Research
JAMA Ophthalmology | Original Investigation
Association of Oxymetazoline Hydrochloride, 0.1%, Solution Administration With Visual Field in Acquired Ptosis A Pooled Analysis of 2 Randomized Clinical Trials Charles B. Slonim, MD; Shane Foster, OD; Mark Jaros, PhD; Shane R. Kannarr, OD; Michael S. Korenfeld, MD; Robert Smyth-Medina, MD; David L. Wirta, MD Invited Commentary IMPORTANCE Treatment of acquired blepharoptosis (ptosis) is currently limited to surgical
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intervention. OBJECTIVE To examine the efficacy and safety of oxymetazoline hydrochloride,
0.1%, ophthalmic solution (oxymetazoline, 0.1%) in participants with acquired ptosis. DESIGN, SETTING, AND PARTICIPANTS This pooled analysis of 2 randomized, double-masked, placebo-controlled, multicenter phase 3 clinical trials included participants 9 years and older with acquired ptosis and superior visual field deficit. The 2 studies were conducted across 16 and 27 sites in the United States. Patients were enrolled from May 2015 to April 2019. Analyses for the individual trials were initiated after database lock and completed on September 6, 2017, and May 16, 2019. Pooled analysis was completed on August 25, 2019. INTERVENTIONS Participants (randomized 2:1) received oxymetazoline, 0.1%, or vehicle, self-administered as a single drop per eye, once daily, for 42 days. MAIN OUTCOMES AND MEASURES The primary efficacy end point was change from baseline in the number of points seen on the Leicester Peripheral Field Test, a test to detect superior visual field deficits due to ptosis, on days 1 (6 hours after instillation) and 14 (2 hours after instillation). The secondary end point, change from baseline in marginal reflex distance 1, was assessed at the same time points. RESULTS In total, 304 participants were enrolled (mean [SD] age, 63.8 [13.8] years; 222 women [73%]). Overall, 97.5% (198 of 203) of participants receiving oxymetazoline, 0.1%, and 97.0% (98 of 101) of participants receiving vehicle completed the studies. Oxymetazoline, 0.1%, was associated with a significant increase in the mean (SD) number of points seen on the Leicester Peripheral Field Test vs vehicle (day 1: 5.9 [6.4] vs 1.8 [4.1]; mean difference, 4.07 [95% CI, 2.74-5.39]; P < .001; day 14: 7.1 [5.9] vs 2.4 [5.5]; mean difference, 4.74 [95% CI, 3.43-6.04]; P < .001). Oxymetazoline, 0.1%, also was associated with a significant increase in marginal reflex distance 1 from baseline (mean [SD]: day 1: 0.96 [0.89] mm vs 0.50 [0.81] mm; mean difference, 0.47 mm [95% CI, 0.27-0.67]; P < .001; day 14: 1.16 [0.87] mm vs 0.50 [0.80] mm; mean difference, 0.67 mm [95% CI, 0.46-0.88]; P < .001). Treatment-emergent adverse events (TEAEs) occurred in 31.0% (63 of 203) of participants receiving oxymetazoline, 0.1%, and 35.6% (36 of 101) of participants receiving vehicle. Among participants receiving oxymetazoline, 0.1%, with a TEAE, 81% (51 of 63) had a maximum TEAE intensity of mild, and 62% (39 of 63) had no TEAE suspected of being treatment related. CONCLUSIONS AND RELEVANCE Oxymetazoline, 0.1%, was associated with positive outcomes and was well tolerated in phase 3 trials after instillation at days 1 and 14, demonstrating its potential promise for the treatment of acquired ptosis, although further study is needed to elucidate the clinical relevance of these findings beyond 6 weeks.
JAMA Ophthalmol. doi:10.1001/jamaophthalmol.2020.3812 Published online October 1, 2020.
Author Affiliations: Department of Ophthalmology, University of South Florida Morsani College of Medicine, Tampa (Slonim); Athens Eye Care, Athens, Ohio (Foster); Summit Analytical, Denver, Colorado (Jaros); Kannarr Eye Care, Pittsburg, Kansas (Kannarr); Comprehensive Eye Care Ltd, Washington, Missouri (Korenfeld); North Valley Eye Medical Group, Mission Hills, California (Smyth-Medina); Aesthetic Eye Care Institute & Eye Research Foundation, Newport Beach, California (Wirta). Corresponding Author: Charles B. Slonim, MD, Department of Ophthalmology, University of South Florida Morsani College of Medicine, 2409 S Dundee St, Tampa, FL 33629 ([email protected]).
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Research Original Investigation
Association of Oxymetazoline Hydrochloride, 0.1%, Solution Administration With Visual Field in Acquired Ptosis
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lepharoptosis (or ptosis) is an abnormal drooping of the upper eyelid margin with the eye in primary gaze.1 In addition to the characteristic asymmetric or sleepy appearance caused by ptosis, obstruction of the pupil by the upper eyelid can lead to superior visual field deficits.2 Reduced visual function can diminish independence in activities of daily living,3-5 and patients with ptosis report elevated levels of anxiety, depression, and appearance-related distress.6 Current evidence identifies ptosis as a common disorder of the eyelid, particularly among elderly patients.7-9 Ptosis is broadly categorized as either congenital or acquired,10 with the acquired form classified based on underlying etiology as involutional (aponeurotic), neurogenic, myogenic, traumatic, or mechanical.11 Transient or persistent ptosis can also occur following ocular procedures, such as glaucoma or cataract surgery,12,13 and has been associated with contact lens wear.14-16 Standard of care is surgery, often targeting the upper eyelid retractor muscles.3,17,18 While effective in improving visual function and quality-of-life measures,3 there are risks associated with surgical intervention, including asymmetry, overcorrection/undercorrection, bleeding, lagophthalmos, and infection.11 An effective, noninvasive, pharmacologic treatment option might enable treatment of a wider range of affected individuals. The superior tarsal, or Müller, muscle arises from the levator muscle and inserts on the tarsus, where it helps maintain upper eyelid elevation provided by the levator, while providing 2 to 3 mm of additional elevation.19,20 Therefore, Müller muscle is a common surgical target. 3,17,18 Because it expresses adrenergic receptors,21 Müller muscle is also a target for pharmacologic intervention. A limited number of studies have described the use of adrenergic drugs (phenylephrine, apraclonidine) for ptosis treatment.22-27 Oxymetazoline hydrochloride, 0.1%, ophthalmic solution (oxymetazoline, 0.1%; RVL Pharmaceuticals Inc) is a novel pharmacologic agent approved for the treatment of acquired ptosis. Oxymetazoline is a potent, direct-acting α-adrenergic receptor agonist that binds the α 1 and α 2 subtypes.28,29 It is used, at low concentrations, as a topical nasal decongestant, and ocular administration of less than 0.025% oxymetazoline has been shown to reduce hyperemia.30 It is hypothesized that oxymetazoline, 0.1%, stimulates α-adrenergic receptors on Müller muscle,21 causing muscle contraction and upper eyelid lift. The objective of this analysis was to examine the efficacy and safety of oxymetazoline, 0.1%, for the treatment of acquired ptosis, when administered once daily as a single drop in each eye after instillation at 1 and 14 days, and then followed up with continued treatment for 6 weeks in 2 randomized clinical trials.
