An 8-week Study to Evaluate Safety and Efficacy of NGF Eye Drops Solution Versus Vehicle in Patients With Dry Eye

• Sponsor: Dompé Farmaceutici S.p.A (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03019627
• Collaborator: (none)
• Enrollment: 150
• Location: 1
• Arms: 2
• Actual Duration (Months): 7.3
• Patients Per Site Per Month: 20.5

Study Details

Study Description

Brief Summary

The primary objective of this study was to assess the efficacy and safety of rhNGF when administered as eye drops to patients with dry eye

The secondary objectives of this study were:

• To assess change from baseline in Symptom Assessment In Dry Eye (SANDE) scores (without imputation), corneal and conjunctival staining according to National Eye Institute (NEI) scale, and in Tear Film Break-up Time (TFBUT) and Schirmer test I, following 4 and 8 weeks of treatment.

• To assess change in levels of inflammatory biomarker matrix metallopeptidase 9 (MMP-9) in tears following 8 weeks of treatment.

• To assess the incidence and frequency of treatment-emergent adverse events (TEAEs) following 8 weeks of treatment.

Condition or Disease	Intervention/Treatment	Phase
Dry Eye	Drug: NGF; Other: Vehicle	Phase 2

Detailed Description

The proposed phase II study is a single-center, randomized, double-masked, parallel-arm, vehicle-controlled trial, designed to evaluate the safety and efficacy of Recombinant Human Nerve Growth Factor (rhNGF) eye drops at 20 μg/ml concentration administered six times daily for 8 weeks in patients with dry eye. After confirmation of inclusion and exclusion criteria all eligible patients will be randomized at 2:1 ratio to rhNGF or vehicle control treatment with 8 weeks of study treatments administration with 4 weeks Follow-up.

Study Design

• Study Type: Interventional
• Actual Enrollment: 150 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Masking Description: The identity of the treatments was concealed from the patient, Investigator, site staff, and Dompé's clinical research personnel until the study was unmasked for the final statistical analysis (after data base lock) except in case of specific events that required unmasking of the patient.
• Primary Purpose: Treatment
• Official Title: An 8-week, Phase II, Single-center, Randomized, Double-masked, Vehicle-controlled, Parallel-group Study With 4 Weeks of Follow-up to Evaluate Safety and Efficacy of rhNGF Eye Drops Solution vs Vehicle in Patients With Dry Eye
• Actual Study Start Date: Jan 20, 2017
• Actual Primary Completion Date: Aug 31, 2017
• Actual Study Completion Date: Aug 31, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: rhNGF 20μg/mL Recombinant Human Nerve Growth Factor (rhNGF) at 20 μg/mL eye drops six times daily	Drug: NGF; Eye Drop 20 μg/mL; Other Names: cenegermin
Placebo Comparator: Vehicle vehicle eye drops six times daily	Other: Vehicle; Vehicle Eye Drop; Other Names: Placebo

Outcome Measures

Primary Outcome Measures

1. Symptom Assessment in Dry Eye (SANDE) Scores [week 8]

   Change from baseline with Last Observation Carried Forward (LOCF) imputation. LOCF is a method of imputing missing data in longitudinal studies and tests for difference in mean rates of change in controlled repeated measurements designs with dropouts. The SANDE score is calculated by taking the square root of the product of the frequency of symptoms score and the severity of symptoms score. The SANDE scale ranges from 0 to 100 with 100 being the maximal amount of dry eye symptoms and 0 being the minimal amount of dry eye symptoms.

Secondary Outcome Measures

1. SANDE Scores [Week 4, week 8, week 12]

   Change from baseline with Last Observation Carried Forward (LOCF) imputation. LOCF is a method of imputing missing data in longitudinal studies and tests for difference in mean rates of change in controlled repeated measurements designs with dropouts. The SANDE score is calculated by taking the square root of the product of the frequency of symptoms score and the severity of symptoms score. The SANDE scale ranges from 0 to 100 with 100 being the maximal amount of dry eye symptoms and 0 being the minimal amount of dry eye symptoms.

2. Cornea Vital Staining [week 4, week 8, week 12]

   Changes from baseline on National Eye Institute (NEI) scale. The NEI/Industry Workshop guidelines were used for grading the scale of corneal and conjunctival damage. The cornea was divided into five sectors (central, superior, inferior, nasal and temporal), each of which was scored on a scale of 0-3, with a maximal total corneal staining score of 15. Both nasally and temporally, the conjunctiva was divided into a superior paralimbal area, an inferior paralimbal area, and a peripheral area with a grading scale of 0-3 and with a maximal total score of 9 for the nasal and temporal conjunctiva (overall the total score ranged from 0-18). Briefly, grade 0 reflected normal/healthy situation, whereas grade 3 reflected a severe damage in the considered sector.

