Study of the Safety and Efficacy of RVL-1201 in the Treatment of Acquired Blepharoptosis

• Sponsor: RVL Pharmaceuticals, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02436759
• Collaborator: (none)
• Enrollment: 140
• Locations: 14
• Arms: 2
• Duration (Months): 18.1
• Patients Per Site: 10
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

This is a Phase 3 study is to evaluate the safety and efficacy of RVL-1201 Ophthalmic Solution in the treatment of acquired blepharoptosis (ptosis) and to assess the safety and comfort of RVL-1201 Ophthalmic Solution for an extended dosing period of 6 weeks.

Condition or Disease	Intervention/Treatment	Phase
Acquired Blepharoptosis	Drug: RVL-1201; Drug: RVL-1201 Vehicle Placebo	Phase 3

Detailed Description

Ptosis is experienced by approximately 12% of adults over the age of 50 . It is a unilateral or bilateral abnormal drooping of the upper eyelid that usually occurs from a partial or complete dysfunction of the muscle(s) that elevate the upper eyelid: the levator palpebrae superioris and/or Müller's muscle.

Treatment for acquired ptosis usually involves surgery, with risks of infection, bleeding, over or undercorrection, reduced vision, and lagophthalmos (inability to close the eyelids completely) or mechanical treatment e.g scleral contact lenses with a bar to lift the eyelid, eyelid ptosis crutches attached to glasses, or adhesive tape or putty to affix the upper eyelid to the supraorbital structures.

RVL-201 ophthalmic solution is being developed to provide a reversible pharmacologic option for patients with acquired ptosis who are not candidates for surgery or do not wish to undergo surgery.

The objective of this study is to evaluate the safety and efficacy of RVL-1201 ophthalmic solution in the treatment of acquired blepharoptosis and to assess the safety and comfort of RVL-1201 ophthalmic solution for an extended dosing period of 6 weeks. Subjects will be randomized (2:1) to one of 2 treatment arms and treated for 42 days:

• RVL-1201 0.1% one full drop in each eye QD in the morning (N = 100)

• RVL-1201 vehicle (placebo) 1 full drop per eye QD in the morning (N = 50)

Efficacy will be assessed with the LPFT, a validated visual field test using the HVF Analyzer and photographic measurement of MRD (the distance from the pupillary light reflex to the central margin of the upper lid) and PFD (the distance from the upper lid margin to the lower lid margin through the central visual axis). Safety assessment will include bilateral SLE/CFS, measurement of PD from external photographs, dilated ophthalmoscopy/fundus examination, tonometry, Snellen VA using recent correction, vital signs (BP/HR), and collection of adverse events (AEs).

Study Design

• Study Type: Interventional
• Actual Enrollment: 140 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-Masked, Placebo-Controlled Phase 3 Study of the Safety and Efficacy of RVL-1201 in the Treatment of Acquired Blepharoptosis
• Study Start Date: May 1, 2015
• Actual Primary Completion Date: Nov 1, 2016
• Actual Study Completion Date: Nov 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: RVL-1201 RVL-1201 Ophthalmic Solution 0.1% 1 drop per eye QD for 6 weeks	Drug: RVL-1201; RVL-1201 Ophthalmic Solution 0.1%; Other Names: Oxymetazoline Hydrochloride Ophthalmic Solution 0.1%
Placebo Comparator: RVL-1201 Vehicle Placebo RVL-1201 Ophthalmic Solution vehicle (placebo) 1 drop per eye QD for 6 weeks	Drug: RVL-1201 Vehicle Placebo; RVL-1201 Vehicle Placebo; Other Names: RVL-1201 Ophthalmic Solution 0.1% Placebo

Outcome Measures

Primary Outcome Measures

1. Mean Change in Number of Points Seen on the Leicester Peripheral Field Test (LPFT) in RVL-1201 Group vs. Vehicle Group [Mean change from Baseline (Day 1, Hour 0) compared with Day 1, Hour 6 and Day 14, Hour 2]

   LPFT Total Score is the number of points seen in the top 4 rows on the LPFT. Possible scores range from 0 (no points seen) to 35 (all points seen).