Methods Studies This analysis combines data from 2 randomized, doublemasked, placebo-controlled, multicenter phase 3 clinical trials E2
Key Points Question Is administration of a single drop of oxymetazoline hydrochloride, 0.1%, ophthalmic solution (oxymetazoline, 0.1%) for 6 weeks associated with improved superior visual field and reduced upper eyelid droop in acquired blepharoptosis? Findings In a pooled analysis from 2 randomized, double-masked, placebo-controlled, multicenter phase 3 clinical trials, treatment with oxymetazoline, 0.1%, was associated with improved superior visual field and upper eyelid elevation vs vehicle after instillation at 1 and 14 days. Meaning Oxymetazoline, 0.1%, may be a promising treatment option for patients with acquired blepharoptosis, although further study is needed to assess the clinical relevance of this effect beyond 2 weeks.
(study RVL-1201-201 [NCT02436759] and study RVL-1201202 [NCT03565887]). Study RVL-1201-201 recruited participants from May 2015 to October 2016, and study RVL-1201202 recruited participants from June 2018 to April 2019. Both studies were conducted In the United States and in accordance with the principles of the Declaration of Helsinki31 and Good Clinical Practice and International Conference on Harmonisation guidelines. Protocols and informed consent forms were approved by a central institutional review board (Alpha IRB, San Clemente, California) prior to study initiation. All study participants provided written informed consent at screening and were compensated financially. Participant information and data were handled per Health Insurance Portability and Accountability Act provisions. Studies RVL-1201-201 and RVL-1201-202 enrolled 140 participants across 16 sites and 164 participants across 27 sites, respectively. Both studies revealed significant effects of oxymetazoline, 0.1%, in participants with acquired ptosis (eTable 2 in the Supplement). Data were pooled based on consistency in study design, inclusion/exclusion criteria, treatment regimen, duration, and end points. Study rationale, methodology, results, and conclusions are reported in accordance with Consolidated Standards of Reporting Trials (CONSORT) reporting guideline.
Study Participants The key inclusion criteria for both studies were acquired ptosis and a superior visual field deficit in at least 1 eye at screening (3-7 days before treatment day 1) and baseline (treatment day 1). The presence of acquired ptosis was confirmed based on 2 criteria. First was the participant’s inability to detect at least 8 of 17 points in the top 2 rows on the Leicester Peripheral Field Test (LPFT; a validated visual field test using a Humphrey visual field [HVF] analyzer, designed to assess superior visual field loss due to ptosis), and the ability to detect at least 9 of 35 total points in the top 4 rows.32 Second was marginal reflex distance 1 (MRD-1; distance from the central pupillary light reflex to the central inferior margin of the upper eyelid, ≤2 mm). Before treatment initiation, performance on the LPFT was tested twice at screening (hour 0 and hour 6) and once
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Association of Oxymetazoline Hydrochloride, 0.1%, Solution Administration With Visual Field in Acquired Ptosis
at baseline (hour 0) to ensure the participant’s ability to perform the test reliably. Performance was tested no more than twice in a visit to help mitigate learning effects that might introduce false-positive measures. Inclusion required 4 or less points’ variability between LPFT assessments at screening and baseline. For all LPFT assessments through treatment day 14, reliability was assessed in an automated manner, by the test apparatus (HVF analyzer). If the HVF analyzer detected loss of fixation or a false positive/negative during testing, then the test was automatically flagged as unreliable, at which point it could be retaken at most once. For enrolled participants, both eyes were evaluated, and the eye with the smaller MRD-1 was defined as the study eye (eMethods in the Supplement). Individuals were excluded from either study if they had congenital ptosis, Horner syndrome, myasthenia gravis, mechanical ptosis, or visual field loss from any cause other than ptosis. Participants with pseudoptosis or substantial dermatochalasis (redundant eyelid skin occurring within 3 mm of the upper eyelid margin) in the study eye were also excluded. Study RVL-1201-201 required that participants be 18 years or older. Study RVL-1201-202 required that patients be 9 years or older.
Randomization and Treatment Participants in both studies were randomized 2:1 to treatment with oxymetazoline, 0.1%, or vehicle. Randomization schemes were created by an independent biostatistician using a block design (eMethods in the Supplement). Participants, investigators, staff, and study management personnel were masked to the identity of treatment until after final database lock. Treatments were self-administered by participants as a single drop per eye, once daily in the morning, for 42 days. Study visits occurred on treatment days 1, 14, and 42.