3. Conjunctival Vital Staining [week 4, week 8, week 12]

   Changes from baseline on National Eye Institute (NEI) scale. The NEI/Industry Workshop guidelines were used for grading the scale of corneal and conjunctival damage. The cornea was divided into five sectors (central, superior, inferior, nasal and temporal), each of which was scored on a scale of 0-3, with a maximal total corneal staining score of 15. Both nasally and temporally, the conjunctiva was divided into a superior paralimbal area, an inferior paralimbal area, and a peripheral area with a grading scale of 0-3 and with a maximal total score of 9 for the nasal and temporal conjunctiva (overall the total score ranged from 0-18). Briefly, grade 0 reflected normal/healthy situation, whereas grade 3 reflected a severe damage in the considered sector.

4. Change in Tear Film Break-up Time (TFBUT) [week 4, week 8, week 12]

   TFBUT was measured by determining the time to tear break-up. The TFBUT was performed after instillation of 5 μL of 2% preservative-free sodium fluorescein solution into the inferior conjunctival cul-de-sac of each eye. The patient was instructed to blink several times to thoroughly mix the fluorescein with the tear film.

5. Change From Baseline in Wetting Distance [week 8]

   The Schirmer test without anesthesia was performed to measure aqueous tear secretion prior to the instillation of any dilating or eye drops

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Patients (male or female) must be ≥ 18 years of age.

2. Patients must be diagnosed with any type of dry eye (e.g. Meibomian Gland Dysfunction, Blepharitis, Keratoconjunctivitis sicca etc) at least 3 months before enrollment.

3. Patients must present dry eye pathology characterized by the following clinical features:

4. Corneal and/or conjunctival staining with fluorescein and lissamine green using National Eye Institute (NEI) grading system > 3

5. Mean Symptom Assessment in Dry Eye (SANDE) questionnaire ≥30

6. Schirmer test without anesthesia < 10 mm/5 minutes and/or tear film break-up time (TFBUT) < 10 seconds in the study eye

7. The same eye (study eye) must fulfill all the above criteria.

8. Patients must have best corrected distance visual acuity (BCDVA) score of ≥ 0.1 decimal units in both eyes at the time of study enrollment.

9. Female patients must have negative pregnancy test if at childbirth potential.

10. Only patients who satisfy all requirements for informed consent may be included in the study. Written Informed Consent must be obtained before the initiation of any study specific procedures.

11. Patients must have the ability and willingness to comply with study procedures.

Exclusion Criteria:

1. Best corrected distance visual acuity (BCDVA) score of < 0.1 decimal units in either eye.

2. Evidence of an active ocular infection in either eye.

3. Presence or history of any ocular disorder or condition, including ocular surgery, trauma, or disease that could possibly interfere with the interpretation of study results in the opinion of the Investigator.

4. Intraocular inflammation defined as Tyndall score >0.

5. Active or recent diagnosis of malignancy (i.e., currently under chemo/radiotherapy).

6. Systemic disease not stabilized within 1 month before baseline visit (e.g., uncontrolled diabetes; 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.

7. Patients who have 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 containing carboxymethylcellulose (CMC) (in the opinion of the Investigator).

8. Use of topical cyclosporine, topical corticosteroids, or any other topical medication for the treatment of dry eye in either eye until the day of study enrollment.

9. Contact lenses or punctal plug use during the study (previous use not an exclusion criteria, but must be discontinued at the baseline visit.

10. An anticipated need of additional systemic treatments for dry eye during the study (all prior treatment must be continued for the entire duration of the study).

11. Females of childbearing potential (those who are not surgically sterilized or postmenopausal for at least 1 year) are excluded from participation in the study if they meet any one of the following conditions:

12. are currently pregnant or,

13. have a positive result at the urine pregnancy test (Baseline/Day 0) or,

14. intend to become pregnant during the study treatment period or,

15. are breast-feeding or,

16. are not willing to use highly effective birth control measures, such as: hormonal contraceptives - oral, implanted, transdermal, or injected - and/or mechanical barrier methods - spermicide in conjunction with a barrier such as a condom or diaphragm or a intrauterine device (IUD) - during the entire course of and 30 days after the study treatment periods.

