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

NCT01744704 | Completed Phase 1 Results

• 2 other identifiers: NGF01122012-004302-10
• Study Type: interventional
• Target: 74
• Locations: 2 countries
• Sites: 2

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.

Conditions

Healthy

Keywords

Nerve Growth Factor; Ophthalmic Solutions; Eye Drops; rh-NGF

Outcome Measures

Primary Outcomes (6)

• 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

Study Arms (11)

rhNGF 0.5 µg/mL Sentinel

EXPERIMENTAL

1 x 35 µL drop 3 subjects

Drug: rhNGF 0.5 µg/mL Sentinel

rhNGF 5 µg/mL Sentinel

EXPERIMENTAL

1 x 35 µL drop 3 subjects

Drug: rhNGF 5 µg/mL Sentinel

rhNGF 60 µg/mL Part A

EXPERIMENTAL

3 x 35 µL drops applied at 4 h intervals 6 subjects

Drug: rhNGF 60 µg/mL Part A

rhNGF 20 µg/mL Sentinel

EXPERIMENTAL

1 x 35 µL drop 3 subjects

Drug: rhNGF 20 µg/mL Sentinel

rhNGF 20 µg/mL Part A

EXPERIMENTAL

3 x 35 µL drops applied at 4 h intervals 6 subjects

Drug: rhNGF 20 µg/mL Part A

rhNGF 180 µg/mL Part A

EXPERIMENTAL

3 x 35 µL drops applied at 4 h intervals 6 subjects

Drug: rhNGF 180 µg/mL Part A

Placebo Part A

PLACEBO COMPARATOR

3 x 35 µL drops applied at 4 h intervals 6 subjects

Drug: Placebo Part A

rhNGF 20 µg/mL Part B

EXPERIMENTAL

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

rhNGF 60 µg/mL Part B

EXPERIMENTAL

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

rhNGF 180 µg/mL Part B

EXPERIMENTAL

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

Placebo Part B

PLACEBO COMPARATOR

3 x 35 µL drops applied at 4 h intervals per day during 5 consecutive days 10 subjects

Drug: Placebo Part B

Interventions

rhNGF 0.5 µg/mL Sentinel DRUG

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

Also known as: Recombinant Human Nerve Growth Factor

rhNGF 0.5 µg/mL Sentinel

rhNGF 5 µg/mL Sentinel DRUG

Part 0 represented a sentinel group.

Also known as: Recombinant Human Nerve Growth Factor

rhNGF 5 µg/mL Sentinel

rhNGF 20 µg/mL Sentinel DRUG

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

Also known as: Recombinant Human Nerve Growth Factor

rhNGF 20 µg/mL Sentinel

rhNGF 20 µg/mL Part A DRUG

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.

Also known as: Recombinant Human Nerve Growth Factor

rhNGF 20 µg/mL Part A

rhNGF 60 µg/mL Part A DRUG

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.

Also known as: Recombinant Human Nerve Growth Factor

rhNGF 60 µg/mL Part A

rhNGF 180 µg/mL Part A DRUG

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.

Also known as: Recombinant Human Nerve Growth Factor

rhNGF 180 µg/mL Part A

rhNGF 20 µg/mL Part B DRUG

In Part B, as planned 3 dose levels of rh-NGF or placebo eye drops were studied in a total of 40 healthy subjects.

Also known as: Recombinant Human Nerve Growth Factor

rhNGF 20 µg/mL Part B

rhNGF 60 µg/mL Part B DRUG

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.

Also known as: Recombinant Human Nerve Growth Factor

rhNGF 60 µg/mL Part B

rhNGF 180 µg/mL Part B DRUG

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.

Also known as: Recombinant Human Nerve Growth Factor

rhNGF 180 µg/mL Part B

Placebo Part A DRUG

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.

Also known as: Vehicle

Placebo Part A

Placebo Part B DRUG

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.

Also known as: Vehicle

Placebo Part B

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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)

You may not qualify if:

• 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).
• 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.

Sponsors & Collaborators

• Dompé Farmaceutici S.p.A: lead
• Covance: collaborator

Study Sites (2)

Covance Basel Research Unit AG - Lettenweg 118 -

Allschwil, CH - 4123, Switzerland

Location

COVANCE CLINICAL RESEARCH UNIT Ltd - Springfield House - Hyde Street

Leeds, LS2 9LH, United Kingdom

Location

Related Publications (9)

• Apfel SC, Kessler JA, Adornato BT, Litchy WJ, Sanders C, Rask CA. Recombinant human nerve growth factor in the treatment of diabetic polyneuropathy. NGF Study Group. Neurology. 1998 Sep;51(3):695-702. doi: 10.1212/wnl.51.3.695.