Efficacy Outcome Measures The primary efficacy end point in both studies was the change from baseline in the number of points seen in the top 4 rows on the LPFT on day 1 (6 hours after instillation) and day 14 (2 hours after instillation). These times were selected to assess duration (6 hours) and onset (2 hours) of effect. The LPFT, performed using an HVF analyzer, is a validated test for the measurement of superior visual field loss due to ptosis.32 It is an automated, observer-independent, static perimetry test in which the center of fixation is shifted 15 ° inferiorly to allow for maximum superior field testing, more natural eyelid positioning, and to prevent compensatory brow elevation. The LPFT examines a 48 ° range in the superior visual field, using a 35-point grid comprising the top 4 rows of the field. Fourteen points are also tested in the inferior visual field as a reference. The LPFT demonstrates high sensitivity (98.8%), specificity (92.5%), positive predictive value (96.6%), and negative predictive value (97.4%) in detecting ptosis.32 The secondary efficacy end point, change from baseline in MRD-1 on day 1 (6 hours) and day 14 (2 hours), was measured using digital photographs taken at the study sites. Care was taken to ensure consistent ambient lighting for photography at all sites and time points. A standardized selfjamaophthalmology.com
Original Investigation Research
adhesive millimeter-scale ruler was placed vertically on each participant’s forehead, centered above the eyebrows, and used by investigators at each site to take standardized MRD-1 measurements from digital photographs using calipers. Photographs were also used to measure pupil diameter and palpebral fissure distance (study RVL-1201-201 only). Compliance was measured by comparing the numbers of returned and dispensed treatment vials.
Safety Outcome Measures Treatment-emergent adverse events (TEAEs) were monitored and reported throughout both studies and evaluated with respect to severity and relationship to treatment. Vital signs, Snellen visual acuity, pupil diameter, slitlamp examination, and corneal fluorescein staining were examined at all study visits. Intraocular pressure tonometry and dilated ophthalmoscopy/fundus examinations were conducted at screening and day 42.
Statistical Analysis Analyses were conducted using the combined intent-to-treat population (participants receiving ≥1 treatment dose). Efficacy was analyzed using data from the study eye, while safety was analyzed for both eyes. Because less than 5% of data points were missing in both treatment groups, with no evidence of either group being particularly subject to missing data, efficacy analysis used the intent-to-treat population, with the last observation carried forward for missing data. Descriptive statistics of the observed and change from baseline for efficacy end points were tabulated by visit and treatment group, using common time points across studies. Differences between treatment groups were compared using an analysis of covariance model with treatment as a fixed factor and baseline score as a covariate. Treatments were compared using pairwise comparison from the model. Statistical tests were 2-sided, with P < .05 considered statistically significant for the primary outcome. Analyses for the individual trials were initiated after database lock and completed on September 6, 2017, and May 16, 2019. Pooled analysis was completed on August 25, 2019.
Results Participant Disposition In total, 304 participants were enrolled and randomized to receive oxymetazoline, 0.1% (203 [66.8%]), or vehicle (101 [33.2%]) (Table 1 and Figure 1). Demographic characteristics were similar across treatment groups (Table 1). Study completion rates (oxymetazoline, 0.1%: 198 of 203 [97.5%]; vehicle: 98 of 101 [97.0%]) and treatment compliance (mean [SD]: oxymetazoline, 0.1%: 98.1% [8.7%]; vehicle: 97.2% [10.7%]) were high, and mean treatment exposure was 42 days in both groups (Table 1).
Primary Efficacy: LPFT At baseline, the mean (SD) number of points seen in the top 4 rows on the LPFT was the same across treatment groups (Reprinted) JAMA Ophthalmology Published online October 1, 2020
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Research Original Investigation
Association of Oxymetazoline Hydrochloride, 0.1%, Solution Administration With Visual Field in Acquired Ptosis
Table 1. Participant Disposition and Demographicsa No. (%) Characteristic
Oxymetazoline, 0.1% (n = 203)
Enrolled, No.
203
101
Completed all visits
198 (97.5)
98 (97.0)
Compliance with treatment, mean (SD), %b
98.1 (8.7)
97.2 (10.7)
Treatment exposure, mean (SD), d
42.1 (4.6)
42.2 (5.3)
Age, mean (SD) [range], y
64.1 (13.4) [20-92]
63.3 (14.7) [14-85]
Female
151 (74.4)
71 (70.3)
Male
52 (25.6)
30 (29.7)
White
177 (87.2)
92 (91.1)
Black
18 (8.9)
6 (5.9)
Asian
6 (3.0)
3 (3.0)
American Indian
2 (1.0)
0
Not Hispanic/Latino
170 (83.7)
84 (83.2)
Hispanic/Latino
33 (16.3)
17 (16.8)
Mean (SD)
17.3 (4.7)
17.3 (5.3)
Median (range)
17.0 (8-27)
17.0 (2-26)
Mean (SD)
1.09 (0.70)
1.05 (0.69)
Median (range)
1.00 (0-3.0)
1.00 (0-2.0)
Vehicle (n = 101)
Sex
Race
Ethnicity
Baseline points seen, top 4 rows, LPFT
Baseline MRD-1, mm
Abbreviations: LPFT, Leicester Peripheral Field Test; MRD-1, marginal reflex distance. a
Data were similar in the individual studies (eTable 1 in the Supplement).
b
Percentage of opened vials returned relative to the number of vials that should have been used during the treatment period.
(oxymetazoline, 0.1%: 17.3 [4.7]; vehicle: 17.3 [5.3]; Table 1), suggesting an equivalent superior visual field deficit. On day 1 (6 hours), the mean (SD) number of points seen increased to 23.1 (6.5) in the oxymetazoline, 0.1%, group and 19.1 (6.1) in the vehicle group, with a significantly greater mean change in the oxymetazoline, 0.1% group (mean [SD], 5.9 [6.4] vs 1.8 [4.1]; mean difference, 4.07 [95% CI, 2.74-5.39]; P < .001; Figure 2A). Two hours after instillation of oxymetazoline, 0.1%, or vehicle on day 14, the mean (SD) numbers of points seen were 24.3 (6.0) and 19.5 (6.0), respectively, with a significantly greater mean (SD) change from baseline in the oxymetazoline, 0.1%, group (7.1 [5.9] vs 2.4 [5.5]; mean difference, 4.74 [95% CI, 3.43-6.04]; P < .001; Figure 2A).
