Safety and Efficacy Study of RVL-1201 in Acquired Blepharoptosis

Study Overview
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Brief Summary
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This is an exploratory, proof of concept study to evaluate the safety and efficacy of RVL-1201 dosed once or twice daily for 14 days compared to a placebo (vehicle) control in patients with ptosis.

Detailed Description
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This is an exploratory, proof-of-concept study. The objectives include establishing the efficacy and duration of effect of once daily (QD) or twice daily (BID) administration of RVL-1201 and the safety profile following 14 days of treatment in 72 subjects (24 per arm) with acquired blepharoptosis. Efficacy will be assessed at each treatment visit by the Humphrey Visual Field 36-point ptosis protocol test, photographic measurement of marginal reflex distance, palpebral fissure distance and contrast sensitivity in the study eye only and Visual Acuity assessment in both eyes. Safety assessments will include slit lamp examination/corneal fluorescein staining, pupil size measurement, ophthalmoscopy/ fundus examination, tonometry, visual acuity; urine pregnancy test (for women of childbearing potential only), vital signs (Heart Rate/Blood Pressure); and collection of adverse events. Subject rating of study medication comfort and assessment of ongoing tolerability will also be obtained. Primary efficacy endpoint is the mean increase from baseline in points seen on the HVF 36-point ptosis protocol test at various timepoints according to a hierarchical analysis. Analysis of exploratory endpoints will provide characterization of the efficacy and duration of effect of RVL-1201 with a variety of efficacy measures, as well as the potential additional effect of BID over QD dosing and safety profile of BID administration of RVL-1201. Exploratory endpoints will be analyzed by each regimen against placebo and between regimens and will include: The change from baseline in HVF, MRD, PFD, VA, and CS. The change from baseline in BP/HR

Official Title
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A Randomized, Double-Masked, Placebo-Controlled Phase 1/2a Study of the Efficacy and Safety of Two Dosing Regimens of RVL-1201 in the Treatment of Acquired Blepharoptosis