17. History of drug addiction or alcohol abuse.

18. Any prior ocular surgery (including refractive palpebral and cataract surgery) if within 90 days before the screening visit.

19. Participation in a clinical trial with a new active substance during the past 30 days.

20. Participation in another clinical trial study at the same time as the present study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Penn Dry Eye and Ocular Surface Center, University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104

Sponsors and Collaborators

• Dompé Farmaceutici S.p.A

Investigators

• Principal Investigator: Giacomina Massaro Giordano, MD, Penn Dry Eye and Oc. Surf. Center, Univ. of Pennsylvania, Scheie Eye Institute

Study Documents (Full-Text)

• Study Protocol - Oct 27, 2016
• Statistical Analysis Plan - Oct 5, 2017

More Information

Publications

None provided.

• Responsible Party: Dompé Farmaceutici S.p.A
• ClinicalTrials.gov Identifier: NCT03019627
• Other Study ID Numbers: NGF0216
• First Posted: Jan 12, 2017
• Last Update Posted: Feb 8, 2019
• Last Verified: Oct 1, 2018

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Dry Eye Syndromes; Keratoconjunctivitis Sicca

Study Results

Participant Flow

Recruitment Details	After confirmation of inclusion and exclusion criteria all eligible patients were randomized at 2:1 ratio to rhNGF or vehicle control treatment with 8 weeks of study treatments administration with 4 weeks Follow-up. rhNGF and vehicle were administered as eye drops at 20 μg/mL concentration, six times daily for 8 weeks in patients with dry eye

Arm/Group Title	rhNGF 20μg/mL	Vehicle
Arm/Group Description	Recombinant Human Nerve Growth Factor (rhNGF) at 20 μg/mL eye drops six times daily NGF: Eye Drop 20 μg/mL	vehicle eye drops six times daily Vehicle: Vehicle Eye Drop
Period Title: Overall Study
STARTED	100	50
COMPLETED	85	42
NOT COMPLETED	15	8

Baseline Characteristics

Arm/Group Title	rhNGF 20μg/mL	Vehicle	Total
Arm/Group Description	Recombinant Human Nerve Growth Factor (rhNGF) at 20 μg/mL eye drops six times daily NGF: Eye Drop 20 μg/mL	vehicle eye drops six times daily Vehicle: Vehicle Eye Drop	Total of all reporting groups
Overall Participants	100	50	150
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	57.5 (11.89)	57.7 (10.33)	57.5 (11.36)
Sex: Female, Male (Count of Participants)
Female	85 85%	46 92%	131 87.3%
Male	15 15%	4 8%	19 12.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 1%	2 4%	3 2%
Not Hispanic or Latino	99 99%	48 96%	147 98%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	100 100%	50 100%	150 100%
Number of baseline participants (Count of Participants)
Count of Participants [Participants]	100 100%	50 100%	150 100%

Outcome Measures

1. Primary Outcome

Title	Symptom Assessment in Dry Eye (SANDE) Scores
Description	Change from baseline with Last Observation Carried Forward (LOCF) imputation. LOCF is a method of imputing missing data in longitudinal studies and tests for difference in mean rates of change in controlled repeated measurements designs with dropouts. The SANDE score is calculated by taking the square root of the product of the frequency of symptoms score and the severity of symptoms score. The SANDE scale ranges from 0 to 100 with 100 being the maximal amount of dry eye symptoms and 0 being the minimal amount of dry eye symptoms.
Time Frame	week 8

Outcome Measure Data

Analysis Population Description

Full analysis set population

Arm/Group Title	rhNGF 20μg/mL	Vehicle
Arm/Group Description	Recombinant Human Nerve Growth Factor (rhNGF) at 20 μg/mL eye drops six times daily NGF: Eye Drop 20 μg/mL	vehicle eye drops six times daily Vehicle: Vehicle Eye Drop
Measure Participants	97	48
Frequency	-38.8 (28.97)	-34.0 (26.67)
Severity	-32.2 (31.04)	-31.07 (28.32)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	rhNGF 20μg/mL, Vehicle
	Comments	Frequency statistical analysis
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.428
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	difference in least square means
	Estimated Value	-3.83
	Confidence Interval	(2-Sided) 95%; -13.34 to 5.68
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	rhNGF 20μg/mL, Vehicle
	Comments	Severity statistical analysis
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.974
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	difference in least square means
	Estimated Value	0.16
	Confidence Interval	(2-Sided) 95%; -9.45 to 9.76
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	SANDE Scores
Description	Change from baseline with Last Observation Carried Forward (LOCF) imputation. LOCF is a method of imputing missing data in longitudinal studies and tests for difference in mean rates of change in controlled repeated measurements designs with dropouts. The SANDE score is calculated by taking the square root of the product of the frequency of symptoms score and the severity of symptoms score. The SANDE scale ranges from 0 to 100 with 100 being the maximal amount of dry eye symptoms and 0 being the minimal amount of dry eye symptoms.
Time Frame	Week 4, week 8, week 12