Secondary Efficacy: MRD-1 Mean (SD) baseline MRD-1 in the study eye was similar across treatment groups (oxymetazoline, 0.1%: 1.09 [0.70] mm; vehicle: 1.05 [0.69] mm; Table 1). Mean (SD) change from baseline on day 1 (6 hours) was 0.96 (0.89) mm with oxymetazoline, 0.1%, and 0.50 (0.81) mm with vehicle (mean difference, 0.47 mm [95% CI, 0.27-0.67]; P < .001; Figure 2B and Figure 3). On day 14 (2 hours), mean (SD) change from baseline in MRD-1 E4
was 1.16 (0.87) mm and 0.50 (0.80) mm in the oxymetazoline, 0.1%, and vehicle groups, respectively (mean difference, 0.67 mm [95% CI, 0.46-0.88]; P < .001; Figure 2B and Figure 3).
Safety There were 129 TEAEs in 63 participants (31.0%) receiving oxymetazoline, 0.1%, and 73 TEAEs in 36 participants (35.6%) receiving vehicle (Table 2). Among participants receiving oxymetazoline, 0.1%, and reporting a TEAE, 51 of 63 (81.0%) had a maximum TEAE intensity of mild, and 39 of 63 (61.9%) had no TEAE suspected of being treatment related. Among participants receiving vehicle with a reported TEAE, 25 of 36 (69.4%) had a maximum TEAE intensity of mild, and 27 of 36 (75.0%) had no TEAE suspected of being treatment related. Two participants (1.0%) receiving oxymetazoline, 0.1%, reported serious TEAEs (hyperparathyroidism; cerebrovascular accident), and 1 participant (1.0%) receiving vehicle had a serious TEAE (lower gastrointestinal hemorrhage). No serious TEAE was suspected of being treatment related, and all were resolved. Three participants (1.5%) in the oxymetazoline, 0.1%, group and 2 participants (2.0%) in the vehicle group discontinued owing to a TEAE. TEAEs occurring in 2% or more of participants in either group were punctate keratitis (oxymetazoline, 0.1%: 11 of 203 [5.4%]; vehicle: 3 of 101 [3.0%]), blurred vision (oxymetazoline, 0.1%: 7 of 203 [3.4%]; vehicle: 0), conjunctival hyperemia (oxymetazoline, 0.1%: 6 of 203 [3.0%]; vehicle: 1 of 101 [1.0%]), and instillation site pain (oxymetazoline, 0.1%: 6 of 203 [3.0%]; vehicle: 0) (Table 2). Punctate keratitis, blurred vision, and conjunctival hyperemia were each suspected of being treatment related in 2 participants (1.0%) receiving oxymetazoline, 0.1%. Instillation site pain was suspected of being treatment related in all 6 participants reporting it. There were no mean shifts from baseline in vital signs, or intraocular pressure, Snellen visual acuity, pupil diameter, slitlamp or ophthalmoscopy/fundus examination results in either eye judged to be clinically relevant. Mean (SD) changes from baseline in the right pupil diameter with oxymetazoline, 0.1%, and vehicle, respectively, were 0.4 (0.8) mm and 0 (0.6) mm on day 1, 0.1 (0.7) mm and −0.1 (0.8) mm on day 14, and −0.1 (0.8) mm and −0.2 (0.8) mm on day 42.
Discussion These clinical study results support the efficacy and safety of oxymetazoline, 0.1%, for the treatment of acquired ptosis, a potentially important finding given the lack of other approved pharmacologic options for this condition, as well as the barriers to and potential risks11 associated with surgery. Reliable visual field testing is essential to accurately assessing the effect of any potential therapy for ptosis. While the LPFT used for the primary outcome in these trials has been shown to detect functional disability (superior visual field loss) in patients with ptosis with high specificity, owing to the wide superior visual field tested and inferior shift in the target of
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Association of Oxymetazoline Hydrochloride, 0.1%, Solution Administration With Visual Field in Acquired Ptosis
Original Investigation Research
Figure 1. Participant Disposition Flowchart: Study RVL-1201-201, Study RVL-1201-202, and Pooled Analysis Study RVL-1201-202
Study RVL-1201-201 336 Assessed for eligibility
358 Assessed for eligibility
196 Excluded (did not meet inclusion criteria)
194 Excluded (did not meet inclusion criteria)
140 Randomized
164 Randomized
94 Allocated to RVL-1201 group and received 1 drop per eye, self-administered once daily, for 42 d
46 Allocated to vehicle group and received 1 drop per eye, self-administered once daily, for 42 d
109 Allocated to RVL-1201 group and received 1 drop per eye, self-administered once daily, for 42 d
55 Allocated to vehicle group and received 1 drop per eye, self-administered once daily, for 42 d
4 Discontinued intervention 3 Adverse events 1 Protocol deviation
1 Discontinued intervention (noncompliance)
1 Discontinued intervention (adverse event)
2 Discontinued intervention (withdrawal of consent)
94 Analyzed
46 Analyzed
109 Analyzed
55 Analyzed
203 Included in RVL-1201 group in pooled analysis
101 Included in vehicle group in pooled analysis
In study RVL-1201-201, the first participant was enrolled on May 29, 2015, and the last participant completed on October 24, 2016. In study RVL-1201-202, first enrollment was on June 20, 2018, and last completion was on April 10, 2019. Study RVL-1201-201’s sample size was defined to establish more than 99% power to detect an effect size of 1.0 using a 2-group t test with a .05 two-sided significance level. Study RVL-1201-202’s sample size was based on establishing 90% power to detect a difference of 3.50 on the primary end point using a 2-group t test with a .05 two-sided significance level.
