Dry Eye
Conditions
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.
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.
Interventions
DRUGNGF
Eye Drop 20 μg/mL
OTHERVehicle
Vehicle Eye Drop
Sponsors
Dompé Farmaceutici S.p.A
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, 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.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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: 1. Corneal and/or conjunctival staining with fluorescein and lissamine green using National Eye Institute (NEI) grading system \> 3 2. Mean Symptom Assessment in Dry Eye (SANDE) questionnaire ≥30 3. Schirmer test without anesthesia \< 10 mm/5 minutes and/or tear film break-up time (TFBUT) \< 10 seconds in the study eye 4. The same eye (study eye) must fulfill all the above criteria. 5. Patients must have best corrected distance visual acuity (BCDVA) score of ≥ 0.1 decimal units in both eyes at the time of study enrollment. 6. Female patients must have negative pregnancy test if at childbirth potential. 7. 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. 8. 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
| 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 |
Countries
United States
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
Participants by arm
| Arm | Count |
|---|---|
| rhNGF 20μg/mL Recombinant Human Nerve Growth Factor (rhNGF) at 20 μg/mL eye drops six times daily
NGF: Eye Drop 20 μg/mL | 100 |
| Vehicle vehicle eye drops six times daily
Vehicle: Vehicle Eye Drop | 50 |
| Total | 150 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 8 | 0 |
| Overall Study | Lost to Follow-up | 2 | 1 |
| Overall Study | not compliance | 2 | 2 |
| Overall Study | Other | 2 | 2 |
| Overall Study | Unrelated to adverse event | 1 | 3 |
Baseline characteristics
| Characteristic | Vehicle | Total | rhNGF 20μg/mL |
|---|---|---|---|
| Age, Continuous | 57.7 years STANDARD_DEVIATION 10.33 | 57.5 years STANDARD_DEVIATION 11.36 | 57.5 years STANDARD_DEVIATION 11.89 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 3 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 48 Participants | 147 Participants | 99 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Number of baseline participants | 50 Participants | 150 Participants | 100 Participants |
| Region of Enrollment United States | 50 participants | 150 participants | 100 participants |
| Sex: Female, Male Female | 46 Participants | 131 Participants | 85 Participants |
| Sex: Female, Male Male | 4 Participants | 19 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 100 | 0 / 50 |
| other Total, other adverse events | 97 / 100 | 38 / 50 |
| serious Total, serious adverse events | 5 / 100 | 0 / 50 |
Outcome results
Primary
Symptom Assessment in Dry Eye (SANDE) Scores
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
Population: Full analysis set population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| rhNGF 20μg/mL | Symptom Assessment in Dry Eye (SANDE) Scores | Frequency | -38.8 units on a scale | Standard Deviation 28.97 |
| rhNGF 20μg/mL | Symptom Assessment in Dry Eye (SANDE) Scores | Severity | -32.2 units on a scale | Standard Deviation 31.04 |
| Vehicle | Symptom Assessment in Dry Eye (SANDE) Scores | Frequency | -34.0 units on a scale | Standard Deviation 26.67 |
| Vehicle | Symptom Assessment in Dry Eye (SANDE) Scores | Severity | -31.07 units on a scale | Standard Deviation 28.32 |
Comparison: Frequency statistical analysisp-value: =0.42895% CI: [-13.34, 5.68]ANCOVA
Comparison: Severity statistical analysisp-value: =0.97495% CI: [-9.45, 9.76]ANCOVA
Secondary
Change From Baseline in Wetting Distance
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
Population: Full analysis set population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| rhNGF 20μg/mL | Change From Baseline in Wetting Distance | 2.4 millimeters | Standard Deviation 11.41 |
| Vehicle | Change From Baseline in Wetting Distance | -3.1 millimeters | Standard Deviation 8.66 |
p-value: =0.00395% CI: [2.02, 9.48]ANCOVA
Secondary
Change in Tear Film Break-up Time (TFBUT)
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
Population: Full analysis set population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| rhNGF 20μg/mL | Change in Tear Film Break-up Time (TFBUT) | week 4 | 0.4 seconds | Standard Deviation 1.68 |
| rhNGF 20μg/mL | Change in Tear Film Break-up Time (TFBUT) | week 8 | 0.5 seconds | Standard Deviation 1.74 |
