Safety and Efficacy of rhNGF Eye Drops at Different Doses in Patients With Dry Eye

Study Overview
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Brief Summary
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The primary objective of this study was to assess the efficacy and safety of different doses of rhNGF when administered as eye drops to patients with dry eye.

Detailed Description
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This is an open-label study evaluating safety and efficacy of recombinant human nerve growth factor (rhNGF) eye drops at different doses in patients with Dry Eye

Official Title
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An Open-label Study Evaluating Safety and Efficacy of Recombinant Human Nerve Growth Factor (rhNGF) Eye Drops at Different Doses in Patients With Dry Eye

Conditions
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Dry Eye Syndrome

Intervention / Treatment
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* Drug: rhNGF 20 µg/mL
* Drug: rhNGF 4 µg/mL


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patients, ≥ 18 years old; Required use of artificial tears for the treatment of Dry Eye within the 3 months prior to study enrolment; Current use or recommended use of artificial tears for the treatment of Dry Eye; Average VAS score for typical symptoms of Dry Eye (foreign body sensation, burning/stinging, itching, pain, stick feeling, blurred vision and photophobia) ≥ 25 mm; Corneal staining score with lissamine green > 3 using the NEI corneal grading system in the worse eye (study eye); Conjunctival staining score > 3 using the NEI conjunctival grading system in the worse eye (study eye); Schirmer test without anaesthesia ≤ 10 mm/5 minutes in the worse eye (study eye); Tear film break-up time (TBUT) ≤ 10 seconds in the worse eye (study eye); A negative urine pregnancy test if female of childbearing potential and must use adequate birth control throughout the study period Exclusion Criteria: Patient not suitable to participate in the study in the opinion of the investigator; Patient with a mild or moderate Dry Eye condition (severity level less than 3 according to the Report of the International Dry Eye Workshop -DEWS, 2007) if fourteen (14) patients with mild or moderate dry eye condition have been already enrolled in the current treatment group (Group 1 and Group 2 separately); Patient has had a serious adverse reaction or significant hypersensitivity to any drug or chemically related compounds or has a clinically significant allergy to drugs, foods, amide local anaesthetics or other materials including commercial artificial tears containing Hypromellose (in the opinion of the investigator); Use of topical cyclosporine, topical corticosteroids or any other topical medication for the treatment of dry eye in either eye within 30 days of study enrolment. Use of own artificial tears is allowed until Visit 2; Any ocular disease other than Dry Eye requiring treatment with topical medications in either eye within 30 days 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 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 within 30 days of study enrolment; History of ocular surgery in the study eye, including corneal refractive procedures, within 90 days of study enrolment; 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1 - rhNGF 20 μg/mL<br>(first planned dose): drop (35 μL) corresponding to 0.70 μg of rhNGF (recombinant human Nerve Growth Factor) was instilled into each eye twice a day (b.i.d.) every 12±2 h for a total daily dose of 2.8 μg (both eyes), for 28 consecutive days. The total dose was 78.4 μg/28 days. | Drug: rhNGF 20 µg/mL<br>* 1 drop for each eye, twice daily for 28 day<br>* Other names: cenegermin, recombinant human Nerve Growth Factor;|
| Experimental: Group 2 - rhNGF 4 μg/mL<br>after completion of Group 1 treatment, one drop (35 μL) corresponding to 0.14 μg of rhNGF (recombinant human Nerve Growth Factor) instilled into each eye b.i.d. every 12±2 h for a total daily dose of 0.56 μg, for 28 consecutive days. Total dose was 15.68 μg/28 days. | Drug: rhNGF 4 µg/mL<br>* 1 drop each eye, twice daily for 28 day<br>* Other names: cenegermin, recombinant human Nerve Growth Factor;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Frequency of Dry Eye Symptoms (SANDE) | The SANDE is a short questionnaire to evaluate the frequency of ocular dryness and/or irritation symptoms. For the assessment, the patients mark on a 100 mm Visual Analogue Scale (VAS) line the point that they feel represents their perception of their current state. The VAS score is determined by measuring in millimetres from the left hand end of the line to the point that the patient marks. The SANDE scores (0-100) will be then evaluated for frequency per day. | Baseline, Day 1, Day 8, Day 29 and Day 56 | 
| Change From Baseline in Severity of Dry Eye Symptoms (SANDE) | The SANDE is a short questionnaire to evaluate the severity of ocular dryness and/or irritation symptoms. For the assessment, the patients mark on the 100 mm VAS line the point that they feel represents their perception of their current state. The VAS score is determined by measuring in millimetres from the left-hand end of the line to the point that the patient marks. The SANDE scores (0-100) will be then evaluated for severity. The higher the score, the worse the outcome. | Baseline, Day 1, Day 8, Day 29 and Day 56 | 
