Blepharoptosis
Conditions
Keywords
Blepharoptosis, Ptosis
Brief summary
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
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
Interventions
DRUGRVL-1201
RVL-1201 0.1% Ophthalmic Solution
RVL-1201 Vehicle Placebo
Sponsors
RVL Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Humphrey Visual Field | Baseline (Day 0, Hour 0), Visit 4 (Day 13, Hour 2) and Visit 4 (Day 13, Hour 6) | 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: 1. Hour 6 on Visit 4 (Day 13) for the BID regimen versus vehicle 2. Hour 6 on Visit 4 (Day 13) for the QD regimen versus vehicle 3. Hour 2 on Visit 4 (Day 13) for the BID regimen versus vehicle 4. 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Marginal Reflex Distance | Baseline (Day 0, Hour 0), Visit 4 (Day 13, Hour 2) and Visit 4 (Day 13, Hour 6) | 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. |
| Palpebral Fissure Distance Measurement | Baseline (Day 0, Hour 0), Visit 4 (Day 13, Hour 2) and Visit 4 (Day 13, Hour 6) | 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. |
| Contrast Sensitivity | Baseline (Day 0, Hour 0), Visit 4 (Day 13, Hour 2) and Visit 4 (Day 13, Hour 6) | 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). |
| Corrected Snellen Visual Acuity | Baseline (Day 0, Hour 0), Visit 4 (Day 13, Hour 2) and Visit 4 (Day 13, Hour 6) | 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). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| RVL-1201 QD 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
RVL-1201: RVL-1201 0.1% Ophthalmic Solution | 15 |
| RVL-1201 BID RVL-1201 0.1% ophthalmic solution dosed one full drop per eye BID; approximately 8 hours between the morning dose and the afternoon dose
RVL-1201: RVL-1201 0.1% Ophthalmic Solution | 16 |
| RVL-1201 Vehicle (Placebo) BID RVL 1201 ophthalmic solution vehicle (placebo) dosed one full drop per eye BID; approximately 8 hours between the morning dose and the afternoon dose
RVL-1201 Vehicle Placebo: RVL-1201 Vehicle Placebo | 15 |
| Total | 46 |
Baseline characteristics
| Characteristic | RVL-1201 QD | RVL-1201 BID | RVL-1201 Vehicle (Placebo) BID | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 7 Participants | 3 Participants | 5 Participants | 15 Participants |
| Age, Categorical Between 18 and 65 years | 8 Participants | 13 Participants | 10 Participants | 31 Participants |
| Age, Continuous | 64.3 years STANDARD_DEVIATION 10.33 | 58.7 years STANDARD_DEVIATION 10.47 | 58.3 years STANDARD_DEVIATION 11.23 | 60.4 years STANDARD_DEVIATION 10.8 |
| Age, Customized | 63 years | 60 years | 60 years | 61.5 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 11 Participants | 9 Participants | 9 Participants | 29 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants | 7 Participants | 6 Participants | 17 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Iris Color OD/OS Iris Color OD Blue | 4 Participants | 4 Participants | 1 Participants | 9 Participants |
| Iris Color OD/OS Iris Color OD Brown | 10 Participants | 11 Participants | 13 Participants | 34 Participants |
| Iris Color OD/OS Iris Color OD Green | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Iris Color OD/OS Iris Color OD Grey | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Iris Color OD/OS Iris Color OD Hazel | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Iris Color OD/OS Iris Color OD Other | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Iris Color OD/OS Iris Color OS Blue | 4 Participants | 4 Participants | 1 Participants | 9 Participants |
| Iris Color OD/OS Iris Color OS Brown | 10 Participants | 11 Participants | 13 Participants | 34 Participants |
| Iris Color OD/OS Iris Color OS Green | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Iris Color OD/OS Iris Color OS Grey | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Iris Color OD/OS Iris Color OS Hazel | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Iris Color OD/OS Iris Color OS Other | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Lens Status OD/OS Lens Status OD Aphakic, a person with a natural lens was extracted and no intraocular lens was implanted. | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Lens Status OD/OS Lens Status OD Phakic, a person with an intact natural lens | 9 Participants | 11 Participants | 11 Participants | 31 Participants |
| Lens Status OD/OS Lens Status OD Pseudophakic, a person who has had a lens extracted and an intraocular lens placed | 6 Participants | 5 Participants | 4 Participants | 15 Participants |
| Lens Status OD/OS Lens Status OS Aphakic, a person with a natural lens was extracted and no intraocular lens was implanted. | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Lens Status OD/OS Lens Status OS Phakic, a person with an intact natural lens | 9 Participants | 12 Participants | 11 Participants | 32 Participants |
| Lens Status OD/OS Lens Status OS Pseudophakic, a person who has had a lens extracted and an intraocular lens placed | 6 Participants | 4 Participants | 4 Participants | 14 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 15 Participants | 14 Participants | 12 Participants | 41 Participants |
| Region of Enrollment United States | 15 Participants | 16 Participants | 15 Participants | 46 Participants |
| Sex: Female, Male Female | 13 Participants | 10 Participants | 11 Participants | 34 Participants |
| Sex: Female, Male Male | 2 Participants | 6 Participants | 4 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 15 | 0 / 16 | 0 / 15 |
| other Total, other adverse events | 4 / 15 | 5 / 16 | 1 / 15 |
| serious Total, serious adverse events | 0 / 15 | 0 / 16 | 0 / 15 |
Outcome results
Primary
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: 1. Hour 6 on Visit 4 (Day 13) for the BID regimen versus vehicle 2. Hour 6 on Visit 4 (Day 13) for the QD regimen versus vehicle 3. Hour 2 on Visit 4 (Day 13) for the BID regimen versus vehicle 4. 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.
