Module Measured by Impact of Dry Eye on Everyday Life [IDEEL] Questionnaire at Week 8 and Week 16	Satisfaction with Treatment Effectiveness - week 8	7.7 score on a scale	Standard Deviation 36.4
Vehicle (FAS)	Change From Baseline in Treatment Satisfaction & Bother Module Measured by Impact of Dry Eye on Everyday Life [IDEEL] Questionnaire at Week 8 and Week 16	Satisfaction with Treatment Effectiveness - week 16	1.2 score on a scale	Standard Deviation 35.9
Vehicle (FAS)	Change From Baseline in Treatment Satisfaction & Bother Module Measured by Impact of Dry Eye on Everyday Life [IDEEL] Questionnaire at Week 8 and Week 16	Treatment- Related Bother / Inconvenience - week 8	2.7 score on a scale	Standard Deviation 28.1

Comparison: IDEEL - Satisfaction with Treatment Effectiveness - Week 8p-value: 0.16t-test, 2 sided

Comparison: IDEEL - Treatment- Related Bother / Inconvenience - Week 8p-value: 0.009t-test, 2 sided

Comparison: IDEEL - Satisfaction with Treatment Effectiveness - Week 16p-value: 0.076t-test, 2 sided

Comparison: IDEEL - Treatment- Related Bother / Inconvenience - Week 16p-value: 0.128t-test, 2 sided

Secondary

Key Secondary Outcome: Change From Baseline in Cornea and Conjunctiva Vital Staining With Fluorescein (National Eye Institute [NEI] Scales) at Weeks 4, 8, 12

Time frame: At weeks 4, 8, 12

Arm	Measure	Group	Value (LEAST_SQUARES_MEAN)
Oxervate (FAS)	Key Secondary Outcome: Change From Baseline in Cornea and Conjunctiva Vital Staining With Fluorescein (National Eye Institute [NEI] Scales) at Weeks 4, 8, 12	Week 4	-4.107 score on a scale
Oxervate (FAS)	Key Secondary Outcome: Change From Baseline in Cornea and Conjunctiva Vital Staining With Fluorescein (National Eye Institute [NEI] Scales) at Weeks 4, 8, 12	Week 8	-4.442 score on a scale
Oxervate (FAS)	Key Secondary Outcome: Change From Baseline in Cornea and Conjunctiva Vital Staining With Fluorescein (National Eye Institute [NEI] Scales) at Weeks 4, 8, 12	Week 12	-3.714 score on a scale
Vehicle (FAS)	Key Secondary Outcome: Change From Baseline in Cornea and Conjunctiva Vital Staining With Fluorescein (National Eye Institute [NEI] Scales) at Weeks 4, 8, 12	Week 4	-2.588 score on a scale
Vehicle (FAS)	Key Secondary Outcome: Change From Baseline in Cornea and Conjunctiva Vital Staining With Fluorescein (National Eye Institute [NEI] Scales) at Weeks 4, 8, 12	Week 8	-2.668 score on a scale
Vehicle (FAS)	Key Secondary Outcome: Change From Baseline in Cornea and Conjunctiva Vital Staining With Fluorescein (National Eye Institute [NEI] Scales) at Weeks 4, 8, 12	Week 12	-2.490 score on a scale

Comparison: Herein Week 4 was considered. The change from baseline in Cornea and conjunctiva vital staining with fluorescein NEI scale was analyzed by means of an MMRM adjusting by pre-defined factors (gender, age class, NEI scale baseline value, treatment, visit, and treatment by visit interaction; subject was considered as a random effect).p-value: 0.04595% CI: [-3.005, -0.031]MMRM

Comparison: Herein Week 8 was considered. The change from baseline in Cornea and conjunctiva vital staining with fluorescein NEI scale was analyzed by means of an MMRM adjusting by pre-defined factors (gender, age class, NEI scale baseline value, treatment, visit, and treatment by visit interaction; subject was considered as a random effect).p-value: 0.03895% CI: [-3.446, -0.101]MMRM

Comparison: Herein Week 12 was considered. The change from baseline in Cornea and conjunctiva vital staining with fluorescein NEI scale was analyzed by means of an MMRM adjusting by pre-defined factors (gender, age class, NEI scale baseline value, treatment, visit, and treatment by visit interaction; subject was considered as a random effect).p-value: 0.295% CI: [-3.096, 0.649]MMRM

Secondary

Key Secondary Outcome: Change From Baseline in Quality of Life Module Measured by Impact of Dry Eye on Everyday Life [IDEEL] Questionnaire at Week 12 and at Week 4

Time frame: At Weeks 12 and 4

Population: The Full Analysis Set (FAS) population consisted of all patients randomized, who received at least one dose of IP. 3 patients in Cenegermin group and 2 patients in vehicle group had imputed values of missing data for Impact on Daily Activities and Emotional Impact due to dry eye. For Impact on work due to dry eye the number of participants considered in the model was 30 in Cenegermin group and 34 in the Vehicle group, of which 4 and 6 had imputed values.

