(233 days)
Luminopia One is a software-only digital therapeutic designed to be used with commercially available Head-Mounted Displays (HMDs) which are compatible with the software application. Luminopia One is indicated for improvement in visual acuity in amblyopia patients, aged 4-7, associated with anisometropia and/or with mild strabismus, having received treatment instructions (frequency and duration) as prescribed by a trained eye-care professional. Luminopia One is intended for both previously treated and untreated patients; however, patients with more than 12 months of prior treatment (other than refractive correction) have not been studied. Luminopia One is intended to be used as an adjunct to full-time refractive correction, such as glasses, which should also be worn under the HMD during Luminopia One therapy. Luminopia One is intended for prescription use only, in an at-home environment.
Luminopia One is a Software as a Medical Device (SaMD) intended to improve visual acuity in pediatric patients with amblyopia (also known as lazy eye). The device is indicated for improvement in visual acuity at 12 weeks of use in amblyopia patients aged 4-7. The software is designed to be used with commercially available head-mounted displays (HMDs) and is intended for at-home use. In this submission, the Samsung Gear HMD has been validated to be compatible with Luminopia One. The Patient should wear their refractive correction, such as glasses, under the HMD during treatment. The software allows patients to select videos to watch. Treatment is provided through algorithms that apply modifications to the videos to encourage use of the amblyopic eve. The video presented to the fellow eye (the stronger eye) is different from the video presented to the amblyopic eve (weaker eye). When a video begins in the software application, the patient will see a modified version of the original video through each eye. This is intended to rebalance the visual input to the eyes and encourage weaker eye usage. The treatment regimen is the following: the patient watches the video 1 hour per day, 6 days per week for a total of 12 weeks. Luminopia One also includes a Patient Portal. The Patient/Caregiver will also have access to an online Patient Portal where they can review the Patient's adherence and select their favorite videos to watch in the HMD. The Patient Portal enables the Caregiver to review the patient's progress and treatment plan and curate content for the patient to watch. The Patient Portal is designed to be used by the Caregiver.
Here's a detailed breakdown of the acceptance criteria and the study proving the Luminopia One device meets them, based on the provided document:
1. Acceptance Criteria and Reported Device Performance
Bench/Non-Clinical Performance Testing
| Test | Acceptance Criteria | Reported Device Performance |
|---|---|---|
| HMD Temperature measurements | IEC 60601-1; Temperature does not exceed 41°C on the human contacting parts of the HMD | Passed |
| Luminance and its uniformity | Minimum luminance should not be lower than 48 candela per square meter (Cd/m2). The percent deviation from the average luminance at each location should not be higher than 50% | Passed |
| Contrast measurements | At least 90% at each location | Passed |
| HMD resolution | At least 14 pixels per degree | Passed |
| Crosstalk testing | Light entered from one eyepiece to another is not significantly higher than background levels. | Passed |
| Labeling comprehension testing | Testing demonstrated that caregivers and patients understood the directions of use and could use the device successfully. There were minimal use errors in the use of the device. | Passed |
Clinical Performance Testing (Effectiveness)
| Performance Metric | Acceptance Criteria (Implicit from study design as superiority) | Reported Device Performance (Relative to Control Group) |
|---|---|---|
| Primary Effectiveness Endpoint: Mean improvement from baseline in amblyopic eye's Best Corrected Visual Acuity (BCVA) at 12 weeks | Statistically significant difference between treatment and control groups, demonstrating superiority of Luminopia One. | Treatment group: -0.180 logMAR (1.8 lines) improvement. Control group: -0.080 logMAR (0.8 lines) improvement. Average difference: 1.0 line improvement (90% CI: 0.5, 1.5 lines). p=0.0012 (Interim Analysis). Final analysis (N=117): Difference 0.96 lines (90% CI: 0.45-1.47 lines), p=0.0011. |
| Secondary Effectiveness Endpoint: Percentage of subjects with ≥ 2 lines BCVA improvement at 12 weeks | Not explicitly stated as an acceptance criterion, but implicitly that a meaningful percentage in the treatment group achieves this. | 61.9% of Luminopia One subjects (95% CI: 45.6-76.4%) vs. 32.6% of control subjects (95% CI: 19.5-48.0%) at final analysis. |
Clinical Performance Testing (Safety)
| Performance Metric | Acceptance Criteria (Implicit: not cause unacceptable harm) | Reported Device Performance (Relative to Control Group) |
|---|---|---|
| Co-Primary Safety Endpoint: Adverse Events (AEs) | Moderate probability of device-related adverse events. | Overall AE rate: 25% (Luminopia One) vs. 13.6% (control). Higher rates in Luminopia One for headaches (14.3% vs. 1.7%), eye strain (3.6% vs. 0%), and "other" (7.1% vs. 0%). All non-serious except one severe case of "worsening night terrors" in the treatment group, however, this was a pre-existing condition and led to child's withdraw from study. |
| Co-Primary Safety Endpoint: Mean change non-amblyopic (fellow) eye BCVA from baseline | Non-inferiority to control group. | Interim Analysis: Difference -0.02 logMAR, upper 95% CL 0.010, p<0.0001 (for non-inferiority). Final Analysis: Difference -0.018 logMAR, upper 95% CL 0.006, p<0.0001 (for non-inferiority). Both indicate no additional risk for the fellow eye. |
2. Sample size used for the test set and the data provenance
- Test Set Sample Size: For the clinical study, the interim analysis involved 105 subjects (51 Luminopia One therapeutic group, 54 control group). The final analysis included 117 subjects (58 Luminopia One therapeutic group, 59 control group).
