Glaucoma
Conditions
Brief summary
The primary objective of the study is to assess the safety and tolerability of a 180μg/ml TID dose regimen of recombinant human nerve growth factor (rhNGF) eye drop solution administered over 8 weeks versus a vehicle control in patients with progressive primary open-angle glaucoma despite IOP control. The secondary objectives are to measure the changes in BCDVA, visual field, ERG and structural changes in ganglion cell layer and nerve fiber layer thickness measured by optical coherence tomography. The secondary outcomes will be examined at 1, 4 and 8 weeks of therapy, and at 4 and 24 weeks after cessation of therapy (Week 12 visit and Week 32 visit), and will include functional assessments to investigate evidence of a persistent biological effect after discontinuation of the study treatment.
Detailed description
This is an 8 Week phase Ib, monocentric, randomized, double-masked, vehicle controlled, parallel groups, study with a 24 Week follow-up period to evaluate the safety and potential efficacy of a 180 μg/ml recombinant human nerve growth factor (rhNGF) eye drops solution versus vehicle in 60 study participants with chronic primary open angle glaucoma. Participants may qualify with either progressive optic neuropathy despite maximal current therapy (i.e. IOP reduction), or with stabilized IOP but diminished vision (central or peripheral). Participants with a qualifying eye will be randomized 2:1 to topical recombinant human nerve growth factor (rhNGF) therapy or vehicle placebo control. Examinations for safety and efficacy will occur one week following initiation of therapy, and at 4, 8, 12 and 32 weeks. All participants in either arm will be followed clinically at 4 weeks after cessation of therapy.
Interventions
DRUGrhNGF
Recombinant Human Nerve Growth Factor 180μg/ml (one 35 μl drop equals to 6.30 μg of rhNGF) reconstituted solution three times a day (TID) for 8 weeks of treatment.
DRUGVehicle
Ophthalmic Placebo solution of the same composition as the test product with the exception of rhNGF reconstituted solution times a day (TID) for 8 weeks of treatment.
Sponsors
Cromsource
Dompé Farmaceutici S.p.A
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 90 Years
Healthy volunteers
No
Inclusion criteria
1. Patients 18 years of age or older. Participant must understand and sign the informed consent. If the participant's vision is impaired to the point where he/she cannot read the informed consent document, the document will be read to the participant in its entirety. 2. Participant's clinical diagnosis must be consistent with glaucoma characterized by the following features: a) clinical evidence of progressive RGC dysfunction and degeneration using visual field and/or a structural modality. There must be at least 3 reliable visual fields within 14 months prior to entering into the study; b) residual visual field preservation in at least 1 quadrant. 3. Participant must be medically able to undergo the testing required in the flowsheet of exam procedures. 4. Females of childbearing potential must agree to use an effective form of birth control.