Figure 2. Mean Change on the Leicester Peripheral Field Test (LPFT) and Marginal Reflex Distance 1 (MRD-1) After Instillation of 1 Drop Oxymetazoline, 0.1%, or Vehicle A Change from baseline in points seen
B
Change from baseline in MRD-1
in top 4 rows on LPFT 16 P
JAMA Ophthalmology | Original Investigation
Association of Oxymetazoline Hydrochloride, 0.1%, Solution Administration With Visual Field in Acquired Ptosis A Pooled Analysis of 2 Randomized Clinical Trials Charles B. Slonim, MD; Shane Foster, OD; Mark Jaros, PhD; Shane R. Kannarr, OD; Michael S. Korenfeld, MD; Robert Smyth-Medina, MD; David L. Wirta, MD Invited Commentary IMPORTANCE Treatment of acquired blepharoptosis (ptosis) is currently limited to surgical
Supplemental content
intervention. OBJECTIVE To examine the efficacy and safety of oxymetazoline hydrochloride,
0.1%, ophthalmic solution (oxymetazoline, 0.1%) in participants with acquired ptosis. DESIGN, SETTING, AND PARTICIPANTS This pooled analysis of 2 randomized, double-masked, placebo-controlled, multicenter phase 3 clinical trials included participants 9 years and older with acquired ptosis and superior visual field deficit. The 2 studies were conducted across 16 and 27 sites in the United States. Patients were enrolled from May 2015 to April 2019. Analyses for the individual trials were initiated after database lock and completed on September 6, 2017, and May 16, 2019. Pooled analysis was completed on August 25, 2019. INTERVENTIONS Participants (randomized 2:1) received oxymetazoline, 0.1%, or vehicle, self-administered as a single drop per eye, once daily, for 42 days. MAIN OUTCOMES AND MEASURES The primary efficacy end point was change from baseline in the number of points seen on the Leicester Peripheral Field Test, a test to detect superior visual field deficits due to ptosis, on days 1 (6 hours after instillation) and 14 (2 hours after instillation). The secondary end point, change from baseline in marginal reflex distance 1, was assessed at the same time points. RESULTS In total, 304 participants were enrolled (mean [SD] age, 63.8 [13.8] years; 222 women [73%]). Overall, 97.5% (198 of 203) of participants receiving oxymetazoline, 0.1%, and 97.0% (98 of 101) of participants receiving vehicle completed the studies. Oxymetazoline, 0.1%, was associated with a significant increase in the mean (SD) number of points seen on the Leicester Peripheral Field Test vs vehicle (day 1: 5.9 [6.4] vs 1.8 [4.1]; mean difference, 4.07 [95% CI, 2.74-5.39]; P < .001; day 14: 7.1 [5.9] vs 2.4 [5.5]; mean difference, 4.74 [95% CI, 3.43-6.04]; P < .001). Oxymetazoline, 0.1%, also was associated with a significant increase in marginal reflex distance 1 from baseline (mean [SD]: day 1: 0.96 [0.89] mm vs 0.50 [0.81] mm; mean difference, 0.47 mm [95% CI, 0.27-0.67]; P < .001; day 14: 1.16 [0.87] mm vs 0.50 [0.80] mm; mean difference, 0.67 mm [95% CI, 0.46-0.88]; P < .001). Treatment-emergent adverse events (TEAEs) occurred in 31.0% (63 of 203) of participants receiving oxymetazoline, 0.1%, and 35.6% (36 of 101) of participants receiving vehicle. Among participants receiving oxymetazoline, 0.1%, with a TEAE, 81% (51 of 63) had a maximum TEAE intensity of mild, and 62% (39 of 63) had no TEAE suspected of being treatment related. CONCLUSIONS AND RELEVANCE Oxymetazoline, 0.1%, was associated with positive outcomes and was well tolerated in phase 3 trials after instillation at days 1 and 14, demonstrating its potential promise for the treatment of acquired ptosis, although further study is needed to elucidate the clinical relevance of these findings beyond 6 weeks.
JAMA Ophthalmol. doi:10.1001/jamaophthalmol.2020.3812 Published online October 1, 2020.
Author Affiliations: Department of Ophthalmology, University of South Florida Morsani College of Medicine, Tampa (Slonim); Athens Eye Care, Athens, Ohio (Foster); Summit Analytical, Denver, Colorado (Jaros); Kannarr Eye Care, Pittsburg, Kansas (Kannarr); Comprehensive Eye Care Ltd, Washington, Missouri (Korenfeld); North Valley Eye Medical Group, Mission Hills, California (Smyth-Medina); Aesthetic Eye Care Institute & Eye Research Foundation, Newport Beach, California (Wirta). Corresponding Author: Charles B. Slonim, MD, Department of Ophthalmology, University of South Florida Morsani College of Medicine, 2409 S Dundee St, Tampa, FL 33629 ([email protected]).
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Research Original Investigation
Association of Oxymetazoline Hydrochloride, 0.1%, Solution Administration With Visual Field in Acquired Ptosis
B
lepharoptosis (or ptosis) is an abnormal drooping of the upper eyelid margin with the eye in primary gaze.1 In addition to the characteristic asymmetric or sleepy appearance caused by ptosis, obstruction of the pupil by the upper eyelid can lead to superior visual field deficits.2 Reduced visual function can diminish independence in activities of daily living,3-5 and patients with ptosis report elevated levels of anxiety, depression, and appearance-related distress.6 Current evidence identifies ptosis as a common disorder of the eyelid, particularly among elderly patients.7-9 Ptosis is broadly categorized as either congenital or acquired,10 with the acquired form classified based on underlying etiology as involutional (aponeurotic), neurogenic, myogenic, traumatic, or mechanical.11 Transient or persistent ptosis can also occur following ocular procedures, such as glaucoma or cataract surgery,12,13 and has been associated with contact lens wear.14-16 Standard of care is surgery, often targeting the upper eyelid retractor muscles.3,17,18 While effective in improving visual function and quality-of-life measures,3 there are risks associated with surgical intervention, including asymmetry, overcorrection/undercorrection, bleeding, lagophthalmos, and infection.11 An effective, noninvasive, pharmacologic treatment option might enable treatment of a wider range of affected individuals. The superior tarsal, or Müller, muscle arises from the levator muscle and inserts on the tarsus, where it helps maintain upper eyelid elevation provided by the levator, while providing 2 to 3 mm of additional elevation.19,20 Therefore, Müller muscle is a common surgical target. 3,17,18 Because it expresses adrenergic receptors,21 Müller muscle is also a target for pharmacologic intervention. A limited number of studies have described the use of adrenergic drugs (phenylephrine, apraclonidine) for ptosis treatment.22-27 Oxymetazoline hydrochloride, 0.1%, ophthalmic solution (oxymetazoline, 0.1%; RVL Pharmaceuticals Inc) is a novel pharmacologic agent approved for the treatment of acquired ptosis. Oxymetazoline is a potent, direct-acting α-adrenergic receptor agonist that binds the α 1 and α 2 subtypes.28,29 It is used, at low concentrations, as a topical nasal decongestant, and ocular administration of less than 0.025% oxymetazoline has been shown to reduce hyperemia.30 It is hypothesized that oxymetazoline, 0.1%, stimulates α-adrenergic receptors on Müller muscle,21 causing muscle contraction and upper eyelid lift. The objective of this analysis was to examine the efficacy and safety of oxymetazoline, 0.1%, for the treatment of acquired ptosis, when administered once daily as a single drop in each eye after instillation at 1 and 14 days, and then followed up with continued treatment for 6 weeks in 2 randomized clinical trials.
