Efficacy & Safety of RPh201 Treatment in Patients With Previous Nonarteritic Anterior Ischemic Optic Neuropathy (NAION)

Study Overview
=================
Brief Summary
-----------------
This study is designed as a double-masked, randomized, placebo-controlled, clinical study to evaluate the efficacy and safety of subcutaneous (SC) administration of RPh201 in participants with previous NAION. All participants enrolled in Cohort A of the study will have a documented history of NAION for at least 12 months and at most, five years prior to enrollment. Participants enrolled in Cohort B of the study will have a documented history of NAION for at least 6 months and at most, three years prior to enrollment.

Detailed Description
-----------------
This study is designed as a double-masked, randomized, placebo-controlled, clinical study to evaluate the efficacy and safety of SC administration of RPh201 in participants with previous NAION. Following a screening phase of 1-8 weeks, participants will attend a baseline visit in which they will undergo testing and visual function assessments. Participants then will be randomized to receive RPh201 or control. Cohort A After randomization, participants will begin a 26-week schedule consisting of twice-weekly treatment. Participants will return to the clinic for visits at Week 1, Week 4, Week 12 and Week 26 and Week 52 Cohort B After randomization, participants will begin a 12-week schedule consisting of four-times-per-week treatment. Participants will return to the clinic for visits at Week 4 and Week 12. Safety and efficacy parameters will be recorded throughout the duration of the study.

Official Title
-----------------
A Double-Masked Clinical Study Evaluating the Efficacy and Safety of RPh201 Treatment in Participants With Previous NAION

Conditions
-----------------
Nonarteritic Anterior Ischemic Optic Neuropathy

Intervention / Treatment
-----------------
* Drug: RPh201 Cohort A
* Other: Placebo Cohort A
* Drug: RPh201 Cohort B
* Other: Placebo Cohort B


