Study to Evaluate Safety, Tolerability and Pharmacokinetics of rhNGF Eye Drops in Healthy Volunteers

Study Overview
=================
Brief Summary
-----------------
The primary objective of this study is to assess the safety and tolerability of single and multiple ascending doses of rhNGF when administered as eye drops in healthy subjects.

Detailed Description
-----------------
This is a Phase I, randomised, double-masked, placebo-controlled eye drops administration study of rh-NGF in healthy male and female subjects. This study consists of a single ascending dose part (part 0 one drop single application). Then single ascending dose part (part A; one drop three times a day) and a multiple ascending dose part (part B; one drop three times a day for five days). All parts of the study will consist of 3 ascending dose levels. In order to support the dose escalation MAD phase from Covance, Basel to Covance, Leeds, an additional cohort (0M) will be conducted at Covance, Leeds at the same dose level as cohort 1M to ensure a degree of consistency between the two sites, i.e. that no dose escalation stopping criteria were met at either site. In Part 0, each ascending dose cohort will include 3 subjects treated with one dose of rh-NGF. In part A, each ascending dose cohort will include 6 subjects treated with rh-NGF and 2 with placebo. In part B, each ascending dose cohort will include 9 subjects treated with rh-NGF drug and 3 with placebo, in addition to cohort 0M, which will include 3 subjects treated with rh-NGF and 1 with placebo

Official Title
-----------------
Phase I, Randomised, Double-masked, Placebo-controlled, Combined Single and Multiple Ascending Dose Study to Evaluate Safety, Tolerability and Pharmacokinetics of rhNGF Eye Drops in Healthy Male and Female Volunteers

Conditions
-----------------
Healthy

Intervention / Treatment
-----------------
* Drug: rhNGF 0.5 µg/mL Sentinel
* Drug: rhNGF 5 µg/mL Sentinel
* Drug: rhNGF 20 µg/mL Sentinel
* Drug: rhNGF 20 µg/mL Part A
* Drug: rhNGF 60 µg/mL Part A
* Drug: rhNGF 180 µg/mL Part A
* Drug: rhNGF 20 µg/mL Part B
* Drug: rhNGF 60 µg/mL Part B
* Drug: rhNGF 180 µg/mL Part B
* Drug: Placebo Part A
* Drug: Placebo Part B