Methods Studies This analysis combines data from 2 randomized, doublemasked, placebo-controlled, multicenter phase 3 clinical trials E2
Key Points Question Is administration of a single drop of oxymetazoline hydrochloride, 0.1%, ophthalmic solution (oxymetazoline, 0.1%) for 6 weeks associated with improved superior visual field and reduced upper eyelid droop in acquired blepharoptosis? Findings In a pooled analysis from 2 randomized, double-masked, placebo-controlled, multicenter phase 3 clinical trials, treatment with oxymetazoline, 0.1%, was associated with improved superior visual field and upper eyelid elevation vs vehicle after instillation at 1 and 14 days. Meaning Oxymetazoline, 0.1%, may be a promising treatment option for patients with acquired blepharoptosis, although further study is needed to assess the clinical relevance of this effect beyond 2 weeks.
(study RVL-1201-201 [NCT02436759] and study RVL-1201202 [NCT03565887]). Study RVL-1201-201 recruited participants from May 2015 to October 2016, and study RVL-1201202 recruited participants from June 2018 to April 2019. Both studies were conducted In the United States and in accordance with the principles of the Declaration of Helsinki31 and Good Clinical Practice and International Conference on Harmonisation guidelines. Protocols and informed consent forms were approved by a central institutional review board (Alpha IRB, San Clemente, California) prior to study initiation. All study participants provided written informed consent at screening and were compensated financially. Participant information and data were handled per Health Insurance Portability and Accountability Act provisions. Studies RVL-1201-201 and RVL-1201-202 enrolled 140 participants across 16 sites and 164 participants across 27 sites, respectively. Both studies revealed significant effects of oxymetazoline, 0.1%, in participants with acquired ptosis (eTable 2 in the Supplement). Data were pooled based on consistency in study design, inclusion/exclusion criteria, treatment regimen, duration, and end points. Study rationale, methodology, results, and conclusions are reported in accordance with Consolidated Standards of Reporting Trials (CONSORT) reporting guideline.
Study Participants The key inclusion criteria for both studies were acquired ptosis and a superior visual field deficit in at least 1 eye at screening (3-7 days before treatment day 1) and baseline (treatment day 1). The presence of acquired ptosis was confirmed based on 2 criteria. First was the participant’s inability to detect at least 8 of 17 points in the top 2 rows on the Leicester Peripheral Field Test (LPFT; a validated visual field test using a Humphrey visual field [HVF] analyzer, designed to assess superior visual field loss due to ptosis), and the ability to detect at least 9 of 35 total points in the top 4 rows.32 Second was marginal reflex distance 1 (MRD-1; distance from the central pupillary light reflex to the central inferior margin of the upper eyelid, ≤2 mm). Before treatment initiation, performance on the LPFT was tested twice at screening (hour 0 and hour 6) and once
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Association of Oxymetazoline Hydrochloride, 0.1%, Solution Administration With Visual Field in Acquired Ptosis
at baseline (hour 0) to ensure the participant’s ability to perform the test reliably. Performance was tested no more than twice in a visit to help mitigate learning effects that might introduce false-positive measures. Inclusion required 4 or less points’ variability between LPFT assessments at screening and baseline. For all LPFT assessments through treatment day 14, reliability was assessed in an automated manner, by the test apparatus (HVF analyzer). If the HVF analyzer detected loss of fixation or a false positive/negative during testing, then the test was automatically flagged as unreliable, at which point it could be retaken at most once. For enrolled participants, both eyes were evaluated, and the eye with the smaller MRD-1 was defined as the study eye (eMethods in the Supplement). Individuals were excluded from either study if they had congenital ptosis, Horner syndrome, myasthenia gravis, mechanical ptosis, or visual field loss from any cause other than ptosis. Participants with pseudoptosis or substantial dermatochalasis (redundant eyelid skin occurring within 3 mm of the upper eyelid margin) in the study eye were also excluded. Study RVL-1201-201 required that participants be 18 years or older. Study RVL-1201-202 required that patients be 9 years or older.
Randomization and Treatment Participants in both studies were randomized 2:1 to treatment with oxymetazoline, 0.1%, or vehicle. Randomization schemes were created by an independent biostatistician using a block design (eMethods in the Supplement). Participants, investigators, staff, and study management personnel were masked to the identity of treatment until after final database lock. Treatments were self-administered by participants as a single drop per eye, once daily in the morning, for 42 days. Study visits occurred on treatment days 1, 14, and 42.