- Data Provenance: The document does not explicitly state the country of origin. However, given the FDA regulatory context, it is highly likely that the study was conducted within the United States or followed international clinical trial guidelines accepted by the FDA. The study was a prospective, randomized controlled clinical study.
3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts
The document does not specify the number of experts, nor their individual qualifications, used to establish the ground truth (visual acuity measurements) for the clinical study. However, visual acuity measurements (BCVA) are a standard clinical outcome typically assessed by trained ophthalmologists, optometrists, or certified ophthalmic technicians following standardized protocols (e.g., using logMAR charts). The American Academy of Ophthalmology (AAO) definition for amblyopia is referenced, suggesting adherence to established clinical standards for diagnosis and measurement.
4. Adjudication method (e.g., 2+1, 3+1, none) for the test set
The document does not describe any specific adjudication method for visual acuity measurements, which are generally direct, objective clinical assessments rather than subjective interpretations requiring adjudication.
5. If a multi reader multi case (MRMC) comparative effectiveness study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance
No, a multi-reader multi-case (MRMC) comparative effectiveness study was not done. Luminopia One is a "digital therapeutic" that directly treats the patient; it is not a diagnostic AI tool that assists human readers (e.g., radiologists interpreting images). Therefore, it directly improves patient outcomes rather than assisting human readers. The clinical study compares patient outcomes with the device to a control group without the device.
The effect size of the device's direct impact on patients was a mean improvement of 1.0 line (interim analysis) to 0.96 lines (final analysis) in amblyopic eye BCVA (superiority) compared to the control group.
6. If a standalone (i.e., algorithm only without human-in-the-loop performance) was done
Yes, in essence, the clinical study assessed the standalone performance of the Luminopia One algorithm (device) as a therapeutic intervention. While it requires a physician's prescription and is used at home by patients with HMDs, the "performance" directly refers to the algorithm's therapeutic effect on visual acuity, not its ability to assist a human in decision-making. The clinical trial directly evaluated the device's ability to improve visual acuity in patients compared to a control group, which is a standalone assessment of its therapeutic efficacy.
7. The type of ground truth used (expert consensus, pathology, outcomes data, etc.)
The primary ground truth for effectiveness was clinical outcomes data, specifically:
- Best Corrected Visual Acuity (BCVA) measured in logMAR and converted to lines of improvement.
- The definition of amblyopia based on AAO guidelines (interocular difference of 2 lines or more or VA worse than or equal to 20/30 with best optical correction).
Ground truth for safety involved the reporting and assessment of adverse events.
8. The sample size for the training set
The document does not provide information on the sample size used for training the Luminopia One algorithm. As a digital therapeutic, the "training" may refer to the development and refinement of the dichoptic presentation algorithms rather than a typical machine learning model training on a large dataset of patient images/data. The focus of the regulatory submission is on the clinical validation of the final product.
9. How the ground truth for the training set was established
The document does not specify how the ground truth for any potential training set was established. Given the nature of a "therapeutic algorithm" that modifies video presentations, the development likely involved principles of amblyopia therapy and visual neuroscience; "ground truth" in this context might refer to established physiological responses to dichoptic stimuli rather than labeled patient data for machine learning training.
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DE NOVO CLASSIFICATION REQUEST FOR LUMINOPIA ONE
REGULATORY INFORMATION
FDA identifies this generic type of device as:
Digital therapy device for amblyopia. A digital therapy device for amblyopia is a device that incorporates dichoptic presentations on visual displays through therapeutic algorithms to treat amblyopia or to improve visual acuity of patients with amblyopia.
NEW REGULATION NUMBER: 21 CFR 886.5500
CLASSIFICATION: Class II
PRODUCT CODE: QQU
BACKGROUND
DEVICE NAME: Luminopia One
SUBMISSION NUMBER: DEN210005
DATE DE NOVO RECEIVED: March 1, 2021
SPONSOR INFORMATION:
Luminopia, Inc. 955 Massachusetts Ave #335 Cambridge, Massachusetts 02139
INDICATIONS FOR USE
Luminopia One is a software-only digital therapeutic designed to be used with commercially available Head-Mounted Displays (HMDs) which are compatible with the software application. Luminopia One is indicated for improvement in visual acuity in amblyopia patients, aged 4-7, associated with anisometropia and/or with mild strabismus, having received treatment instructions (frequency and duration) as prescribed by a trained eye-care professional. Luminopia One is intended for both previously treated and untreated patients; however, patients with more than 12 months of prior treatment (other than refractive correction) have not been studied. Luminopia One is intended to be used as an adjunct to full-time refractive correction, such as glasses, which should also be worn under the HMD during Luminopia One therapy. Luminopia One is intended for prescription use only, in an at-home environment.