Outcome Measure Data

Analysis Population Description

Full analysis set population

Arm/Group Title	rhNGF 20μg/mL	Vehicle
Arm/Group Description	Recombinant Human Nerve Growth Factor (rhNGF) at 20 μg/mL eye drops six times daily NGF: Eye Drop 20 μg/mL	vehicle eye drops six times daily Vehicle: Vehicle Eye Drop
Measure Participants	97	48
Frequency - week 4	-22.1 (24.08)	-20.4 (20.66)
Frequency - week 8	-39.6 (28.55)	-34.6 (27.60)
Frequency - week 12	-44.8 (28.69)	-28.2 (28.94)
Severity - week 4	-19.9 (25.20)	-22.2 (24.31)
Severity - week 8	-32.6 (30.64)	-33.1 (28.30)
Severity - week 12	-38.8 (29.20)	-24.3 (28.43)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	rhNGF 20μg/mL, Vehicle
	Comments	frequency statistical analysis - week 4
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.783
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Difference in least square means
	Estimated Value	-1.12
	Confidence Interval	(2-Sided) 95%; -9.14 to 6.91
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	rhNGF 20μg/mL, Vehicle
	Comments	Frequency statistical analysis - week 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.461
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	difference in least square means
	Estimated Value	-3.82
	Confidence Interval	(2-Sided) 95%; -14.1 to 6.41
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	rhNGF 20μg/mL, Vehicle
	Comments	Frequency statistical analysis - week 12
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.004
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	difference in least square means
	Estimated Value	-15.3
	Confidence Interval	(2-Sided) 95%; -25.6 to -4.97
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	rhNGF 20μg/mL, Vehicle
	Comments	Severity statistical analysis - week 4
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.544
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	difference in least square means
	Estimated Value	2.55
	Confidence Interval	(2-Sided) 95%; -5.72 to 10.82
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	rhNGF 20μg/mL, Vehicle
	Comments	Severity statistical analysis - week 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.837
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	difference in least square means
	Estimated Value	1.06
	Confidence Interval	(2-Sided) 95%; -9.12 to 11.24
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	rhNGF 20μg/mL, Vehicle
	Comments	Severity statistical analysis - week 12
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.007
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	difference in least square means
	Estimated Value	-13.8
	Confidence Interval	(2-Sided) 95%; -23.7 to 3.88
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Cornea Vital Staining
Description	Changes from baseline on National Eye Institute (NEI) scale. The NEI/Industry Workshop guidelines were used for grading the scale of corneal and conjunctival damage. The cornea was divided into five sectors (central, superior, inferior, nasal and temporal), each of which was scored on a scale of 0-3, with a maximal total corneal staining score of 15. Both nasally and temporally, the conjunctiva was divided into a superior paralimbal area, an inferior paralimbal area, and a peripheral area with a grading scale of 0-3 and with a maximal total score of 9 for the nasal and temporal conjunctiva (overall the total score ranged from 0-18). Briefly, grade 0 reflected normal/healthy situation, whereas grade 3 reflected a severe damage in the considered sector.
Time Frame	week 4, week 8, week 12