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male or female subjects, aged between 18 and 60 years, inclusive. Subject has to be able to communicate well with the investigator, understands and complies with the requirements of the study, and understands and signs the written volunteer informed consent form. Subject's systemic and ocular medical history must be considered normal in the opinion of the investigator at the Screening and Baseline visits. Best corrected distance visual acuity (BCDVA) score ≤ 0.00 LogMAR (≥83 ETDRS letters, 20/20 Snellen or 1.0 decimal fraction) in each eye at the Screening and Baseline visits. Normal anterior segment on external and slit lamp examination in both eyes at the Screening and Baseline visits. Normal posterior segment on fundus ophthalmoscopic examination in both eyes at the Screening and Baseline visits. Subject must be considered in good systemic health in the opinion of the investigator at the Screening and Baseline visits, as determined by: Subject's body mass index is between 18.5 and 30.4 kg/m2 inclusive A pre-study physical examination with no clinically significant abnormalities. Vital signs within clinically acceptable ranges for the purposes of the study (sitting systolic blood pressure [BP] ≥ 90 mmHg and ≤ 150 mmHg; diastolic BP ≥ 50 mmHg and ≤ 95 mmHg; heart rate (pulse rate) ≥ 40 and ≤ 100 beats per minute; oral body temperature ≥ 35.5°C and ≤ 37.5°C). An ECG with no clinically significant abnormalities, in the opinion of the Investigator. Pre-study clinical laboratory findings within normal range or not deemed clinically significant in the opinion of the investigator if outside of the normal range Female subjects will be: either post menopausal where post menopause is defined as the period following peri-menopause, i.e. postmenopausal after 12 months without a menstrual period and with a serum FSH value within the reference range for postmenopausal females at Screening or permanently sterilised (e.g. tubal occlusion, hysterectomy, bilateral salpingectomy) or be using 2 different forms of highly effective contraception throughout the study. Male subjects with female partners of child-bearing potential must use 2 different forms of highly effective contraception throughout the study and for a further 3 months after the follow-up visit and all male subjects must be willing to avoid donating sperm during this time. Exclusion Criteria: Subject has had a clinically significant illness in the 6 weeks before screening in the opinion of the investigator. Subject is not suitable to participate in the study in the opinion of the investigator Subject has participated in any clinical study with an investigational drug/device within 3 months prior to the first day of dosing. Subject 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 or other materials (in the opinion of the investigator). Administration of any topical ocular (prescription or over the counter including artificial tears) or systemic medication including herbal product or fish oil preparations within 14 days before the first dose of study drug. Vitamins and mineral supplements not containing other substances are allowed until 96 hours before each dose if considered by the Investigator unlikely to interfere with the study results. Paracetamol at doses of at most 2 grams per day and ibuprofen at doses of at most 1200 mg per day for no more than 3 consecutive days or 6 non-consecutive days are allowed. Oral, injectable and implantable hormonal contraceptives are allowed without restrictions for female subjects. Longer exclusion periods apply for: amiodarone and hydroxychloroquine (210 days), monoclonal antibodies/ immunoglobulins/ other therapeutic proteins (120 days) Experimental drugs with a half life known to the Study Unit: Five half lives plus 2 weeks Experimental drugs with a half life unknown to the Study Unit: 120 days chloroquine and flunarizine (100 days) fluoxetine (75 days), benzodiazepines different from midazolam, lorazepam and triazolam, chlorpromazine, mephenytoin, nortryptyline, phenobarbital, primidone, carbamazepine, phenytoin and phenprocoumon (35 days). Subject has a significant history of drug/solvent abuse (within the last 2 years) or a positive drugs of abuse test at any time during the study. Subject has a history of alcohol abuse (within the last 2 years) or currently drinks in excess of 28 units per week or has a positive alcohol breath test at any time during the study. Subject is a smoker or has smoked in the 6 months prior to dosing. Subject who has a positive human immunodeficiency virus (HIV) screen, hepatitis B screen or hepatitis C screen. Subject has donated blood or blood products (e.g., plasma or platelets) within the 3 months prior to screening. Subject has a partner who will be pregnant or breastfeeding during the study Pregnant or breastfeeding female or those with a positive pregnancy test or who will not use a medically acceptable contraceptive method from selection and during the study Subject having used any glucocorticosteroid by any route in the last 30 days whichever the route of administration, or any medication by ocular or nasal administration route from 30 days before screening. Subjects currently diagnosed with any active ocular disease, even if mild, other than refractive error. Subject with history of ocular surgery, including laser refractive surgery Subject using a contact lens within 7 days prior administration of the first dose Intraocular pressure (IOP) >= 22 mmHg in either eye Presence of any corneal opacity or corneal fluorescein staining >0.5 grade using the modified Oxford scale Schirmer's test without anesthesia <= 9 mm/5 minutes Tear film break up time < 8 seconds