Conditions
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Blepharoptosis

Intervention / Treatment
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* Drug: RVL-1201
* Drug: RVL-1201 Vehicle Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult male or female subjects 18 years of age and older. Presence of all of the following at Screening: Loss on HVF 36-point ptosis protocol test of ≥ 8 points in points not seen at or above 10° from fixation in the superior visual field; AND Marginal reflex distance (MRD), the distance from the central pupillary light reflex to the upper lid margin, of ≤ 2.5 mm in the same eye as Inclusion Criterion #2a; AND Corrected Snellen visual acuity (VA) of 20/40 or better (refraction must be within 6 months of Visit 1) in the same eye as Inclusion Criteria #2a and #2b. No contraindications for treatment of both eyes as specified in Exclusion Criteria #1-14. Female subjects must be 1-year postmenopausal, surgically sterilized, or women of childbearing potential with a negative urine pregnancy test at Visit 1. Women of childbearing potential must use an acceptable form of contraception throughout the study. Provide informed consent prior to undergoing any study-related procedures. Exclusion Criteria: In either eye: Congenital ptosis Pseudoptosis Horner syndrome Marcus Gunn jaw-winking syndrome Myasthenia gravis Mechanical ptosis, including ptosis due to orbital or lid tumor, cicatricial processes affecting the movements of the upper lid, and enophthalmos Dermatochalasis as the sole cause of the signs of ptosis Previous ptosis surgery Lid position affected by lid or conjunctival scarring Current use of prescribed dry eye medication or punctal plugs; artificial tears are allowed Visual field loss from any cause other than ptosis Inability to fixate on the central fixation target of the HVF Primary open-angle glaucoma or ocular hypertension, intraocular pressure (IOP) > 24 mm Hg, or current use/use within 1 month prior to Visit 1 of any antiglaucoma medications. History of closed/narrow angle glaucoma (unless patent peripheral iridotomy has been performed > 3 months prior to Visit 1 and IOP < 20 mm Hg) or normal-tension glaucoma Use of over-the-counter vasoconstrictor/decongestant eye medication (eg, Visine® L.R.®) or any α-adrenergic agonist (including OTC products) at any time during the study Contact lens wear during the study period General: Resting heart rate (HR) outside the normal range (60 - 100 beats per minute) Hypertension diastolic blood pressure (BP) > 105 mm Hg Use of monoamine oxidase inhibitors (MAOIs; eg, isocarboxazid, phenelzine, tranylcypromine) within 14 days prior to Visit 1 or during the study Use of beta blockers (eg, propranolol, metoprolol, labetalol) within 14 days prior to Visit 1 or during the study Use of maprotiline, selective serotonin reuptake inhibitors ([SSRIs] eg, citalopram, escitalopram, paroxetine, fluoxetine, fluvoxamine, sertraline) or tricyclic antidepressants (eg, amitriptyline, doxepin, nortriptyline, amoxapine, clomipramine, desipramine, imipramine, protriptyline, trimipramine) at any time during the study A history of myocardial infarction, angina, arrhythmia, or irregular pulse Advanced arteriosclerotic disease History of thyroid disease Insulin-dependent diabetes or diabetes requiring oral hypoglycemic drugs; diet-controlled diabetes is allowed Pregnancy or lactation Diagnosed benign prostatic hypertrophy requiring medicinal therapy. History of contact or systemic allergic reaction to oxymetazoline or other sympathomimetic drugs (eg, phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine, fepradinol, or methoxamine)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: RVL-1201 once daily<br>RVL-1201 0.1% ophthalmic solution dosed one full drop per eye in the morning; one full drop of vehicle (placebo) per eye approximately 8 hours after the morning dose | Drug: RVL-1201<br>* RVL-1201 0.1% Ophthalmic Solution<br>* Other names: Oxymetazoline Hydrochloride Ophthalmic Solution 0.1%;|
| Experimental: RVL-1201 twice daily<br>RVL-1201 0.1% ophthalmic solution dosed one full drop per eye BID; approximately 8 hours between the morning dose and the afternoon dose | Drug: RVL-1201<br>* RVL-1201 0.1% Ophthalmic Solution<br>* Other names: Oxymetazoline Hydrochloride Ophthalmic Solution 0.1%;|
| Placebo Comparator: RVL-1201 vehicle (placebo)<br>RVL 1201 ophthalmic solution vehicle (placebo) dosed one full drop per eye BID; approximately 8 hours between the morning dose and the afternoon dose | Drug: RVL-1201 Vehicle Placebo<br>* RVL-1201 Vehicle Placebo<br>* Other names: RVL-1201 Ophthalmic Solution 0.1% Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Humphrey Visual Field | The mean change from baseline (Day 0, Hour 0) in number of points seen on the HVF 36-point ptosis protocol test according to a pre-planned hierarchical analysis as follows: Hour 6 on Visit 4 (Day 13) for the BID regimen versus vehicle Hour 6 on Visit 4 (Day 13) for the QD regimen versus vehicle Hour 2 on Visit 4 (Day 13) for the BID regimen versus vehicle Hour 2 on Visit 4 (Day 13) for the QD regimen versus vehicle Testing was performed using a Humphrey perimeter at a grid of 36 points confined to the superior hemifield extending 55° to either side of fixation and 45° superior to fixation. Testing was accomplished in the standard fashion using a varying 4-mm2 or 5-mm2 stimulus to determine the visual sensitivity for each grid point in the field (Riemann et al, 2000). A 4-mm2 stimulus was acceptable, but a 5-mm2 stimulus was preferred, if available. | Baseline (Day 0, Hour 0), Visit 4 (Day 13, Hour 2) and Visit 4 (Day 13, Hour 6) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Marginal Reflex Distance | Change from baseline in MRD by regimen against placebo and between regimen. The distance from the pupillary light reflex to the central margin of the upper eyelid is the MRD. The MRD will be measured from the external photograph using calipers and the millimeter ruler as the legend. | Baseline (Day 0, Hour 0), Visit 4 (Day 13, Hour 2) and Visit 4 (Day 13, Hour 6) | 
| Palpebral Fissure Distance Measurement | Change from baseline in PFD by regimen against placebo and between regimen. The PFD is the distance from the upper lid margin to the lower lid margin measured through the central visual axis. It will be measured from the external photograph using handheld calipers and the millimeter ruler as the legend. | Baseline (Day 0, Hour 0), Visit 4 (Day 13, Hour 2) and Visit 4 (Day 13, Hour 6) | 
| Contrast Sensitivity | Change from baseline in CS by regimen against placebo and between regimen. The Pelli-Robson contrast sensitivity chart will be used at a distance of 1 meter. The subject was instructed to begin reading the letters at the top of the chart and to continue reading across and down the chart. Testing was discontinued when 2 of 3 letters were named incorrectly. The test was scored using the letter-by-letter method where a value of 0.05 log CS is given per correct letter (Haymes et al, 2006). | Baseline (Day 0, Hour 0), Visit 4 (Day 13, Hour 2) and Visit 4 (Day 13, Hour 6) | 
| Corrected Snellen Visual Acuity | Change from baseline in VA by regimen against placebo and between regimen. Corrected Snellen VA measurement was performed with the Snellen eye chart using subjects current corrective lens prescription at a distance equivalent to 20 feet (6 meters). | Baseline (Day 0, Hour 0), Visit 4 (Day 13, Hour 2) and Visit 4 (Day 13, Hour 6) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Blepharoptosis, Ptosis