| Change From Baseline in Ocular Surface Vital Staining (National Eye Institute [NEI] Scale) | The cornea is divided into five sectors (central, superior, inferior, nasal and temporal), each of which is scored on a scale of 0-3, with a maximal score of 15. Both nasally and temporally, the conjunctiva is 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 score of 9 for the nasal and temporal conjunctiva. Staining was derived as the sum of scores in the various sectors. The higher the total score the more compromised is the ocular surface. | Baseline, Day 1, Day 8, Day 29 and Day 56 | 
| Change From Baseline in Tear Wetting Distance as Determined by Schirmer Tear Test I - Study Eye | The Schirmer test type I (without anaesthesia) was performed to measure aqueous tear secretion prior to the instillation of any dilating or anaesthetic eye drops. The rounded tip of a standardized paper strip is inserted into the lower fornix of the eye, and the wetted length extending out from the lower lid is recorded after 5 min of eye closure. Both eyes could be tested at the same time. Changes from baseline in values of Schirmer's test type I are summarised by eye and evaluation visit, and stratified by severity level. The longer the wetted length the healthier the status of the eye. Only study eye's results are reported hereunder. | Baseline, Day 1, Day 8, Day 29 and Day 56 | 
| Number of Participants With Treatment-emergent Adverse Events (TEAEs), | The treatment-emergent adverse events were recorded throughout the whole study. | Throughout the study up to day 56 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Ocular Tolerability (Visual Analogue Scale, VAS) | A ocular tolerability score was determined using a 100 mm VAS on which 0 meant No symptoms and 100 meant the Worst possible discomfort. The patients subjectively evaluated their ocular symptoms (foreign body sensation, burning or stinging, itching, pain, sticky feeling, blurred vision and photophobia) using the VAS giving the value they were feeling from none to an extreme value. The ocular symptoms were evaluated by the patients through the scale. Only the study eye's results are reported hereunder. | Baseline, Day 1, Day 8, Day 29 and Day 56 | 
| Change From Baseline in Slit Lamp Examination | SLE grading of the eyelids, lashes, conjunctiva, cornea, lens, iris and anterior chamber was done according to the following scales: Eyelid - Meibomian glands (evaluation of the central ten Meibomian gland openings in the mid-portion of the upper eyelid): 0, 1, 2, 3 = None, Mild, Moderate, Severe gland plugging Eyelid - Erythema 0, 1, 2, 3,4 = None, Mild, Moderate, Severe, Very severe redness of lid margin and/or skin Eyelid - Oedema 0, 1, 2, 3,4 = None, Mild, Moderate, Severe, Very severe oedema Lashes 0 = Normal 1 = Abnormal Conjunctiva - Erythema 0, 1, 2, 3, 4 = None, Mild, Moderate, Severe erythema Conjunctiva - Oedema 0, 1, 2, 3, 4 = None, Mild, Moderate, Severe, Very severe swelling Lens 0, 1, 2, 3 = No, Mild, Moderate, Severe opacification N/A = Patient with artificial lens Iris 0 = Normal 1 = Abnormal. Anterior Chamber Inflammation 0, 1, 2, 3, = No, Mild, Moderate, Severe, Very severe Tyndall effect Only the study eye's results are reported hereunder. | Baseline, Day 1, Day 8, Da 29 and Day 56 | 
| Change From Baseline in Tear Wetting Distance as Determined by Schirmer Tear Test II - Study Eye | The Schirmer test type II (with anaesthesia) was performed to measure aqueous tear secretion following the instillation of a preservative-free anaesthetic eye drop (Oxybuprocaine Chlorhydrate 0.4%). The rounded tip of a standardized paper strip is inserted into the lower fornix of the eye, and the wetted length extending out from the lower lid is recorded after 5 min of eye closure. Both eyes could be tested at the same time. Changes from baseline in values of Schirmer's test type I are summarised by eye and evaluation visit and stratified by severity level. The longer the wetted length the healthier the status of the eye. Only study eye's results are reported hereunder. | Baseline, Day 1, Day 8, Day 29 and Day 56 | 
| Change From Baseline 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. With the aid of a slit lamp at 10X magnification using cobalt blue illumination, the examiner will monitor the integrity of the tear film, noting the time it takes to form lacunae (clear spaces in the tear film) from the time that the eye is opened after the last blink. The longer the time the better the integrity of the tear film. Only Study eye's results are reported hereunder. | Baseline, Day 1, Day 8, Day 29 and Day 56 | 
| Change From Baseline in Corneal Fluorescein Staining | Fluorescein staining of the cornea is a methodology to visualize corneal epithelial defects under slit lamp microscopy in patients with suspicious or known Dry Eye Disease (DED). Fluorescein dyed - impregnated paper strips were used. Before placing the strip in the lower fornix of the eye, a drop of sterile saline was added to the strip. 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 global score of 15. For a better reading under the slit lamp, no intense illumination beam was used, since it could reduce the contrast and lead to an underestimation of grading. The lower the score the lower the corneal damage. | Baseline, Day 1, Day 8, Day 29 and Day 56 | 
