Clinical trial NCT03836859: Study to Evaluate Safety, Tolerability & PK of rhNGF in Healthy Volunteers
Official title: Phase I, Randomized, Double-masked, Placebo-controlled Study (6 Days) to Evaluate the Safety, Tolerability and Pharmacokinetics of Recombinant Human Nerve Growth Factor Eye Drops in Healthy Male and Female Volunteers of Japanese Ethnicity
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy Volunteers
Keywords: Tolerability and PK
Lead sponsor: Dompé Farmaceutici S.p.A
Sponsor class: INDUSTRY
Collaborators: name: Cromsource
First posted: 2019-02-11
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Parallel assignment
Primary purpose: TREATMENT

Brief summary: The primary objective of this study is to assess the safety and tolerability of a single short-term and a multiple dose scheme of rhNGF when administered as eye drops in healthy subjects of Japanese ethnicity.

The secondary objective of this study is to assess the pharmacokinetics of single and multiple doses of rhNGF when administered as eye drops in healthy subjects of Japanese ethnicity.

Detailed description: This is a Phase I, randomized, double-masked, placebo-controlled eye drops administration study of rhNGF in healthy male and female subjects of Japanese Ethnicity to evaluate the Safety, Tolerability and Pharmacokinetics of Recombinant Human Nerve Growth Factor Eye Drops (rhNGF 20 μg/mL -formulation containing L-methionine as excipient) versus vehicle (vehicle control containing L-methionine as excipient) in Healthy Male and Female Volunteers of Japanese Ethnicity. The IMP was administered in the study Eye with the following scheme:

Day 1: One drop instilled into study eye (35 μL, corresponding to 0.70 μg of rhNGF).

Day 2, 3, 4, 5, 6: One drop six times a day (every 2h) into study eye (210 μL, corresponding to 4.20 μg of rhNGF).

Total dose in the study eye will be 31 drops (1085 μL, equivalent to 21.7 μg rhNGF) over 6 days.

The reference product (vehicle) was administered in the study eye with the following scheme:

Day 1: One drop instilled into study eye (35 μL, corresponding to 0 μg of rhNGF\].

Day 2, 3, 4, 5, 6: One drop six times a day (every 2h) into study eye (210 μL, corresponding to 0 μg of rhNGF).

A total dose of placebo vehicle in the study eye will be 31 drops (1085 μL, 0 μg rhNGF) over 6 days.

For the Fellow (Non-Study) Eye for all subjects, the scheme was the following:

Day 1: One drop instilled into a fellow eye (35 μL, corresponding to 0 μg of rhNGF).

Day 2, 3, 4, 5, 6: One drop six times a day (every 2h) into a fellow eye (210 μL, corresponding to 0 μg of rhNGF).

A total dose of placebo vehicle in the fellow eye will be 31 drops (1085 μL, 0 μg rhNGF) over 6 days.

Eligibility criteria: Inclusion Criteria:

To be eligible for inclusion into this study, each subject must fulfil the following inclusion criteria.Each subject must meet all of the following inclusion criteria at the pre-study Screening visit (within 20 days prior to admission in the Unit for the dosing period) in order to participate in this study.

1. Male or female subjects of Japanese ethnicity, aged between 18 and 60 years inclusive, who must have all four Japanese grandparents who were born in Japan.
2. 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.
3. Subject's systemic and ocular medical history must be considered normal in the opinion of the investigator at the Screening and Baseline visits.
4. Subject with Best corrected distance visual acuity (BCDVA) score ≥83 ETDRS letters, ≤ 0.00 LogMAR \[20/20 Snellen or 1.0 decimal fraction\] in each eye at the Screening and Baseline visits.
5. Normal anterior segment on external and slit lamp examination in both eyes at the Screening and Baseline visits.
6. Normal posterior segment on fundus ophthalmoscopic examination in both eyes at the Screening and Baseline visits.
7. 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 ≥ 40 and ≤ 100 beats per minute; oral body temperature ≥ 35.5°C and ≤ 37.5°C).
   4. An ECG with no clinically significant abnormalities.
   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
8. Woman subject who meets the criteria for post-menopausal stage (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 woman subject using oral, injected or implanted hormonal methods of contraception or with a double barrier methods of contraception: condom and occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository. A female condom and a male condom should not be used together as friction between the two can result in either product failing.
9. 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. The following methods of contraception are considered to be highly effective: established use of oral, injected or implanted hormonal contraception; placement of an intrauterine device or intrauterine system; use of a barrier method of contraception (condom or occlusive cap with use of a spermicide); male sterilisation (post-vasectomy documentation of the absence of sperm in the ejaculate must be provided).

Exclusion Criteria:

Subjects meeting any of the following criteria at Screening will be excluded from entry into the study:

1. Subject has had a clinically significant illness in the 6 weeks before screening in the opinion of the investigator.
2. Subject is not suitable to participate in the study in the opinion of the investigator
3. Subject has participated in any clinical study with an investigational drug/device within 3 months prior to the first day of dosing.
4. 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).
5. 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).
6. Subject has a significant history of drug/solvent abuse or a positive drugs of abuse test at any time during the study.
7. Subject has a history of alcohol abuse or currently drinks in excess of 28 units per week or has a positive alcohol breath test at any time during the study.
8. Subject is a smoker or has smoked in the 6 months prior to dosing.
9. Subject who has a positive human immunodeficiency virus (HIV) screen, hepatitis B screen or hepatitis C screen.
10. Subject has donated blood or blood products (e.g., plasma or platelets) within the 3 months prior to screening.
11. Subject has a partner who will be pregnant or breastfeeding during the study
12. 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
13. Subject having used corticosteroid sporadically in the last 30 days whichever the route of administration, or any medication by ocular or nasal administration route
14. Subjects diagnosed with any ocular disease other than refractive error
15. Subject with history of ocular surgery, including laser refractive surgery
16. Subject using a contact lens within 7 days prior administration of the first dose
17. Intraocular pressure (IOP) ≥ 22 mmHg in either eye at screening or baseline
18. Presence of any corneal opacity or corneal fluorescein staining \>0.5 grade using the modified Oxford scale in either eye at screening or baseline
19. Schirmer's test without anesthesia ≤ 9 mm/5 minutes in either eye at screening or baseline
20. Tear film break up time (TFBUT) \< 8 seconds in either eye at screening or baseline Note: Alcoholic beverages should not be taken from 48 h before first drug administration until discharge from the Study center.