Arm	Measure	Group	Value (LEAST_SQUARES_MEAN)
Oxervate (FAS)	Key Secondary Outcome: Change From Baseline in Quality of Life Module Measured by Impact of Dry Eye on Everyday Life [IDEEL] Questionnaire at Week 12 and at Week 4	Impact on daily activities - week 12	13.301 score on a scale
Oxervate (FAS)	Key Secondary Outcome: Change From Baseline in Quality of Life Module Measured by Impact of Dry Eye on Everyday Life [IDEEL] Questionnaire at Week 12 and at Week 4	Emotional impact due to dry eye - week 12	16.069 score on a scale
Oxervate (FAS)	Key Secondary Outcome: Change From Baseline in Quality of Life Module Measured by Impact of Dry Eye on Everyday Life [IDEEL] Questionnaire at Week 12 and at Week 4	Impact on work due to dry eye - week 12	18.619 score on a scale
Oxervate (FAS)	Key Secondary Outcome: Change From Baseline in Quality of Life Module Measured by Impact of Dry Eye on Everyday Life [IDEEL] Questionnaire at Week 12 and at Week 4	Impact on daily activities - week 4	11.524 score on a scale
Oxervate (FAS)	Key Secondary Outcome: Change From Baseline in Quality of Life Module Measured by Impact of Dry Eye on Everyday Life [IDEEL] Questionnaire at Week 12 and at Week 4	Emotional impact due to dry eye - week 4	14.385 score on a scale
Oxervate (FAS)	Key Secondary Outcome: Change From Baseline in Quality of Life Module Measured by Impact of Dry Eye on Everyday Life [IDEEL] Questionnaire at Week 12 and at Week 4	Impact on work due to dry eye - week 4	17.591 score on a scale
Vehicle (FAS)	Key Secondary Outcome: Change From Baseline in Quality of Life Module Measured by Impact of Dry Eye on Everyday Life [IDEEL] Questionnaire at Week 12 and at Week 4	Emotional impact due to dry eye - week 4	11.955 score on a scale
Vehicle (FAS)	Key Secondary Outcome: Change From Baseline in Quality of Life Module Measured by Impact of Dry Eye on Everyday Life [IDEEL] Questionnaire at Week 12 and at Week 4	Impact on daily activities - week 12	9.223 score on a scale
Vehicle (FAS)	Key Secondary Outcome: Change From Baseline in Quality of Life Module Measured by Impact of Dry Eye on Everyday Life [IDEEL] Questionnaire at Week 12 and at Week 4	Impact on daily activities - week 4	9.364 score on a scale
Vehicle (FAS)	Key Secondary Outcome: Change From Baseline in Quality of Life Module Measured by Impact of Dry Eye on Everyday Life [IDEEL] Questionnaire at Week 12 and at Week 4	Emotional impact due to dry eye - week 12	10.519 score on a scale
Vehicle (FAS)	Key Secondary Outcome: Change From Baseline in Quality of Life Module Measured by Impact of Dry Eye on Everyday Life [IDEEL] Questionnaire at Week 12 and at Week 4	Impact on work due to dry eye - week 4	14.291 score on a scale
Vehicle (FAS)	Key Secondary Outcome: Change From Baseline in Quality of Life Module Measured by Impact of Dry Eye on Everyday Life [IDEEL] Questionnaire at Week 12 and at Week 4	Impact on work due to dry eye - week 12	15.144 score on a scale

Comparison: Emotional Impact due to Dry eye at week 4.p-value: 0.49295% CI: [-4.5, 9.362]MMRM

Comparison: Impact on daily activities at week 4.p-value: 0.46895% CI: [-3.668, 7.988]MMRM

Comparison: Impact on Work due to Dry Eye at week 4.p-value: 0.5195% CI: [-6.511, 13.111]MMRM

