Ocular Discomfort
Conditions
Keywords
Ocular discomfort after cataract and refractive surgery, cataract surgery, refractive surgery
Brief summary
The primary objective of this exploratory study is to assess preliminary efficacy and safety of rhNGF when administered as eye drops to patients after cataract and refractive surgery. The main criteria for evaluation were: * Change from baseline in SANDE scores for severity and frequency assessed at 8 weeks of treatment (primary efficacy endpoint) * Changes in Cornea vital staining with fluorescein (National Eye Institute \[NEI\] scales) assessed at 8 weeks of treatment (co-primary efficacy endpoint) * Changes in conjunctiva vital staining with fluorescein (NEI scales) (secondary efficacy endpoint); * Changes in Tear Film Break-Up Time (TFBUT)(secondary efficacy endpoint); * Changes in Cochet-Bonnet corneal aesthesiometry (secondary efficacy endpoint); * Changes in Nerve count and morphology at scanning laser in vivo corneal confocal microscopy (only patients who had Laser-Assisted In situ Keratomileusis \[LASIK\] surgery) (secondary efficacy endpoint); * Changes in SANDE scores (face values) for severity and frequency (secondary efficacy endpoint); * Incidence and frequency of treatment-emergent adverse events (TEAEs), assessed throughout the study (safety endpoint).
Detailed description
The proposed phase II study is a single-centre, randomized, double masked, parallel arm, vehicle-controlled trial, designed to evaluate the preliminary efficacy and safety of rhNGF eye drops at 20 µg/ml concentration administered six times daily for 8 weeks in patients who underwent cataract and corneal refractive surgery, both known to damage the corneal sensory nerve plexus. 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
DRUGrhNGF
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
For the whole duration of the trial, treatment was unknown to the patient, the Investigator and the site staff.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Male or female ≥18 years old 2. Patients who are characterized by the following clinical features: 1. History of cataract or refractive corneal surgery in the study eye(s) in the previous 6 months; 2. Mean Symptom Assessment in Dry Eye (SANDE) score for severity and frequency of at least 30 at baseline 3. The same eye (study eye) must fulfill all the above criteria 4. Best corrected distance visual acuity (BCDVA) score of ≥ 0.1 decimal units in both eyes at the time of study enrolment 5. Female patients must have negative pregnancy urine test if at childbirth potential. 6. 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. 7. Patients must have the ability and willingness to comply with study procedures
Exclusion criteria
1. Any ocular disease other than Dry Eye requiring treatment with topical medications in either eye at the time of study enrolment. 2. Any active ocular infection or active inflammation in either eye unrelated to Dry Eye. 3. Presence or history of any systemic or ocular disorder, condition or disease (with particular attention to malignancies and neuro-oncological diseases) that could possibly interfere with the conduct of the required study procedures or the interpretation of the study results. 4. Use of therapeutic or Refractive Contact lenses in either eye at the time of study enrolment; 5. History of ocular surgery in the study eye(s), excluding corneal refractive or cataract procedures, within 90 days of study enrolment. 6. 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 0) 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, 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 IUD (Intrauterine device) - during the entire course of and 30 days after the study treatment periods. 7. Participation in another clinical study at the same time as the present and within 30 days of study enrolment; 8. History of drug, medication or alcohol abuse or addiction.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in SANDE Scores for Frequency and Severity Assessed at 8 Weeks of Treatment. | Baseline and Week 8 | The Symptom Assessment in Dry Eye (SANDE) questionnaire is a short questionnaire to evaluate both dry eye intensity and frequency by using a 100 mm visual analogue scale (VAS). The patient symptoms of ocular dryness and/or irritation were quantified on the scale based on two questions that assessed both the severity and frequency of symptoms. 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. |
