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A Dose Ranging Study to Evaluate the Safety and Potential Efficacy of rhNGF in Patients With Retinitis Pigmentosa (RP) (Lumos)

Primary Purpose

Retinitis Pigmentosa

Status

Completed

Phase

Phase 1

Locations

Italy

Study Type

Interventional

Intervention

rhNGF 60 µg/ml eye drops solution

rhNGF 180 µg/ml eye drops solution

Placebo

About this trial

This is an interventional treatment trial for Retinitis Pigmentosa focused on measuring Cone-Rod Degenerations, Cone-Rod Dystrophy, Cone-Rod Dystrophy 2, Cone-Rod Retinal Dystrophy, Pigmentary Retinopathy, Retinal Cone-Rod Dystrophy, Rod Cone Dystrophies, Rod-Cone Dystrophy, Tapetoretinal Degeneration

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Patients 18 years of age or older.
Patients with typical forms of RP characterized by the following clinical features: classic fundus appearance (i.e. intraretinal pigment deposits, thinning and atrophy of the retinal pigment epithelium (RPE) in the mid- and far peripheral retina, with relative RPE preservation in the macula, waxy pallor of the optic disc, attenuation of the retinal vessels), reduced and delayed ERG responses, visual field constriction
Best corrected distance visual acuity (BCDVA) score of ≥ 48 ETDRS letters (equivalent to 20/100 Snellen, +0.7 LogMar, or 0.2 decimal fraction) in either eye at the time of study enrollment.
Documented evidence of disease progression within the 12 months prior to enrollment in the study as demonstrated by ERG (≥20% decrease in b wave amplitude in scotopic conditions or ≥25% in photopic conditions) and/or visual field testing (≥10% of Goldman Visual Field expressed as area square or ≥3 dB decrease of Humphrey Visual Field Mean Deviation).
Only patients who satisfy all Informed Consent requirements may be included in the study. The patient and/or his/her impartial witness must read, sign and date the Informed Consent document before any study-related procedures are performed. The Informed Consent form signed by patients and/or impartial witness must have been approved by the Ethics Committee (IEC) for the current study.
Patients must have the ability and willingness to comply with study procedures.

Exclusion Criteria:

Patients with atypical, early onset (first decade) or syndromic forms of RP (e.g. paravenous, pericentral sector or unilateral RP, Leber's congenital amaurosis, Refsum disease, Usher syndrome, Bardet-Biedl syndrome, etc).
Patients with non-recordable 30 Hz cone ERG in either eye.
Patients with Goldman visual field less than 20º using the V4e target or residual central visual field less than -35 dB as evaluated by the 24-2 program of the Humphrey visual field in either eye.
Evidence of an active ocular infection in either eye.
History of uveitis or evidence of intraocular inflammation in either eye.
History or evidence of glaucoma or an intraocular pressure (IOP) greater than or equal 21 mmHg in either eye at the time of study enrollment.
Patients with foveal thickness ≥ 250 micrometers (as evaluated with OCT).
History of cystoid macular oedema or presence of cystoid macular oedema on OCT at the time of study enrolment.
Anterior segment abnormalities or media opacities obscuring the view of the posterior pole in either eye.
History of any ocular surgery (including laser or refractive surgical procedures) in either eye within the 120 days before study enrolment. Ocular surgery will not be allowed during the study treatment period and elective ocular surgery procedures should not be planned during the duration of the follow-up period.
Treatment with corticosteroids (systemic, periocular or intravitreal) or any other non-approved, experimental, investigational or neuroprotectant therapy (systemic, topical, intravitreal) in either eye within 90 days of study enrollment.
Use of any medication other than the study medication for the treatment of ocular diseases with the exception of artificial tears during the study period.