Comparison: Quality of life - Impact on daily activities - Week 12p-value: 0.26895% CI: [-3.142, 11.299]MMRM

Comparison: Quality of life - Emotional Impact due to Dry eye - Week 12p-value: 0.22795% CI: [-3.462, 14.562]MMRM

Comparison: Quality of life - Impact on Work due to Dry Eye - Week 12p-value: 0.50195% CI: [-6.651, 13.601]MMRM

Secondary

Key Secondary Outcome: Change From Baseline in Symptom Bother Module Measured by Impact of Dry Eye on Everyday Life [IDEEL] Questionnaire at Weeks 12 and 4

Time frame: at Weeks 12 and 4

Arm	Measure	Group	Value (LEAST_SQUARES_MEAN)
Oxervate (FAS)	Key Secondary Outcome: Change From Baseline in Symptom Bother Module Measured by Impact of Dry Eye on Everyday Life [IDEEL] Questionnaire at Weeks 12 and 4	week 12	-16.323 score on a scale
Oxervate (FAS)	Key Secondary Outcome: Change From Baseline in Symptom Bother Module Measured by Impact of Dry Eye on Everyday Life [IDEEL] Questionnaire at Weeks 12 and 4	week 4	-10.241 score on a scale
Vehicle (FAS)	Key Secondary Outcome: Change From Baseline in Symptom Bother Module Measured by Impact of Dry Eye on Everyday Life [IDEEL] Questionnaire at Weeks 12 and 4	week 12	-7.533 score on a scale
Vehicle (FAS)	Key Secondary Outcome: Change From Baseline in Symptom Bother Module Measured by Impact of Dry Eye on Everyday Life [IDEEL] Questionnaire at Weeks 12 and 4	week 4	-9.435 score on a scale

Comparison: IDEEL - Symptom Bother module - week 4p-value: 0.80295% CI: [-7.086, 5.476]MMRM

Comparison: IDEEL - Symptom Bother module - week 12p-value: 0.01995% CI: [-16.16, -1.418]MMRM

Secondary

Key Secondary Outcome: Change From Baseline in Symptoms Assessment in Dry Eye (SANDE) Score for Frequency at Week 12

The SANDE questionnaire is comprised of two questions: 1) How often do your eyes feel dry and/or irritated? And 2) How severe you feel your symptoms of dryness and/or irritation are? This questionnaire uses a 100 mm horizontal line for each question to assess ocular discomfort and/or dryness experienced by the patients. In the SANDE questionnaire, frequency of symptoms ranges from rarely (0) to all of the time (100) and the severity of symptoms ranges from very mild (0) to very severe (100). At each visit, patients were asked to place a mark on the two given lines based on the extent of their symptoms. The locations of the marks made by the patients on the 100 mm horizontal lines were measured in mm from left to right and recorded. 0 was the best condition and 100 marked the worst condition. Global score from the SANDE questionnaire was calculated by multiplying the frequency score by the severity score and obtaining the square root. Means are adjusted means.

Time frame: At week 12

Population: The Full Analysis Set (FAS) population consisted of all patients who were randomized and received at least one dose of the investigational product. The number of participants effectively analyzed was 49 in Cenegermin group and 49 in the Vehicle group. In fact 3 patients in Cenegermin group and 2 patients in vehicle group had imputed values of missing data via a MI approach.

Arm	Measure	Value (MEAN)
Oxervate (FAS)	Key Secondary Outcome: Change From Baseline in Symptoms Assessment in Dry Eye (SANDE) Score for Frequency at Week 12	-24.546 score on a scale
Vehicle (FAS)	Key Secondary Outcome: Change From Baseline in Symptoms Assessment in Dry Eye (SANDE) Score for Frequency at Week 12	-21.793 score on a scale

Comparison: This endpoint was analyzed by means of an ANCOVA adjusting by pre-defined baseline factors (treatment, gender, age class, baseline SANDE score for severity as fixed effects and site as random effect).p-value: 0.57295% CI: [-12.303, 6.798]ANCOVA regression model

Secondary

Key Secondary Outcome: Change From Baseline in Symptoms Assessment in Dry Eye (SANDE) Score for Severity at Week 12