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LIMITATIONS
Luminopia One is intended to be used as an adjunct to fulltime refractive correction such as glasses, which should also be worn under the Head-Mounted Display (HMD) headset during Luminopia One therapy.
Federal law restricts this digital therapeutic to sale by or on the order of an ophthalmologist or optometrist.
As outlined in the Indications for Use, Luminopia One is a prescription device for children ages 4 to 7 to improve visual acuity for certain medical conditions and should be used under the direct supervision of a trained eye-care professional. The device is indicated for use with compatible, commercially available head-mounted displays (HMDs). Currently, the Samsung Gear HMD is the only compatible HMD. For all other uses of such HMD, users should follow the user manual and instructional information for the specific HMD used with Luminopia One, including the age range specified by the HMD manufacturer.
Patients should only use HMDs that are compatible with Luminopia One, as described in the "Directions for Use" labeling. The Luminopia One device is currently authorized to be used with the following commercially available HMDs that have been validated as compatible with the software application:
- Samsung Gear HMD .
Patients with an interpupillary distance of less than 52 mm should not use the Luminopia One device. The Luminopia One device has not been studied on patients with interpupillary distances of less than 52 mm. Attempting to use the Luminopia One device on these patients may result in decreased effectiveness of treatment and increased risk of adverse symptoms.
Because the Luminopia One clinical study did not follow patients after 12 weeks of use, limitations include:
- Safety and effectiveness of Luminopia One therapy beyond 12 weeks is unknown ● and was not evaluated in the clinical study.
- The durability of benefit from the Luminopia One device after treatment cessation is unknown (i.e., unknown whether visual acuity improvement at 12 weeks will be maintained or regress over time).
- . The long-term effects of Head-Mounted Display (HMD) use in patients 4-7 years of age are unknown.
In the 12-week clinical study, use of Luminopia One did not demonstrate a clinically meaningful improvement in stereoacuity (depth perception).
Please refer to Luminopia One "Directions for Use" for a complete list of WARNINGS, PRECAUTIONS AND CONTRAINDICATIONS, as well as a description of CLINICAL STUDY OUTCOMES.
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DEVICE DESCRIPTION
Luminopia One is a Software as a Medical Device (SaMD) intended to improve visual acuity in pediatric patients with amblyopia (also known as lazy eye). The device is indicated for improvement in visual acuity at 12 weeks of use in amblyopia patients aged 4-7. The software is designed to be used with commercially available head-mounted displays (HMDs) (Figure 1) and is intended for at-home use. In this submission, the Samsung Gear HMD has been validated to be compatible with Luminopia One. The Patient should wear their refractive correction, such as glasses, under the HMD during treatment.
Image /page/2/Figure/2 description: The image shows two diagrams of a person wearing a virtual reality headset. The diagram on the left shows the person facing forward, with the headset covering their eyes. A dashed line runs down the center of the person's face. The diagram on the right shows the person in profile, with the headset covering their eyes and a dashed line indicating the eye level.
Figure 1. Luminopia One is used with compatible head-mounted displays.
Image /page/2/Figure/4 description: The image shows a screen display of movies and TV shows. The top row displays movie content thumbnails, including titles such as "Deepsea," "Sandman," and "Polar Explorer." Below the movies are TV shows, displayed as circular thumbnails with various cartoon characters. The bottom of the screen shows logos for Netflix and Molang.
The software allows patients to select videos to watch (Figure 2).
Figure 2. Selection menus for TV shows and movies
Treatment is provided through algorithms that apply modifications to the videos to encourage use of the amblyopic eve. The video presented to the fellow eye (the stronger eye) is different from the video presented to the amblyopic eve (weaker eye) (Figure 3). When a video begins in the software application, the patient will see a modified version of the original video through
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each eye. This is intended to rebalance the visual input to the eyes and encourage weaker eye usage. The treatment regimen is the following: the patient watches the video 1 hour per day, 6 days per week for a total of 12 weeks.
Image /page/3/Picture/1 description: The image shows a side-by-side comparison of two video screens, labeled "WEAKER EYE" and "STRONGER EYE." Both screens display video content with a progress bar and playback controls at the bottom. The progress bar indicates that there are 23 minutes remaining in both videos. The video on the left is labeled "WEAKER EYE" and the video on the right is labeled "STRONGER EYE."
Figure 3. Left: Videos presented to the amblyopic eye (weaker eye); Right: video presented to the fellow eye (stronger eye).
Luminopia One also includes a Patient Portal. The Patient/Caregiver will also have access to an online Patient Portal where they can review the Patient's adherence and select their favorite videos to watch in the HMD. The Patient Portal enables the Caregiver to review the patient's progress and treatment plan
and curate content for the patient to watch. The Patient Portal is designed to be used by the Caregiver.
