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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:
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| rhNGF 20 µg/ml | Experimental | Recombinant Human Nerve Growth Factor (rhNGF) at 20 μg/mL eye drops six times daily |
|
| Vehicle | Placebo Comparator | Vehicle eye drops six times daily |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| rhNGF | Drug | Eye Drop 20 μg/mL |
|
|
| Measure | Description | Time Frame |
|---|---|---|
| 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. | Baseline and Week 8 |
| 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). | Baseline and Week 8 |
| Measure | Description | Time Frame |
|---|---|---|
| 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. |
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Inclusion Criteria:
Male or female ≥18 years old
Patients who are characterized by the following clinical features:
The same eye (study eye) must fulfill all the above criteria
Best corrected distance visual acuity (BCDVA) score of ≥ 0.1 decimal units in both eyes at the time of study enrolment
Female patients must have negative pregnancy urine test if at childbirth potential.
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.
Patients must have the ability and willingness to comply with study procedures
Exclusion Criteria:
Any ocular disease other than Dry Eye requiring treatment with topical medications in either eye at the time of study enrolment.
Any active ocular infection or active inflammation in either eye unrelated to Dry Eye.
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.
Use of therapeutic or Refractive Contact lenses in either eye at the time of study enrolment;
History of ocular surgery in the study eye(s), excluding corneal refractive or cataract procedures, within 90 days of study enrolment.
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:
Participation in another clinical study at the same time as the present and within 30 days of study enrolment;
History of drug, medication or alcohol abuse or addiction.
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| Name | Affiliation | Role |
|---|---|---|
| Leonardo Mastropasqua, MD | Univ. G. D'Annunzio- Clinica Oftalmologica Chieti | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Univ. G. D'Annunzio-Clinica Oftalmologica-Chieti | Chieti | Italy |
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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.
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| ID | Title | Description |
|---|---|---|
| FG000 | 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 |
| FG001 | Vehicle | Vehicle eye drops six times daily Vehicle: Vehicle Eye Drop |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Treatment Period |
|
| |||||||||||||||||||||
| Follow-up Period |
|
Analysed for safety (SAF) population
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| ID | Title | Description |
|---|---|---|
| BG000 | 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 |
| BG001 | Vehicle | Vehicle eye drops six times daily Vehicle: Vehicle Eye Drop |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | Full Analysis Set Population. Last observation carried forward (LOCF) imputation method | Posted | Mean | Standard Deviation | score on a scale | Baseline and Week 8 |
|
Adverse events were collected at each time point of the study (ie. Baseline visit, Week 4, Week 8 and week 12 (follow-up visit)
Overall Summary of Adverse Events is calculated on the Analysed for safety (SAF) population, i.e. 115 patients in the rhNGF group and 59 in the vehicle group.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Appendicitis | Infections and infestations | MedDRA 20.0 | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Eye pain | Eye disorders | MedDRA 20.0 | Systematic Assessment |
LImitations and caveats non specified
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Clinical Development & Operations | Dompé farmaceutici s.p.a. | +39 02 583831 | clinical.trials@dompe.com |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Apr 12, 2017 | Jan 25, 2019 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Jul 11, 2017 | Jan 25, 2019 | SAP_001.pdf |
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| ID | Term |
|---|---|
| D020932 | Nerve Growth Factor |
| ID | Term |
|---|---|
| D009414 | Nerve Growth Factors |
| D036341 | Intercellular Signaling Peptides and Proteins |
| D010455 | Peptides |
| D000602 | Amino Acids, Peptides, and Proteins |
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For the whole duration of the trial, treatment was unknown to the patient, the Investigator and the site staff.
| Vehicle |
| Other |
Vehicle Eye Drop |
|
| From baseline to weeks 4, 8 and 12 |
| 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. | From baseline to weeks 4, 8 and 12 |
| 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. | From baseline to week 8 |
| 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. | From baseline to weeks 4, 8 and 12 |
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|
|
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
Recombinant Human Nerve Growth Factor (rhNGF) at 20 μg/mL eye drops six times daily
rhNGF: Eye Drop 20 μg/mL
| OG001 | Vehicle | Vehicle eye drops six times daily Vehicle: Vehicle Eye Drop |
|
|
|
| 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). | Full Analysis Set population. Last observation carried forward (LOCF) imputation method. | Posted | Mean | Standard Deviation | score on a scale | Baseline and Week 8 |