| rhNGF 20μg/mL | Change in Tear Film Break-up Time (TFBUT) | week 12 | 0.5 seconds | Standard Deviation 2.34 |
| Vehicle | Change in Tear Film Break-up Time (TFBUT) | week 4 | 0.8 seconds | Standard Deviation 1.57 |
| Vehicle | Change in Tear Film Break-up Time (TFBUT) | week 8 | 0.7 seconds | Standard Deviation 1.89 |
| Vehicle | Change in Tear Film Break-up Time (TFBUT) | week 12 | 0.9 seconds | Standard Deviation 1.42 |
Comparison: week 4p-value: =0.32395% CI: [-0.76, 0.25]ANCOVA
Comparison: week 8p-value: =0.90895% CI: [-0.55, 0.62]ANCOVA
Comparison: week 12p-value: =0.70295% CI: [-0.76, 0.52]ANCOVA
Secondary
Conjunctival Vital Staining
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
Population: Full analysis set population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| rhNGF 20μg/mL | Conjunctival Vital Staining | week 4 | -4.7 units on a scale | Standard Deviation 3.94 |
| rhNGF 20μg/mL | Conjunctival Vital Staining | week 8 | -6.7 units on a scale | Standard Deviation 4.16 |
| rhNGF 20μg/mL | Conjunctival Vital Staining | week 12 | -7.2 units on a scale | Standard Deviation 4.23 |
| Vehicle | Conjunctival Vital Staining | week 4 | -4.1 units on a scale | Standard Deviation 3.45 |
| Vehicle | Conjunctival Vital Staining | week 8 | -5.9 units on a scale | Standard Deviation 4.07 |
| Vehicle | Conjunctival Vital Staining | week 12 | -7.0 units on a scale | Standard Deviation 3.9 |
Comparison: week 4p-value: =0.26595% CI: [-1.95, 0.54]ANCOVA
Comparison: week 8p-value: =0.02695% CI: [-2.59, -0.17]ANCOVA
Comparison: week 12p-value: =0.36195% CI: [-1.9, 0.7]ANCOVA
Secondary
Cornea Vital Staining
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
Population: Full analysis set population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| rhNGF 20μg/mL | Cornea Vital Staining | week 4 | -3.5 units on a scale | Standard Deviation 2.32 |
| rhNGF 20μg/mL | Cornea Vital Staining | week 8 | -4.2 units on a scale | Standard Deviation 2.92 |
| rhNGF 20μg/mL | Cornea Vital Staining | week 12 | -4.4 units on a scale | Standard Deviation 2.8 |
| Vehicle | Cornea Vital Staining | week 4 | -3.0 units on a scale | Standard Deviation 2.27 |
| Vehicle | Cornea Vital Staining | week 8 | -4.4 units on a scale | Standard Deviation 2.7 |
| Vehicle | Cornea Vital Staining | week 12 | -5.1 units on a scale | Standard Deviation 2.93 |
Comparison: week 4p-value: =0.04695% CI: [-1.38, -0.01]ANCOVA
Comparison: week 8p-value: =0.42595% CI: [-1.05, 0.44]ANCOVA
Comparison: week 12p-value: =0.78895% CI: [-0.76, 0.58]ANCOVA
Secondary
SANDE Scores
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
Population: Full analysis set population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| rhNGF 20μg/mL | SANDE Scores | Frequency - week 4 | -22.1 units on a scale | Standard Deviation 24.08 |
| rhNGF 20μg/mL | SANDE Scores | Frequency - week 8 | -39.6 units on a scale | Standard Deviation 28.55 |
| rhNGF 20μg/mL | SANDE Scores | Frequency - week 12 | -44.8 units on a scale | Standard Deviation 28.69 |
| rhNGF 20μg/mL | SANDE Scores | Severity - week 4 | -19.9 units on a scale | Standard Deviation 25.2 |
| rhNGF 20μg/mL | SANDE Scores | Severity - week 8 | -32.6 units on a scale | Standard Deviation 30.64 |
| rhNGF 20μg/mL | SANDE Scores | Severity - week 12 | -38.8 units on a scale | Standard Deviation 29.2 |
| Vehicle | SANDE Scores | Severity - week 8 | -33.1 units on a scale | Standard Deviation 28.3 |
| Vehicle | SANDE Scores | Frequency - week 4 | -20.4 units on a scale | Standard Deviation 20.66 |
| Vehicle | SANDE Scores | Severity - week 4 | -22.2 units on a scale | Standard Deviation 24.31 |
| Vehicle | SANDE Scores | Frequency - week 8 | -34.6 units on a scale | Standard Deviation 27.6 |
| Vehicle | SANDE Scores | Severity - week 12 | -24.3 units on a scale | Standard Deviation 28.43 |
| Vehicle | SANDE Scores | Frequency - week 12 | -28.2 units on a scale | Standard Deviation 28.94 |
Comparison: frequency statistical analysis - week 4p-value: =0.78395% CI: [-9.14, 6.91]ANCOVA
Comparison: Frequency statistical analysis - week 8p-value: =0.46195% CI: [-14.1, 6.41]ANCOVA
Comparison: Frequency statistical analysis - week 12p-value: =0.00495% CI: [-25.6, -4.97]ANCOVA
Comparison: Severity statistical analysis - week 4p-value: =0.54495% CI: [-5.72, 10.82]ANCOVA
Comparison: Severity statistical analysis - week 8p-value: =0.83795% CI: [-9.12, 11.24]ANCOVA
Comparison: Severity statistical analysis - week 12p-value: =0.00795% CI: [-23.7, 3.88]ANCOVA