SUMMARY OF NONCLINICAL/BENCH STUDIES
| Test | Purpose | Method | Acceptance Criteria | Results |
|---|---|---|---|---|
| HMDTemperaturemeasurements | To prevent thermalinjury and/or adverseevents | Human subject wore the HMDwith multiple temperature probesplaced at different locations ofHMD | IEC 60601-1;Temperature does notexceed 41°C on thehuman contactingparts of the HMD | Passed |
| Luminanceand itsuniformity | To ensure luminance issufficiently high anduniform across thevisual display | IEC63145-20-10: Eyewear display- Part 20-10: Fundamentalmeasurement methods - Opticalproperties. Luminancemeasurements at 9 or morelocations in the field of view(FOV) using a uniform whitetesting pattern to determine theluminance and uniformity acrossthe FOV. | Minimum luminanceshould not be lowerthan 48 candela persquare meter (Cd/m2).The percent deviationfrom the averageluminance at eachlocation should not behigher than 50% | Passed |
| Contrastmeasurements | To ensure the visualdisplay has sufficient | IEC63145-20-10: Eyewear display- Part 20-10: Fundamental | At least 90% at eachlocation | Passed |
PERFORMANCE TESTING - BENCH
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| contrast to displayquality video and videomodificationsimplemented bysoftware | measurement methods - Opticalproperties. Contrast measurementsat 9 or more locations in the fieldof view using a test pattern, such asa grille pattern. Contrast can becalculated using the Michelsoncontrast equation | |||
|---|---|---|---|---|
| HMDresolution | To ensure the quality ofthe video | Calculate the horizontal andvertical pixels per degree bymeasuring horizontal and verticalfield of view and the number ofpixels in the test image. | At least 14 pixels perdegree | Passed |
| Crosstalktesting | To ensure that lightfrom one eyepiece ofthe HMD cannot beseen by the other eye toprevent interferencewith the treatment | Measure luminance with thefollowing combinations: (1) Botheyepieces have a uniform blacktest pattern (off); (2) Eyepiece 1has a uniform white test pattern(on) and eyepiece 2 is off; (3)Eyepiece 1 is off and eyepiece 2 ison.See Information DisplayMeasurements Standard 1.03(IDMSv1.03) as reference. | Light entered from oneeyepiece to another isnot significantlyhigher thanbackground levels. | Passed |
| Labelingcomprehensiontesting | To ensure that theDirection of Use (DFU)conveys clearinstructions to theparent/caregiver | DFU comprehension testing anddevice use testing: (1) caregiverand child pairs are tested throughthe knowledge tasks todemonstrate their understanding ofthe DFU; (2) caregiver and childpairs are tested through theperformance tasks to demonstratethat they can use devicesuccessfully. | Testing demonstratedthat caregivers andpatients understoodthe directions of useand could use thedevice successfully.There were minimaluse errors in the use ofthe device. | Passed |
SOFTWARE
Luminopia One is a Software as a Medical Device (SaMD). It was reviewed according to the FDA Guidance document, "Guidance for the Content of Premarket Submissions for Software Contained in Medical Devices," issued May 11, 2005. The software was found to have a MODERATE level of concern because a failure of the device may result in a minor injury to a patient prior to risk mitigation. FDA reviewed the software documentation provided in support of Luminopia One and found it acceptable.
Software controls have been implemented in Luminopia One to minimize overuse of the device. The user will be presented a pop-up warning when the daily use of the device exceeds the prescribed length of time. A software control will implement a lock-out at the end of entire prescribed treatment regimen.
SUMMARY OF CLINICAL INFORMATION
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A randomized controlled clinical study was conducted that evaluated 117 subjects age 4-7 years. treated for 12 weeks with Luminopia One (1 hour daily, 6 days a week, for 12 weeks) along with fulltime refractive correction, as compared to control treatment with refractive correction alone. with final assessment at the 12-week visit. Amblyopia is clinically defined as reduction of visual acuity (VA) that cannot be attributed to ocular or visual system abnormality or refractive error. The American Academy of Ophthalmology (AAO) considers amblyopia as an interocular difference of 2 lines or more or VA worse than or equal to 20/30 with best optical correction '. The Luminopia One clinical study inclusion criterion for VA met the AAO definition. Interim analysis was conducted per protocol after 75% of subjects completed the 12-week follow up visit. At that time there were 105 subjects (51 Luminopia One therapeutic group, 54 control group). The study was stopped early for success, per protocol, when 75% of subjects completed the 12-week visit, since primary effectiveness and safety endpoints were achieved at interim analysis. Final analysis included 117 subjects (58 Luminopia One therapeutic group, 59 control group), reported as descriptive outcome information in the device labeling.
The mean age of all study participants was 6.0±1.0 years (n = 117). Among them, 56.4% (66/117) were male and 43.6% (51/117) were female. The mean age for the Luminopia One treatment group was 6.2 ± 0.9 (n = 58) years. In the treatment group, 60.3% (35/58) of the subjects were male and 39.7% (23/58) were female. The mean age for the control group (refractive correction only) was 5.9 ± 1.1 (n = 59). In the control group, 52.5% (31/59) of the subjects were male and 47.5% (28/59) were female.
In terms of ethnicity, 22.4% (13/58) of the subjects in the treatment group were Hispanic or Latino and 77.6% (45/58) were not Hispanic or Latino. In the control group, 10.2% (6/59) of the subjects were Hispanic or Latino and 89.8% (53/59) were not Hispanic or Latino.
