PATIENTS• A total of 348 eligible patients were randomized (AKL-T01, n=180; active control, n=168) between May 26, 2016 and

July 31, 2017 (Table 1). Efficacy data are presented for the intent-to-treat (ITT) population. Not all patients in the ITT population completed all post-intervention measures and, thus, patient numbers differed for each outcome measure.

EFFICACYPRIMARY AND SECONDARY ENDPOINTS• For the T.O.V.A.® test API pre- to post-intervention, AKL-T01 demonstrated significant improvement versus active control

(adjusted p=0.006; Wilcoxon rank-sum test; Figure 3). – In post-hoc within-group analyses (Wilcoxon signed-rank test), AKL-T01 showed significant improvement

(unadjusted p0.0001); active control showed no improvement (unadjusted p=0.672).

• For IRS pre- to post-intervention, AKL-T01 and active control did not differentiate (adjusted p=0.344; unadjusted p=0.097; Wilcoxon rank-sum test; Figure 4).

– In post-hoc within-group analyses (Wilcoxon signed-rank test), significant improvements were observed with both AKL-T01 (unadjusted p0.0001) and active control (unadjusted p=0.0002).

• For ADHD-RS total and sub-scales pre- to post-intervention, AKL-T01 and active control did not differentiate on ADHD-RS (adjusted p=0.915; unadjusted p=0.401; Wilcoxon rank-sum test), ADHD-RS-I (adjusted p=0.764; unadjusted p=0.272; Wilcoxon rank-sum test), or ADHD-RS-H (adjusted p=0.992; unadjusted p=0.608; Wilcoxon rank-sum test) (Figure 5).

– In post-hoc within-group analyses (Wilcoxon signed-rank test), significant improvements were observed with both AKL-T01 and active control for ADHD-RS, ADHD-RS-I, and ADHD-RS-H (all unadjusted p0.0001).

• For CGI-I at post-intervention only, AKL-T01 and active control did not differentiate (mean [SE] score 3.4 [0.07] for both treatments; adjusted p=1.000; unadjusted p=0.861; Wilcoxon rank-sum test).

• Pre- to post-intervention, AKL-T01 and active control did not differentiate on either BRIEF-Parent Inhibit percentile (mean [SE] change −2.8 [1.0] and −3.5 [0.7] for AKL-T01 and active control, respectively; adjusted p=0.999; unadjusted p=0.747; Wilcoxon rank-sum test) or Working Memory percentile (mean [SE] change −3.1 [0.6] and −3.3 [0.8] for AKL-T01 and active control, respectively; adjusted p=0.993; unadjusted p=0.617; Wilcoxon rank-sum test).

– In post-hoc within-group analyses (Wilcoxon signed-rank test), improvements pre- to post-intervention were observed with both AKL-T01 and active control on the above secondary endpoints (all unadjusted p0.01).

• In post-hoc analyses for the subgroup of patients that switched from stimulant medication (Figure 6), AKL-T01 differentiated from active control on change in score pre- to post-intervention on ADHD-RS (p=0.027), ADHD-RS-I (p=0.025), and CGI-I (p=0.034), and showed a similar numeric trend on ADHD-RS-H (p=0.058) and IRS (p=0.087) (all unadjusted p-values; Wilcoxon rank-sum test).

Poster presented at the Children and Adults with Attention-Deficit/Hyperactivity Disorder (CHADD) Annual Meeting, St. Louis, MO, USA, November 8-11, 2018

A MULTICENTER, RANDOMIZED, ACTIVE-CONTROL REGISTRATION TRIAL (STARS-ADHD) TO ASSESS THE EFFICACY AND SAFETY OF A NOVEL, HOME-BASED, DIGITAL TREATMENT FOR PEDIATRIC ADHDS.H. Kollins,1 J. Bower,2 T. Ala’ilima,2 R.L. Findling,3 R Keefe,1,4 J.N. Epstein,5 A.J. Cutler,6 R. White,7 L. Aberle,7 D. DeLoss,2 E. Cañadas,2 S.V. Faraone8

1Psychiatry and Behavioral Sciences, Duke University, Durham, NC, USA; 2Akili Interactive, Boston, MA, USA; 3Child and Adolescent Psychiatry, Johns Hopkins University/Kennedy Krieger Institute, Baltimore, MD, USA; 4NeuroCog Trials, Inc., Durham, NC, USA; 5Behavioral Medicine and Clinical Psychology, Cincinnati Children’s Hospital, Cincinnati, OH, USA; 6Psychiatry, Meridien Research, Tampa, FL, USA; 7Duke Clinical Research Institute, Durham, NC, USA; 8Psychiatry and Neuroscience & Physiology, SUNY Upstate Medical University, New York, NY, USA

• There are well-established pharmacologic and non-pharmacologic treatments for attention-deficit hyperactivity disorder (ADHD),1-4 but limitations to these treatments likely contribute to poor adherence over time. There is an ongoing need for novel approaches to ADHD treatment.

• AKL-T01 is an investigational therapeutic digital intervention in development for the treatment of attention and inhibitory control deficits in pediatric ADHD.

• We present primary efficacy and safety results of the randomized Software Treatment for Actively Reducing Severity of ADHD (STARS-ADHD) trial of AKL-T01 versus an active control in pediatric patients with ADHD.

INTRODUCTION

STUDY DESIGN AND PATIENTS• STARS-ADHD (NCT02674633) was a multicenter, randomized, active-control, double-blind registration trial

conducted across 20 centers in the United States (Figure 1).

• Main eligibility criteria: Children 8-12 years of age; confirmed ADHD diagnosis and baseline scores on the ADHD Rating Scale-IV (ADHD-RS-IV) 28 and Test of Variables of Attention-Attention Performance Index (T.O.V.A.® test API) –1.8; no comorbid psychiatric diagnoses. Parents provided informed consent and patients provided assent.

• AKL-T01 is an investigational digital treatment using the Selective Stimulus Management (SSME™) engine delivered through a video game-like interface designed to target neural networks involved in cognitive control, using adaptive algorithms that personalize the treatment to each patient (Figure 2).

OUTCOMES• The primary efficacy endpoint was the effect of AKL-T01 versus active control on attentional function, measured

via change in score of the T.O.V.A.® test API from pre- to post-intervention. – The T.O.V.A.® test is a validated, computerized continuous performance test that objectively measures

attention and inhibitory control.5 The API score is a composite variable that summarizes the overall T.O.V.A.® test summary statistics.5

• Secondary efficacy endpoints included evaluation of the effect of AKL-T01 versus active control on the following, measured via change in score from pre- to post-intervention:

– Impairment Rating Scale (IRS) – ADHD-RS, sum of inattention (ADHD-RS-I) and hyperactivity-impulsivity (ADHD-RS-H) sub-scales – Clinical Global Impressions-Improvement (CGI-I) (clinician-rated at post-intervention only) – Behavior Rating Inventory of Executive Function-Parent (BRIEF-Parent) Inhibit and Working Memory percentiles.

• Adverse events (AEs) spontaneously reported at study visits were captured and tabulated.

• Post-hoc efficacy objectives included assessment of the following: – Changes within treatment groups (AKL-T01 or active control) from pre- to post-intervention on primary and

major secondary endpoints – Effect on primary and secondary endpoints based on the patients who discontinued stimulant medication

up to 30 days prior to start of the study.

ANALYSES• The alpha criterion for statistical significance for the primary endpoint was adjusted to 0.041 due to an interim

sample size re-estimation.

• Type 1 error was controlled for by a resampling bootstrap method for secondary endpoints.

• Post-hoc analyses were not controlled for multiple endpoints.

METHODS

• Results from this pivotal trial show that AKL-T01 improved inattention and inhibitory control as evidenced by a statistically significant improvement in the primary outcome, the T.O.V.A.® test API, compared with active control.

• Although AKL-T01 also improved symptomatic and functional outcomes, these improvements did not differentiate from the active control.

• The subgroup of patients that discontinued stimulant medication and received AKL-T01 showed improvements in ADHD symptoms (ADHD-RS and ADHD-RS-I), and clinical impressions (CGI-I), compared with the active control.

• AKL-T01 was well tolerated with a low incidence of AEs and high adherence with treatment.

• Further studies are needed to determine the effects of AKL-T01 in the broader ADHD population, including those with comorbid disorders and those receiving medication.

• Overall, results from this study suggest that AKL-T01 is an effective and novel digital treatment option for inattention and inhibitory control in children with ADHD that should be considered as part of an ADHD treatment program.

CONCLUSIONS

REFERENCES1. Cortese S et al. Lancet Psychiatry 2018; 5: 727-738.

2. Catalá-López F et al. PLoS One 2017; 12: e0180355.

3. Kollins SH. JAMA Pediatr 2018; 172: 901-902.

4. Faraone SV, Antshel KM. Child Adolesc Psychiatr Clin N Am 2014; 23: 965-972.

5. Leark RA et al. T.O.V.A.® Professional Manual 2018. Available at: http://files.tovatest.com/documentation/9/print-only/Professional%20Manual.pdf

ACKNOWLEDGMENTSThis study was sponsored by Akili Interactive Labs.

Medical writing support, under the direction of the authors, was provided by Jennifer Arnold, PhD, of CMC CONNECT, a division of Complete Medical Communications Ltd, Radnor, PA, USA, with funding from Akili Interactive Labs, Boston, MA, USA, in accordance with Good Publication Practice (GPP3) guidelines.

Primary and key secondary data for STARS-ADHD were previously presented in a poster presentation at the American Academy for Child and Adolescent Psychiatry (AACAP) Annual Meeting on October 24, 2018.

DISCLOSURESSHK: Consultant and principal investigator for Akili Interactive; research support and/or consulting fees from Alcobra, Arbor, Bose, EPA, FDA, Ironshore, Jazz, KemPharm, Medgenics/Aevi, Neos, National Institutes of Health, Otsuka, Rhodes, Shire, Sunovion, and Tris. JB, TA, DD, EC: Employed by Akili Interactive. RLF: Research support, consultant and/or speaker’s bureau for Aevi, Akili, Alcobra, Amerex, American Academy of Child & Adolescent Psychiatry, American Psychiatric Press, Bracket, Epharma Solutions, Forest, Genentech, Ironshore, KemPharm, Lundbeck, National Institutes of Health, Neurim, Nuvelution, Otsuka, PCORI, Pfizer, Physicians Postgraduate Press, Roche, Sage, Shire, Sunovion, Supernus Pharmaceuticals, Syneurx, Teva, Tris, TouchPoint, and Validus. RK: Paid consultant to Akili and 35 other commercial entities over the past 3 years; owner of NeuroCog Trials, which provided support for this trial. JNE: Consultant, grant support, research support and/or royalties from the American Academy of Pediatrics, American Board of Pediatrics, National Institutes of Health, Institute for Educational Sciences, Akili Interactive, Multi-Health Systems, Inc., IXICO plc. AJC: Advisory board member for Aevi Genomics, Akili, Allergan, Arbor, Ironshore, Neos, NLS, Otsuka, Rhodes, Shire, Sunovion, Supernus; consultant for Aevi Genomics, Akili, Allergan, Arbor, Ironshore, KemPharm, Neos, Otsuka, Purdue, Rhodes, Shire, Sunovion, Supernus, Tris; research support from Aevi Genomics, Akili, Allergan, Arbor, Ironshore, KemPharm, Neos, Otsuka, Purdue, Rhodes, Shire, Sunovion, Supernus; speaker’s bureau for Allergan, Arbor, Neos, Otsuka, Shire, Sunovion; member, Neuroscience Education Institute Board. RW, LA: No disclosures. SVF: Income, potential income, travel expenses continuing education support and/or research support from Akili Interactive Labs, Alcobra, Arbor, Enzymotec, Genomind, Ironshore, KenPharm, Lundbeck, NeuroLifeSciences, Otsuka, Rhodes, Shire, and Sunovion. US patent US20130217707 A1 for the use of sodium-hydrogen exchange inhibitors in the treatment of ADHD.

TABLE 1 PATIENT DEMOGRAPHICS AND BASELINE DISEASE CHARACTERISTICS (ITT POPULATION)

AKL-T01 (N=180) Active control (N=168)

Age, mean years (SD) 9.7 (1.3) 9.6 (1.3)

Male/female, N 125/55 123/45

Baseline score, mean (SD) T.O.V.A.® test API IRS ADHD-RS ADHD-RS-I ADHD-RS-H CGI-Sa

−5.1 (3.0)5.5 (1.1)39.0 (6.8)21.9 (3.5)17.1 (6.0)4.5 (0.7)

−4.9 (3.1)5.5 (1.2)38.3 (6.6)21.6 (3.7)16.7 (5.4)4.6 (0.6)

aCGI-S was only assessed at baseline.ADHD-RS, ADHD Rating Scale; ADHD-RS-H, ADHD-RS hyperactivity-impulsivity; ADHD-RS-I, ADHD-RS inattention; API, Attention Performance Index; CGI-S, Clinical Global Impressions-Severity; IRS, Impairment Rating Scale; ITT, intent-to-treat; SD, standard deviation; T.O.V.A.® test, Test of Variables of Attention test.

TABLE 2 SUMMARY OF TREATMENT-RELATED AEs (SAFETY POPULATION)

AEs, n (%) AKL-T01 (N=180) Active control (N=168)

Patients with any treatment-related AE 12 (6.7) 3 (1.8)

Patients with any serious treatment-related AE 0 0

Patients with any discontinuation due to AE 0 0

Treatment-related AEs reported Nauseaa

Headacheb

Dizzinessb

Frustration tolerance decreasedc

Emotional disorderc,d

Aggressionc

1 (0.6)3 (1.7)1 (0.6)5 (2.8)2 (1.1)1 (0.6)

02 (1.2)

00

1 (0.6)0

One patient who received AKL-T01 reported two AEs: dizziness and nausea.aGastrointestinal disorders; bnervous system disorders; cpsychiatric disorders; dthe lower-level term “emotional reaction” better describes the verbatim term reported from the site.AE, adverse event.

FIGURE 1 STARS-ADHD STUDY DESIGN

On treatment

Day 0

Active control (N=168)

AKL-T01 (N=180)

Day 28Days –7 to –3

25 min/day; 5 days/week; 4 weeksWashout

Day −7 to −3 = Washout period; Day 0 = Baseline; Days 1-27 = Treatment; From Day 28 = Post-intervention assessments.

FIGURE 3PRIMARY ENDPOINT: T.O.V.A.® TEST API (ITT POPULATION) MEAN (SE) CHANGE PRE- TO POST-INTERVENTION

0.00

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*Adjusted p0.05; pre-specified Wilcoxon rank-sum test.▲, Median change pre- to post-intervention.API, Attention Performance Index; ITT, intent-to-treat; T.O.V.A.® test, Test of Variables of Attention test; SE, standard error.

FIGURE 4 SECONDARY ENDPOINT: IRS (ITT POPULATION) MEAN (SE) CHANGE PRE- TO POST-INTERVENTION

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Active controlN=161

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▲, Median change pre- to post-intervention.IRS, Impairment Rating Scale; ITT, intent-to-treat; SE, standard error.

FIGURE 6SWITCHED FROM STIMULANT MEDICATION SUBGROUP: A) T.O.V.A.® TEST API, B) IRS, C) ADHD-RS, D) ADHD-RS-I, E) ADHD-RS-H, F) CGI-I, G) BRIEF-PARENT WORKING MEMORY, AND H) BRIEF-PARENT INHIBIT (ITT POPULATION) MEAN (SE) CHANGE PRE- TO POST-INTERVENTION

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*Active control

N=33AKL-T01N=31

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AKL-T01N=32

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*Unadjusted p0.05; post-hoc Wilcoxon rank-sum test.▲, Median change pre- to post-intervention.ADHD-RS, ADHD Rating Scale; ADHD-RS-H, ADHD-RS hyperactivity-impulsivity; ADHD-RS-I, ADHD-RS inattention; API, Attention Performance Index; BRIEF-Parent, Behavior Rating Inventory of Executive Function-Parent; CGI-I, Clinical Global Impressions-Improvement; IRS, Impairment Rating Scale; ITT, intent-to-treat; SE, standard error; T.O.V.A.® test, Test of Variables of Attention test.

FIGURE 5SECONDARY ENDPOINT: A) ADHD-RS, B) ADHD-RS-I, AND C) ADHD-RS-H (ITT POPULATION) MEAN (SE) CHANGE PRE- TO POST-INTERVENTION

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▲, Median change pre- to post-intervention.ADHD-RS, ADHD Rating Scale; ADHD-RS-H, ADHD-RS hyperactivity-impulsivity; ADHD-RS-I, ADHD-RS inattention; ITT, intent-to-treat; SE, standard error.

ADHERENCE AND SAFETY• The proportion of patients playing the minimum required sessions (50% of expected play) was 85.6% (n=154/180)

with AKL-T01 and 94.6% (n=159/168) with active control.

• Treatment-related AEs were uncommon in patients receiving AKL-T01 and active control (Table 2).

FIGURE 2 SAMPLE SCREENSHOTS FROM AKL-T01

RESULTS