Exclusion criteria
1. Participant has another optic nerve or retinal degenerative disease or co-morbidity causing significant vision loss, irrespective of whether it is currently treated or untreated, that could limit the possibility of visual recovery. 2. Participant is blind in one eye. 3. Participant has a requirement of acyclovir and/or related products during study duration. 4- Participant has evidence of corneal opacification or lack of optical clarity. 4. Participant has evidence of corneal opacification or lack of optical clarity. 5. Participant has undergone lens removal in the last 3 months, with or without intra-ocular lens implantation, or has undergone intra-ocular lens replacement within 3 months, or has undergone any other ocular surgery within 9 months prior to initiation of study drug. 6. Participant is receiving systemic steroids or other immunosuppressive medications. 7. Participant is currently participating in or has within the last 3 months participated in any other clinical trial of a non-clinically approved drug by ocular or systemic administration. 8. Participant has uveitis or other ocular inflammatory disease. 9. Participant has diabetic macular edema. 10. Participant has a history of ocular herpes zoster. 11. Participant is on chemotherapy. 12. Participant has a history of malignancy, not counting basal cell carcinomas, UNLESS it was treated successfully 2 years prior to inclusion in the trial. 13. Known hypersensitivity to one of the components of the study or procedural medications. 14. History of drug, medication or alcohol abuse or addiction. 15. Females of childbearing potential (those who are not surgically sterilized or post- menopausal for at least 1 year) are excluded from participation in the study if they meet any one of the following conditions: 1. are currently pregnant or, 2. have a positive result on the urine pregnancy test at the Screening/Baseline Visit or, 3. intend to become pregnant during the study treatment period or, 4. are breast-feeding or, 5. not willing to use highly effective birth control measures, such as: Hormonal contraceptives - oral, implanted, transdermal, or injected and/or mechanical barrier methods - spermicide in conjunction with a barrier such as a condom or diaphragm or IUD during the entire course of and 30 days after the study treatment periods.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Events as of Primary Safety Outcomes | At day 56/end of treatment | Unexpected Severe Progression Of Optic Neuropathy (USPON) is a composed parameter which required at least 28 single evaluations; it occurred if the subject answered Yes to any of the following 4 questions on unexpected severe progression: * Best Corrected Distance Visual Acuity (BCDVA): 'Yes' for at least one treated eye at any Follow-Up Visit after first study drug dose * Humphrey Visual Field (HVF): 'Yes' for at least one treated eye in at least one assessment during treatment or follow-up period * Electroretinography (ERG): 'Yes' for at least one treated eye at any Follow-Up Visit after first study drug dose * Optical Coherence tomography (OCT): 'Yes' for at least one treated eye at any Follow-Up Visit after first study drug dose Intolerance and allergy to the drug was identified based on preferred term of treatment-emergent adverse events. URAEs are unexpected related AE affecting ocular function. Local/systemic toxicities were identified via the AE form |
| Change From Baseline in Visual Analogue Scale (VAS) Ocular Tolerability Score | Change from baseline to days 7, 28 and 56 (Treatment period), and Day 84 (Follow up) | A ocular tolerability score was determined using a 100 mm VAS on which 0 meant No symptoms and 100 meant the Worst possible discomfort. The patients subjectively evaluated their ocular symptoms (foreign body sensation, burning or stinging, itching, pain, sticky feeling, blurred vision and photophobia) using the VAS giving the value they were feeling from none to an extreme value. The ocular symptoms were evaluated by the patients through the scale. Only overall values for primary eye and secondary eye are reported here under. An eye was considered as Primary eye, if * the eye was treated and * the investigator considered this eye as qualifying eye. * If both eyes were considered as qualifying eye, the right eye was chosen. The other eye was then considered as Secondary eye, if the eye was treated. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| rhNGF rhNGF (Recombinant Human Nerve Growth Factor) 180 μg/ml eye drops solution
rhNGF: Recombinant Human Nerve Growth Factor 180μg/ml (one 35 μl drop equals to 6.30 μg of rhNGF) reconstituted solution three times a day (TID) for 8 weeks of treatment. | 40 |
| Vehicle Ophthalmic Placebo solution
Vehicle: Ophthalmic Placebo solution of the same composition as the test product with the exception of rhNGF reconstituted solution times a day (TID) for 8 weeks of treatment. | 20 |
| Total | 60 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Lost to Follow-up | 4 | 0 |
Baseline characteristics
| Characteristic | rhNGF | Vehicle | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 25 Participants | 8 Participants | 33 Participants |
| Age, Categorical Between 18 and 65 years | 15 Participants | 12 Participants | 27 Participants |
| Age, Continuous | 68.0 years STANDARD_DEVIATION 13.98 | 62.2 years STANDARD_DEVIATION 13.28 | 66.1 years STANDARD_DEVIATION 13.92 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 1 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 38 Participants | 19 Participants | 57 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment United States | 40 participants | 20 participants | 60 participants |
| Sex: Female, Male Female | 14 Participants | 9 Participants | 23 Participants |
| Sex: Female, Male Male | 26 Participants | 11 Participants | 37 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 40 | 0 / 20 |
| other Total, other adverse events | 31 / 40 | 9 / 20 |
| serious Total, serious adverse events | 3 / 40 | 2 / 20 |
Outcome results
Primary
Change From Baseline in Visual Analogue Scale (VAS) Ocular Tolerability Score
A ocular tolerability score was determined using a 100 mm VAS on which 0 meant No symptoms and 100 meant the Worst possible discomfort. The patients subjectively evaluated their ocular symptoms (foreign body sensation, burning or stinging, itching, pain, sticky feeling, blurred vision and photophobia) using the VAS giving the value they were feeling from none to an extreme value. The ocular symptoms were evaluated by the patients through the scale. Only overall values for primary eye and secondary eye are reported here under. An eye was considered as Primary eye, if * the eye was treated and * the investigator considered this eye as qualifying eye. * If both eyes were considered as qualifying eye, the right eye was chosen. The other eye was then considered as Secondary eye, if the eye was treated.