The percentages of subjects whose right eye is amblyopic are 45.6% (26/57) for the treatment group and 47.5% (28/59) for the control group. The percentages of subjects whose left eye is amblyopic are 54.4% (31/57) for the treatment group and 52.5% (31/59) for the control group.
- Evidence of clinical benefit for Luminopia One as used in the clinical study with refractive correction:
o Primary Effectiveness Endpoint: Mean improvements from baseline in amblyopic eye's best corrected visual acuity (BCVA) after 12-week treatment show statistically significant difference between the treatment and control groups; superiority of the treatment was demonstrated and the endpoint was met:
· Interim analysis (N=105. n=84): Mean change -0.180 (SD=0.15) logMAR in the therapeutic group, -0.080 (SD=0.14) logMAR in the control group (see Table 1 below). Average difference between groups -0.10 logMAR, greater improvement in the treatment group compared to control group (p=0.0012). Mean BCVA improvement in amblyopic eye was 1.8 lines in the treatment group vs. 0.8 lines
1 https://www.aao.org/disease-review/amblyopia-types-diagnosis-treatment-new-perspectiv
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| Table 1: Amblyopic Eye BCVA1 - Intention-to-Treat (ITT) Population at InterimAnalysis | Results | |||||
|---|---|---|---|---|---|---|
| TreatmentGroupN=51 | Control GroupN=54 | Difference inChange inBCVA2(90% CI) | P-value3 | Stage 1AlphaLevel | Decision | |
| Improvement fromBaseline at 12Weeks (lines)4 | 1.8 ± 1.5 (41)2.0 (-2.0, 6.0)[1.3, 2.3] | 0.8 ± 1.4 (43)1.0 (-2.0, 4.0)[0.4, 1.3] | 1.0(0.5, 1.5) | 0.0012 | 0.0176 | Reject H0 |
| Change fromBaseline at 12Weeks (logMAR) | -0.18 ± 0.15 (41)-0.20 (-0.60, 0.20)[-0.23, -0.13] | -0.08 ± 0.14 (43)-0.10 (-0.40, 0.20)[-0.13, -0.04] | ||||
| Baseline (logMAR) | 0.54 ± 0.21 (41)0.50 (0.30, 1.00) | 0.50 ± 0.19 (43)0.40 (0.30, 1.00) | ||||
| 12 Weeks (logMAR) | 0.36 ± 0.23 (41)0.30 (0.00, 1.10) | 0.42 ± 0.21 (43)0.40 (0.00, 1.00) | ||||
| 1Based on participants with available data at baseline and in-window 12-week visits. Data presented as mean ± standard deviation (N) median (min, max). Change from baseline also includes [95% CI].2Difference between groups (treatment - control) and 90% confidence interval are based on the coefficient associatedtreatment group from an ANOVA model. Positive difference between groups represents larger improvement in the treatment group. |
in control group. Point estimate difference in improvement is 1.0 line (90% CI: 0.5-1.5 lines).
P value is based on a one-sided F-test for the coefficient associated with treatment group from an ANOVA model
"Original visual acuity measurements captured using inprovement from baseline corresponds to a change of -0.10 lgMAR
The bar chart below (Figure 4) shows the mean BCVA improvements in the treatment group vs. the control group after 4, 8 and 12 weeks of treatment.
Image /page/6/Figure/5 description: The image is a bar graph comparing the improvement in BCVA (Lines) between a treatment group and a control group at different follow-up visits (4, 8, and 12 weeks). The y-axis represents the improvement in BCVA, ranging from 0 to 2.5 lines. At each follow-up visit, the treatment group (green bars) shows a greater improvement in BCVA compared to the control group (blue bars), with statistically significant differences indicated by asterisks.
Figure 4. Improvement in amblyopic eye BCVA from baseline - ITT population at interim analysis at 4, 8, and 12 weeks (error bars denote ± SEM, * denotes p < 0.05)
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· Final analysis (N=117, n=88): Mean change was -0.181 logMAR (SD=0.15) in the therapeutic group and -0.085 logMAR (SD=0.14) in the control group (see Table 2 below). The average difference between groups was -0.096 logMAR, larger improvement in Luminopia One group (p = 0.0011), consistent with interim analysis results. BCVA improved by 1.8 lines in the treatment group vs. 0.85 lines in the control group. Point estimate of difference between groups is 0.96 line (90% CI: 0.45-1.47 lines).