The SANDE questionnaire is comprised of two questions: 1) How often do your eyes feel dry and/or irritated? And 2) How severe you feel your symptoms of dryness and/or irritation are? This questionnaire uses a 100 mm horizontal line for each question to assess ocular discomfort and/or dryness experienced by the patients. In the SANDE questionnaire, frequency of symptoms ranges from rarely (0) to all of the time (100) and the severity of symptoms ranges from very mild (0) to very severe (100). At each visit, patients were asked to place a mark on the two given lines based on the extent of their symptoms. The locations of the marks made by the patients on the 100 mm horizontal lines were measured in mm from left to right and recorded. 0 was the best condition and 100 marked the worst condition. Global score from the SANDE questionnaire was calculated by multiplying the frequency score by the severity score and obtaining the square root. Means are adjusted means.

Time frame: at Week 12

Population: The Full Analysis Set (FAS) population consisted of all patients who were randomized and received at least one dose of the investigational product. The number of participants effectively analyzed was 49 in Cenegermin group and 49 in the Vehicle group at Week 8 and Week 12, and 50 in Cenegermin group and 49 in Vehicle group at Week 16.

Arm	Measure	Value (MEAN)
Oxervate (FAS)	Key Secondary Outcome: Change From Baseline in Symptoms Assessment in Dry Eye (SANDE) Score for Severity at Week 12	-31.445 score on a scale
Vehicle (FAS)	Key Secondary Outcome: Change From Baseline in Symptoms Assessment in Dry Eye (SANDE) Score for Severity at Week 12	-26.713 score on a scale

Secondary

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

Time frame: At weeks 4, 8, 12

Arm	Measure	Group	Value (LEAST_SQUARES_MEAN)
Oxervate (FAS)	Key Secondary Outcome: Change From Baseline in Tear Film Break-Up Time (TFBUT) at Week 4, Week 8, Week 12	Week 4	1.808 seconds
Oxervate (FAS)	Key Secondary Outcome: Change From Baseline in Tear Film Break-Up Time (TFBUT) at Week 4, Week 8, Week 12	Week 8	2.010 seconds
Oxervate (FAS)	Key Secondary Outcome: Change From Baseline in Tear Film Break-Up Time (TFBUT) at Week 4, Week 8, Week 12	Week 12	1.973 seconds
Vehicle (FAS)	Key Secondary Outcome: Change From Baseline in Tear Film Break-Up Time (TFBUT) at Week 4, Week 8, Week 12	Week 4	0.167 seconds
Vehicle (FAS)	Key Secondary Outcome: Change From Baseline in Tear Film Break-Up Time (TFBUT) at Week 4, Week 8, Week 12	Week 8	0.876 seconds
Vehicle (FAS)	Key Secondary Outcome: Change From Baseline in Tear Film Break-Up Time (TFBUT) at Week 4, Week 8, Week 12	Week 12	0.613 seconds

Comparison: Herein week 4 was considered. The change from baseline in TFBUT values was analyzed by means of a MMRM adjusting by pre-defined factors (gender, age class, TFBUT baseline value, treatment, visit, and treatment by visit interaction; subject was considered as a random effect).p-value: 0.01695% CI: [0.3, 2.98]MMRM

Comparison: Herein week 8 was considered. The change from baseline in TFBUT values was analyzed by means of a MMRM adjusting by pre-defined factors (gender, age class, TFBUT baseline value, treatment, visit, and treatment by visit interaction; subject was considered as a random effect).p-value: 0.12995% CI: [-0.329, 2.596]MMRM

Comparison: Herein week 12 was considered. The change from baseline in TFBUT values was analyzed by means of a MMRM adjusting by pre-defined factors (gender, age class, TFBUT baseline value, treatment, visit, and treatment by visit interaction; subject was considered as a random effect).p-value: 0.0595% CI: [-0.002, 2.722]MMRM

Secondary

Key Secondary Outcome: Change From Baseline in Treatment Satisfaction & Bother Module Measured by Impact of Dry Eye on Everyday Life [IDEEL] Questionnaire at Weeks 12 and 4

Time frame: at Weeks 12 and 4

Population: The Full Analysis Set (FAS) population consisted of all patients who were randomized and received at least one dose of the investigational product. 3 patients in Cenegermin group and 4 patients in vehicle group had imputed values of missing data for Satisfaction with Treatment Effectiveness. For Treatment- Related Bother / Inconvenience, 4 patients in Cenegermin group and 3 patients in vehicle group had imputed values of missing data.