Sites / Locations

Azienda Ospedaliero Universitaria Careggi
Azienda Ospedaliera San Paolo - U.O. Oculistica
A.O. Seconda Università Degli Studi di Napoli - Nuovo Policlinico - UOC Oftalmologia
Università Cattolica del Sacro Cuore - Policlinico Gemelli - Istituto di Oftalmologia
IRCCS Fondazione G.B. Bietti per lo Studio e la Ricerca in Oftalmologia

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Placebo Comparator

Arm Label

rhNGF 60µg/ml

rhNGF 180 µg/ml

Vehicle

Arm Description

rhNGF 60 µg/ml eye drops solution, one drop 3 times a day for 24 weeks in both eyes

rhNGF 180 µg/ml eye drops solution, one drop 3 times a day for 24 weeks in both eyes.

Placebo eye drops solution, one drop 3 times a day for 24 weeks in both eyes.

Outcomes

Primary Outcome Measures

Number of Participants With Serious and Non-Serious Adverse Events

Twenty-seven patients of the Safety population experienced at least one treatment-emergent adverse event, 11 patients in the rhNGF 60 μg/ml arm, 13 patients in the rhNGF 180 μg/ml arm and 3 patients in the vehicle arm.

Change in Ocular Tolerability - VAS

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. Specific ocular symptoms to be assessed with the VAS included: foreign body sensation, burning/stinging, itching, pain, sticky feeling, blurred vision, photophobia. For ocular tolerability analysis, mixed models for repeated measures were applied using various ocular tolerability parameters as response variable, treatment, visit and treatment by visit interaction as fixed effects, and baseline value as covariate.

Change in Best Corrected Distance Visual Acuity (BCDVA) (ETDRS Chart)

Best-Corrected Distance Visual Acuity (BCDVA) was assessed for each eye at each visit using an ETDRS visual acuity chart at 4 meters.

Change in Intraocular Pressure (IOP)

Intraocular Pressure was measured using either Goldmann applanation tonometry or a handheld applanation tonometer (e.g. Tonopen) after the instillation of a topical anesthetic.IOP was assessed for each eye at day 0 and at week 2, 12 and 24

Number of Participants With Normal or Abnormal Findings by Slit Lamp Examination

Slit Lamp Examination (SLE) (Biomicroscopy) was performed before the instillation of any dilating or anesthetic eye drops or fluorescein agents. SLE was executed to assess eyelids, lashes, conjunctiva, cornea, lens, iris and anterior chamber.

External Ocular Examination

External ocular examinations were done to assess, for each eye and at each visit, the motility of extraocular muscles, appearance and function of the eyelids.

Change in Ocular Tolerability - Dilated Fundus Ophthalmoscopy

Dilated fundus ophthalmoscopy was assessed for each eye evaluating the retina, macula, choroid and optic nerve head.

Presence of Anti-NGF Antibodies

Anti-NGF antibodies tests were performed at screening and at the end of treatment

Secondary Outcome Measures

Change From Baseline in Contrast Sensitivity

Contrast sensitivity was assessed using a Mars chart and is expressed as a log contrast sensitivity (log CS) score given by the log CS value at the lowest contrast numeral just prior to two incorrectly identified numerals, minus a scoring correction. The higher is the number of characters properly read by the patient, the higher is the contrast sensitivity.

Change From Baseline in Humphrey Visual Field 24-2

The Humphrey Visual Field (HVF) analyzer is a tool for measuring the human visual field by providing information regarding the location of any disease processes or lesion(s) throughout the visual pathway. In particular, Humphrey Visual Field 24-2 was used to assess static perimetry by measuring 24 degrees temporally and 30 degrees nasally and tests 54 points. The Analyser projects a series of white light stimuli of varying intensities (brightness), throughout a uniformly illuminated bowl. The higher is the number of stimuli perceived by the patient, the better is the retina's ability to detect a stimulus at specific points within the visual field.

Change in Goldmann Visual Field

The Goldmann field exam was performed to assess kinetic perimetry on all enrolled patients.

Fundus Imaging

A recordable fundus image (photo or other electronic format) showing the central 30 degrees was captured through a dilated pupil to document the appearance of the posterior pole.