| Table 2: Amblyopic Eye BCVA1 - ITT Population at Final Analysis | |||
|---|---|---|---|
| Treatment GroupN=58 | Control GroupN=59 | Difference inChange in BCVA2(90% CI) | |
| Improvement fromBaselineat 12 Weeks (lines)4 | 1.81 ± 1.52 (42)2.0 (-2.0, 6.0)[1.34, 2.28] | 0.85 ± 1.35 (46)1.0 (-2.0, 4.0)[0.45, 1.25] | 0.96(0.45, 1.47) |
| Change from Baselineat 12 Weeks (logMAR) | -0.181 ± 0.152 (42)-0.200 (-0.600, 0.200)[-0.228, -0.134] | -0.085 ± 0.135 (46)-0.100 (-0.400, 0.200)[-0.125, -0.045] | |
| Baseline (logMAR) | 0.536 ± 0.212 (42)0.500 (0.300, 1.000) | 0.507 ± 0.190 (46)0.400 (0.300, 1.000) | |
| 12 Weeks (logMAR) | 0.355 ± 0.231 (42)0.300 (0.000, 1.100) | 0.422 ± 0.202 (46)0.400 (0.000, 1.000) |
1Based on participants with available data at baseline and in-window 12-week visits. Data presented as mean ± standard deviation (N) median (min, max). Change from baseline also includes [9
2Difference between groups (treatment - control) and 90% confidence interval are based on the
coefficient associated treatment group from an ANOVA model. Positive difference between groups represents larg in the treatment group.
P-value is based on a one-sided F-test for the coefficient associated with treatment group from an ANOVA mo
*Original visual acuity measurements captured using logMAR. A 1-line improvement from baseline corresponds
*Although the results from the interim analysis constitute the statistical conclusions from the study, the results analysis are based on data from all enrolled participants
o Secondary Effectiveness Endpoint: Amblyopic eye BCVA improvement 2 or more lines from baseline after 12 weeks, 62% of Luminopia subjects (95% CI: 46-76%) vs. 33% of control subjects (95% CI: 20-48%) (see the Table 3 below). This is part of the final analysis that was pre-specified as descriptive analysis only.
| Table 3: Improvement in Amblyopic Eye BCVA ≥ 2 Lines1 – ITT Population at Final Analysis | ||
|---|---|---|
| Treatment GroupN=58 | Control GroupN=59 | |
| Improvement ≥ 2 linesfrom Baseline to 4 weeks | 34.0% (17/50)[21.2%, 48.8%] | 24.5% (12/49)[13.3%, 38.9%] |
| Improvement ≥ 2 linesfrom Baseline to 8 weeks | 50.0% (24/48)[35.2%, 64.8%] | 31.8% (14/44)[18.6%, 47.6%] |
| Improvement ≥ 2 linesfrom Baseline to 12 weeks | 61.9% (26/42)[45.6%, 76.4%] | 32.6% (15/46)[19.5%, 48.0%] |
| 1Based on participants with available data at baseline and in-window visits. Data presented as: % (n/N) [95% CI]. |
P-value from post-hoc Chi-square test.
*Although the results from the interim analysis conclusions from the study, the results from the fina analysis are based on data from all enrolled participants
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o Supplemental analysis: Lines of improvement in BCVA: Luminopia One group demonstrates better visual acuity improvement outcome than control group at 4, 8 and 12 weeks (see the Table 4 below).
| Table 4: Amblyopic Eye Change in BCVA by Visit¹ - ITT Population at Final Analysis | ||||||
|---|---|---|---|---|---|---|
| 4 Weeks | 8 Weeks | 12 Weeks | ||||
| Number ofLines Change(follow-up -baseline)² | Tx | Control | Tx | Control | Tx | Control |
| 6-lineimprovement | 0.0%(0/50) | 0.0%(0/49) | 0.0%(0/48) | 0.0%(0/44) | 2.4%(1/42) | 0.0% (0/46) |
| 4-lineimprovement | 4.0%(2/50) | 0.0%(0/49) | 6.3%(3/48) | 6.8%(3/44) | 2.4%(1/42) | 2.2% (1/46) |
| 3-lineimprovement | 10.0%(5/50) | 8.2%(4/49) | 12.5%(6/48) | 13.6%(6/44) | 31.0%(13/42) | 10.9% (5/46) |
| 2-lineimprovement | 20.0%(10/50) | 16.3%(8/49) | 31.3%(15/48) | 11.4%(5/44) | 26.2%(11/42) | 19.6% (9/46) |
| 1-lineimprovement | 32.0%(16/50) | 22.4%(11/49) | 29.2%(14/48) | 31.8%(14/44) | 23.8%(10/42) | 19.6% (9/46) |
| No change | 24.0%(12/50) | 32.7%(16/49) | 14.6%(7/48) | 15.9%(7/44) | 7.1%(3/42) | 34.8% (16/46) |
| 1-line decrease | 8.0%(4/50) | 10.2%(5/49) | 6.3%(3/48) | 13.6%(6/44) | 2.4%(1/42) | 10.9% (5/46) |
| 2-line decrease | 2.0%(1/50) | 6.1%(3/49) | 0.0%(0/48) | 6.8%(3/44) | 4.8%(2/42) | 2.2% (1/46) |
| 3-line decrease | 0.0%(0/50) | 2.0%(1/49) | 0.0%(0/48) | 0.0%(0/44) | 0.0%(0/42) | 0.0% (0/46) |
| 7-line decrease | 0.0%(0/50) | 2.0%(1/49) | 0.0%(0/48) | 0.0%(0/44) | 0.0%(0/42) | 0.0% (0/46) |
| ¹Based on participants with available data and in-window visits. Categorical variables presented as n/N (%) where N is the |
'Based on participants with available data and in-window visits. Categorical variables presented as n/N (%) where N is the
number of participants with available data.