|
|
|
|
| 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. | 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 | Posted | Mean | Standard Deviation | units on a scale | From baseline to weeks 4, 8 and 12 |
|
|
|
| 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. | 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 | Posted | Mean | Standard Deviation | seconds | From baseline to weeks 4, 8 and 12 |
|
|
|
| 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. | As of this secondary endpoint, FAS Population was taken into account, but the last observation carried forward (LOCF) imputation method was not applied. | Posted | Mean | Standard Deviation | cm | From baseline to week 8 |
|
|
|
| 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. | Full Analysis Set Population. Observed values are reported. | Posted | Mean | Standard Deviation | score on a scale | From baseline to weeks 4, 8 and 12 |
|
|
|
|
| 0 |
| 115 |
| 1 |
| 115 |
| 50 |
| 115 |
| EG001 | Vehicle | Vehicle eye drops six times daily Vehicle: Vehicle Eye Drop | 0 | 59 | 0 | 59 | 19 | 59 |
| Eye irritation | Eye disorders | MedDRA 20.0 | Systematic Assessment |
|
| Vision blurred | Eye disorders | MedDRA 20.0 | Systematic Assessment |
|
| Myopia | Eye disorders | MedDRA 20.0 | Systematic Assessment |
|
| Dry eye | Eye disorders | MedDRA 20.0 | Systematic Assessment |
|
| Eye swelling | Eye disorders | MedDRA 20.0 | Systematic Assessment |
|
| photophobia | Eye disorders | MedDRA 20.0 | Systematic Assessment |
|
| Eyelid oedema | Eye disorders | MedDRA 20.0 | Systematic Assessment |
|
| foreign body sensation in eyes | Eye disorders | MedDRA 20.0 | Systematic Assessment |
|
| Visual impairment | Eye disorders | MedDRA 20.0 | Systematic Assessment |
|
| Diplopia | Eye disorders | MedDRA 20.0 | Systematic Assessment |
|
| Eye pruritus | Eye disorders | MedDRA 20.0 | Systematic Assessment |
|
| Ocular hyperaemia | Eye disorders | MedDRA 20.0 | Systematic Assessment |
|
| Blepharospasm | Eye disorders | MedDRA 20.0 | Systematic Assessment |
|
| Conjunctival irritation | Eye disorders | MedDRA 20.0 | Systematic Assessment |
|
| Corneal epithelium defect | Eye disorders | MedDRA 20.0 | Systematic Assessment |
|
| Ocular discomfort | Eye disorders | MedDRA 20.0 | Systematic Assessment |
|
| Photopsia | Eye disorders | MedDRA 20.0 | Systematic Assessment |
|
| Headache | Nervous system disorders | MedDRA 20.0 | Systematic Assessment |
|
| Burning sensation | Nervous system disorders | MedDRA 20.0 | Systematic Assessment |
|
| Dizziness | Nervous system disorders | MedDRA 20.0 | Systematic Assessment |
|
| Nausea | Gastrointestinal disorders | MedDRA 20.0 | Systematic Assessment |
|
| Toothache | Gastrointestinal disorders | MedDRA 20.0 | Systematic Assessment |
|
| Dyspepsia | Gastrointestinal disorders | MedDRA 20.0 | Systematic Assessment |
|
| Gastrointestinal disorder | Gastrointestinal disorders | MedDRA 20.0 | Systematic Assessment |
|
| Mouth ulceration | Gastrointestinal disorders | MedDRA 20.0 | Systematic Assessment |
|
| Rhinitis | Infections and infestations | MedDRA 20.0 | Systematic Assessment |
|
| Influenza | Infections and infestations | MedDRA 20.0 | Systematic Assessment |
|
| Appendicitis | Infections and infestations | MedDRA 20.0 | Systematic Assessment |
|
| Ear infection | Infections and infestations | MedDRA 20.0 | Systematic Assessment |
|
| Sinusitis | Infections and infestations | MedDRA 20.0 | Systematic Assessment |
|
| Rhinalgia | Respiratory, thoracic and mediastinal disorders | MedDRA 20.0 | Systematic Assessment |
|
| Nasal dryness | Respiratory, thoracic and mediastinal disorders | MedDRA 20.0 | Systematic Assessment |
|
| Rhinitis allergic | Respiratory, thoracic and mediastinal disorders | MedDRA 20.0 | Systematic Assessment |
|
| Eye burns | Injury, poisoning and procedural complications | MedDRA 20.0 | Systematic Assessment |
|
| Corneal abrasion | Injury, poisoning and procedural complications | MedDRA 20.0 | Systematic Assessment |
|
| Fatigue | General disorders | MedDRA 20.0 | Systematic Assessment |
|
| Swelling | General disorders | MedDRA 20.0 | Systematic Assessment |
|
| Drug hypersensitivity | Immune system disorders | MedDRA 20.0 | Systematic Assessment |
|
| Anxiety | Psychiatric disorders | MedDRA 20.0 | Systematic Assessment |
|
| Pruritus | Skin and subcutaneous tissue disorders | MedDRA 20.0 | Systematic Assessment |
|
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| D011506 | Proteins |
| D009419 | Nerve Tissue Proteins |
| D001685 | Biological Factors |
| week 8 |
|
|
| week 12 |
|
|
| week 8 |
|
|
| week 12 |
|
|
| superior temporal |
|
| inferior temporal |
|
| Frequency - week 8 |
|
|
| Frequency - week 12 |
|
|
| Severity - week 4 |
|
|
| Severity - week 8 |
|
|
| Severity - week 12 |
|
|
| =0.926 |
| difference in least square means |
| -0.31 |
| 2-Sided |
| 95 |
| -6.96 |
| 6.33 |
| Superiority |
| Frequency - Week 12 | ANCOVA | =0.426 | difference in least square means | -2.29 | 2-Sided | 95 | -7.97 | 3.38 | Superiority |
| Severity - Week 4 | ANCOVA | =0.828 | Difference in least square means | 0.62 | 2-Sided | 95 | -5.04 | 6.29 | Superiority |
| Severity - Week 8 | ANCOVA | =0.394 | difference in least square means | 2.86 | 2-Sided | 95 | -3.75 | 9.47 | Superiority |
| Severeity - Week 12 | ANCOVA | =0.552 | difference in least square means | -1.49 | 2-Sided | 95 | -6.41 | 3.44 | Superiority |