Study to Evaluate Safety, Tolerability and Pharmacokinetics of rhNGF Eye Drops in Healthy Volunteers
Condition: Healthy
Intervention: rhNGF 0.5 µg/mL Sentinel; rhNGF 5 µg/mL Sentinel; rhNGF 20 µg/mL Sentinel; rhNGF 20 µg/mL Part A; rhNGF 60 µg/mL Part A; rhNGF 180 µg/mL Part A; rhNGF 20 µg/mL Part B; rhNGF 60 µg/mL Part B; rhNGF 180 µg/mL Part B; Placebo Part A; Placebo Part B
Intervention description: 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; Part 0 represented a sentinel group.; 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; 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.; 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.; 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.; In Part B, as planned 3 dose levels of rh-NGF or placebo eye drops were studied in a total of 40 healthy subjects.; 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.; 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.; 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.; 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.
Intervention MeSH terms: Mitogens
Phase: Phase 1
Study type: Interventional
Primary purpose: Basic Science
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 74.0
Sex: All
Minimum age: 18 Years
Maximum age: 60 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: Nerve Growth Factor; Ophthalmic Solutions; Eye Drops; rh-NGF

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.
    

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:

               1. Subject's body mass index is between 18.5 and 30.4 kg/m2 inclusive

               2. A pre-study physical examination with no clinically significant abnormalities.

               3. 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).

               4. An ECG with no clinically significant abnormalities, in the opinion of the
                  Investigator.

               5. 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:

               1. amiodarone and hydroxychloroquine (210 days),

               2. monoclonal antibodies/ immunoglobulins/ other therapeutic proteins (120 days)

               3. Experimental drugs with a half life known to the Study Unit: Five half lives plus
                  2 weeks

               4. Experimental drugs with a half life unknown to the Study Unit: 120 days

               5. chloroquine and flunarizine (100 days)

               6. fluoxetine (75 days),

               7. 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