²Original visual acuity measurements captured using logMAR. A 1-line improvement from baseline corresponds to a change
of -0.10 logMAR.
*Although the results from the interim analysis constitute the statistical conclusions from the study, the results from the final
analysis are based on data from all enrolled participants.
o Exploratory Analyses:
• Stereoacuity (depth perception) did not show meaningful difference between groups.
· Mean Treatment Adherence with Luminopia One device was 75.7% from baseline to 12 weeks (note: 99% adherence with refractive correction was similar between groups).
- Evidence of clinical safety for Luminopia One as used in clinical study with refractive correction:
Co-Primary Safety Endpoints:
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o Adverse Events (AEs) demonstrate moderate probability of device-related adverse events. AE categories below demonstrate clinically meaningful higher rate in the Luminopia One group than in the control group (see Table 5 below):
· Overall AE rate: 25% of Luminopia One group (14 subjects, 25 events) vs.
13.6% of control group (all mild except one AE "worsening night terrors" severe) · Headaches: 14.3% Luminopia One group (8 subjects, 9 events) vs. 1.7% control group (1 subject, 1 event) - All intermittent and mild, no Rx treatments, no OTC medication, all resolved without sequelae.
· Eye strain: 3.6% (2 subjects, 3 events) Luminopia One group vs. 0% control group
· "Other" includes "increased frequency of night terrors*, facial redness, eyelidtwitch, dizziness, parent-reported intermittent eve turning when tired": 7.1% (4 subjects, 5 events) Luminopia One group vs. 0% control group.
[*1 subject had prior history of night terrors, parent reported increase frequency of night terrors after beginning treatment, investigator graded as severe, parent withdrew child from the study.]
| Table 5: Non-Serious Adverse Events¹ - As-Treated (AT) Population² at Final Analysis | ||
|---|---|---|
| Treatment Group² (N=56) | Control Group² (N=59) | |
| Diplopia | 0 (0.0%) [0] [0.0%, 6.4%] | 1 (1.7%) [1] [0.0%, 9.1%] |
| New heterotropia | 4 (7.1%) [4] [2.0%, 17.3%] | 4 (6.8%) [4] [1.9%, 16.5%] |
| Worsening heterotropia | 0 (0.0%) [0] [0.0%, 6.4%] | 1 (1.7%) [1] [0.0%, 9.1%] |
| Worsening BCVA | 3 (5.4%) [4] [1.1%, 14.9%] | 4 (6.8%) [4] [1.9%, 16.5%] |
| Headache | 8 (14.3%) [9] [6.4%, 26.2%] | 1 (1.7%) [1] [0.0%, 9.1%] |
| Nausea | 0 (0.0%) [0] [0.0%, 6.4%] | 0 (0.0%) [0] [0.0%, 6.1%] |
| Eye strain | 2 (3.6%) [3] [0.4%, 12.3%] | 0 (0.0%) [0] [0.0%, 6.1%] |
| Other³ | 4 (7.1%) [5] [2.0%, 17.3%] | 0 (0.0%) [0] [0.0%, 6.1%] |
| Overall | 14 (25.0%) [25][14.4%, 38.4%] | 8 (13.6%) [11][6.0%, 25.0%] |
| ¹Includes events classified with Possible, Probable, or Definite relation to study treatment. Data presented as: n (%) [m][95% CI], where n is number of participants with event and m is thenumber of events. Participants may experience more than one AE. | ||
| ²AT is defined as subjects with > 0% adherence of device use are in the treatment arm,otherwise control; there are no control subjects treated with the device. | ||
| ³Other AEs in treatment group include: Eye Twitch, Facial Redness, Increase in Frequency of Night Terrors, Dizziness,Parent reported intermitted eye turning when tired |
o Mean change non-amblyopic (fellow) eye BCVA from baseline, Luminopia One treatment group demonstrated non-inferiority to control group:
· Interim analysis (N=105, n=84): Mean change in fellow eye BCVA was -0.03 logMAR (SD=0.08) in therapeutic group and -0.02 logMAR (SD=0.06) in control group, indicating both groups had improvement in fellow eye vision. Difference
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between groups was -0.02 logMAR with upper 95% confidence limit of 0.010 and p-value <0.0001 for non-inferiority test, outcome suggests no additional risk for fellow eye vision and reverse amblyopia associated with Luminopia One.
· Final analysis (N=117, n=88): mean change in fellow eye BCVA from baseline to 12 weeks was -0.036 logMAR in therapeutic group and -0.017 in control group. The difference between groups was -0.018 logMAR with upper 95% confidence limit of 0.006 and p-value <0.0001 for non-inferiority
LABELING
Directions for Use (DFU) labeling provides product description, Indications for Use, software (the operating system) and hardware requirements for device operation, the compatible HMD. and instructions for how to operate the device. The DFU also provides a brief description of the clinical study design including the treatment duration and a summary of the study outcomes including the adverse events. The DFU includes warnings and precautions describing limitations and risks of the device. The DFU labeling is sufficient and satisfies the requirements of 21 CFR § 801.109 for prescription devices.