Efficacy Outcome Measures The primary efficacy end point in both studies was the change from baseline in the number of points seen in the top 4 rows on the LPFT on day 1 (6 hours after instillation) and day 14 (2 hours after instillation). These times were selected to assess duration (6 hours) and onset (2 hours) of effect. The LPFT, performed using an HVF analyzer, is a validated test for the measurement of superior visual field loss due to ptosis.32 It is an automated, observer-independent, static perimetry test in which the center of fixation is shifted 15 ° inferiorly to allow for maximum superior field testing, more natural eyelid positioning, and to prevent compensatory brow elevation. The LPFT examines a 48 ° range in the superior visual field, using a 35-point grid comprising the top 4 rows of the field. Fourteen points are also tested in the inferior visual field as a reference. The LPFT demonstrates high sensitivity (98.8%), specificity (92.5%), positive predictive value (96.6%), and negative predictive value (97.4%) in detecting ptosis.32 The secondary efficacy end point, change from baseline in MRD-1 on day 1 (6 hours) and day 14 (2 hours), was measured using digital photographs taken at the study sites. Care was taken to ensure consistent ambient lighting for photography at all sites and time points. A standardized selfjamaophthalmology.com
Original Investigation Research
adhesive millimeter-scale ruler was placed vertically on each participant’s forehead, centered above the eyebrows, and used by investigators at each site to take standardized MRD-1 measurements from digital photographs using calipers. Photographs were also used to measure pupil diameter and palpebral fissure distance (study RVL-1201-201 only). Compliance was measured by comparing the numbers of returned and dispensed treatment vials.
Safety Outcome Measures Treatment-emergent adverse events (TEAEs) were monitored and reported throughout both studies and evaluated with respect to severity and relationship to treatment. Vital signs, Snellen visual acuity, pupil diameter, slitlamp examination, and corneal fluorescein staining were examined at all study visits. Intraocular pressure tonometry and dilated ophthalmoscopy/fundus examinations were conducted at screening and day 42.
Statistical Analysis Analyses were conducted using the combined intent-to-treat population (participants receiving ≥1 treatment dose). Efficacy was analyzed using data from the study eye, while safety was analyzed for both eyes. Because less than 5% of data points were missing in both treatment groups, with no evidence of either group being particularly subject to missing data, efficacy analysis used the intent-to-treat population, with the last observation carried forward for missing data. Descriptive statistics of the observed and change from baseline for efficacy end points were tabulated by visit and treatment group, using common time points across studies. Differences between treatment groups were compared using an analysis of covariance model with treatment as a fixed factor and baseline score as a covariate. Treatments were compared using pairwise comparison from the model. Statistical tests were 2-sided, with P < .05 considered statistically significant for the primary outcome. Analyses for the individual trials were initiated after database lock and completed on September 6, 2017, and May 16, 2019. Pooled analysis was completed on August 25, 2019.
Results Participant Disposition In total, 304 participants were enrolled and randomized to receive oxymetazoline, 0.1% (203 [66.8%]), or vehicle (101 [33.2%]) (Table 1 and Figure 1). Demographic characteristics were similar across treatment groups (Table 1). Study completion rates (oxymetazoline, 0.1%: 198 of 203 [97.5%]; vehicle: 98 of 101 [97.0%]) and treatment compliance (mean [SD]: oxymetazoline, 0.1%: 98.1% [8.7%]; vehicle: 97.2% [10.7%]) were high, and mean treatment exposure was 42 days in both groups (Table 1).
Primary Efficacy: LPFT At baseline, the mean (SD) number of points seen in the top 4 rows on the LPFT was the same across treatment groups (Reprinted) JAMA Ophthalmology Published online October 1, 2020
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Research Original Investigation
Association of Oxymetazoline Hydrochloride, 0.1%, Solution Administration With Visual Field in Acquired Ptosis
Table 1. Participant Disposition and Demographicsa No. (%) Characteristic
Oxymetazoline, 0.1% (n = 203)
Enrolled, No.
203
101
Completed all visits
198 (97.5)
98 (97.0)
Compliance with treatment, mean (SD), %b
98.1 (8.7)
97.2 (10.7)
Treatment exposure, mean (SD), d
42.1 (4.6)
42.2 (5.3)
Age, mean (SD) [range], y
64.1 (13.4) [20-92]
63.3 (14.7) [14-85]
Female
151 (74.4)
71 (70.3)
Male
52 (25.6)
30 (29.7)
White
177 (87.2)
92 (91.1)
Black
18 (8.9)
6 (5.9)
Asian
6 (3.0)
3 (3.0)
American Indian
2 (1.0)
0
Not Hispanic/Latino
170 (83.7)
84 (83.2)
Hispanic/Latino
33 (16.3)
17 (16.8)
Mean (SD)
17.3 (4.7)
17.3 (5.3)
Median (range)
17.0 (8-27)
17.0 (2-26)
Mean (SD)
1.09 (0.70)
1.05 (0.69)
Median (range)
1.00 (0-3.0)
1.00 (0-2.0)
Vehicle (n = 101)
Sex
Race
Ethnicity
Baseline points seen, top 4 rows, LPFT
Baseline MRD-1, mm
Abbreviations: LPFT, Leicester Peripheral Field Test; MRD-1, marginal reflex distance. a
Data were similar in the individual studies (eTable 1 in the Supplement).
b
Percentage of opened vials returned relative to the number of vials that should have been used during the treatment period.
(oxymetazoline, 0.1%: 17.3 [4.7]; vehicle: 17.3 [5.3]; Table 1), suggesting an equivalent superior visual field deficit. On day 1 (6 hours), the mean (SD) number of points seen increased to 23.1 (6.5) in the oxymetazoline, 0.1%, group and 19.1 (6.1) in the vehicle group, with a significantly greater mean change in the oxymetazoline, 0.1% group (mean [SD], 5.9 [6.4] vs 1.8 [4.1]; mean difference, 4.07 [95% CI, 2.74-5.39]; P < .001; Figure 2A). Two hours after instillation of oxymetazoline, 0.1%, or vehicle on day 14, the mean (SD) numbers of points seen were 24.3 (6.0) and 19.5 (6.0), respectively, with a significantly greater mean (SD) change from baseline in the oxymetazoline, 0.1%, group (7.1 [5.9] vs 2.4 [5.5]; mean difference, 4.74 [95% CI, 3.43-6.04]; P < .001; Figure 2A).