Time frame: Change from baseline to days 7, 28 and 56 (Treatment period), and Day 84 (Follow up)
Population: The Safety Set includes all randomized subjects who received at least one dose of study medication. This safety population is used in the analysis of all safety endpoints. All analyses based on the SAF are summarized by the treatment received.~Please note that there were major protocol deviations, so that no complete VAS data was reported during treatment period; for this reason the numbers of participants analyzed per row may differ from the Overall Numbers of Participants.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| rhNGF | Change From Baseline in Visual Analogue Scale (VAS) Ocular Tolerability Score | Day 7 - primary eye | 2.8 score on a scale | Standard Deviation 9.09 |
| rhNGF | Change From Baseline in Visual Analogue Scale (VAS) Ocular Tolerability Score | Day 56 - primary eye | 3.6 score on a scale | Standard Deviation 16.08 |
| rhNGF | Change From Baseline in Visual Analogue Scale (VAS) Ocular Tolerability Score | Day 28 - primary eye | 4.0 score on a scale | Standard Deviation 11.22 |
| rhNGF | Change From Baseline in Visual Analogue Scale (VAS) Ocular Tolerability Score | Day 84 - primary eye | -0.3 score on a scale | Standard Deviation 11.81 |
| rhNGF | Change From Baseline in Visual Analogue Scale (VAS) Ocular Tolerability Score | Day 7 - secondary eye | 2.1 score on a scale | Standard Deviation 9.44 |
| rhNGF | Change From Baseline in Visual Analogue Scale (VAS) Ocular Tolerability Score | Day 28 - secondary eye | 4.6 score on a scale | Standard Deviation 13.25 |
| rhNGF | Change From Baseline in Visual Analogue Scale (VAS) Ocular Tolerability Score | Day 56 - secondary eye | 4.5 score on a scale | Standard Deviation 16.64 |
| rhNGF | Change From Baseline in Visual Analogue Scale (VAS) Ocular Tolerability Score | Day 84 - secondary eye | -0.7 score on a scale | Standard Deviation 12.95 |
| Vehicle | Change From Baseline in Visual Analogue Scale (VAS) Ocular Tolerability Score | Day 84 - secondary eye | 1.5 score on a scale | Standard Deviation 10.71 |
| Vehicle | Change From Baseline in Visual Analogue Scale (VAS) Ocular Tolerability Score | Day 7 - secondary eye | -1.4 score on a scale | Standard Deviation 6.45 |
| Vehicle | Change From Baseline in Visual Analogue Scale (VAS) Ocular Tolerability Score | Day 7 - primary eye | -2.1 score on a scale | Standard Deviation 5.95 |
| Vehicle | Change From Baseline in Visual Analogue Scale (VAS) Ocular Tolerability Score | Day 56 - secondary eye | 0.6 score on a scale | Standard Deviation 10.6 |
| Vehicle | Change From Baseline in Visual Analogue Scale (VAS) Ocular Tolerability Score | Day 28 - primary eye | 1.0 score on a scale | Standard Deviation 11.85 |
| Vehicle | Change From Baseline in Visual Analogue Scale (VAS) Ocular Tolerability Score | Day 56 - primary eye | -0.9 score on a scale | Standard Deviation 6.51 |
| Vehicle | Change From Baseline in Visual Analogue Scale (VAS) Ocular Tolerability Score | Day 28 - secondary eye | 1.2 score on a scale | Standard Deviation 12.16 |