Ocular Coherence Tomography (OCT)

Ocular coherence tomography was performed to evaluate the cross-sectional anatomy of the macula and to document areas of retinal atrophy.

Microperimetry

MP1 microperimetry was analyzed to provide a more accurate measurement of retinal sensitivity in the central visual field, even in patients with unstable or extrafoveal fixation.

Binocular Estermann Visual Field

Binocular visual field with Estermann grid testing a stimulus array of 120 points spread over an area extending approximately ±75° horizontally, 35° superiorly and 55° inferiorly while the patient looked steadily at the fixation target.

Electrorethinogram (ERG)

A full field and 30 Hz flicker ERG was performed according to international standards. Patients were treated with anesthetic and dilating drops prior to the ERG procedure.

Full Information

NCT ID

NCT02110225

First Posted

April 8, 2014

Last Updated

April 23, 2019

Sponsor

Dompé Farmaceutici S.p.A

1. Study Identification

Unique Protocol Identification Number

NCT02110225

Brief Title

A Dose Ranging Study to Evaluate the Safety and Potential Efficacy of rhNGF in Patients With Retinitis Pigmentosa (RP)

Acronym

Lumos

Official Title

A 24 Week Phase Ib/II, Multicenter, Randomized, Controlled, Parallel Group, Dose Ranging Study With a 24 Week Follow-up to Evaluate Safety and Potential Efficacy of 2 Doses (60, 180 µg/ml) of rhNGF Solution vs Vehicle in Patients With RP.

Study Type

Interventional

2. Study Status

Record Verification Date

April 2019

Overall Recruitment Status

Completed

Study Start Date

January 2014 (Actual)

Primary Completion Date

November 2015 (Actual)

Study Completion Date

November 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Dompé Farmaceutici S.p.A

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

The primary objective of the study is to assess the safety and tolerability of two dose regimens of recombinant human nerve growth factor (rhNGF) eye drops solution administered over 6 months versus a vehicle control in patients with typical retinitis pigmentosa. The secondary objective of this study is to attempt to show a dose response by assessing the potential efficacy of the rhNGF dose regimens for improving or slowing the deterioration of visual function outcomes at 3 and 6 months. During a 6 month follow-up period patients will be monitored to determine if there is evidence of a persistent biological effect after discontinuation of the study treatment.

Detailed Description

This is a 24-week phase Ib/II, multicenter, randomized, double-masked, vehicle controlled, parallel-group, dose-ranging study with a 24-week follow-up period to evaluate the safety and potential efficacy of two doses (60 μg/ml and 180 μg/ml) of recombinant human nerve growth factor (rhNGF) eye drops solution versus vehicle in patients with typical retinitis pigmentosa (RP).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Retinitis Pigmentosa

Keywords

Cone-Rod Degenerations, Cone-Rod Dystrophy, Cone-Rod Dystrophy 2, Cone-Rod Retinal Dystrophy, Pigmentary Retinopathy, Retinal Cone-Rod Dystrophy, Rod Cone Dystrophies, Rod-Cone Dystrophy, Tapetoretinal Degeneration

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

50 (Actual)

8. Arms, Groups, and Interventions

Arm Title

rhNGF 60µg/ml

Arm Type

Experimental

Arm Description

rhNGF 60 µg/ml eye drops solution, one drop 3 times a day for 24 weeks in both eyes

Arm Title

rhNGF 180 µg/ml

Arm Type

Experimental

Arm Description

rhNGF 180 µg/ml eye drops solution, one drop 3 times a day for 24 weeks in both eyes.

Arm Title

Vehicle

Arm Type

Placebo Comparator

Arm Description

Placebo eye drops solution, one drop 3 times a day for 24 weeks in both eyes.