Secondary Outcome Measures

1. Mean Change From Baseline in Marginal Reflex Distance (MRD) in the Study Eye [Baseline Day 1 (Hour 0) and Day 1, Day 14, and Day 42]

   MRD is the distance from the center pupillary light reflex to the central margin of the upper eyelid. The MRD is measured from an external photograph.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Male or female subjects 18 years of age and older.

2. Presence of all of the following at Screening :

1. Loss on a reliable LPFT of ≥ 8 points in the top 2 rows (LPFT Eligibility Score); subjects must see at least 9 total points in the top 4 rows (LPFT Total Score).

2. This criteria must be met at both the Visit 1 Hour 0 (V1H0) and Visit 1 Hour 6 (V1H6) LPFT assessments

1. There must be ≤ 4 points of variance between the V1H0 and the V1H6 LPFT Eligibility Score;; AND

1. The MRD, the distance from the central pupillary light reflex to the central margin of the upper lid, must be ≤ 2 mm (no visible central pupillary light reflex defaults to 0) in the same eye as Inclusion Criterion #2a

AND

1. Snellen visual acuity (VA) of 20/80 or better in the same eye as Inclusion Criteria #2a and #2b.

1. Presence of all of the following at Baseline:

1. Loss on a reliable LPFT of ≥ 8 points in the top 2 rows (LPFT Eligibility Score) in the same eye as Inclusion Criterion #2a; subjects must see at least 9 total points in the top 4 rows (LPFT Total Score).

2. This criteria must be met at the Visit 2 Hour 0 (V2H0) LPFT assessment. ii. There must be ≤ 4 points of variance between the V1H6 and the V2H0 LPFT Eligibility Score;

AND

1. Marginal Reflex Distance (MRD), the distance from the central pupillary light reflex to the central margin of the upper lid, must be ≤ 2 mm (no visible central pupillary light reflex defaults to 0) in the same eye as Inclusion Criterion #2a;

AND

1. Snellen VA of 20/80 or better in the same eye as Inclusion Criteria #2a and #2b.

1. 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. Acceptable methods include the use of at least one of the following: intrauterine (intrauterine device), hormonal (oral, injection, patch, implant, ring), barrier with spermicide (condom, diaphragm), or abstinence.

2. Able to self-administer study medication or to have the study medication administered by a caregiver throughout the study period.

3. Subjects must be able to understand and sign an IRB approved informed consent form prior to participation in any study-related procedures.

Exclusion Criteria:

In either eye

1. Congenital ptosis.

2. Presence of either of the following:

3. Pseudoptosis (upper eyelid dermatochalasis that overhangs the upper eyelid margin) or

4. Dermatochalasis that extends less than 3 mm above the upper eyelid margin.

5. Horner syndrome.

6. Marcus Gunn jaw winking syndrome.

7. Myasthenia gravis.

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

9. Previous ptosis surgery (previous blepharoplasty [only] is allowed provided the surgery took place > 3 months prior to Visit 1).

10. Lid position affected by lid or conjunctival scarring.

11. Visual field loss from any cause other than ptosis.

12. History of herpes keratitis.

13. History of closed/narrow angle glaucoma (unless patent peripheral iridotomy has been performed > 3 months prior to Visit 1).

14. Periocular neurotoxin (eg, Botox, Xeomin, Dysport, Myobloc) injections within 3 months prior to Visit 1 and during the study.

15. Topical application of bimatoprost (ie, Latisse®) to the eyelashes within 7 days prior to Visit 1 and during the study.