| Vehicle | Change From Baseline in Visual Analogue Scale (VAS) Ocular Tolerability Score | Day 84 - primary eye | 0.3 score on a scale | Standard Deviation 6.78 |
Comparison: These statistics refer to Day 7 and primary eyep-value: 0.0495% CI: [0.2, 9.2]ANCOVA
Comparison: These statistics refer to Day 28 and primary eyep-value: 0.45795% CI: [-4.1, 9]ANCOVA
Comparison: These statistics refer to Day 56 and primary eyep-value: 0.28395% CI: [-3.5, 11.5]ANCOVA
Comparison: These statistics refer to Day 7 and secondary eyep-value: 0.14795% CI: [-1.3, 8.3]ANCOVA
Comparison: These statistics refer to Day 28 and secondary eyep-value: 0.42195% CI: [-4.4, 10.4]ANCOVA
Comparison: These statistics refer to Day 56 and secondary eyep-value: 0.32795% CI: [-4.4, 13]ANCOVA
Primary
Incidence of Events as of Primary Safety Outcomes
Unexpected Severe Progression Of Optic Neuropathy (USPON) is a composed parameter which required at least 28 single evaluations; it occurred if the subject answered Yes to any of the following 4 questions on unexpected severe progression: * Best Corrected Distance Visual Acuity (BCDVA): 'Yes' for at least one treated eye at any Follow-Up Visit after first study drug dose * Humphrey Visual Field (HVF): 'Yes' for at least one treated eye in at least one assessment during treatment or follow-up period * Electroretinography (ERG): 'Yes' for at least one treated eye at any Follow-Up Visit after first study drug dose * Optical Coherence tomography (OCT): 'Yes' for at least one treated eye at any Follow-Up Visit after first study drug dose Intolerance and allergy to the drug was identified based on preferred term of treatment-emergent adverse events. URAEs are unexpected related AE affecting ocular function. Local/systemic toxicities were identified via the AE form
Time frame: At day 56/end of treatment
Population: Safety Set (SAF). The Safety Set includes all randomized subjects who received at least one dose of study medication. This safety population is used in the analysis of all safety endpoints. All analyses based on the SAF are summarized by the treatment received
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| rhNGF | Incidence of Events as of Primary Safety Outcomes | USPON | 0 Number of events |
| rhNGF | Incidence of Events as of Primary Safety Outcomes | Ocular URAEs | 1 Number of events |
| rhNGF | Incidence of Events as of Primary Safety Outcomes | USPON during treatment period | 0 Number of events |
| rhNGF | Incidence of Events as of Primary Safety Outcomes | Local/systemic toxicities | 0 Number of events |
| rhNGF | Incidence of Events as of Primary Safety Outcomes | Intolerance to the drug | 6 Number of events |
| Vehicle | Incidence of Events as of Primary Safety Outcomes | Local/systemic toxicities | 0 Number of events |
| Vehicle | Incidence of Events as of Primary Safety Outcomes | USPON | 2 Number of events |
| Vehicle | Incidence of Events as of Primary Safety Outcomes | Intolerance to the drug | 0 Number of events |
| Vehicle | Incidence of Events as of Primary Safety Outcomes | Ocular URAEs | 1 Number of events |
| Vehicle | Incidence of Events as of Primary Safety Outcomes | USPON during treatment period | 0 Number of events |