| Changes in Cornea Vital Staining With Fluorescein (National Eye Institute [NEI] Scales) | Baseline and Week 8 | Corneal Staining was derived as the sum of scores of the five corneal sectors (central, superior, inferior, nasal, and temporal) each of which was scored on a scale of 0-3, with a minimum score of 0 and a maximal score of 15 (sum \> 3 out of 15 is abnormal). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Changes in Conjunctiva Vital Staining With Fluorescein (National Eye Institute [NEI] Scales) | From baseline to weeks 4, 8 and 12 | Conjunctival Staining was derived as the sum of scores of the conjunctival area (nasal-superior paralimbal, nasal-inferior paralimbal, nasal-peripheral, temporal-superior paralimbal, temporal-inferior paralimbal, temporal-peripheral) with a grading scale of 0-3 and with a minimum score of 0 and a maximal score of 18 (18 indicates the most abnormal score). Grades increase with the number and density of dots. Data for the main eye are reported. |
| Changes in Tear Film Break-Up Time (TFBUT) | From baseline to weeks 4, 8 and 12 | The TFBUT measurement was performed after instillation of 5 microliters of 2% 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. Data for the main eye are reported. |
| Changes in Cochet-Bonnet Corneal Aesthesiometry | From baseline to week 8 | Corneal sensation was measured in both eyes in each of the four quadrants of the cornea using the Cochet Bonnet aesthesiometer before the instillation of any dilating or anesthetic eye drops. The handheld esthesiometer (Cochet-Bonnet) is a device that contains a thin, retractable, nylon monofilament that extends up to 6 cm in length. Variable pressure can be applied by the device by adjusting the length. The monofilament ranges from 60 mm to 5 mm and as the length is decreased the pressure increases from 11 mm/gm to 200 mm/gm. Data for the main eye are reported. |
| Changes in SANDE Scores (Face Values) for Frequency and Severity | From baseline to weeks 4, 8 and 12 | The Symptom Assessment in Dry Eye (SANDE) questionnaire is a short questionnaire to evaluate both dry eye intensity and frequency by using a 100 mm visual analogue scale (VAS). The patient symptoms of ocular dryness and/or irritation were quantified on the scale based on two questions that assessed both the severity and frequency of symptoms. 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. |
Countries
Italy
Participant flow
Recruitment details
Eligible patients were randomized in a 2:1 ratio to rhNGF eye drops solution at 20 μg/ml (120 patients) or vehicle eye drops solution (60 patients) 6 times per day for 8 weeks, followed by 4 weeks of follow-up with no further treatment.
Participants by arm
| Arm | Count |
|---|---|
| rhNGF 20 µg/ml Recombinant Human Nerve Growth Factor (rhNGF) at 20 μg/mL eye drops six times daily
rhNGF: Eye Drop 20 μg/mL | 115 |
| Vehicle Vehicle eye drops six times daily
Vehicle: Vehicle Eye Drop | 59 |
| Total | 174 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Follow-up Period | Adverse Event | 1 | 0 |
| Follow-up Period | Lost to Follow-up | 6 | 2 |
| Follow-up Period | Other | 3 | 2 |
| Follow-up Period | Physician Decision | 1 | 0 |
| Treatment Period | Adverse Event | 1 | 0 |
| Treatment Period | Other | 3 | 1 |
Baseline characteristics
| Characteristic | rhNGF 20 µg/ml | Vehicle | Total |
|---|---|---|---|
| Age, Continuous | 38.0 years STANDARD_DEVIATION 12.8 | 34.4 years STANDARD_DEVIATION 11.2 | 36.8 years STANDARD_DEVIATION 12.36 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 2 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 115 Participants | 57 Participants | 172 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment Italy | 115 participants | 59 participants | 174 participants |
| Sex: Female, Male Female | 71 Participants | 33 Participants | 104 Participants |
| Sex: Female, Male Male | 44 Participants | 26 Participants | 70 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 115 | 0 / 59 |
| other Total, other adverse events | 50 / 115 | 19 / 59 |
| serious Total, serious adverse events | 1 / 115 | 0 / 59 |
Outcome results
Primary
Change From Baseline in SANDE Scores for Frequency and Severity Assessed at 8 Weeks of Treatment.