Intervention Type

Drug

Intervention Name(s)

rhNGF 60 µg/ml eye drops solution

Other Intervention Name(s)

recombinant human nerve growth factor 60 µg/ml solution

Intervention Description

rhNGF 60 µg/ml eye drops solution, one drop 3 times a day for 24 weeks in both eyes

Intervention Type

Drug

Intervention Name(s)

rhNGF 180 µg/ml eye drops solution

Other Intervention Name(s)

recombinant human nerve growth factor 180 µg/ml solution

Intervention Description

rhNGF 180 µg/ml eye drops solution, one drop 3 times a day for 24 weeks in both eyes

Intervention Type

Drug

Intervention Name(s)

Placebo

Other Intervention Name(s)

Vehicle

Intervention Description

Placebo eye drops solution, one drop 3 times a day for 24 weeks in both eyes

Primary Outcome Measure Information:

Title

Number of Participants With Serious and Non-Serious Adverse Events

Description

Time Frame

up to 48 weeks

Title

Change in Ocular Tolerability - VAS

Description

Time Frame

Weeks 1, 2, 6, 12, 24

Title

Change in Best Corrected Distance Visual Acuity (BCDVA) (ETDRS Chart)

Description

Best-Corrected Distance Visual Acuity (BCDVA) was assessed for each eye at each visit using an ETDRS visual acuity chart at 4 meters.

Time Frame

Weeks 1, 2, 6, 12, 24, 36, 48

Title

Change in Intraocular Pressure (IOP)

Description

Time Frame

Weeks 2,12 and 24

Title

Number of Participants With Normal or Abnormal Findings by Slit Lamp Examination

Description

Time Frame

Day 0; Weeks 1, 2, 6, 12, 24, 36 and 48

Title

External Ocular Examination

Description

External ocular examinations were done to assess, for each eye and at each visit, the motility of extraocular muscles, appearance and function of the eyelids.

Time Frame

Day 0, Weeks 1, 2, 6, 12, 24

Title

Change in Ocular Tolerability - Dilated Fundus Ophthalmoscopy

Description

Dilated fundus ophthalmoscopy was assessed for each eye evaluating the retina, macula, choroid and optic nerve head.

Time Frame

Day 0, Weeks 12, 24 and 48

Title

Presence of Anti-NGF Antibodies

Description

Anti-NGF antibodies tests were performed at screening and at the end of treatment

Time Frame

At Day 0 and at week 24

Secondary Outcome Measure Information:

Title

Change From Baseline in Contrast Sensitivity

Description

Time Frame

Weeks 12, 24, 36 and 48

Title

Change From Baseline in Humphrey Visual Field 24-2

Description

Time Frame

Weeks 12, 24, 36 and 48

Title

Change in Goldmann Visual Field

Description

The Goldmann field exam was performed to assess kinetic perimetry on all enrolled patients.

Time Frame

Weeks 12, 24, 36 and 48

Title

Fundus Imaging

Description

A recordable fundus image (photo or other electronic format) showing the central 30 degrees was captured through a dilated pupil to document the appearance of the posterior pole.

Time Frame

Day 0, Weeks 24 and 48

Title

Ocular Coherence Tomography (OCT)

Description

Ocular coherence tomography was performed to evaluate the cross-sectional anatomy of the macula and to document areas of retinal atrophy.

Time Frame

Day 0, Weeks 12, 24, 36 and 48

Title

Microperimetry

Description

MP1 microperimetry was analyzed to provide a more accurate measurement of retinal sensitivity in the central visual field, even in patients with unstable or extrafoveal fixation.

Time Frame

Day 0, Weeks 12, 24, 36 and 48

Title

Binocular Estermann Visual Field

Description

Time Frame

Day 0, Weeks 12, 24, 36 and 48

Title

Electrorethinogram (ERG)

Description

A full field and 30 Hz flicker ERG was performed according to international standards. Patients were treated with anesthetic and dilating drops prior to the ERG procedure.