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: rhNGF 0.5 µg/mL Sentinel<br>1 x 35 µL drop 3 subjects | Drug: rhNGF 0.5 µg/mL Sentinel<br>* In Part 0, all subjects received one 35-μL drop of rh-NGF at an appropriate concentration in the study eye (right or left) according to the randomisation list to achieve the required dose level<br>* Other names: Recombinant Human Nerve Growth Factor;|
| Experimental: rhNGF 5 µg/mL Sentinel<br>1 x 35 µL drop 3 subjects | Drug: rhNGF 5 µg/mL Sentinel<br>* Part 0 represented a sentinel group.<br>* Other names: Recombinant Human Nerve Growth Factor;|
| Experimental: rhNGF 60 µg/mL Part A<br>3 x 35 µL drops applied at 4 h intervals 6 subjects | Drug: rhNGF 60 µg/mL Part A<br>* In Part A, all subjects received one 35-μL drop of rh-NGF at an appropriate concentration or placebo in their study eye (right or left) according to the randomisation list (and 1 drop of placebo in the non-study eye). This occurred q4h on Day 1 to achieve the required fractionated single dose level.<br>* Other names: Recombinant Human Nerve Growth Factor;|
| Experimental: rhNGF 20 µg/mL Sentinel<br>1 x 35 µL drop 3 subjects | Drug: rhNGF 20 µg/mL Sentinel<br>* In Part 0, all subjects received one 35-μL drop of rh-NGF at an appropriate concentration in the study eye (right or left) according to the randomisation list to achieve the required dose level<br>* Other names: Recombinant Human Nerve Growth Factor;|
| Experimental: rhNGF 20 µg/mL Part A<br>3 x 35 µL drops applied at 4 h intervals 6 subjects | Drug: rhNGF 20 µg/mL Part A<br>* In Part A, all subjects received one 35-μL drop of rh-NGF at an appropriate concentration or placebo in their study eye (right or left) according to the randomisation list (and 1 drop of placebo in the non-study eye). This occurred q4h on Day 1 to achieve the required fractionated single dose level.<br>* Other names: Recombinant Human Nerve Growth Factor;|
| Experimental: rhNGF 180 µg/mL Part A<br>3 x 35 µL drops applied at 4 h intervals 6 subjects | Drug: rhNGF 180 µg/mL Part A<br>* In Part A, all subjects received one 35-μL drop of rh-NGF at an appropriate concentration or placebo in their study eye (right or left) according to the randomisation list (and 1 drop of placebo in the non-study eye). This occurred q4h on Day 1 to achieve the required fractionated single dose level.<br>* Other names: Recombinant Human Nerve Growth Factor;|
| Placebo Comparator: Placebo Part A<br>3 x 35 µL drops applied at 4 h intervals 6 subjects | Drug: Placebo Part A<br>* In Part A, all subjects received one 35-μL drop of rh-NGF at an appropriate concentration or placebo in their study eye (right or left) according to the randomisation list (and 1 drop of placebo in the non-study eye). This occurred q4h on Day 1 to achieve the required fractionated single dose level.<br>* Other names: Vehicle;|
| Experimental: rhNGF 20 µg/mL Part B<br>3 x 35 µL drops applied at 4 h intervals per day during 5 consecutive days 12 subjects | Drug: rhNGF 20 µg/mL Part B<br>* In Part B, as planned 3 dose levels of rh-NGF or placebo eye drops were studied in a total of 40 healthy subjects.<br>* Other names: Recombinant Human Nerve Growth Factor;|
| Experimental: rhNGF 60 µg/mL Part B<br>3 x 35 µL drops applied at 4 h intervals per day during 5 consecutive days 9 subjects | Drug: rhNGF 60 µg/mL Part B<br>* In Part B, all subjects received one 35-μL drop of rh-NGF at an appropriate concentration or placebo in their study eye (right or left) according to the randomisation list (and 1 drop of placebo in the non-study eye). This occurred q4h for 5 days to achieve the required multiple fractionated dose level.<br>* Other names: Recombinant Human Nerve Growth Factor;|
| Experimental: rhNGF 180 µg/mL Part B<br>3 x 35 µL drops applied at 4 h intervals per day during 5 consecutive days 9 subjects | Drug: rhNGF 180 µg/mL Part B<br>* In Part B, all subjects received one 35-μL drop of rh-NGF at an appropriate concentration or placebo in their study eye (right or left) according to the randomisation list (and 1 drop of placebo in the non-study eye). This occurred q4h for 5 days to achieve the required multiple fractionated dose level.<br>* Other names: Recombinant Human Nerve Growth Factor;|
| Placebo Comparator: Placebo Part B<br>3 x 35 µL drops applied at 4 h intervals per day during 5 consecutive days 10 subjects | Drug: Placebo Part B<br>* In Part B, all subjects received one 35-μL drop of rh-NGF at an appropriate concentration or placebo in their study eye (right or left) according to the randomisation list (and 1 drop of placebo in the non-study eye). This occurred q4h for 5 days to achieve the required multiple fractionated dose level.<br>* Other names: Vehicle;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in VAS Ocular Tolerability | A global ocular discomfort score was determined using a 100 mm visual analogue scale (VAS) on which 0 means no symptoms and 100 means the worst possible discomfort. This evaluation was performed before any ophthalmic assessment at a given study visit. Specific ocular symptoms to be assessed with the VAS included: foreign body sensation, burning/stinging, itching, pain, sticky feeling, blurred vision, photophobia. Part 0: VAS evaluated on days -1, 1, 3, 10 (FU) Part A: VAS evaluated on days -1, 1, 3, 10 (FU) Part B: VAS evaluated on days -1, 1, 5, 15 (FU) Follow up (FU) refers to participants' last available assessment. The Outcome Measure Time Points and Data Table refers to Part B. | Day -1, Day 1, Day 5, Day 15 (FU) | 
| Change in Best Corrected Distance Visual Acuity (BCDVA) | Best corrected distance visual acuity measured using the ETDRS (Early Treatment Diabetic Retinopathy Study) score. In this population, the scores range from -6 (worse visus) to 3 (best visus). The study includes Part 0, Part A and Part B. In Part B BCDVA was evaluated on days -1, 1, 5, 15 (FU). Follow up (FU) refers to participants' last available assessment. | Day -1, Day 1, Day 5, Day 15 (FU) | 
| Change in Mean Tear Film Break up Time (TFBUT) | Tear film break-up time was assessed by slit lamp examination (SLE). The shorter is the tear film break-up time, the worse is the dry eye symptom severity. The study includes Part 0, Part A and Part B. In Part B this endpoint was evaluated on days -1, 1, 5, 15 (FU). Follow up (FU) refers to participants' last available assessment. | Day -1, Day 1, Day 5, Day 15 (FU) | 
| Change in Mean Corneal Fluorescein Staining | Slit lamp examination was used to assess the eyelid margin, conjunctiva, cornea, anterior chamber, iris and lens with the instillation of fluorescein to evaluate corneal fluorescein staining (modified Oxford scale). This is 7-point ordinal scale that scores 0, 0.5, and 1 to 5. On this scale the score 0 corresponds to no staining dots (complete corneal clearing) and the score 0.5 corresponds to three or less staining dots. The higher is the number of dots, the higher and worse is the score. The study includes Part 0, Part A and Part B. In Part B the endpoint was evaluated on days -1, 1, 5, 15 (FU). | Day -1, Day 1, Day 5, Day 15 (FU) | 
| Change in Intraocular Pressure (IOP) | Intraocular pressure was determined using Goldmann applanation tonometry. The study includes Part 0, Part A and Part B. In Part B this endpoint was evaluated at screening and on days 7, 15 (FU). Follow up (FU) refers to participants' last available assessment. | Screening, Day 7, Day 15 (FU) | 
| Percentage of Abnormal Findings in Dilated Fundus Ophthalmoscopy | Dilated fundus ophthalmoscopy (DFO) is used to view the eye's interior, allowing assessment of the retina/macula/choroid, optic nerve head, blood vessels, and other features. The outcome can be normal or abnormal. The study includes Part 0, Part A and Part B. In Part B this endpoint was evaluated on day 7. | Part B - Day 7 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Nerve Growth Factor, Ophthalmic Solutions, Eye Drops, rh-NGF