The Symptom Assessment in Dry Eye (SANDE) questionnaire is a short questionnaire to evaluate both dry eye intensity and frequency by using a 100 mm visual analogue scale (VAS). The patient symptoms of ocular dryness and/or irritation were quantified on the scale based on two questions that assessed both the severity and frequency of symptoms. 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: Baseline and Week 8
Population: Full Analysis Set Population. Last observation carried forward (LOCF) imputation method
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| rhNGF 20 µg/ml | Change From Baseline in SANDE Scores for Frequency and Severity Assessed at 8 Weeks of Treatment. | Frequency | -37.2 score on a scale | Standard Deviation 24.85 |
| rhNGF 20 µg/ml | Change From Baseline in SANDE Scores for Frequency and Severity Assessed at 8 Weeks of Treatment. | Severity | -37.8 score on a scale | Standard Deviation 27.2 |
| Vehicle | Change From Baseline in SANDE Scores for Frequency and Severity Assessed at 8 Weeks of Treatment. | Frequency | -35.7 score on a scale | Standard Deviation 26.04 |
| Vehicle | Change From Baseline in SANDE Scores for Frequency and Severity Assessed at 8 Weeks of Treatment. | Severity | -37.3 score on a scale | Standard Deviation 20.43 |
Comparison: Frequency statistical analysisp-value: =0.97495% CI: [-6.85, 6.63]ANCOVA
Comparison: Statistical analysis related to severityp-value: =0.39995% CI: [-3.85, 9.61]ANCOVA
Primary
Changes in Cornea Vital Staining With Fluorescein (National Eye Institute [NEI] Scales)
Corneal Staining was derived as the sum of scores of the five corneal sectors (central, superior, inferior, nasal, and temporal) each of which was scored on a scale of 0-3, with a minimum score of 0 and a maximal score of 15 (sum \> 3 out of 15 is abnormal).
Time frame: Baseline and Week 8
Population: Full Analysis Set population. Last observation carried forward (LOCF) imputation method.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| rhNGF 20 µg/ml | Changes in Cornea Vital Staining With Fluorescein (National Eye Institute [NEI] Scales) | -2.5 score on a scale | Standard Deviation 2.11 |
| Vehicle | Changes in Cornea Vital Staining With Fluorescein (National Eye Institute [NEI] Scales) | -2.2 score on a scale | Standard Deviation 1.81 |
p-value: =0.21495% CI: [-0.02, 0.1]ANCOVA
Secondary
Changes in Cochet-Bonnet Corneal Aesthesiometry
Corneal sensation was measured in both eyes in each of the four quadrants of the cornea using the Cochet Bonnet aesthesiometer before the instillation of any dilating or anesthetic eye drops. The handheld esthesiometer (Cochet-Bonnet) is a device that contains a thin, retractable, nylon monofilament that extends up to 6 cm in length. Variable pressure can be applied by the device by adjusting the length. The monofilament ranges from 60 mm to 5 mm and as the length is decreased the pressure increases from 11 mm/gm to 200 mm/gm. Data for the main eye are reported.