  PMID: 9748012 BACKGROUND

• Apfel SC, Schwartz S, Adornato BT, Freeman R, Biton V, Rendell M, Vinik A, Giuliani M, Stevens JC, Barbano R, Dyck PJ. Efficacy and safety of recombinant human nerve growth factor in patients with diabetic polyneuropathy: A randomized controlled trial. rhNGF Clinical Investigator Group. JAMA. 2000 Nov 1;284(17):2215-21. doi: 10.1001/jama.284.17.2215.

  PMID: 11056593 BACKGROUND

• Bonini S, Lambiase A, Rama P, Caprioglio G, Aloe L. Topical treatment with nerve growth factor for neurotrophic keratitis. Ophthalmology. 2000 Jul;107(7):1347-51; discussion 1351-2. doi: 10.1016/s0161-6420(00)00163-9.

  PMID: 10889110 BACKGROUND

• Lambiase A, Rama P, Bonini S, Caprioglio G, Aloe L. Topical treatment with nerve growth factor for corneal neurotrophic ulcers. N Engl J Med. 1998 Apr 23;338(17):1174-80. doi: 10.1056/NEJM199804233381702.

  PMID: 9554857 BACKGROUND

• Liu Q, McDermott AM, Miller WL. Elevated nerve growth factor in dry eye associated with established contact lens wear. Eye Contact Lens. 2009 Sep;35(5):232-7. doi: 10.1097/ICL.0b013e3181b3e87f.

  PMID: 19672199 BACKGROUND

• Petty BG, Cornblath DR, Adornato BT, Chaudhry V, Flexner C, Wachsman M, Sinicropi D, Burton LE, Peroutka SJ. The effect of systemically administered recombinant human nerve growth factor in healthy human subjects. Ann Neurol. 1994 Aug;36(2):244-6. doi: 10.1002/ana.410360221.

  PMID: 8053664 BACKGROUND

• Qi H, Li DQ, Shine HD, Chen Z, Yoon KC, Jones DB, Pflugfelder SC. Nerve growth factor and its receptor TrkA serve as potential markers for human corneal epithelial progenitor cells. Exp Eye Res. 2008 Jan;86(1):34-40. doi: 10.1016/j.exer.2007.09.003. Epub 2007 Sep 15.

  PMID: 17980361 BACKGROUND

• Schifitto G, Yiannoutsos C, Simpson DM, Adornato BT, Singer EJ, Hollander H, Marra CM, Rubin M, Cohen BA, Tucker T, Koralnik IJ, Katzenstein D, Haidich B, Smith ME, Shriver S, Millar L, Clifford DB, McArthur JC; AIDS Clinical Trials Group Team 291. Long-term treatment with recombinant nerve growth factor for HIV-associated sensory neuropathy. Neurology. 2001 Oct 9;57(7):1313-6. doi: 10.1212/wnl.57.7.1313.

  PMID: 11591856 BACKGROUND

• Ferrari MP, Mantelli F, Sacchetti M, Antonangeli MI, Cattani F, D'Anniballe G, Sinigaglia F, Ruffini PA, Lambiase A. Safety and pharmacokinetics of escalating doses of human recombinant nerve growth factor eye drops in a double-masked, randomized clinical trial. BioDrugs. 2014 Jun;28(3):275-83. doi: 10.1007/s40259-013-0079-5.

  PMID: 24327173 DERIVED

MeSH Terms

Conditions

Hereditary Sensory and Autonomic Neuropathies

Interventions

cenegermin

Condition Hierarchy (Ancestors)

Nervous System Malformations; Nervous System Diseases; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Polyneuropathies; Peripheral Nervous System Diseases; Neuromuscular Diseases; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Genetic Diseases, Inborn

Limitations and Caveats

No limitations and caveats area defined.

Results Point of Contact

• Title: Clinical Development & Operations
• Organization: Dompé farmaceutici s.p.a.

clinical.trials@dompe.com

+39 02 583831

Study Officials

• Thierry Kamtchoua, MD

  Covance Basel Research Unit AG

  PRINCIPAL INVESTIGATOR

• Ashley Brooks, MBChB

  Covance

  PRINCIPAL INVESTIGATOR

• Pier Adelchi Ruffini, MD

  Dompé s.p.a.Via San Martino, 12 - 20122 Milan, Italy

  STUDY DIRECTOR

• Mauro P Ferrari, PharmD

  Dompé s.p.a. - Via San Martino, 12 - 20122 Milan, Italy

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 5, 2012
• First Posted: December 7, 2012
• Study Start: July 1, 2012
• Primary Completion: February 1, 2013
• Study Completion: March 1, 2013
• Last Updated: April 19, 2024
• Results First Posted: September 9, 2019

Record last verified: 2023-12

Locations

GB (1); CH (1)