16. Use of topical ophthalmic medications (including anti-allergy [eg, antihistamines], dry eye [ie, Restasis®] and anti-inflammatory drugs [including nonsteroidal anti-inflammatory drugs (NSAIDs) and steroids] other than the assigned study medication within 7 days prior to Visit 1 and during the study. Topical ophthalmic prostaglandin analogues for the treatment of elevated intraocular pressure are permitted if dosed in the evening in accordance with the approved prescribing information. All other topical antiglaucoma medications are prohibited

17. Intravitreal injections (eg, Lucentis®, Eylea®, Avastin®, Triesence®) within 7 days prior to Visit 1 and during the study.

18. Current punctal plugs or placement of punctal plugs during the study.

19. Use of over the counter (OTC) vasoconstrictor/decongestant eye medication (eg, Visine® L.R.®) or any ophthalmic or non-ophthalmic α adrenergic agonist including OTC products (eg, Afrin®) at any time during the study; nonpreserved artificial tears are allowed.

General

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

2. Hypertension with resting diastolic blood pressure (BP) > 105 mm Hg.

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

4. Advanced arteriosclerotic disease or history of cerebrovascular accident (CVA).

5. History of hyperthyroidism or thyroid eye disease (ie, exophthalmos, upper eyelid retraction, diplopia secondary to extraocular muscle involvement). Hypothyroidism that is controlled on medication is allowed.

6. Patients with diabetic retinopathy may not be enrolled. However, patients with insulin dependent diabetes, diabetes requiring oral hypoglycemic drugs, or diet controlled diabetes are allowed.

7. Pregnancy or lactation.

8. Diagnosed benign prostatic hypertrophy requiring medicinal therapy; previous prostatectomy is allowed.

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Artesia	California	United States	90701
2		Newport Beach	California	United States	92663
3		Rancho Cordova	California	United States	95670
4		Santa Maria	California	United States	93454
5		Fort Myers	Florida	United States	33901
6		Largo	Florida	United States	33773
7		Plantation	Florida	United States	33324
8		Sarasota	Florida	United States	34239
9		Roswell	Georgia	United States	30076
10		Pittsburg	Kansas	United States	66762
11		Shawnee Mission	Kansas	United States	66204
12		Mason	Ohio	United States	45040
13		Kingston	Pennsylvania	United States	18704
14		Nashville	Tennessee	United States	37215

Sponsors and Collaborators

• RVL Pharmaceuticals, Inc.

Investigators

• Principal Investigator: Chuck Slonim, MD, Oculos Clinical Research

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: RVL Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT02436759
• Other Study ID Numbers: RVL-1201-201
• First Posted: May 7, 2015
• Last Update Posted: Oct 28, 2021
• Last Verified: Oct 1, 2021

• Additional relevant MeSH terms: Blepharoptosis; Phenylephrine; Oxymetazoline; Pharmaceutical Solutions; Ophthalmic Solutions

Study Results

Participant Flow

Recruitment Details	Planned sample size approx 150 subjects, 100 subjects in the RVL-1201 group, and 50 in the Vehicle group, to be enrolled at approx 20 clinical sites in the US.

Arm/Group Title	RVL-1201	Vehicle
Arm/Group Description	RVL-1201 (oxymetazoline hydrochloride) Ophthalmic Solution 0.1%, one drop each eye QD in the morning	Vehicle Placebo Ophthalmic Solution, one drop each eye QD in the morning
Period Title: Overall Study
STARTED	94	46
Subjects Randomized	94	46
Subjects Treated	94	46
COMPLETED	90	45
NOT COMPLETED	4	1