Time frame: From baseline to week 8
Population: As of this secondary endpoint, FAS Population was taken into account, but the last observation carried forward (LOCF) imputation method was not applied.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| rhNGF 20 µg/ml | Changes in Cochet-Bonnet Corneal Aesthesiometry | superior nasal | -0.1 cm | Standard Deviation 0.31 |
| rhNGF 20 µg/ml | Changes in Cochet-Bonnet Corneal Aesthesiometry | inferior nasal | -0.2 cm | Standard Deviation 0.32 |
| rhNGF 20 µg/ml | Changes in Cochet-Bonnet Corneal Aesthesiometry | superior temporal | -0.2 cm | Standard Deviation 0.36 |
| rhNGF 20 µg/ml | Changes in Cochet-Bonnet Corneal Aesthesiometry | inferior temporal | -0.1 cm | Standard Deviation 0.41 |
| Vehicle | Changes in Cochet-Bonnet Corneal Aesthesiometry | inferior temporal | 0.0 cm | Standard Deviation 0.64 |
| Vehicle | Changes in Cochet-Bonnet Corneal Aesthesiometry | superior nasal | -0.2 cm | Standard Deviation 0.31 |
| Vehicle | Changes in Cochet-Bonnet Corneal Aesthesiometry | superior temporal | -0.2 cm | Standard Deviation 0.34 |
| Vehicle | Changes in Cochet-Bonnet Corneal Aesthesiometry | inferior nasal | -0.1 cm | Standard Deviation 0.64 |
Secondary
Changes in Conjunctiva Vital Staining With Fluorescein (National Eye Institute [NEI] Scales)
Conjunctival Staining was derived as the sum of scores of the conjunctival area (nasal-superior paralimbal, nasal-inferior paralimbal, nasal-peripheral, temporal-superior paralimbal, temporal-inferior paralimbal, temporal-peripheral) with a grading scale of 0-3 and with a minimum score of 0 and a maximal score of 18 (18 indicates the most abnormal score). Grades increase with the number and density of dots. Data for the main eye are reported.
Time frame: From baseline to weeks 4, 8 and 12
Population: As of this secondary endpoint, FAS Population was taken into account, but the last observation carried forward (LOCF) imputation method was not applied. Due to the reason mentioned above, the patients actually analysed (n) were the following:~Week 4 - 110 rhNGF; 58 vehicle Week 8 - 107 rhNGF; 58 vehicle Week 12 - 107 rhNGF; 55 vehicle
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| rhNGF 20 µg/ml | Changes in Conjunctiva Vital Staining With Fluorescein (National Eye Institute [NEI] Scales) | week 12 | 0.0 units on a scale | Standard Deviation 0 |
| rhNGF 20 µg/ml | Changes in Conjunctiva Vital Staining With Fluorescein (National Eye Institute [NEI] Scales) | week 4 | 0.0 units on a scale | Standard Deviation 0 |
| rhNGF 20 µg/ml | Changes in Conjunctiva Vital Staining With Fluorescein (National Eye Institute [NEI] Scales) | week 8 | 0.0 units on a scale | Standard Deviation 0 |
| Vehicle | Changes in Conjunctiva Vital Staining With Fluorescein (National Eye Institute [NEI] Scales) | week 8 | 0.0 units on a scale | Standard Deviation 0 |
| Vehicle | Changes in Conjunctiva Vital Staining With Fluorescein (National Eye Institute [NEI] Scales) | week 4 | 0.0 units on a scale | Standard Deviation 0 |
| Vehicle | Changes in Conjunctiva Vital Staining With Fluorescein (National Eye Institute [NEI] Scales) | week 12 | 0.0 units on a scale | Standard Deviation 0 |
Secondary
Changes in SANDE Scores (Face Values) for Frequency and Severity
The Symptom Assessment in Dry Eye (SANDE) questionnaire is a short questionnaire to evaluate both dry eye intensity and frequency by using a 100 mm visual analogue scale (VAS). The patient symptoms of ocular dryness and/or irritation were quantified on the scale based on two questions that assessed both the severity and frequency of symptoms. 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: From baseline to weeks 4, 8 and 12