Arm	Measure	Group	Value (LEAST_SQUARES_MEAN)
Oxervate (FAS)	Key Secondary Outcome: Change From Baseline in Treatment Satisfaction & Bother Module Measured by Impact of Dry Eye on Everyday Life [IDEEL] Questionnaire at Weeks 12 and 4	Satisfaction with Treatment Effectiveness - week 12	12.733 score on a scale
Oxervate (FAS)	Key Secondary Outcome: Change From Baseline in Treatment Satisfaction & Bother Module Measured by Impact of Dry Eye on Everyday Life [IDEEL] Questionnaire at Weeks 12 and 4	Treatment- Related Bother / Inconvenience - week 12	6.482 score on a scale
Oxervate (FAS)	Key Secondary Outcome: Change From Baseline in Treatment Satisfaction & Bother Module Measured by Impact of Dry Eye on Everyday Life [IDEEL] Questionnaire at Weeks 12 and 4	Satisfaction with Treatment Effectiveness - week 4	13.879 score on a scale
Oxervate (FAS)	Key Secondary Outcome: Change From Baseline in Treatment Satisfaction & Bother Module Measured by Impact of Dry Eye on Everyday Life [IDEEL] Questionnaire at Weeks 12 and 4	Treatment- Related Bother / Inconvenience - week 4	9.505 score on a scale
Vehicle (FAS)	Key Secondary Outcome: Change From Baseline in Treatment Satisfaction & Bother Module Measured by Impact of Dry Eye on Everyday Life [IDEEL] Questionnaire at Weeks 12 and 4	Treatment- Related Bother / Inconvenience - week 4	8.432 score on a scale
Vehicle (FAS)	Key Secondary Outcome: Change From Baseline in Treatment Satisfaction & Bother Module Measured by Impact of Dry Eye on Everyday Life [IDEEL] Questionnaire at Weeks 12 and 4	Satisfaction with Treatment Effectiveness - week 12	16.938 score on a scale
Vehicle (FAS)	Key Secondary Outcome: Change From Baseline in Treatment Satisfaction & Bother Module Measured by Impact of Dry Eye on Everyday Life [IDEEL] Questionnaire at Weeks 12 and 4	Satisfaction with Treatment Effectiveness - week 4	14.428 score on a scale
Vehicle (FAS)	Key Secondary Outcome: Change From Baseline in Treatment Satisfaction & Bother Module Measured by Impact of Dry Eye on Everyday Life [IDEEL] Questionnaire at Weeks 12 and 4	Treatment- Related Bother / Inconvenience - week 12	4.239 score on a scale

Comparison: IDEEL Treatment satisfaction \& Bother Module Satisfaction with Treatment Effectiveness - week 4p-value: 0.92495% CI: [-11.82, 10.723]MMRM

Comparison: IDEEL Treatment satisfaction \& Bother Module - Treatment- Related Bother / Inconvenience - week 4p-value: 0.74595% CI: [-5.398, 7.542]MMRM

Comparison: IDEEL Treatment satisfaction \& Bother Module - Satisfaction with Treatment Effectiveness - week 12p-value: 0.46795% CI: [-15.53, 7.118]MMRM

Comparison: IDEEL Treatment satisfaction \& Bother Module - Treatment- Related Bother / Inconvenience - week 12p-value: 0.56495% CI: [-5.387, 9.874]MMRM

Secondary

Key Secondary Outcome: Number of Patients Reaching a Value of Schirmer I Test (Without Anaesthesia) > 10mm/5min at Week 8

The Schirmer test type I (without anaesthesia) was performed to measure aqueous tear secretion. The rounded bend end of a sterile strip was inserted into the lower conjunctival sac over the temporal one-third of the lower eyelid margin. After 5 minutes had elapsed, the Schirmer's test strip was removed and the length of the tear absorption on the strip was measured (millimeters/5 minutes). The longer and the wetted length, the healthier the status of the eye.