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria (Cohort A): The participant must be 50 years of age or older at the time of the NAION episode in the study eye. This means that the participant's age at enrollment must be greater than or equal to the sum of 50 plus the number of years since NAION (e.g., at least 52 years of age if the episode was two years prior). The participant must understand the nature of the procedure and provide written informed consent prior to any study procedure. The participant has a definitive clinical diagnosis of NAION in the study eye that developed at least 12 months before randomization. Specifically, the disc swelling must have been observed and documented (by examination, OCT or photograph) by an ophthalmologist or neuro-ophthalmologist who previously examined the participant at the time of the NAION episode in the study eye during the acute episode. The participant's study eye must have disc pallor (global or segmental) present. The participant's study eye must have stable visual acuity (see Sections 5.3.3 and 5.3.4). Using the study eye, the participant must read at least 20 and at most 66 EVA letters with best-corrected vision, at each Screening visit. The participant's study eye must have a HVF 24-2 SITA Standard visual field using spot size III with mean deviation -5 dB or worse and with a visual field defect compatible with NAION in the study eye (criteria in the MOP). Exclusion Criteria (Cohort A): The participant has received treatment for cancer within 12 months prior to enrollment (excluding localized basal cell carcinoma or localized squamous cell carcinoma) or had past diagnosis of cancer adjacent to the afferent visual pathway or had past diagnosis of metastatic cancer. The participant had surgery, requiring general anesthesia with intubation, within 30 days prior to enrollment. The participant is pregnant or a woman of child-bearing potential not using an acceptable method of contraception (per Section 4.1 of the protocol). The participant is breast-feeding or plans to breast-feed. The participant has had treatment with drugs that have potential neuroprotective or toxic effects on the optic nerve or retina (e.g., ethambutol, amiodarone, linezolid, hydroxychloroquine, fingolimod, brimonidine) within 6 months prior to enrollment. The participant has participated in another interventional clinical trial within 60 days prior to enrollment, or previously participated in another clinical trial of RPh201 at any time. The participant has been receiving or has received within three months prior to enrollment, corticosteroids (except topical steroids, steroid inhalers or intermittent injections into a joint or back), or immunosuppressive drugs. The participant has a medical condition, social or psychological issue, or other condition which, in the judgment of the investigator, could be a safety concern or preclude the individual from completing the protocol. The participant has a known allergy to cottonseed oil. The participant is planning to move and not relocate near a study site and is unwilling to travel for appointments. The participant cannot self-administer or arrange for administration of the IP. The participant has one or more of the following abnormal test results at screening: Erythrocyte Sedimentation Rate (ESR) above age/2 for men or [age + 10]/2 for women, as measured by Westergren method or equivalent. Platelets >400,000 mm3 C-reactive protein (CRP) greater than two times the laboratory upper limit of normal. Severe anemia (Hgb < 10) The participant has symptoms, signs, and/or diagnosis of giant cell arteritis at any time. The participant has any other optic neuropathies (e.g., optic neuritis or glaucoma) in either or both eyes (other than self-limited optic neuropathies in the non-study eye, such as past traumatic optic neuropathy or past transient steroid-induced glaucoma due to localized steroid administration). The participant has systemic inflammatory or infectious disease associated with optic neuropathy or ocular disease. The participant has a history of uveitis in the study eye within the last 10 years. The participant's study eye has an ocular condition that appears consistent with a reduction in visual acuity to <20/25, diabetic retinopathy beyond mild non-proliferative diabetic retinopathy not involving the macula, or vision-threatening macula disease. The participant has a visual field defect with homonymous non-altitudinal features or a defect that respects the vertical meridian. Inclusion Criteria (Cohort B): The participant must be 50 years of age or older at the time of the NAION episode in the study eye. This means that the participant's age at enrollment must be greater than or equal to the sum of 50 plus the number of years since NAION (e.g., at least 52 years of age if the episode was two years prior). The participant must understand the nature of the procedure and provide written informed consent prior to any study procedure. The participant has a definitive clinical diagnosis of NAION in the study eye that developed at least 6 months and no more than 3 years before randomization. Specifically, the disc swelling must have been observed and documented (by examination, OCT or photograph) by an ophthalmologist or neuro-ophthalmologist who previously examined the participant at the time of the NAION episode in the study eye during the acute episode. The participant's study eye must have disc pallor (global or segmental) present. The participant's study eye must have stable visual acuity (see Sections 5.3.3 and 5.3.4). Using the study eye, the participant must read at least 20 and at most 66 EVA letters with best-corrected vision, at each Screening visit. Exclusion Criteria (Cohort B): The participant has received treatment for cancer within 12 months prior to enrollment (excluding localized basal cell carcinoma or localized squamous cell carcinoma) or had past diagnosis of cancer adjacent to the afferent visual pathway or had past diagnosis of metastatic cancer. The participant had surgery, requiring general anesthesia with intubation, within 30 days prior to enrollment. The participant is pregnant or a woman of child-bearing potential not using an acceptable method of contraception (per Section 4.1 of the protocol). The participant is breast-feeding or plans to breast-feed. The participant has had treatment with drugs that have potential neuroprotective or toxic effects on the optic nerve or retina (e.g., ethambutol, amiodarone, linezolid, hydroxychloroquine, fingolimod, brimonidine) within 6 months prior to enrollment. The participant has participated in another interventional clinical trial within 60 days prior to enrollment, or previously participated in another clinical trial of RPh201 at any time. Participants who were randomized into the placebo arm of Cohort A of this protocol are eligible for screening for Cohort B. The participant has been receiving or has received within three months prior to enrollment, corticosteroids (except topical steroids, steroid inhalers or intermittent injections into a joint or back), or immunosuppressive drugs. The participant has a medical condition, social or psychological issue, or other condition which, in the judgment of the investigator, could be a safety concern or preclude the individual from completing the protocol. The participant has a known allergy to cottonseed oil. The participant is planning to move and not relocate near a study site and is unwilling to travel for appointments. The participant cannot self-administer or arrange for administration of the IP. The participant has one or more of the following abnormal test results at screening: Erythrocyte Sedimentation Rate (ESR) above age/2 for men or [age + 10]/2 for women, as measured by Westergren method or equivalent. Platelets >400,000 mm3 C-reactive protein (CRP) greater than two times the laboratory upper limit of normal. Severe anemia (Hgb < 10 g/dL) The participant has symptoms, signs, and/or diagnosis of giant cell arteritis at any time. The participant has any other optic neuropathies (e.g., optic neuritis or glaucoma) in either or both eyes (other than self-limited optic neuropathies in the non-study eye, such as past traumatic optic neuropathy or past transient steroid-induced glaucoma due to localized steroid administration). The participant has systemic inflammatory or infectious disease associated with optic neuropathy or ocular disease. The participant has a history of uveitis in the study eye within the last 10 years. The participant's study eye has an ocular condition that appears consistent with a reduction in visual acuity to <20/25, diabetic retinopathy beyond mild non-proliferative diabetic retinopathy not involving the macula, or vision-threatening macula disease. The participant has a visual field defect with homonymous non-altitudinal features or a defect that respects the vertical meridian.

