Safety and Efficacy Study of RVL-1201 in Acquired Blepharoptosis

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

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.

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

Inclusion Criteria:

1. Adult male or female subjects 18 years of age and older.

2. Presence of all of the following at Screening:

   1. 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
   2. 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
   3. 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.

3. No contraindications for treatment of both eyes as specified in Exclusion Criteria #1-14.

4. 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.

5. Provide informed consent prior to undergoing any study-related procedures.

Exclusion Criteria:

In either eye:

1. Congenital ptosis

2. Pseudoptosis

3. Horner syndrome

4. Marcus Gunn jaw-winking syndrome

5. Myasthenia gravis

6. Mechanical ptosis, including ptosis due to orbital or lid tumor, cicatricial processes affecting the movements of the upper lid, and enophthalmos

7. Dermatochalasis as the sole cause of the signs of ptosis

8. Previous ptosis surgery

9. Lid position affected by lid or conjunctival scarring

10. Current use of prescribed dry eye medication or punctal plugs; artificial tears are allowed

11. Visual field loss from any cause other than ptosis

12. Inability to fixate on the central fixation target of the HVF

13. 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.

14. 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

15. 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

16. Contact lens wear during the study period

    General:

17. Resting heart rate (HR) outside the normal range (60 - 100 beats per minute)

18. Hypertension diastolic blood pressure (BP) > 105 mm Hg

19. Use of monoamine oxidase inhibitors (MAOIs; eg, isocarboxazid, phenelzine, tranylcypromine) within 14 days prior to Visit 1 or during the study

20. Use of beta blockers (eg, propranolol, metoprolol, labetalol) within 14 days prior to Visit 1 or during the study

21. 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

22. A history of myocardial infarction, angina, arrhythmia, or irregular pulse

23. Advanced arteriosclerotic disease

24. History of thyroid disease

25. Insulin-dependent diabetes or diabetes requiring oral hypoglycemic drugs; diet-controlled diabetes is allowed

26. Pregnancy or lactation

27. Diagnosed benign prostatic hypertrophy requiring medicinal therapy.

28. History of contact or systemic allergic reaction to oxymetazoline or other sympathomimetic drugs (eg, phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine, fepradinol, or methoxamine)