Time frame: at Week 8

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Oxervate (FAS)	Key Secondary Outcome: Number of Patients Reaching a Value of Schirmer I Test (Without Anaesthesia) > 10mm/5min at Week 8	18 Participants
Vehicle (FAS)	Key Secondary Outcome: Number of Patients Reaching a Value of Schirmer I Test (Without Anaesthesia) > 10mm/5min at Week 8	2 Participants

Comparison: This key secondary endpoint was analyzed by means of a logistic regression model with the number 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 fixed effects and site as random effect.p-value: <0.00195% CI: [3.091, 82.31]Regression, Logistic

Secondary

Number of Patients Who Experienced a Worsening in Symptoms Scores (SANDE) and/or NEI Score > = 50% at Week 4

Symptoms Scores (SANDE) and/or NEI Score were punctually described in the previous outcome descriptions. For Sande score, the scale ranges from 0 to 100 for both severity and frequency, where 0 was the best condition and 100 marked the worst condition. Hence the higher the score, the worse the outcome. For NEI score, the maximum score (worst outcome) was 15, and the minimum (best outcome) was 0; hence the higher the score, the worse the outcome.

Time frame: at week 4

Population: The Full Analysis Set (FAS) population consisted of all patients who were randomized and received at least one dose of the investigational product.

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Oxervate (FAS)	Number of Patients Who Experienced a Worsening in Symptoms Scores (SANDE) and/or NEI Score > = 50% at Week 4	4 Participants
Vehicle (FAS)	Number of Patients Who Experienced a Worsening in Symptoms Scores (SANDE) and/or NEI Score > = 50% at Week 4	11 Participants

p-value: 0.0455Chi-squared

Other Pre-specified

Incidence and Frequency of TEAEs, Assessed Throughout the Study.

TEAE=any AE started on or after the date of the first dose of study medication or started prior to first dose and worsened in severity after the first dose.

Time frame: From Screening to Visit 7 (follow-up, week 24)

Population: The SAF population consisted of all randomized patients who received at least one dose of the investigational product. SAF set was analysed according to the actual treatment received. The SAF population was used to present results on safety data.

Arm	Measure	Group	Value (COUNT_OF_PARTICIPANTS)
Oxervate (FAS)	Incidence and Frequency of TEAEs, Assessed Throughout the Study.	non-serious TEAE	37 Participants
Oxervate (FAS)	Incidence and Frequency of TEAEs, Assessed Throughout the Study.	Adverse Drug Reaction (ADR) - Ophtalmic	34 Participants
Oxervate (FAS)	Incidence and Frequency of TEAEs, Assessed Throughout the Study.	Severe TEAE - Non Opthalmic	2 Participants
Oxervate (FAS)	Incidence and Frequency of TEAEs, Assessed Throughout the Study.	Adverse Drug Reaction - Non Ophtalmic	4 Participants
Oxervate (FAS)	Incidence and Frequency of TEAEs, Assessed Throughout the Study.	TEAE - Ophtalmic	35 Participants
Oxervate (FAS)	Incidence and Frequency of TEAEs, Assessed Throughout the Study.	Serious ADR	1 Participants
Oxervate (FAS)	Incidence and Frequency of TEAEs, Assessed Throughout the Study.	Serious TEAE - Ophtalmic	1 Participants
Oxervate (FAS)	Incidence and Frequency of TEAEs, Assessed Throughout the Study.	TEAE leading to IMP discontinuation	2 Participants
Oxervate (FAS)	Incidence and Frequency of TEAEs, Assessed Throughout the Study.	Severe TEAE - Ophtamic	5 Participants
Oxervate (FAS)	Incidence and Frequency of TEAEs, Assessed Throughout the Study.	TEAE leading to study discontinuation	0 Participants
Oxervate (FAS)	Incidence and Frequency of TEAEs, Assessed Throughout the Study.	Serious TEAE - Non Ophtalmic	2 Participants
Oxervate (FAS)	Incidence and Frequency of TEAEs, Assessed Throughout the Study.	TEAE leading to death	0 Participants
Oxervate (FAS)	Incidence and Frequency of TEAEs, Assessed Throughout the Study.	TEAE - Non Ophtalmic	16 Participants
Vehicle (FAS)	Incidence and Frequency of TEAEs, Assessed Throughout the Study.	TEAE leading to death	0 Participants
Vehicle (FAS)	Incidence and Frequency of TEAEs, Assessed Throughout the Study.	TEAE - Ophtalmic	13 Participants
Vehicle (FAS)	Incidence and Frequency of TEAEs, Assessed Throughout the Study.	TEAE - Non Ophtalmic	9 Participants
Vehicle (FAS)	Incidence and Frequency of TEAEs, Assessed Throughout the Study.	Severe TEAE - Ophtamic	1 Participants
Vehicle (FAS)	Incidence and Frequency of TEAEs, Assessed Throughout the Study.	Severe TEAE - Non Opthalmic	1 Participants
Vehicle (FAS)	Incidence and Frequency of TEAEs, Assessed Throughout the Study.	Serious TEAE - Ophtalmic	0 Participants
Vehicle (FAS)	Incidence and Frequency of TEAEs, Assessed Throughout the Study.	Serious TEAE - Non Ophtalmic	1 Participants
Vehicle (FAS)	Incidence and Frequency of TEAEs, Assessed Throughout the Study.	Adverse Drug Reaction (ADR) - Ophtalmic	8 Participants
Vehicle (FAS)	Incidence and Frequency of TEAEs, Assessed Throughout the Study.	Adverse Drug Reaction - Non Ophtalmic	2 Participants
Vehicle (FAS)	Incidence and Frequency of TEAEs, Assessed Throughout the Study.	Serious ADR	0 Participants
Vehicle (FAS)	Incidence and Frequency of TEAEs, Assessed Throughout the Study.	TEAE leading to IMP discontinuation	1 Participants
Vehicle (FAS)	Incidence and Frequency of TEAEs, Assessed Throughout the Study.	TEAE leading to study discontinuation	1 Participants
Vehicle (FAS)	Incidence and Frequency of TEAEs, Assessed Throughout the Study.	non-serious TEAE	15 Participants