Ages Eligible for Study
-----------------
Minimum Age: 50 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: RPh201 Cohort A<br>A 26-week schedule consisting of twice-weekly subcutaneous administration of 400 μL of the Investigational Medical Product (IMP) (20 mg RPh201). | Drug: RPh201 Cohort A<br>* RPh201 is a proprietary, isolated botanical extract of gum mastic for treatment of nonarteritic anterior ischemic optic neuropathy (NAION).<br>|
| Placebo Comparator: Placebo Cohort A<br>A 26-week schedule consisting of twice-weekly subcutaneous administration of 400 μL of the vehicle control. | Other: Placebo Cohort A<br>* The placebo is composed of RPh-201 excipients (cottonseed oil stabilized with butylated hydroxytoluene [BHT]).<br>* Other names: Cottonseed oil;|
| Experimental: RPh201 Cohort B<br>A 12-week schedule consisting of four-times-per-week subcutaneous administration of 400 μL of the Investigational Medical Product (IMP) (20 mg RPh201). | Drug: RPh201 Cohort B<br>* RPh201 is a proprietary, isolated botanical extract of gum mastic for treatment of nonarteritic anterior ischemic optic neuropathy (NAION).<br>|
| Placebo Comparator: Placebo Cohort B<br>A 12-week schedule consisting of four-times-per-week subcutaneous administration of 400 μL of the vehicle control. | Other: Placebo Cohort B<br>* The placebo is composed of RPh-201 excipients (cottonseed oil stabilized with butylated hydroxytoluene [BHT]).<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The change in number of best-corrected visual acuity (BCVA) letters from baseline to Week 26 (Cohort A) measured using electronic visual acuity (EVA). | Visual acuity | Week 26 or Week 12 | 
| The change in number of best-corrected visual acuity (BCVA) letters from baseline to Week 12 (Cohort B) measured using electronic visual acuity (EVA). | Visual acuity | Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The proportion of study eyes improving by a 15-letter score or more in BCVA from baseline to Week 26 using EVA (Cohort A). | Visual acuity | Week 26 | 
| The proportion of study eyes improving by a 15-letter score or more in BCVA from baseline to Week 12 (Cohort B). | Visual acuity | Week 12 | 
| The proportion of study eyes improving from baseline in five or more locations of the Humphrey visual field (HVF) 24-2 full-threshold with the size V stimulus on the glaucoma change probability map (GCPM) at the 5% level by group. | Humphrey visual field (HVF) | Week 26 | 
| The proportion of study eyes improving by a 10-letter score or more in BCVA from baseline to Week 26 (Cohort A) using EVA. | Visual acuity | Week 26 | 
| The proportion of study eyes improving by a 10-letter score or more in BCVA from baseline to Week 12 (Cohort B) using EVA. | Visual acuity | Week 12 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
NAION, ischemic optic neuropathy