Outcome Measure Data

Analysis Population Description

Full analysis set population

Arm/Group Title	rhNGF 20μg/mL	Vehicle
Arm/Group Description	Recombinant Human Nerve Growth Factor (rhNGF) at 20 μg/mL eye drops six times daily NGF: Eye Drop 20 μg/mL	vehicle eye drops six times daily Vehicle: Vehicle Eye Drop
Measure Participants	97	48
week 4	-3.5 (2.32)	-3.0 (2.27)
week 8	-4.2 (2.92)	-4.4 (2.70)
week 12	-4.4 (2.80)	-5.1 (2.93)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	rhNGF 20μg/mL, Vehicle
	Comments	week 4
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.046
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Difference in least square means
	Estimated Value	-0.70
	Confidence Interval	(2-Sided) 95%; -1.38 to -0.01
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	rhNGF 20μg/mL, Vehicle
	Comments	week 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.425
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Difference in least square means
	Estimated Value	-0.30
	Confidence Interval	(2-Sided) 95%; -1.05 to 0.44
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	rhNGF 20μg/mL, Vehicle
	Comments	week 12
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.788
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Difference in least square means
	Estimated Value	-0.09
	Confidence Interval	(2-Sided) 95%; -0.76 to 0.58
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Conjunctival Vital Staining
Description	Changes from baseline on National Eye Institute (NEI) scale. The NEI/Industry Workshop guidelines were used for grading the scale of corneal and conjunctival damage. The cornea was divided into five sectors (central, superior, inferior, nasal and temporal), each of which was scored on a scale of 0-3, with a maximal total corneal staining score of 15. Both nasally and temporally, the conjunctiva was divided into a superior paralimbal area, an inferior paralimbal area, and a peripheral area with a grading scale of 0-3 and with a maximal total score of 9 for the nasal and temporal conjunctiva (overall the total score ranged from 0-18). Briefly, grade 0 reflected normal/healthy situation, whereas grade 3 reflected a severe damage in the considered sector.
Time Frame	week 4, week 8, week 12

Outcome Measure Data

Analysis Population Description

Full analysis set population

Arm/Group Title	rhNGF 20μg/mL	Vehicle
Arm/Group Description	Recombinant Human Nerve Growth Factor (rhNGF) at 20 μg/mL eye drops six times daily NGF: Eye Drop 20 μg/mL	vehicle eye drops six times daily Vehicle: Vehicle Eye Drop
Measure Participants	97	48
week 4	-4.7 (3.94)	-4.1 (3.45)
week 8	-6.7 (4.16)	-5.9 (4.07)
week 12	-7.2 (4.23)	-7.0 (3.90)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	rhNGF 20μg/mL, Vehicle
	Comments	week 4
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.265
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Difference in least square means
	Estimated Value	-0.71
	Confidence Interval	(2-Sided) 95%; -1.95 to 0.54
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	rhNGF 20μg/mL, Vehicle
	Comments	week 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.026
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Difference in least square means
	Estimated Value	-1.38
	Confidence Interval	(2-Sided) 95%; -2.59 to -0.17
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	rhNGF 20μg/mL, Vehicle
	Comments	week 12
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.361
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Difference in least square means
	Estimated Value	-0.60
	Confidence Interval	(2-Sided) 95%; -1.90 to 0.70
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Change in Tear Film Break-up Time (TFBUT)
Description	TFBUT was measured by determining the time to tear break-up. The TFBUT was performed after instillation of 5 μL of 2% preservative-free sodium fluorescein solution into the inferior conjunctival cul-de-sac of each eye. The patient was instructed to blink several times to thoroughly mix the fluorescein with the tear film.
Time Frame	week 4, week 8, week 12

Outcome Measure Data

Analysis Population Description

Full analysis set population

Arm/Group Title	rhNGF 20μg/mL	Vehicle
Arm/Group Description	Recombinant Human Nerve Growth Factor (rhNGF) at 20 μg/mL eye drops six times daily NGF: Eye Drop 20 μg/mL	vehicle eye drops six times daily Vehicle: Vehicle Eye Drop
Measure Participants	97	48
week 4	0.4 (1.68)	0.8 (1.57)
week 8	0.5 (1.74)	0.7 (1.89)
week 12	0.5 (2.34)	0.9 (1.42)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	rhNGF 20μg/mL, Vehicle
	Comments	week 4
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.323
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Difference in least square means
	Estimated Value	-0.25
	Confidence Interval	(2-Sided) 95%; -0.76 to 0.25
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	rhNGF 20μg/mL, Vehicle
	Comments	week 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.908
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Difference in least square means
	Estimated Value	0.03
	Confidence Interval	(2-Sided) 95%; -0.55 to 0.62
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	rhNGF 20μg/mL, Vehicle
	Comments	week 12
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.702
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Difference in least square means
	Estimated Value	-0.12
	Confidence Interval	(2-Sided) 95%; -0.76 to 0.52
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Change From Baseline in Wetting Distance
Description	The Schirmer test without anesthesia was performed to measure aqueous tear secretion prior to the instillation of any dilating or eye drops
Time Frame	week 8