RISKS TO HEALTH
The table below identifies the risks to health that may be associated with use of a digital therapy device for amblyopia and the measures necessary to mitigate these risks.
| Identified Risks to Health | Mitigation Measures |
|---|---|
| Adverse events due to device treatment (e.g.,headache, new or worsening heterotropia,worsened vision in either eye, eye strain, eyetwitching, facial redness, increased nightterrors, thermal injury, dizziness, seizure,nausea, or double vision) | Clinical performance testingLabeling |
| Ineffective treatment leading to worsening ofcondition | Clinical performance testingSoftware verification, validation, and hazardanalysisLabeling |
| Therapeutic effect not sustained leading todelay of treatment | Clinical performance testingLabeling |
| Software malfunction leading to delay oftreatment | Software verification, validation, and hazardanalysisLabeling |
| Improper use of the device including HMD orother visual display leading to ineffectivetreatment or adverse events | LabelingLabeling comprehension testing |
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| Performance variations among differentbrands/models of visual displays leading toineffective treatment and/or adverse events | Clinical performance testing |
|---|---|
| Non-clinical performance testing | |
| Labeling | |
| Software verification, validation, and hazardanalysis |
SPECIAL CONTROLS
In combination with the general controls of the FD&C Act, the digital therapy device for amblyopia is subject to the following special controls:
- Clinical performance testing must demonstrate that the device performs as intended (1) under anticipated conditions of use with labeled compatible visual display devices, including evaluation of all adverse events and device performance to improve measures of visual function.
- (2) Software verification, validation, and hazard analysis must be performed. Documentation must include characterizations of the technical specifications of the software.
- (3) Non-clinical performance testing must demonstrate that the device performs as intended under anticipated conditions of use. All visual displays intended for use must undergo compatibility testing to ensure adequate display resolution, luminance, contrast, field of view, image quality, appropriate optical image distance, and verify their compatibility with the software and intended user (such as appropriate interpupillary distance).
- (4) Labeling must include the following:
- (i) The minimum hardware and operating system requirements that support the software of the device:
- (ii) The models of the visual displays validated to be compatible with this device;
- The length of treatment and/or retreatment supported by clinical performance (iii) testing; and
- A summary of the clinical performance testing conducted with the device. (iv)
- Labeling comprehension testing with intended users must be performed. (૨)
BENEFIT-RISK DETERMINATION
The risks of the device are based on the clinical performance testing data collected in a clinical study described above.
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The clinical study has shown that the treatment with Luminopia One was associated with several adverse events with moderate probability. These adverse events include diplopia (double vision), new or worsening heterotropia (strabismus, "eye turn" or "crossed eyes"), worsened vision in in in the amblyopic eye and/or in the fellow eye, headaches, nausea, eye strain (asthenopia), and other events. These events were reversable and considered non-serious. DFU labeling notes that patients should stop using Luminopia One and contact doctor for evaluation and permission to continue treatment if they experience any of these during or after using the device.
The probable benefits of the device are also based on data collected in the clinical study as described above.
The clinical study clearly demonstrated that treatment with Luminopia One improved the visual acuity of the amblyopic eve more than the control (refractive correction alone). Significantly more subjects experienced improvement of the amblyopic eye by BCVA 2 lines or more in the treatment group than in the control group. No reduction in BCVA in the fellow eye was observed between the treatment and control group suggesting no additional risk for fellow eye vision and reverse amblyopia associated with Luminopia One. In addition, Luminopia One provides an alternative for patients who have exhausted currently available treatments.
Although it is unknown whether the benefits of treatment with Luminopia One can be retained beyond 12 weeks, the overall probable benefits of visual acuity improvement in the amblyopic eye outweigh the probable risks of non-serious adverse events associated with the use of Luminopia One.
PATIENT PERSPECTIVES
Patient perspectives considered for Luminopia One included: Questionnaires during the clinical study provided to patients and caregivers during visits and through phone calls. The adverse events reported during the clinical study in Table 5 a demonstrated a clinically meaningful higher rate in the Luminopia One treatment group than in the control group.
BENEFIT/RISK CONCLUSION
In conclusion, given the available information above, for the following indication statement:
Luminopia One is a software-only digital therapeutic designed to be used with commercially available Head-Mounted Displays (HMDs) which are compatible with the software application. Luminopia One is indicated for improvement in visual acuity in amblyopia patients, aged 4-7, associated with anisometropia and/or with mild strabismus, having received treatment instructions (frequency and duration) as prescribed by a trained eye-care professional. Luminopia One is intended for both previously treated and untreated patients: however, patients with more than 12 months of prior treatment (other than refractive correction) have not been studied. Luminopia One is intended to be used as an adiunct to full-time refractive correction. such as glasses, which should also be worn under
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the HMD during Luminopia One therapy. Luminopia One is intended for prescription use only, in an at-home environment.
The probable benefits outweigh the probable risks for the Luminopia One. The device provides benefits, and the risks can be mitigated by the use of general controls and the identified special controls.
CONCLUSION
The De Novo request for the Luminopia One is granted and the device is classified as follows:
Product Code: QQU Device Type: Digital therapy device for amblyopia Regulation Number: 21 CFR 886.5500 Class: II
N/A