Time frame: Baseline (Day 0, Hour 0), Visit 4 (Day 13, Hour 2) and Visit 4 (Day 13, Hour 6)
Population: Intent to Treat Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| RVL-1201 Once Daily | Humphrey Visual Field | Visit 4 (Day 13, Hour 2) | 16.1 Points seen | Standard Deviation 5.35 |
| RVL-1201 Once Daily | Humphrey Visual Field | Base Line (Day 0, Hour 0) | 9.8 Points seen | Standard Deviation 5.07 |
| RVL-1201 Once Daily | Humphrey Visual Field | Visit 4 (Day 13, Hour 6) | 15.9 Points seen | Standard Deviation 5.29 |
| RVL-1201 Twice Daily | Humphrey Visual Field | Visit 4 (Day 13, Hour 2) | 15.7 Points seen | Standard Deviation 4.63 |
| RVL-1201 Twice Daily | Humphrey Visual Field | Base Line (Day 0, Hour 0) | 12.1 Points seen | Standard Deviation 4.64 |
| RVL-1201 Twice Daily | Humphrey Visual Field | Visit 4 (Day 13, Hour 6) | 17.0 Points seen | Standard Deviation 4.51 |
| RVL-1201 Vehicle (Placebo) | Humphrey Visual Field | Base Line (Day 0, Hour 0) | 11.1 Points seen | Standard Deviation 4.74 |
| RVL-1201 Vehicle (Placebo) | Humphrey Visual Field | Visit 4 (Day 13, Hour 6) | 17.1 Points seen | Standard Deviation 5.02 |
| RVL-1201 Vehicle (Placebo) | Humphrey Visual Field | Visit 4 (Day 13, Hour 2) | 15.7 Points seen | Standard Deviation 5.64 |
Secondary
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).
Time frame: Baseline (Day 0, Hour 0), Visit 4 (Day 13, Hour 2) and Visit 4 (Day 13, Hour 6)
Population: Intent to Treat Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| RVL-1201 Once Daily | Contrast Sensitivity | Visit 4 (Day 13, Hour 2) | 34.7 Letters Read | Standard Deviation 4.45 |
| RVL-1201 Once Daily | Contrast Sensitivity | Baseline (Day 0, Hour 0) | 33.1 Letters Read | Standard Deviation 4.05 |
| RVL-1201 Once Daily | Contrast Sensitivity | Visit 4 (Day 13, Hour 6) | 35.5 Letters Read | Standard Deviation 3.81 |
| RVL-1201 Twice Daily | Contrast Sensitivity | Visit 4 (Day 13, Hour 2) | 35.8 Letters Read | Standard Deviation 4.28 |
| RVL-1201 Twice Daily | Contrast Sensitivity | Baseline (Day 0, Hour 0) | 34.7 Letters Read | Standard Deviation 6.14 |
| RVL-1201 Twice Daily | Contrast Sensitivity | Visit 4 (Day 13, Hour 6) | 36.8 Letters Read | Standard Deviation 3.29 |
| RVL-1201 Vehicle (Placebo) | Contrast Sensitivity | Baseline (Day 0, Hour 0) | 33.3 Letters Read | Standard Deviation 5.81 |
| RVL-1201 Vehicle (Placebo) | Contrast Sensitivity | Visit 4 (Day 13, Hour 6) | 35.1 Letters Read | Standard Deviation 4.18 |
| RVL-1201 Vehicle (Placebo) | Contrast Sensitivity | Visit 4 (Day 13, Hour 2) | 35.3 Letters Read | Standard Deviation 4.79 |
Secondary
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).