Source: ClinicalTrials.gov · Data processed: Feb 6, 2026

Safety and Efficacy Study on Cenegermin (Oxervate®) vs Vehicle in Severe Sjogren's Dry Eye Disease (PROTEGO-1 Study)

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Outcome results

Change From Baseline in Symptoms Questionnaire (SANDE) Global Score at Week 12

Number of Patients Reaching a Value of Schirmer I Test (Without Anaesthesia) >10mm/5min at Week 4

Change From Baseline in Cornea and Conjunctiva Vital Staining With Fluorescein (National Eye Institute [NEI] Scales) at Week 16

Change From Baseline in Quality of Life Module Measured by Impact of Dry Eye on Everyday Life [IDEEL] Questionnaire at Weeks 8 and 16

Change From Baseline in Schirmer I Test (Without Anaesthesia) [Time Frame: Week 4, 8, 12 and 16].

Change From Baseline in Symptom Bother Module Measured by Impact of Dry Eye on Everyday Life [IDEEL] Questionnaire at Week 8 and Week 16

Change From Baseline in Symptoms Assessment in Dry Eye (SANDE) Score for Severity at Week 8, Week 12 and Week 16

Change From Baseline in Symptoms Questionnaire (SANDE) Global Score at Week 8, Week 12, Week 16

Change From Baseline in Symptoms Questionnaire (SANDE) Score for Frequency at Week 8, Week 12, Week 16

Change From Baseline in Tear Film Break-Up Time (TFBUT) at Week 16

Change From Baseline in Treatment Satisfaction & Bother Module Measured by Impact of Dry Eye on Everyday Life [IDEEL] Questionnaire at Week 8 and Week 16

Key Secondary Outcome: Change From Baseline in Cornea and Conjunctiva Vital Staining With Fluorescein (National Eye Institute [NEI] Scales) at Weeks 4, 8, 12

Key Secondary Outcome: Change From Baseline in Quality of Life Module Measured by Impact of Dry Eye on Everyday Life [IDEEL] Questionnaire at Week 12 and at Week 4

Key Secondary Outcome: Change From Baseline in Symptom Bother Module Measured by Impact of Dry Eye on Everyday Life [IDEEL] Questionnaire at Weeks 12 and 4

Key Secondary Outcome: Change From Baseline in Symptoms Assessment in Dry Eye (SANDE) Score for Frequency at Week 12

Key Secondary Outcome: Change From Baseline in Symptoms Assessment in Dry Eye (SANDE) Score for Severity at Week 12

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

Key Secondary Outcome: Change From Baseline in Treatment Satisfaction & Bother Module Measured by Impact of Dry Eye on Everyday Life [IDEEL] Questionnaire at Weeks 12 and 4

Key Secondary Outcome: Number of Patients Reaching a Value of Schirmer I Test (Without Anaesthesia) > 10mm/5min at Week 8

Number of Patients Who Experienced a Worsening in Symptoms Scores (SANDE) and/or NEI Score > = 50% at Week 4

Incidence and Frequency of TEAEs, Assessed Throughout the Study.