| Change From Baseline in Corneal Sensitivity to Contact (Cochet-Bonnet Aesthesiometry) | Corneal sensitivity was measured in cm through the Luneau-Cochet-Bonnet aesthesiometer. This contains a thin, retractable, nylon monofilament that extends up to 6 cm in length. Variable pressure can be applied to the cornea by adjusting the monofilament length. The monofilament length ranges from 6 to 0.5 cm. As the monofilament length is decreased the pressure increases from 11 mm/g to 200 mm/g. The filament is retracted incrementally in 0.5 cm until the patient gives a positive reaction indicating that the contact of the monofilament on the cornea has been sensed. The shorter filament lengths indicate decreased corneal sensation. The length of the filament (in cm) at which the patient sensed the contact with the cornea is recorded. Only study eye's results are reported hereunder. | Baseline, Day 1, Day 8, Day 29 and Day 56 | 
| Change From Baseline in Intraocular Pressure (IOP) | IOP was performed using either Goldmann applanation tonometry or a handheld applanation tonometer (e.g. Tonopen) after the instillation of a topical anaesthetic. IOP was measured in both eyes after completion of all other slit lamp examinations to avoid potential interference with the other evaluations. Only study eye's results are reported hereunder. | Baseline, Day 1, Day 8, Day 29 and Day 56 | 
| Change From Baseline in Ocular Surface Disease Index (OSDI) | The OSDI is based on a 12-item questionnaire designed to provide a rapid assessment of the symptoms of ocular irritation consistent with dry eye disease and their impact on vision-related functioning. The 12 items of the OSDI questionnaire are graded on a 0-4 scale as follows: Grade 0 = none Grade 1 = some Grade 2 = half Grade 3 = most Grade 4 = all The total OSDI score was then calculated on the basis of the following formula: OSDI=[(sum of scores for all questions answered) × 100]/[(total number of questions answered) × 4]. Thus, the OSDI total score scales from 0 to 100, with higher scores representing greater disability. | Baseline, Day 1, Day 8, Day 29 and Day 56 | 
| Change From Baseline in Visual Acuity (BCDVA) | Values of Best-Corrected Distance Visual Acuity (BCDVA) scores were measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) score. The ETDRS charts use letters, or a geometric progression in letter size from line to line, under standardized lighting conditions. The patient starts at the top of the chart, or on the last row where he or she can read all of the letters, and reads down the chart until he or she reaches a row where a minimum of three letters on a line cannot be read. The patient is scored by how many letters could be correctly identified. Therefore, the higher the number of letters the higher the visual acuity. Changes in the ETDRS score from baseline (screening visit) are summarised by eye (study eye and non study eye) and evaluation visit, and stratified by severity level. Only study eye's results are reported hereunder. | Baseline, Day 1, Day 8, Day 29 and Day 56 | 
| Number of Participants With a Change in Fundus Ophthalmoscopy | This test allows seeing inside the fundus of the eye and other structures using an ophthalmoscope. The fundus examination included assessments of vitreous, macula, retina and optic nerve head for both eyes. Only the results concerning the study eye are reported hereunder. These structures will be assessed according to the criteria outlined below. Vitreous The examiner will judge the appearance of the vitreous in the visual axis. Normal: Absence of any opacity Abnormal: Presence of opacity Macula, (Peripheral) Retina and Optic Nerve Head The examiner will provide a separate assessment of the macular, choroid and peripheral retina Normal: Absence of any structural or vascular change, inflammation, oedema or haemorrhage. Abnormal: Evidence of any ongoing or previous structural/vascular change, inflammation, oedema or haemorrhage. | Baseline, Day 1, Day 8, Day 29 and Day 56 | 
| Change From Baseline in Tear Film Osmolarity | Values of tear film osmolarity and their changes from baseline (screening visit) are summarised by eye (study eye and non study eye) and evaluation visit and stratified by severity level. Only study eye's results are reported hereunder. | Changes from baseline up to day 56±4 | 
| Change From Baseline in Conjunctival Impression Cytology for Goblet Cells' Count | Four conjunctival impression cytology samples (temporal, nasal, inferior and superior bulbar conjunctiva) for conjunctival goblet cell counts were performed in the worse eye (study eye). Conjunctival epithelium samples are obtained following the instillation of a preservative-free anaesthetic eye drop by slightly pressing on the bulbar conjunctiva a 0.1 μm cellulose acetate filter. When the disc is removed the apical layers of conjunctival epithelium remain impressed on it. Cells on the filter are fixed and stained. The final results will be expressed as mean ± SD of 3 consecutive optic fields for each sample. A higher number of goblet cells indicates a healthier eye. | Baseline, Day 1, Day 8, Day 29 and Day 56 | 
| Mean Frequency of Artificial Tears Use | During the treatment with rhNGF at both doses (from day 1 to day 29), and in the follow-up period (from day 29 to day 56) the mean frequency of daily use of artificial tears was measured. | Day 1-Day 8, Day 9-Day 29, Day 30-Day 56 intervals | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Dry Eye