Time frame: Baseline (Day 0, Hour 0), Visit 4 (Day 13, Hour 2) and Visit 4 (Day 13, Hour 6)
Population: Intent to Treat Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| RVL-1201 Once Daily | Corrected Snellen Visual Acuity | Visit 4 (Day 13, Hour 6) | 0.026 LogMAR | Standard Deviation 0.0891 |
| RVL-1201 Once Daily | Corrected Snellen Visual Acuity | Visit 4 (Day 13, Hour 2) | 0.055 LogMAR | Standard Deviation 0.0739 |
| RVL-1201 Once Daily | Corrected Snellen Visual Acuity | Baseline (Day 0, Hour 0) | 0.071 LogMAR | Standard Deviation 0.0859 |
| RVL-1201 Twice Daily | Corrected Snellen Visual Acuity | Visit 4 (Day 13, Hour 2) | 0.024 LogMAR | Standard Deviation 0.1043 |
| RVL-1201 Twice Daily | Corrected Snellen Visual Acuity | Baseline (Day 0, Hour 0) | 0.086 LogMAR | Standard Deviation 0.0988 |
| RVL-1201 Twice Daily | Corrected Snellen Visual Acuity | Visit 4 (Day 13, Hour 6) | 0.023 LogMAR | Standard Deviation 0.0949 |
| RVL-1201 Vehicle (Placebo) | Corrected Snellen Visual Acuity | Baseline (Day 0, Hour 0) | 0.081 LogMAR | Standard Deviation 0.077 |
| RVL-1201 Vehicle (Placebo) | Corrected Snellen Visual Acuity | Visit 4 (Day 13, Hour 6) | 0.053 LogMAR | Standard Deviation 0.1018 |
| RVL-1201 Vehicle (Placebo) | Corrected Snellen Visual Acuity | Visit 4 (Day 13, Hour 2) | 0.059 LogMAR | Standard Deviation 0.119 |
Secondary
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.
Time frame: Baseline (Day 0, Hour 0), Visit 4 (Day 13, Hour 2) and Visit 4 (Day 13, Hour 6)
Population: Intent to Treat Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| RVL-1201 Once Daily | Marginal Reflex Distance | Visit 4 (Day 13, Hour 2) | 2.4 Millimeters (mm) | Standard Deviation 0.99 |
| RVL-1201 Once Daily | Marginal Reflex Distance | Baseline (Day 0, Hour 0) | 1.6 Millimeters (mm) | Standard Deviation 0.77 |
| RVL-1201 Once Daily | Marginal Reflex Distance | Visit 4 (Day 13, Hour 6) | 2.4 Millimeters (mm) | Standard Deviation 1 |
| RVL-1201 Twice Daily | Marginal Reflex Distance | Visit 4 (Day 13, Hour 2) | 2.3 Millimeters (mm) | Standard Deviation 1.19 |
| RVL-1201 Twice Daily | Marginal Reflex Distance | Baseline (Day 0, Hour 0) | 1.6 Millimeters (mm) | Standard Deviation 0.84 |
| RVL-1201 Twice Daily | Marginal Reflex Distance | Visit 4 (Day 13, Hour 6) | 2.5 Millimeters (mm) | Standard Deviation 1.13 |
| RVL-1201 Vehicle (Placebo) | Marginal Reflex Distance | Baseline (Day 0, Hour 0) | 1.6 Millimeters (mm) | Standard Deviation 0.63 |
| RVL-1201 Vehicle (Placebo) | Marginal Reflex Distance | Visit 4 (Day 13, Hour 6) | 2.2 Millimeters (mm) | Standard Deviation 1.07 |
| RVL-1201 Vehicle (Placebo) | Marginal Reflex Distance | Visit 4 (Day 13, Hour 2) | 2.0 Millimeters (mm) | Standard Deviation 0.95 |
Secondary
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.
Time frame: Baseline (Day 0, Hour 0), Visit 4 (Day 13, Hour 2) and Visit 4 (Day 13, Hour 6)
Population: Intent to Treat Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| RVL-1201 Once Daily | Palpebral Fissure Distance Measurement | Visit 4 (Day 13, Hour 2) | 6.9 Millimeters (mm) | Standard Deviation 1.35 |
| RVL-1201 Once Daily | Palpebral Fissure Distance Measurement | Baseline (Day 0, Hour 0) | 6.2 Millimeters (mm) | Standard Deviation 1.16 |
| RVL-1201 Once Daily | Palpebral Fissure Distance Measurement | Visit 4 (Day 13, Hour 6) | 7.0 Millimeters (mm) | Standard Deviation 1.51 |
| RVL-1201 Twice Daily | Palpebral Fissure Distance Measurement | Visit 4 (Day 13, Hour 2) | 7.1 Millimeters (mm) | Standard Deviation 1.72 |
| RVL-1201 Twice Daily | Palpebral Fissure Distance Measurement | Baseline (Day 0, Hour 0) | 6.5 Millimeters (mm) | Standard Deviation 1.1 |
| RVL-1201 Twice Daily | Palpebral Fissure Distance Measurement | Visit 4 (Day 13, Hour 6) | 7.5 Millimeters (mm) | Standard Deviation 1.45 |
| RVL-1201 Vehicle (Placebo) | Palpebral Fissure Distance Measurement | Baseline (Day 0, Hour 0) | 6.5 Millimeters (mm) | Standard Deviation 1.55 |
| RVL-1201 Vehicle (Placebo) | Palpebral Fissure Distance Measurement | Visit 4 (Day 13, Hour 6) | 6.8 Millimeters (mm) | Standard Deviation 1.35 |
| RVL-1201 Vehicle (Placebo) | Palpebral Fissure Distance Measurement | Visit 4 (Day 13, Hour 2) | 6.6 Millimeters (mm) | Standard Deviation 1.67 |