Primary outcomes:
measure: Number of Treatment Emergent Adverse Events (TEAEs).
timeFrame: On Day 1 (single dose scheme), Days 2-6 (multiple dose scheme), Day 7 (Follow-up [FU] 1), Day 8 (FU 2); Day 16 (FU 3), and Day 35-42 (FU 4)
measure: Number of Treatment Emergent Adverse Events During First Dose Schedule (TEAEs Dose 1).
timeFrame: During first dose schedule (TEAE Dose 1, which started after first dose of study treatment at Day 1 till before administration of the first dose at Treatment Day 2)
measure: Number of Treatment Emergent Adverse Events During Second Dose Schedule (TEAEs Dose 2).
timeFrame: During second dose schedule (TEAE Dose 2, which started on/after the first dose at Treatment Day 2 till before Follow-Up Day 7 (FU1) visit
measure: Change From Baseline in Visual Analogue Scale (VAS) Ocular Tolerability Score in Study Eye: Single Dose
timeFrame: at Treatment Day 2 pre-dose
measure: Change From Baseline in Visual Analogue Scale (VAS) Ocular Tolerability Score in Study Eye: Multiple Dose
timeFrame: at Day 2 8h, Day 3 predose, Day 6 pre-dose, Day 6 8h, Day 7 (FU1), Day 8 (FU2), Day 16 (FU3)
Secondary outcomes:
measure: Number of Follow-Up AEs (FUAE)
timeFrame: on or after Follow-Up Day 7 (FU1)
measure: Number of Ocular TEAEs by Eyes
timeFrame: On Day 1 (single dose scheme), Days 2-6 (multiple dose scheme), Day 7 (Follow-up [FU] 1), Day 8 (FU 2); Day 16 (FU 3), and Day 35-42 (FU 4)
measure: Change From Baseline in Intraocular Pressure (IOP) by Eye Over All Visits
timeFrame: on Day -1 and at Day 8 (Follow up [FU] 2) and Day 16 (FU3)
measure: Change From Baseline in Visual Acuity Score for the Study Eye Over All Visits
timeFrame: On Day 1 (single dose scheme), Days 2,3,6 (multiple dose scheme), Day 7 (Follow-up [FU] 1), Day 8 (FU 2); Day 16 (FU 3)
measure: Change in Baseline in LogMAR [Derived as - Log (Snellen Equivalent Result)] for the Study Eye Over All Visits.
timeFrame: On Day 1 (single dose scheme), Days 2,3,6 (multiple dose scheme), Day 7 (Follow-up [FU] 1), Day 8 (FU 2); Day 16 (FU 3)
measure: Change From Baseline in Tear Film Break-Up Time (TFBUT) for the Study Eye Over All Visits..
timeFrame: On Day 1 (single dose scheme), Days 2,3,6 (multiple dose scheme), Day 7 (Follow-up [FU] 1), Day 8 (FU 2); Day 16 (FU 3)
measure: Change From Baseline in Overall National Eye Institute (NEI) Score for the Study Eye Over All Visits.
timeFrame: On Day 1 (single dose scheme), Days 2,3,6 (multiple dose scheme), Day 7 (Follow-up [FU] 1), Day 8 (FU 2); Day 16 (FU 3)
measure: Course of Visual Analogue Scale (VAS) Ocular Tolerability Score for the Study Eye Over All Visits.
timeFrame: On Day 1 (single dose scheme), Days 2,3,6 (multiple dose scheme), Day 7 (Follow-up [FU] 1), Day 8 (FU 2); Day 16 (FU 3)
measure: Intraindividual Change in VAS Ocular Tolerability Scores Between Study Eye and Fellow (Non-study) Eye at All Study Visits
timeFrame: On Day 1 (single dose scheme), Days 2,3,6 (multiple dose scheme), Day 7 (Follow-up [FU] 1), Day 8 (FU 2); Day 16 (FU 3)
measure: Kinetics of rhNGF Plasma Levels After Single-dose Administration and Multiple-dose Administration Through Enzyme-Linked Immunosorbent Assay I (ELISA I)
timeFrame: Day 1 (Pre-Dose, 0.5, 2, 4, 8, 9, 10, 11, 12, 14, 16 hr) and Day 2 (Pre-Dose, 0.5, 2, 4, 6, 8, 10, 10.5, 11, 12, 13, 14, 16 hr),
measure: Kinetics of rhNGF Plasma Levels After Single-dose Administration and Multiple-dose Administration Through Enzyme-Linked Immunosorbent Assay II (ELISA II)
timeFrame: Day 1 (Pre-Dose, 0.5, 2, 4, 8, 9, 10, 11, 12, 14, 16 hr) and Day 2 (Pre-Dose, 0.5, 2, 4, 8, 9, 10, 10.5, 11, 12, 13, 14, 16 hr)
Other outcomes:
Locations:
city: Cypress
country: United States
facility: WCCT Global
state: California
Study officials:
affiliation: Dompé SpA Milan
name: Flavio Mantelli, MD, PhD
role: STUDY_DIRECTOR
References: