EndeavorOTC
Device Facts
| Record ID | K233496 |
|---|---|
| Device Name | EndeavorOTC |
| Applicant | Akili Interactive Labs, Inc. |
| Product Code | QFT · Obstetrics/Gynecology |
| Decision Date | Jun 14, 2024 |
| Decision | SESE |
| Submission Type | Traditional |
| Regulation | 21 CFR 882.5803 |
| Device Class | Class 2 |
| Attributes | Software as a Medical Device, Therapeutic |
Indications for Use
EndeavorOTC is a digital therapeutic indicated to improve attention function as measured by computer-based testing in patients 18 and older with primarily inattentive or combined type ADHD, who have a demonstrated attention issue. Patients who engage with EndeavorOTC demonstrate improvements in a digitally assessed measure, Test of Variables of Attention (TOVA®) of sustained and selective attention and may not display benefits in typical behavioral symptoms such as hyperactivity. EndeavorOTC is not intended to be a replacement for any form of treatment and should be used as part of a therapeutic program that may include clinician-directed therapy, medication, and/or educational programs, which further address symptoms of the disorder.
Device Story
EndeavorOTC is a mobile-based digital therapeutic (SaMD) for home use by adults with ADHD. It functions as a video game that uses the Selective Stimulus Management Engine (SSME™) to deliver stimuli designed to improve attention. Inputs include device tilt (accelerometer) and screen taps (targeting); outputs are visual and audio game progression. The adaptive algorithm monitors performance and adjusts difficulty in a closed-loop system to keep patients at predefined performance bounds. Patients use the device for approximately 25 minutes/day, 5 days/week, for 6 weeks. The output provides a personalized treatment experience; healthcare providers use the device as an adjunct to other therapies. Benefits include improved sustained and selective attention as measured by TOVA®.
Clinical Evidence
Single-arm, open-label, multicenter study (N=221) in adults 18+ with ADHD. Primary endpoint: change in TOVA-ACS from baseline to day 42. Efficacy population (N=153) showed statistically significant mean improvement of 6.46 (95% CI: 5.349, 7.570; P < 0.0001). Secondary endpoints (ADHD-RS) showed improvements but did not reach the 10-point threshold for clinical significance. Safety profile was favorable; 5.0% experienced mild/moderate adverse events (nausea, headache). No serious adverse events reported.
Technological Characteristics
Software-as-a-medical device (SaMD) running on iOS/Android mobile platforms. Uses proprietary Selective Stimulus Management Engine (SSME™) adaptive algorithm. Closed-loop system adjusts difficulty based on user performance. Complies with ISO 14971:2019, IEC 62304:2015, and IEC 82304-1:2016 standards.
Indications for Use
Indicated for patients 18+ with primarily inattentive or combined-type ADHD and demonstrated attention issues. Not for patients with photo-sensitive epilepsy, color blindness, or physical limitations restricting mobile device use. Not for persons with comorbid psychiatric conditions.
Regulatory Classification
Identification
A digital therapy device for Attention Deficit Hyperactivity Disorder (ADHD) is a software intended to provide therapy for ADHD or any of its individual symptoms as an adjunct to clinician supervised treatment.
Special Controls
In combination with the general controls of the FD&C Act, the digital therapy device for Attention Deficit Hyperactivity Disorder is subject to the following special controls:
*Classification.* Class II (special controls). The special controls for this device are:(1) Clinical performance testing must demonstrate and document the following under the labeled conditions for use, which include considerations for the ability of the device to: (i) Use a validated measure to evaluate effectiveness of device to provide therapy for ADHD or any of its individual symptoms; and (ii) Capture all adverse events. (2) Software must be described and provided in a clear and detailed manner to include all features and functions of the software implementing the digital therapy. Software verification, validation, and hazard analysis must also be provided. (3) The labeling must include the following items: (i) Patient and physician labeling must include instructions for use, including images that demonstrate how to interact with the device; (ii) Patient and physician labeling must list the minimum operating system (OS) requirements that support the software of the device; (iii) Patient and physician labeling must include a warning that the digital therapy device is not intended for use as a standalone therapeutic device; (iv) Patient and physician labeling must include a warning that the digital therapy device does not represent a substitution for the patient's medication; and (v) Physician labeling must include a summary of the clinical performance testing conducted with the device.
Predicate Devices
- EndeavorRx (DEN200026)
Reference Devices
- EndeavorRx (K231337)
Related Devices
- DEN200026 — EndeavorRx · Akili Interactive Labs, Inc. · Jun 15, 2020
- K231337 — EndeavorRx · Akili Interactive Labs, Inc. · Dec 13, 2023
- K243729 — Prismira · Lumos Labs, Inc. · Jun 13, 2025
- K213629 — SMILE · Nu Eyne Co., Ltd. · Feb 12, 2023
Submission Summary (Full Text)
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June 14, 2024
Akili Interactive Labs, Inc. % Bhupinder Singh Head of Quality and Regulatory Affairs 22 Boston Wharf Rd 7th Floor Boston, MA 02110
Re: K233496
Trade/Device Name: EndeavorOTC Regulation Number: 21 CFR 882.5803 Regulation Name: Digital therapy device for attention deficit hyperactivity disorder Regulatory Class: Class II Product Code: QFT Dated: May 16, 2024 Received: May 16, 2024
Dear Bhupinder Singh:
We have reviewed your section 510(k) premarket notification of intent to market the device referenced above and have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments, or to devices that have been reclassified in accordance with the provisions of the Federal Food, Drug, and Cosmetic Act (the Act) that do not require approval of a premarket approval application (PMA). You may, therefore, market the device, subject to the general controls provisions of the Act. Although this letter refers to your product as a device, please be aware that some cleared products may instead be combination products. The 510(k) Premarket Notification Database available at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm identifies combination product submissions. The general controls provisions of the Act include requirements for annual registration, listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading.
If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 898. In addition, FDA may publish further announcements concerning your device in the Federal Register.
Additional information about changes that may require a new premarket notification are provided in the FDA guidance documents entitled "Deciding When to Submit a 510(k) for a Change to an Existing Device"
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(https://www.fda.gov/media/99812/download) and "Deciding When to Submit a 510(k) for a Software Change to an Existing Device" (https://www.fda.gov/media/99785/download).
Your device is also subject to, among other requirements, the Quality System (QS) regulation (21 CFR Part 820), which includes, but is not limited to, 21 CFR 820.30. Design controls; 21 CFR 820.90. Nonconforming product; and 21 CFR 820.100, Corrective and preventive action. Please note that regardless of whether a change requires premarket review, the OS regulation requires device manufacturers to review and approve changes to device design and production (21 CFR 820.30 and 21 CFR 820.70) and document changes and approvals in the device master record (21 CFR 820.181).
Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Part 801); medical device reporting of medical device-related adverse events) (21 CFR Part 803) for devices or postmarketing safety reporting (21 CFR Part 4, Subpart B) for combination products (see https://www.fda.gov/combination-products/guidance-regulatory-information/postmarketing-safety-reportingcombination-products); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820) for devices or current good manufacturing practices (21 CFR Part 4, Subpart A) for combination products; and, if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR Parts 1000-1050.
Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to https://www.fda.gov/medical-device-safety/medical-device-reportingmdr-how-report-medical-device-problems.
For comprehensive regulatory information about mediation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/medicaldevices/device-advice-comprehensive-regulatory-assistance) and CDRH Learn (https://www.fda.gov/training-and-continuing-education/cdrh-learn). Additionally, you may contact the Division of Industry and Consumer Education (DICE) to ask a question about a specific regulatory topic. See the DICE website (https://www.fda.gov/medical-device-advice-comprehensive-regulatoryassistance/contact-us-division-industry-and-consumer-education-dice) for more information or contact DICE by email (DICE@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100).
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Sincerely,
# Robert Kang -S
for Pamela Scott, MS Assistant Director DHT5B: Division of Neuromodulation and Physical Medicine Devices OHT5: Office of Neurological and Physical Medicine Devices Office of Product Evaluation and Quality Center for Devices and Radiological Health
Enclosure
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# Indications for Use
510(k) Number (if known) K233496
Device Name EndeavorOTC
#### Indications for Use (Describe)
EndeavorOTC is a digital therapeutic indicated to improve attention as measured by computer-based testing in patients 18 and older with primarily inattentive or combined type ADHD, who have a demonstrated attention issue. Patients who engage with EndeavorOTC demonstrate improvements in a digitally assessed measure, Test of Variables of Attention (TOVA®) of sustained and selective attention and may not display benefits in typical behavioral symptoms such as hyperactivity. EndeavorOTC is not intended to be a replacement for any form of treatment and should be used as part of a therapeutic program that may include clinician-directed therapy, medicational programs, which further address symptoms of the disorder.
| Type of Use (Select one or both, as applicable) | |
|-------------------------------------------------|--|
|-------------------------------------------------|--|
Prescription Use (Part 21 CFR 801 Subpart D)
X Over-The-Counter Use (21 CFR 801 Subpart C)
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# 7. 510(k) Summary
This 510(k) summary of safety and effectiveness information is prepared in accordance with 21 CFR § 807.92.
| Date Prepared: | October 30, 2023 |
|-------------------------|------------------------------------------------------------------------------------------------------------------------------|
| Legal Manufacturer: | Akili Interactive Labs, Inc.<br>71 Commercial St<br>Mailbox 312<br>Boston, MA 02109 |
| Primary Contact Person: | Bhupinder Singh<br>Head of Quality and Regulatory Affairs<br>Phone: +1 (408) 832-7124<br>E-mail: bsingh@akiliinteractive.com |
Regulatory Information
| Device Trade Name: | EndeavorOTC |
|------------------------------|------------------------------------------------------------------------------|
| Device Classification Name: | Digital Therapeutic Software for Attention Deficit<br>Hyperactivity Disorder |
| Regulation Number: | 21 CFR § 882.5803 |
| Classification Product Code: | QFT |
| Review Advisory Committee: | Neurology |
| Device Classification: | Class II |
| 510(k) Number | K233496 |
| Predicate Device Information | |
| Device Manufacturer: | Akili Interactive Labs, Inc. |
| Submission Number: | DEN200026 |
| Device Name: | EndeavorRx |
| Other Reference Device | EndeavorRx (K231337) |
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#### Device Description:
EndeavorOTC is software-as-a-medical device (SaMD) that resides on the user's mobile device and can be executed at home.
It is an over-the-counter (OTC) digital therapeutic indicated to improve attention function as measured by computer-based testing in patients 18 and older with primarily inattentive or combined type ADHD, who have a demonstrated attention issue. Patients who engage with EndeavorOTC demonstrate improvements in a digitally assessed measure, Test of Variables of Attention (TOVA®) of sustained and selective attention and may not display benefits in typical behavioral symptoms such as hyperactivity. EndeavorOTC is not intended to be a replacement for any form of treatment and should be used as part of a therapeutic program that may include clinician-directed therapy, medication, and/or educational programs, which further address symptoms of the disorder.
The device is built on Akili's proprietary, patented, technology platform. EndeavorOTC uses adaptive algorithms (also known as Selective Stimulus Management Engine, SSME™) to deliver stimuli that are designed to engage the patient in a manner that improves their attention function. In a closed-loop system, the adaptive SSME™ algorithms automatically adjust the difficulty level for a personalized treatment experience that is tailored to the needs of each individual patient.
EndeavorOTC is delivered through a video game experience which leverages art, music, storytelling, and reward cycles to keep patients engaged. The adaptive algorithm constantly pushes patients precisely at predefined performance bounds relative to each individual, such that they are continuously encouraged to exceed their historic performance. The science behind EndeavorOTC was developed at the University of California, San Francisco by Adam Gazzaley, M.D., Ph.D., Founding Director of the University of California San Francisco's Neuroscape and Akili's Chief Science Advisor.
The basic program inputs are steering, which is accomplished by using the mobile device's internal accelerometer to measure the degree to which it is tilted, and tapping, which is accomplished using the touch screen to measure correct and incorrect targeting. The basic outputs are the visual display of the game progression along with audio, which is accomplished by using the internal high resolution display and internal speaker. The program includes features to ensure it is used per the recommended regimen (approximately 25 minutes per day, 5 days per week, for 6 weeks).
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Indications for Use: EndeavorOTC is a digital therapeutic indicated to improve attention function as measured by computer-based testing in patients 18 and older with primarily inattentive or combined type ADHD, who have a demonstrated attention issue. Patients who engage with EndeavorOTC demonstrate improvements in a digitally assessed measure, Test of Variables of Attention (TOVA®) of sustained and selective attention and may not display benefits in typical behavioral symptoms such as hyperactivity. EndeavorOTC is not intended to be a replacement for any form of treatment and should be used as part of a therapeutic program that may include clinician-directed therapy, medication, and/or educational programs, which further address symptoms of the disorder. Limitations EndeavorOTC may not be appropriate for users with photo-sensitive
epilepsy, color blindness, or physical limitations that restrict use of a mobile device. It is recommended that users speak to their health care provider before starting EndeavorOTC treatment. EndeavorOTC is not for persons who have a comorbid psychiatric condition in addition to ADHD. When using this device it is recommended that users seek care from a medical health care provider in conjunction with its use.
NOTE: This single arm study did not include a sham control group and it is therefore possible that observed effects were due to bias or placebo effects. Akili has conducted and published additional studies that support the lack of a placebo effect on the TOVA2-2. Patients and health care providers should consider the totality of the clinical evidence in light of this before using this product.
² Yerys BE, Bertollo JR, Kenworthy L, et al. Brief Report: Pilot Study of a Novel Interactive Digital Treatment to lmprove Cognitive Control in Children with Autism Spectrum Disorder and Co-occurring ADHD Symptoms. J Autism Dev Disord. 2019;49(4):1727-1737. doi:10.1007/s10803-018-3856-7
<sup>2</sup> Keefe RSE, Cañadas E, Farlow D, Etkin A. Digital Intervention for Cognitive Deficits in Major Depression: A Randomized Controlled Trial to Assess Efficacy and Safety in Adults. Am J Psychiatry. 2022;179(7):482-489. doi:10.1176/appi.ajp.21020125
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# Summary of Technological Characteristics
| Attribute | Subject Device:<br>EndeavorOTC | Predicate Device:<br>EndeavorRx (DEN200026) | Comparison |
|-------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Manufacturer | Akili Interactive Labs, Inc. | Akili Interactive Labs, Inc. | Same |
| Device<br>Classification<br>Name | Digital Therapeutic<br>Software for Attention<br>Deficit Hyperactivity<br>Disorder | Digital Therapeutic Software for<br>Attention Deficit Hyperactivity<br>Disorder | Same |
| Product Code | QFT | QFT | Same |
| Regulation<br>Number | 21 CFR § 882.5803 | 21 CFR § 882.5803 | Same |
| Intended use | Digital therapeutic adaptive<br>stimulus software for the<br>closed-loop treatment of<br>psychiatric disorders and<br>cognitive dysfunction<br>associated with medical<br>conditions. | Digital therapeutic adaptive<br>stimulus software for the closed-<br>loop treatment of psychiatric<br>disorders and cognitive<br>dysfunction associated with<br>medical conditions. | Same |
| Indication of<br>Use | EndeavorOTC is an over the<br>counter digital therapeutic<br>indicated to improve<br>attention function as<br>measured by computer-<br>based testing in patients 18<br>and older with primarily<br>inattentive or combined<br>type ADHD, who have a<br>demonstrated attention<br>issue. Patients who engage<br>with EndeavorOTC<br>demonstrate improvements<br>in a digitally assessed<br>measure, Test of Variables<br>of Attention (TOVA®) of<br>sustained and selective<br>attention and may not<br>display benefits in typical<br>behavioral symptoms such<br>as hyperactivity. | EndeavorRx is a digital<br>therapeutic indicated to<br>improve attention function as<br>measured by computer based<br>testing in children ages 8-12<br>years old with primarily<br>inattentive or combined-type<br>ADHD, who have a<br>demonstrated attention issue.<br>Patients who engage with<br>EndeavorRx demonstrate<br>improvements in a digitally<br>assessed measure Tests of<br>Variables of Attention (TOVA) of<br>sustained and selective<br>attention and may not display<br>benefits in typical behavioral<br>symptoms, such as<br>hyperactivity. EndeavorRx<br>should be considered for use as<br>part of a therapeutic program | Substantially<br>equivalent.<br>EndeavorOTC is<br>indicated for 18<br>years of age or<br>older, compared<br>to the predicate<br>device (8-12<br>years). The<br>difference in age<br>range do not<br>change the<br>intended use of<br>the device, and<br>clinical testing<br>demonstrates<br>the subject<br>device is safe<br>and effective in<br>the adult<br>population. |
| | EndeavorOTC is not<br>intended to be a<br>replacement for any form of<br>treatment and should be<br>used as part of a<br>therapeutic program that<br>may include clinician-<br>directed therapy,<br>medication, and/or<br>educational programs,<br>which further address<br>symptoms of the disorder | that may include: clinician-<br>directed therapy, medication,<br>and/or educational programs,<br>which further address symptoms<br>of the disorder. | Product<br>indication was<br>changed from Rx<br>to OTC. See<br>Access row<br>below for<br>further<br>discussion. |
| System<br>Components | Patient facing video game<br>application | Patient facing video game<br>application | Same |
| | Mobile device platform | Mobile device platform | |
| Proprietary<br>Algorithm | Selective Stimulus<br>Management Engine<br>(SSMETM) | Selective Stimulus Management<br>Engine (SSMETM) | Same |
| Basic<br>Operations | Steering, Tapping, Multi-<br>tasking | Steering, Tapping, Multi-tasking | Same |
| Presentation | Structured manner across<br>game "Challenges" and<br>"Worlds" | Structured manner across game<br>"Challenges" and "Worlds" | Same |
| Mobile<br>Platform<br>Compatibility | iOS and Android | iOS and Android | Same |
| Access | Over-the-counter use. It is<br>recommended that patients<br>speak to their health care<br>provider before starting<br>EndeavorOTC treatment.<br>See section, "Summary of<br>Clinical Performance Data"<br>below for supporting data. | Prescription use only.<br>Authorized and overseen by a<br>licensed health care provider. | Labeling<br>modifications<br>were made to<br>support over-<br>the-counter use,<br>and human<br>factors<br>validation<br>testing confirms<br>the change to<br>OTC does not<br>raise different<br>questions. |
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Summary of Non-Clinical Performance Data: Bench software testing has been performed on the EndeavorOTC and demonstrates compliance with the following international and FDArecognized consensus standards and FDA guidance documents:
- ISO 14971:2019 Medical devices - Application of risk management to medical devices
- IEC 62304 Edition 1.1 2015-06 CONSOLIDATED VERSION Medical device software - Software life cycle processes
- IEC 82304-1 Edition 1.0 2016-10 Health software - Part 1: General requirements for product safety
- FDA Guidance Document for Industry and FDA Staff -Content of Premarket Submissions for Device Software Functions - Guidance for Industry and Food and Druq Administration Staff (Final Guidance issued June 14, 2023)
- . FDA Guidance Document for Industry and FDA Staff -Cybersecurity in Medical Devices: Quality System Considerations and Content of Premarket Submissions: Guidance for Industry and Food and Drug Administration Staff (Final Guidance issued September 27, 2023)
The results of bench software verification and validation testing supports that EndeavorOTC functions as intended.
Human factors validation testing was performed to ensure that EndeavorOTC is safe and effective for intended users, use, and use environments, and demonstrates compliance with the following additional standards and guidance document:
- ANSI/AAMI/IEC 62366-1:2015/ Amd 1: 2020 Medical Devices -Part 1: Application of Usability Engineering to Medical Devices - Amendment 1
- ANSI/AAMI/IEC 62366-2:2016 Medical Devices Part 2: ● Guidance on the application of usability engineering to medical devices
- FDA Guidance Document for Industry for Industry and FDA Staff - Applying Human Factors and Usability Engineering to Medical Devices, issued February 3, 2016
The results of the human factors validation testing supports the usability of EndeavorOTC in intended users, for the intended use, in the intended use environment.
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Summary of Clinical Data: Clinical performance testing was conducted to evaluate the efficacy and safety of EndeavorOTC in adults 18 years of age and older. 3 Efficacy was determined primarily by the change from baseline in a digitally assessed measure of sustained and selective attention, the Test of Variables of Attention (TOVA®), after 6 weeks of treatment. The multicenter open-label study enrolled 221 subjects with inattentive or combined-type ADHD. A diagnosis of ADHD was determined in study participants using the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria as confirmed by the Mini-International Neuropsychiatric Interview (MINI) for ADHD adult version 7.0.2. All 221 participants who were enrolled in the adult study were included in the Safety population (also known as ITT or intent to treat population, is all subjects enrolled in the study), and 153 participants were included in the Efficacy Population (also known as the mlTT or modified intent to treat population, is all enrolled subjects with drop outs excluded). Safety population is all participants who were exposed to AKL-T01 intervention. Efficacy population is all participants who took the AKL-T01 intervention home and completed both baseline and day 42 exit visit assessments (including TOVA).
Seventy-five participants (33.9%) discontinued the study: the most common reason for study discontinuation was withdrawal by participant. Reasons for withdrawal by participants include the following: experiencing technical bugs or technical issues; game took too much time away from school, work, or other activities; did not like AKL-T01; did not want to complete the on-site study activities any further. Three (1.7%) participants discontinued the study due to adverse events (1 headache, 2 nausea).
For further description of the adult study in comparison to the predicate studies, see Table 1 - comparison of clinical study design description.
The results of the clinical performance study support the performance and safety of EndeavorOTC in the adult age range. Analysis of the primary efficacy endpoint in the Efficacy Population (N=153) showed a statistically significant positive mean change from baseline to study day 42 in the TOVA of 6.460 (SD 6.9522 [95% Cl: 5.349, 7.570]; P < 0.0001). Figure 1 below compares the mean TOVA-ACS score from participants in the STARS-Adult study (subject study) with STARS-Adolescents (K231337) and STARS-ADHD (DEN200026) studies. Analysis of the
<sup>3</sup> Stamatis, C. A., Mercaldi, C., & Kollins, S. H. (2023). A Single-Arm Pivotal Trial to Assess the Efficacy of Akl-T01, a Novel Digital Intervention for Attention, in Adults Diagnosed With ADHD. Journal of the American Academy of Child & Adolescent Psychiatry, 62(10), S318
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secondary efficacy endpoints in the Efficacy Population (N=153) showed improvements in the ADHD-RS total score by a mean of 8.3 points (SD: 7.74) and in the ADHD-RS inattentive score by a mean of 5.1 points (SD: 4.78). The improvements observed did not meet clinically meaningful improvement, which is estimated as 10-point difference in Total Score based on literature.4 For a comparison of clinical study outcomes between the subject and predicate studies, see Table 2.
#### Figure 1. Mean TOVA-ACS Score Bar Chart Comparison across Subject and Predicate Studies
Image /page/11/Figure/3 description: This image is a bar graph comparing the mean TOVA-ACS with a 95% confidence interval for three age groups: 18y+, 13-17y, and 8-12y. The data is presented for both the baseline and exit stages. The y-axis represents the mean TOVA-ACS with a 95% confidence interval, ranging from -10 to 10. The sample sizes for each age group at baseline are: Ages 18y+ N=221, Ages 13-17y N=162, and Ages 8-12y N=179, while at exit, the sample sizes are: Ages 18y+ N=153, Ages 13-17y N=146, and Ages 8-12y N=170.
Markers represent individual subject values. Two participants in STARS-ADHD-Adults were enrolled that did not meet inclusions criteria of baseline TOVA-ACS ≤ -1.8 and were reported as protocol violations. TOVA-ACS scores below zero suggest performance similar to individuals with ADHD.5
Study results were based on a modified intent-to-treat (mITT, also known as Efficacy population, is all enrolled subjects with drop outs excluded) population. This population included all enrolled participants with sufficient data at baseline and exit to calculate change scores (N=153) instead of the intent-to-treat (ITT, also known as Safety Population, is all subjects enrolled in the study) population (N=221).
<sup>4</sup> Zhang S, Faries DE, Vowles M, Michelson D. ADHD Rating Scale IV: psychometric properties from a multinational study as a clinicianadministered instrument. Int J Methods Psychiatr Res. 2005;14(4):186-201. doi:10.1002/mpr.7
<sup>5</sup> TOVA Clinical Manual 2020, p. 32 of 78: https://files.tovatest.com/documentation/9/Clinical%20Manual.pdf
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A sensitivity analysis using multiple imputation (MI) was performed to assess the impact of missing exit data in the ITT population. Change in TOVA-ACS was generally similar in the ITT population after imputation, with a mean [95% CI] of 6.144 [5.037, 7.273] as compared with the mITT population 6.460 [5.349, 7.570]. See Table 3 for a Modified Intent-to-Treat (mlTT) and Intent-to-Treat (ITT) Analysis with Multiple Imputation (MI) of the Primary Efficacy Endpoint - TOVA-ACS Change from Baseline to Exit.
Overall, 11 (5.0%) subjects experienced a treatment-emergent adverse device event (TE-ADE). Reports include 4 (1.8%) nausea, 3 (1.4%) headaches, 2 (0.9%) decreased frustration tolerance, and 1 each (0.5%) of arthritis, dizziness, fatigue, and somnolence. All TE-ADEs were mild or moderate. There were no serious adverse device events. See Table 4 for a comparison of clinical safety outcomes from the subject study with predicate studies.
Akili has conducted and published additional studies that support the lack of a placebo effect on the TOVA67 . Patients and health care providers should consider the totality of the clinical evidence in light of this before using this product.
The clinical performance study demonstrates that EndeavorOTC is safe and effective for its intended use in the indicated patient population.
NOTE: This single arm study did not include a sham control group and it is therefore possible that observed effects were due to bias or placebo effects. Users should consider the totality of the clinical evidence in light of this before using the product.
Some persons with known comorbid psychiatric conditions were excluded from this study and therefore the risk profile for persons with comorbid psychiatric conditions is not fully known.
<sup>6</sup> Yerys BE, Bertollo JR, Kenworthy L, et al. Brief Report: Pilot Study of a Novel Interactive Digital Treatment to lmprove Cognitive Control in Children with Autism Spectrum Disorder and Co-occurring ADHD Symptoms. J Autism Dev Disord. 2019;49(4):1727-1737. doi:10.1007/s10803-018-3856-7
<sup>7</sup> Keefe RSE, Cañadas E, Farlow D, Etkin A. Digital Intervention for Cognitive Deficits in Major Depression: A Randomized Controlled Trial to Assess Efficacy and Safety in Adults. Am J Psychiatry. 2022;179(7):482-489. doi:10.1176/appi.ajp.21020125
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# Table 1. Clinical study design description comparison
| | Subject Device<br>K233496 | Predicate Device<br>DEN200026 | |
|--------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| | STARS-Adult Study<br>(ages 18+) | STARS Study (ages 8-<br>12) | Comparison describing differences and a<br>rationale why it is acceptable |
| Population | Verified ADHD<br>diagnosis with<br>impaired attention;<br>on or off medication | Verified ADHD<br>diagnosis with<br>impaired attention;<br>medication<br>exclusionary | SIMILAR - the adult study allowed for<br>medication as long as use was stable for<br>≥4 weeks prior to study enrollment and<br>throughout the study. A prior study<br>demonstrated benefits of intervention on<br>the pediatric population with ADHD both<br>on and off medication. |
| Study Design | Single arm, open-<br>label, adaptive<br>design | Randomized clinical<br>trial | DIFFERENT - Presence of attentional<br>improvement from treatment compared<br>to those on active control was established<br>in the STARS study. The adult study<br>investigated the magnitude of<br>improvement and safety in the new age<br>range. |
| | | | The Adult study used an adaptive design<br>based on the total information as<br>measured by the standard error of the<br>primary endpoint which would allow the<br>trial to be stopped prior to recruitment of<br>the 325 participants derived from the<br>sample size calculations. The adaptive<br>design accounts for the uncertainty<br>regarding whether the variation in TOVA-<br>ACS mean change differed between the<br>adult and pediatric ADHD populations. |
| | | | The safety and effectiveness of the exact<br>same device was established in an RCT De<br>Novo in a younger population. The primary<br>endpoint used in the current study was<br>identical to the original STARS RCT. Based<br>on the predicate RCT, the primary<br>outcome measure TOVA demonstrates<br>less susceptibility to placebo effect in the |
| | randomized, controlled trial utilized for<br>the de novo.<br><br>Another consideration for the single arm<br>design is that the TOVA-ACS is less<br>susceptible to placebo effects when<br>measuring attentional control processes<br>within the context of ADHD, as supported<br>by the predicate RCT and multiple<br>published studies in the literature. 8,9,10 | | |
| Intervention | EndeavorRx (AKL-<br>T01) | EndeavorRx (AKL-T01)<br>EVO: Words (Active<br>control) | SIMILAR - All use the same active<br>intervention, minor differences in<br>software. |
| Treatment<br>regimen | 25 minutes/day for 5<br>days/week | 25 minutes per day, 5<br>days per week | SIMILAR |
| Participant<br>Duration | Approximately 6<br>weeks on treatment | Approximately 4<br>weeks on treatment | DIFFERENT - In Adults, treatment duration<br>was adjusted to match duration used in<br>past adult studies using a similar SSME™-<br>driven product |
| Diagnosis of ADHD | Yes - Diagnosis of<br>ADHD combined or<br>inattentive type,<br>required according to<br>Diagnostic and<br>Statistical Manual of<br>Mental Disorders,<br>Fifth Edition (DSM-5)<br>as confirmed by<br>Mini International<br>Neuropsychiatric<br>Interview (MINI) for<br>Attention - Deficit /<br>Hyperactivity | Yes - Confirmed ADHD<br>diagnosis, any<br>presentation, required<br>at Screening based on<br>DSM-V criteria and<br>established via the<br>MINI-KID administered<br>by a<br>trained clinician | SIMILAR - An age-appropriate version of<br>the MINI was used in the adult study. |
| | Disorders Studies<br>(Adult) 7.0.2 | | |
| Sites | Multi-site: 14 sites<br>across the US (a mix<br>of institutional sites<br>and private practice<br>centers) | Multi-site: 20 sites<br>across the US (a mix of<br>institutional sites and<br>private practice<br>centers) | SIMILAR |
| Enrollment | 223 enrolled | 348 enrolled | SIMILAR - the larger N in STARS study<br>takes into account two arms. In Adults,<br>sample size was determined by power<br>calculations. |
| Stably on or off<br>ADHD medications | Stably on or off<br>stimulant medication<br>(≥4 weeks) allowed<br>Stably on or off non-<br>stimulant medication<br>(≥4 weeks) allowed | Stimulant medication<br>use not allowed<br>Use of non- stimulant<br>ADHD medication not<br>allowed | DIFFERENT - Another published study11<br>demonstrated ADHD improvement<br>occurred similarly in patients both stably<br>on and off ADHD medications. This<br>criterion was adopted into the adult study<br>design to better simulate real-world user<br>base<br>The adult study allowed non-stimulant<br>medication use as long as stability 4-<br>weeks before and after study enrollment is<br>maintained to better represent the<br>diversity of patients who may use the<br>device and to generalize to real-world user<br>base. |
| Stably on or off<br>nonpharmacologic<br>al treatments | Stably on or off<br>nonpharmacological<br>treatments (≥4<br>weeks) allowed | Stably on or off<br>nonpharmacological<br>treatments (≥4 weeks)<br>allowed | SIMILAR |
| Absence/Presence<br>of comorbid<br>psychiatric<br>diagnosis and/or<br>treatments that<br>may confound | Presence of<br>comorbid psychiatric<br>diagnosis and/or<br>treatments that may<br>confound study not<br>allowed | Presence of comorbid<br>psychiatric<br>diagnosis and/or<br>treatments that may<br>confound study not<br>allowed | SIMILAR |
| study | |…