Baseline Characteristics

Arm/Group Title	RVL-1201	Vehicle	Total
Arm/Group Description	RVL-1201 (oxymetazoline hydrochloride) Ophthalmic Solution 0.1%, one drop each eye QD in the morning	Vehicle Placebo Ophthalmic Solution, one drop each eye QD in the morning	Total of all reporting groups
Overall Participants	94	46	140
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	38 40.4%	22 47.8%	60 42.9%
>=65 years	56 59.6%	24 52.2%	80 57.1%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	64.7 (12.22)	63.2 (12.45)	64.2 (12.28)
Age, Customized (years) [Number]
Median	68.0	65.5	67.0
Minimum	22	26	22
Maximum	83	85	85
Sex: Female, Male (Count of Participants)
Female	74 78.7%	32 69.6%	106 75.7%
Male	20 21.3%	14 30.4%	34 24.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	20 21.3%	11 23.9%	31 22.1%
Not Hispanic or Latino	74 78.7%	35 76.1%	109 77.9%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	2 2.1%	0 0%	2 1.4%
Asian	2 2.1%	1 2.2%	3 2.1%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	12 12.8%	0 0%	12 8.6%
White	78 83%	3 6.5%	81 57.9%
More than one race	0 0%	42 91.3%	42 30%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	94 100%	46 100%	140 100%
Iris Color OD (right eye) and Iris Color OS (left eye) (Count of Participants)
OD/OS Blue	23 24.5%	14 30.4%	37 26.4%
OD/OS Brown	55 58.5%	22 47.8%	77 55%
OD/OS Green	4 4.3%	1 2.2%	5 3.6%
OD/OS Hazel	12 12.8%	9 19.6%	21 15%
OD/OS Grey	0 0%	0 0%	0 0%
OD/OS Other	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Mean Change in Number of Points Seen on the Leicester Peripheral Field Test (LPFT) in RVL-1201 Group vs. Vehicle Group
Description	LPFT Total Score is the number of points seen in the top 4 rows on the LPFT. Possible scores range from 0 (no points seen) to 35 (all points seen).
Time Frame	Mean change from Baseline (Day 1, Hour 0) compared with Day 1, Hour 6 and Day 14, Hour 2

Outcome Measure Data

Analysis Population Description

Intent-to-Treat (ITT) population: randomized who received at least one dose (total of 140 subjects). Per-Protocol Population (PPP): ITT population with no major protocol deviations (total of 139 subjects). ITT analysis was conducted for the primary endpoint, with Last Observation Carried Forward (LOCF) for missing data.

Arm/Group Title	RVL-1201	Vehicle Ophthalmic Solution
Arm/Group Description	RVL-1201 (oxymetazoline hydrochloride) Ophthalmic Solution 0.1%, one drop each eye QD in the morning	Vehicle Placebo Ophthalmic Solution, one drop each eye QD in the morning
Measure Participants	94	46
Mean LPFT-Day 1 Hour 6	5.2 (5.97)	1.5 (3.93)
Mean LPFT-Day 14 Hour 2	6.4 (5.04)	2.2 (5.80)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	RVL-1201, Vehicle Ophthalmic Solution
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments	Two-sided t-test with treatment as a fixed factor and baseline score as a covariate

2. Secondary Outcome

Title	Mean Change From Baseline in Marginal Reflex Distance (MRD) in the Study Eye
Description	MRD is the distance from the center pupillary light reflex to the central margin of the upper eyelid. The MRD is measured from an external photograph.
Time Frame	Baseline Day 1 (Hour 0) and Day 1, Day 14, and Day 42

Outcome Measure Data

Analysis Population Description

Intent-to-Treat (ITT) population: randomized who received at least one dose (total of 140 subjects). Per-Protocol Population (PPP): ITT population with no major protocol deviations (total of 139 subjects). ITT analysis was conducted for the primary endpoint, with Last Observation Carried Forward (LOCF) for missing data.