Outcome Measure Data

Analysis Population Description

Full analysis set population

Arm/Group Title	rhNGF 20μg/mL	Vehicle
Arm/Group Description	Recombinant Human Nerve Growth Factor (rhNGF) at 20 μg/mL eye drops six times daily NGF: Eye Drop 20 μg/mL	vehicle eye drops six times daily Vehicle: Vehicle Eye Drop
Measure Participants	85	42
Mean (Standard Deviation) [millimeters]	2.4 (11.41)	-3.1 (8.66)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	rhNGF 20μg/mL, Vehicle
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.003
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Difference in least square means
	Estimated Value	5.75
	Confidence Interval	(2-Sided) 95%; 2.02 to 9.48
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Adverse events were collected at each time point of the study (ie. Baseline visit, Week 4, Week 8 and ETV or early termination
Arm/Group Title	rhNGF 20μg/mL		Vehicle
Arm/Group Description	Recombinant Human Nerve Growth Factor (rhNGF) at 20 μg/mL eye drops six times daily NGF: Eye Drop 20 μg/mL		vehicle eye drops six times daily Vehicle: Vehicle Eye Drop
All Cause Mortality
	rhNGF 20μg/mL		Vehicle
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/100 (0%)		0/50 (0%)
Serious Adverse Events
	rhNGF 20μg/mL		Vehicle
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/100 (5%)		0/50 (0%)
Cardiac disorders
Atrial fibrillation	1/100 (1%)	1	0/50 (0%)	0
Infections and infestations
Diverticulitis	1/100 (1%)	1	0/50 (0%)	0
Upper respiratory tract infection	1/100 (1%)	1	0/50 (0%)	0
Nervous system disorders
Paraesthesia	1/100 (1%)	1	0/50 (0%)	0
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	1/100 (1%)	1	0/50 (0%)	0
Other (Not Including Serious) Adverse Events
	rhNGF 20μg/mL		Vehicle
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	97/100 (97%)		38/50 (76%)
Cardiac disorders
Atrial fibrillation	1/100 (1%)	1	0/50 (0%)	0
Palpitations	1/100 (1%)	1	0/50 (0%)	0
Ear and labyrinth disorders
Ear pain	1/100 (1%)	1	0/50 (0%)	0
Vertigo	0/100 (0%)	0	1/50 (2%)	1
Eye disorders
Ocular discomfort	69/100 (69%)	87	10/50 (20%)	17
Eye pain	42/100 (42%)	67	4/50 (8%)	4
Eye irritation	15/100 (15%)	19	10/50 (20%)	11
Vision blurred	13/100 (13%)	14	4/50 (8%)	6
Photophobia	12/100 (12%)	14	3/50 (6%)	3
Eye pruritus	8/100 (8%)	8	5/50 (10%)	5
Eye discharge	9/100 (9%)	13	1/50 (2%)	2
Eyelid disorder	8/100 (8%)	8	0/50 (0%)	0
Eyelid oedema	4/100 (4%)	6	1/50 (2%)	3
Dry eye	4/100 (4%)	4	1/50 (2%)	1
Eyelid pain	5/100 (5%)	5	0/50 (0%)	0
Lacrimation increased	3/100 (3%)	3	2/50 (4%)	2
Ocular hyperaemia	3/100 (3%)	8	1/50 (2%)	1
Blepharospasm	2/100 (2%)	3	2/50 (4%)	2
Eye swelling	4/100 (4%)	5	0/50 (0%)	0
Eyelid margin crusting	2/100 (2%)	2	1/50 (2%)	2
Foreign body sensation in eyes	3/100 (3%)	4	0/50 (0%)	0
Abnormal sensation in eye	1/100 (1%)	1	2/50 (4%)	2
Eyelid pruritus	2/100 (2%)	4	0/50 (0%)	0
Asthenopia	2/100 (2%)	2	0/50 (0%)	0