Population: Full Analysis Set Population. Observed values are reported.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| rhNGF 20 µg/ml | Changes in SANDE Scores (Face Values) for Frequency and Severity | Frequency - week 4 | -35.1 score on a scale | Standard Deviation 22.37 |
| rhNGF 20 µg/ml | Changes in SANDE Scores (Face Values) for Frequency and Severity | Frequency - week 8 | -37.2 score on a scale | Standard Deviation 24.84 |
| rhNGF 20 µg/ml | Changes in SANDE Scores (Face Values) for Frequency and Severity | Frequency - week 12 | -42.1 score on a scale | Standard Deviation 22.94 |
| rhNGF 20 µg/ml | Changes in SANDE Scores (Face Values) for Frequency and Severity | Severity - week 4 | -35.7 score on a scale | Standard Deviation 24.28 |
| rhNGF 20 µg/ml | Changes in SANDE Scores (Face Values) for Frequency and Severity | Severity - week 8 | -37.9 score on a scale | Standard Deviation 27.51 |
| rhNGF 20 µg/ml | Changes in SANDE Scores (Face Values) for Frequency and Severity | Severity - week 12 | -43.5 score on a scale | Standard Deviation 22.7 |
| Vehicle | Changes in SANDE Scores (Face Values) for Frequency and Severity | Severity - week 8 | -37.3 score on a scale | Standard Deviation 20.43 |
| Vehicle | Changes in SANDE Scores (Face Values) for Frequency and Severity | Frequency - week 4 | -33.2 score on a scale | Standard Deviation 25.18 |
| Vehicle | Changes in SANDE Scores (Face Values) for Frequency and Severity | Severity - week 4 | -32.9 score on a scale | Standard Deviation 20.03 |
| Vehicle | Changes in SANDE Scores (Face Values) for Frequency and Severity | Frequency - week 8 | -35.7 score on a scale | Standard Deviation 26.04 |
| Vehicle | Changes in SANDE Scores (Face Values) for Frequency and Severity | Severity - week 12 | -38.4 score on a scale | Standard Deviation 20.23 |
| Vehicle | Changes in SANDE Scores (Face Values) for Frequency and Severity | Frequency - week 12 | -38.6 score on a scale | Standard Deviation 26.25 |
Comparison: Frequency - week 4p-value: =0.88195% CI: [-6.13, 5.27]ANCOVA
Comparison: Frequency - week 8p-value: =0.92695% CI: [-6.96, 6.33]ANCOVA
Comparison: Frequency - Week 12p-value: =0.42695% CI: [-7.97, 3.38]ANCOVA
Comparison: Severity - Week 4p-value: =0.82895% CI: [-5.04, 6.29]ANCOVA
Comparison: Severity - Week 8p-value: =0.39495% CI: [-3.75, 9.47]ANCOVA
Comparison: Severeity - Week 12p-value: =0.55295% CI: [-6.41, 3.44]ANCOVA
Secondary
Changes in Tear Film Break-Up Time (TFBUT)
The TFBUT measurement was performed after instillation of 5 microliters of 2% 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. Data for the main eye are reported.
Time frame: From baseline to weeks 4, 8 and 12
Population: As of this secondary endpoint, FAS Population was taken into account, but the last observation carried forward (LOCF) imputation method was not applied. Due to the reason mentioned above, the patients actually analysed (n) were the following:~Week 4 - 110 rhNGF Week 8 - 107 rhNGF Week 12 - 107 rhNGF
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| rhNGF 20 µg/ml | Changes in Tear Film Break-Up Time (TFBUT) | week 12 | 2.3 seconds | Standard Deviation 2.61 |
| rhNGF 20 µg/ml | Changes in Tear Film Break-Up Time (TFBUT) | week 4 | 2.5 seconds | Standard Deviation 3.07 |
| rhNGF 20 µg/ml | Changes in Tear Film Break-Up Time (TFBUT) | week 8 | 1.9 seconds | Standard Deviation 2.96 |
| Vehicle | Changes in Tear Film Break-Up Time (TFBUT) | week 4 | 2.5 seconds | Standard Deviation 2.37 |
| Vehicle | Changes in Tear Film Break-Up Time (TFBUT) | week 8 | 2.2 seconds | Standard Deviation 2.67 |
| Vehicle | Changes in Tear Film Break-Up Time (TFBUT) | week 12 | 2.7 seconds | Standard Deviation 2.72 |