Arm/Group Title	RVL-1201	Vehicle Ophthalmic Solution
Arm/Group Description	RVL-1201 (oxymetazoline hydrochloride) Ophthalmic Solution 0.1%, one drop each eye QD in the morning	Vehicle Placebo Ophthalmic Solution, one drop each eye QD in the morning
Measure Participants	94	46
Primary Efficacy - Day 1, Hour 6	0.94 (0.924)	0.67 (1.001)
Primary Efficacy - Day 14, Hour 2	1.09 (0.799)	0.58 (0.975)
Post Dose - Day 1, Hour 2	0.99 (0.776)	0.50 (0.803)
Post Dose - Day 1, Hour 8	0.93 (0.958)	0.70 (0.771)
Post Dose - Day 14, Hour 6	1.03 (0.856)	0.70 (0.985)
Post Dose - Day 14, Hour 8	0.88 (0.857)	0.68 (1.023)
Post Dose - Day 42	1.25 (1.036)	0.79 (1.020)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	RVL-1201, Vehicle Ophthalmic Solution
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.12
	Comments
	Method	ANCOVA
	Comments	Two-sided t-test

Adverse Events

Time Frame	Duration of treatment is 6 weeks (42 Days)
Adverse Event Reporting Description	Adverse Events (AEs) spontaneously reported by the subject and/or in response to open-ended questions from study personnel or revealed by observation and are recorded in the Case Report Form (CRF).
Arm/Group Title	RVL-1201		Vehicle
Arm/Group Description	RVL-1201 (oxymetazoline hydrochloride) Ophthalmic Solution 0.1%, one drop each eye QD in the morning		Vehicle Placebo Ophthalmic Solution, one drop each eye QD in the morning
All Cause Mortality
	RVL-1201		Vehicle
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/94 (0%)		0/46 (0%)
Serious Adverse Events
	RVL-1201		Vehicle
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/94 (1.1%)		0/46 (0%)
Endocrine disorders
Hyperparathyroidism	1/94 (1.1%)	1	0/46 (0%)	0
Other (Not Including Serious) Adverse Events
	RVL-1201		Vehicle
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	20/94 (21.3%)		15/46 (32.6%)
Cardiac disorders
Atrial fibrilation	0/94 (0%)	0	1/46 (2.2%)	1
Eye disorders
Punctate keratitis	7/94 (7.4%)	11	2/46 (4.3%)	2
Vision blurred	5/94 (5.3%)	10	0/46 (0%)	0
Ocular hyperaemia	3/94 (3.2%)	5	0/46 (0%)	0
Conjunctival haemorrhage	1/94 (1.1%)	1	1/46 (2.2%)	1
Diabetic retinopathy	0/94 (0%)	0	1/46 (2.2%)	2
Dry eye	0/94 (0%)	0	1/46 (2.2%)	2
Erythema of eyelid	0/94 (0%)	0	1/46 (2.2%)	2
Eye pruritus	0/94 (0%)	0	1/46 (2.2%)	2
Foreign body sensation	0/94 (0%)	0	1/46 (2.2%)	1
Iritis	0/94 (0%)	0	1/46 (2.2%)	1
Vitreous detachment	0/94 (0%)	0	2/46 (4.3%)	2
General disorders
Instillation site pain	4/94 (4.3%)	8	0/46 (0%)	0
Infections and infestations
Upper respiratory tract infection	2/94 (2.1%)	2	1/46 (2.2%)	1
Bronchitis	0/94 (0%)	0	1/46 (2.2%)	1
Nasopharyngitis	0/94 (0%)	0	1/46 (2.2%)	1
Pneumonia	0/94 (0%)	0	1/46 (2.2%)	1
Sinusitis	0/94 (0%)	0	1/46 (2.2%)	1
Investigations
Vital dye staining cornea present	2/94 (2.1%)	4	0/46 (0%)	0
Metabolism and nutrition disorders
Hypoglycaemia	0/94 (0%)	0	1/46 (2.2%)	1
Nervous system disorders
Headache	2/94 (2.1%)	2	0/46 (0%)	0
Dysgeusia	0/94 (0%)	0	1/46 (2.2%)	1
Psychiatric disorders
Stress	0/94 (0%)	0	1/46 (2.2%)	1
Vascular disorders
Hypertension	0/94 (0%)	0	1/46 (2.2%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.