Time Frame

Day 0, Weeks 12, 24, 36 and 48

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Patients 18 years of age or older. Patients with typical forms of RP characterized by the following clinical features: classic fundus appearance (i.e. intraretinal pigment deposits, thinning and atrophy of the retinal pigment epithelium (RPE) in the mid- and far peripheral retina, with relative RPE preservation in the macula, waxy pallor of the optic disc, attenuation of the retinal vessels), reduced and delayed ERG responses, visual field constriction Best corrected distance visual acuity (BCDVA) score of ≥ 48 ETDRS letters (equivalent to 20/100 Snellen, +0.7 LogMar, or 0.2 decimal fraction) in either eye at the time of study enrollment. Documented evidence of disease progression within the 12 months prior to enrollment in the study as demonstrated by ERG (≥20% decrease in b wave amplitude in scotopic conditions or ≥25% in photopic conditions) and/or visual field testing (≥10% of Goldman Visual Field expressed as area square or ≥3 dB decrease of Humphrey Visual Field Mean Deviation). Only patients who satisfy all Informed Consent requirements may be included in the study. The patient and/or his/her impartial witness must read, sign and date the Informed Consent document before any study-related procedures are performed. The Informed Consent form signed by patients and/or impartial witness must have been approved by the Ethics Committee (IEC) for the current study. Patients must have the ability and willingness to comply with study procedures. Exclusion Criteria: Patients with atypical, early onset (first decade) or syndromic forms of RP (e.g. paravenous, pericentral sector or unilateral RP, Leber's congenital amaurosis, Refsum disease, Usher syndrome, Bardet-Biedl syndrome, etc). Patients with non-recordable 30 Hz cone ERG in either eye. Patients with Goldman visual field less than 20º using the V4e target or residual central visual field less than -35 dB as evaluated by the 24-2 program of the Humphrey visual field in either eye. Evidence of an active ocular infection in either eye. History of uveitis or evidence of intraocular inflammation in either eye. History or evidence of glaucoma or an intraocular pressure (IOP) greater than or equal 21 mmHg in either eye at the time of study enrollment. Patients with foveal thickness ≥ 250 micrometers (as evaluated with OCT). History of cystoid macular oedema or presence of cystoid macular oedema on OCT at the time of study enrolment. Anterior segment abnormalities or media opacities obscuring the view of the posterior pole in either eye. History of any ocular surgery (including laser or refractive surgical procedures) in either eye within the 120 days before study enrolment. Ocular surgery will not be allowed during the study treatment period and elective ocular surgery procedures should not be planned during the duration of the follow-up period. Treatment with corticosteroids (systemic, periocular or intravitreal) or any other non-approved, experimental, investigational or neuroprotectant therapy (systemic, topical, intravitreal) in either eye within 90 days of study enrollment. Use of any medication other than the study medication for the treatment of ocular diseases with the exception of artificial tears during the study period.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Flavio Mantelli, MD, PhD

Organizational Affiliation

Dompé farmaceutici S.p.A., Milan

Official's Role

Study Director

Facility Information:

Facility Name

Azienda Ospedaliero Universitaria Careggi

City

Florence

ZIP/Postal Code

50124

Country

Italy

Facility Name

Azienda Ospedaliera San Paolo - U.O. Oculistica

City

Milano

ZIP/Postal Code

20142

Country

Italy

Facility Name

A.O. Seconda Università Degli Studi di Napoli - Nuovo Policlinico - UOC Oftalmologia

City

Naples

ZIP/Postal Code

80129

Country

Italy

Facility Name

Università Cattolica del Sacro Cuore - Policlinico Gemelli - Istituto di Oftalmologia

City

Rome

ZIP/Postal Code

00168

Country

Italy

Facility Name

IRCCS Fondazione G.B. Bietti per lo Studio e la Ricerca in Oftalmologia

City

Rome

ZIP/Postal Code

00198

Country

Italy

12. IPD Sharing Statement

Learn more about this trial

A Dose Ranging Study to Evaluate the Safety and Potential Efficacy of rhNGF in Patients With Retinitis Pigmentosa (RP)

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