Secondary Efficacy: MRD-1 Mean (SD) baseline MRD-1 in the study eye was similar across treatment groups (oxymetazoline, 0.1%: 1.09 [0.70] mm; vehicle: 1.05 [0.69] mm; Table 1). Mean (SD) change from baseline on day 1 (6 hours) was 0.96 (0.89) mm with oxymetazoline, 0.1%, and 0.50 (0.81) mm with vehicle (mean difference, 0.47 mm [95% CI, 0.27-0.67]; P < .001; Figure 2B and Figure 3). On day 14 (2 hours), mean (SD) change from baseline in MRD-1 E4
was 1.16 (0.87) mm and 0.50 (0.80) mm in the oxymetazoline, 0.1%, and vehicle groups, respectively (mean difference, 0.67 mm [95% CI, 0.46-0.88]; P < .001; Figure 2B and Figure 3).
Safety There were 129 TEAEs in 63 participants (31.0%) receiving oxymetazoline, 0.1%, and 73 TEAEs in 36 participants (35.6%) receiving vehicle (Table 2). Among participants receiving oxymetazoline, 0.1%, and reporting a TEAE, 51 of 63 (81.0%) had a maximum TEAE intensity of mild, and 39 of 63 (61.9%) had no TEAE suspected of being treatment related. Among participants receiving vehicle with a reported TEAE, 25 of 36 (69.4%) had a maximum TEAE intensity of mild, and 27 of 36 (75.0%) had no TEAE suspected of being treatment related. Two participants (1.0%) receiving oxymetazoline, 0.1%, reported serious TEAEs (hyperparathyroidism; cerebrovascular accident), and 1 participant (1.0%) receiving vehicle had a serious TEAE (lower gastrointestinal hemorrhage). No serious TEAE was suspected of being treatment related, and all were resolved. Three participants (1.5%) in the oxymetazoline, 0.1%, group and 2 participants (2.0%) in the vehicle group discontinued owing to a TEAE. TEAEs occurring in 2% or more of participants in either group were punctate keratitis (oxymetazoline, 0.1%: 11 of 203 [5.4%]; vehicle: 3 of 101 [3.0%]), blurred vision (oxymetazoline, 0.1%: 7 of 203 [3.4%]; vehicle: 0), conjunctival hyperemia (oxymetazoline, 0.1%: 6 of 203 [3.0%]; vehicle: 1 of 101 [1.0%]), and instillation site pain (oxymetazoline, 0.1%: 6 of 203 [3.0%]; vehicle: 0) (Table 2). Punctate keratitis, blurred vision, and conjunctival hyperemia were each suspected of being treatment related in 2 participants (1.0%) receiving oxymetazoline, 0.1%. Instillation site pain was suspected of being treatment related in all 6 participants reporting it. There were no mean shifts from baseline in vital signs, or intraocular pressure, Snellen visual acuity, pupil diameter, slitlamp or ophthalmoscopy/fundus examination results in either eye judged to be clinically relevant. Mean (SD) changes from baseline in the right pupil diameter with oxymetazoline, 0.1%, and vehicle, respectively, were 0.4 (0.8) mm and 0 (0.6) mm on day 1, 0.1 (0.7) mm and −0.1 (0.8) mm on day 14, and −0.1 (0.8) mm and −0.2 (0.8) mm on day 42.
Discussion These clinical study results support the efficacy and safety of oxymetazoline, 0.1%, for the treatment of acquired ptosis, a potentially important finding given the lack of other approved pharmacologic options for this condition, as well as the barriers to and potential risks11 associated with surgery. Reliable visual field testing is essential to accurately assessing the effect of any potential therapy for ptosis. While the LPFT used for the primary outcome in these trials has been shown to detect functional disability (superior visual field loss) in patients with ptosis with high specificity, owing to the wide superior visual field tested and inferior shift in the target of
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Original Investigation Research
Figure 1. Participant Disposition Flowchart: Study RVL-1201-201, Study RVL-1201-202, and Pooled Analysis Study RVL-1201-202
Study RVL-1201-201 336 Assessed for eligibility
358 Assessed for eligibility
196 Excluded (did not meet inclusion criteria)
194 Excluded (did not meet inclusion criteria)
140 Randomized
164 Randomized
94 Allocated to RVL-1201 group and received 1 drop per eye, self-administered once daily, for 42 d
46 Allocated to vehicle group and received 1 drop per eye, self-administered once daily, for 42 d
109 Allocated to RVL-1201 group and received 1 drop per eye, self-administered once daily, for 42 d
55 Allocated to vehicle group and received 1 drop per eye, self-administered once daily, for 42 d
4 Discontinued intervention 3 Adverse events 1 Protocol deviation
1 Discontinued intervention (noncompliance)
1 Discontinued intervention (adverse event)
2 Discontinued intervention (withdrawal of consent)
94 Analyzed
46 Analyzed
109 Analyzed
55 Analyzed
203 Included in RVL-1201 group in pooled analysis
101 Included in vehicle group in pooled analysis
In study RVL-1201-201, the first participant was enrolled on May 29, 2015, and the last participant completed on October 24, 2016. In study RVL-1201-202, first enrollment was on June 20, 2018, and last completion was on April 10, 2019. Study RVL-1201-201’s sample size was defined to establish more than 99% power to detect an effect size of 1.0 using a 2-group t test with a .05 two-sided significance level. Study RVL-1201-202’s sample size was based on establishing 90% power to detect a difference of 3.50 on the primary end point using a 2-group t test with a .05 two-sided significance level.
Figure 2. Mean Change on the Leicester Peripheral Field Test (LPFT) and Marginal Reflex Distance 1 (MRD-1) After Instillation of 1 Drop Oxymetazoline, 0.1%, or Vehicle A Change from baseline in points seen
B
Change from baseline in MRD-1
in top 4 rows on LPFT 16 P
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