Conjunctival haemorrhage	1/100 (1%)	1	1/50 (2%)	1
Diplopia	1/100 (1%)	1	1/50 (2%)	1
Eye allergy	2/100 (2%)	2	0/50 (0%)	0
Scleral haemorrhage	1/100 (1%)	1	1/50 (2%)	1
visual impairment	2/100 (2%)	2	0/50 (0%)	0
Vitreous floaters	1/100 (1%)	1	1/50 (2%)	1
Eye paraesthesia	1/100 (1%)	3	0/50 (0%)	0
Conjunctival deposit	0/100 (0%)	0	1/50 (2%)	1
Conjunctivitis allergic	0/100 (0%)	0	1/50 (2%)	1
Corneal oedema	1/100 (1%)	1	0/50 (0%)	0
Eye inflammation	0/100 (0%)	0	1/50 (2%)	1
Eyelid irritation	1/100 (1%)	1	0/50 (0%)	0
Eyelid sensory disorder	1/100 (1%)	1	0/50 (0%)	0
Lacrimation decreased	0/100 (0%)	0	1/50 (2%)	1
Photopsia	1/100 (1%)	1	0/50 (0%)	0
Scleral discolouration	0/100 (0%)	0	1/50 (2%)	1
Gastrointestinal disorders
abdominal discomfort	2/100 (2%)	2	1/50 (2%)	1
Diarrhoea	2/100 (2%)	2	0/50 (0%)	0
Abdominal pain upper	1/100 (1%)	1	0/50 (0%)	0
Diverticulum	1/100 (1%)	1	0/50 (0%)	0
Dry mouth	1/100 (1%)	1	0/50 (0%)	0
Glossodynia	1/100 (1%)	1	0/50 (0%)	0
Nausea	1/100 (1%)	1	0/50 (0%)	0
Salivary gland calculus	1/100 (1%)	1	0/50 (0%)	0
Stomatitis	0/100 (0%)	0	1/50 (2%)	1
General disorders
Sensation of foreign body	2/100 (2%)	2	1/50 (2%)	1
Pyrexia	2/100 (2%)	2	0/50 (0%)	0
Fatigue	1/100 (1%)	1	0/50 (0%)	0
Generalized oedema	0/100 (0%)	0	1/50 (2%)	1
Humidity intolerance	1/100 (1%)	1	0/50 (0%)	0
Oedema peripheral	1/100 (1%)	1	0/50 (0%)	0
Pain	1/100 (1%)	1	0/50 (0%)	0
Temperature intolerance	1/100 (1%)	1	0/50 (0%)	0
Immune system disorders
Seasonal allergy	3/100 (3%)	3	0/50 (0%)	0
Hypersensivity	1/100 (1%)	2	0/50 (0%)	0
Graft versus host disease	1/100 (1%)	1	0/50 (0%)	0
Multiple allergies	1/100 (1%)	1	0/50 (0%)	0
Infections and infestations
Viral upper respiratory tract infection	8/100 (8%)	10	5/50 (10%)	5
Sinusitis	2/100 (2%)	2	1/50 (2%)	2
Bronchitis	0/100 (0%)	0	2/50 (4%)	2
Upper respiratory tract infection	2/100 (2%)	2	0/50 (0%)	0
Acute sinusitis	1/100 (1%)	1	0/50 (0%)	0
Cellulitis	1/100 (1%)	1	0/50 (0%)	0
Conjunctivitis	0/100 (0%)	0	1/50 (2%)	1
Conjunctivitis viral	1/100 (1%)	1	0/50 (0%)	0
Diverticulitis	1/100 (1%)	1	0/50 (0%)	0
Ear infection	0/100 (0%)	0	1/50 (2%)	1
Fungal infection	1/100 (1%)	1	0/50 (0%)	0
Herpes simplex	0/100 (0%)	0	1/50 (2%)	1
Herpes virus infection	1/100 (1%)	1	0/50 (0%)	0
Influenza	0/100 (0%)	0	1/50 (2%)	1
Nasopharyngitis	0/100 (0%)	0	1/50 (2%)	1
Ophthalmic herpes simplex	0/100 (0%)	0	1/50 (2%)	1
Pertussis	1/100 (1%)	1	0/50 (0%)	0
Pharyngitis	1/100 (1%)	1	0/50 (0%)	0
Pneumonia	0/100 (0%)	0	1/50 (2%)	1
Pyelonephritis acute	1/100 (1%)	1	0/50 (0%)	0
Vaginal infection	0/100 (0%)	0	1/50 (2%)	1
Injury, poisoning and procedural complications
Foreign body in eye	2/100 (2%)	2	0/50 (0%)	0
Superficial injury of eye	1/100 (1%)	1	1/50 (2%)	1
Contusion	1/100 (1%)	1	0/50 (0%)	0
Eye burns	1/100 (1%)	1	0/50 (0%)	0
Eye contusion	1/100 (1%)	1	0/50 (0%)	0
Eye injury	1/100 (1%)	1	0/50 (0%)	0
Fall	1/100 (1%)	1	0/50 (0%)	0
Investigations
Intraocular pressure test	1/100 (1%)	1	0/50 (0%)	0
Metabolism and nutrition disorders
Glucose tolerance impaired	1/100 (1%)	1	0/50 (0%)	0
Iron deficiency	0/100 (0%)	0	1/50 (2%)	1
Musculoskeletal and connective tissue disorders
Back pain	2/100 (2%)	2	1/50 (2%)	2
Pain in extremity	1/100 (1%)	1	2/50 (4%)	2
Arthralgia	0/100 (0%)	0	1/50 (2%)	1
Bursitis	1/100 (1%)	1	0/50 (0%)	0
Intervertebral disc disorder	0/100 (0%)	0	1/50 (2%)	1
Joint stiffness	0/100 (0%)	0	1/50 (2%)	1
Muscle spasms	1/100 (1%)	1	0/50 (0%)	0
Myalgia	0/100 (0%)	0	1/50 (2%)	1
Myofascial pain syndrome	1/100 (1%)	1	0/50 (0%)	0
plantar fasciitis	0/100 (0%)	0	1/50 (2%)	1
Rotator cuff syndrome	1/100 (1%)	1	0/50 (0%)	0
Tendonitis	1/100 (1%)	1	0/50 (0%)	0
Nervous system disorders
Headache	12/100 (12%)	14	5/50 (10%)	11
Migrane	3/100 (3%)	3	0/50 (0%)	0
Burning sensation	1/100 (1%)	1	1/50 (2%)	1
Paraesthesia	2/100 (2%)	2	0/50 (0%)	0
Autonomic failure syndrome	1/100 (1%)	1	0/50 (0%)	0
Cervical Myelopathy	0/100 (0%)	0	1/50 (2%)	1
Dizziness	1/100 (1%)	1	0/50 (0%)	0
Dysarthria	1/100 (1%)	1	0/50 (0%)	0
Hypoaesthesia	1/100 (1%)	1	0/50 (0%)	0
Neuralgia	1/100 (1%)	1	0/50 (0%)	0
Polyneuropathy idiopathic progressive	1/100 (1%)	1	0/50 (0%)	0
Sciatica	1/100 (1%)	1	0/50 (0%)	0
Sinus headache	1/100 (1%)	1	0/50 (0%)	0
Psychiatric disorders
Depression	1/100 (1%)	1	0/50 (0%)	0
Insomnia	1/100 (1%)	1	0/50 (0%)	0
Panic attack	1/100 (1%)	1	0/50 (0%)	0
Renal and urinary disorders
Lupus nephritis	1/100 (1%)	1	0/50 (0%)	0
Respiratory, thoracic and mediastinal disorders
Nasal discomfort	3/100 (3%)	3	0/50 (0%)	0
Oropharyngeal pain	3/100 (3%)	3	0/50 (0%)	0
Cough	2/100 (2%)	2	0/50 (0%)	0
Sinus congestion	2/100 (2%)	2	0/50 (0%)	0
Asthma	1/100 (1%)	1	0/50 (0%)	0
Asthma exercise induced	1/100 (1%)	1	0/50 (0%)	0
Chronic obstructive pulmonary disease	1/100 (1%)	1	0/50 (0%)	0
Dry throat	1/100 (1%)	1	0/50 (0%)	0
Haemoptysis	1/100 (1%)	1	0/50 (0%)	0
Nasal congestion	1/100 (1%)	1	0/50 (0%)	0
Nasal dryness	1/100 (1%)	1	0/50 (0%)	0
Nasal inflammation	1/100 (1%)	1	0/50 (0%)	0
Skin and subcutaneous tissue disorders
Urticaria	1/100 (1%)	1	3/50 (6%)	8
Pruritus	1/100 (1%)	1	1/50 (2%)	1
Madarosis	1/100 (1%)	2	0/50 (0%)	0
Acne	1/100 (1%)	1	0/50 (0%)	0
Erythema	1/100 (1%)	1	0/50 (0%)	0
Skin discolouration	1/100 (1%)	1	0/50 (0%)	0
Skin irritation	1/100 (1%)	1	0/50 (0%)	0
Surgical and medical procedures
Dental implantation	0/100 (0%)	0	1/50 (2%)	1
Endodontic procedure	1/100 (1%)	1	0/50 (0%)	0
Eye laser surgery	0/100 (0%)	0	1/50 (2%)	1
Haemorrhoid operation	1/100 (1%)	1	0/50 (0%)	0
Tooth extraction	1/100 (1%)	1	0/50 (0%)	0
Vena cava filter removal	0/100 (0%)	0	1/50 (2%)	1
Vascular disorders
Raynaud's phenomenon	1/100 (1%)	1	0/50 (0%)	0
Vein disorder	1/100 (1%)	1	0/50 (0%)	0

Limitations/Caveats

LImitations and caveats are not specified.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.