Beyond Medication: Research Insight for PDT Neurodevelopmental Treatments

In an interview with First Report Managed Care, Scott Kollins, PhD, chief medical officer of Akili Interactive, shares research findings related to prescription digital therapeutic treatments for ADHD.

Please share your name, title, affiliation, and a bit about your background.

My name is Scott Kollins and I am the chief medical officer at Akili Interactive. I have been with the company for a little bit more than 8 months but I actually worked with the company in other capacities for about a decade. I'm a clinical psychologist by training and I've spent almost my whole career in academic medicine. I attended Duke in 2000 and then was a faculty member at their School of Medicine.

Previously, I ran a specialty program, research, and clinic focused specifically on kids, adolescents, and adults with ADHD and their families. Alongside my clinical practice I was also investing my time in clinical trial research, NIH grants, and other industry-supported work. Companies would come to us for help designing and executing research studies for new treatments. We assisted in the development of most of the existing medication products that are on the market related to this field of research.

That is how I first became aware of Akili in 2013 when they approached us for assistance designing and testing prescription digital therapeutics for ADHD. While in my role at the Duke Clinical Research Institute, we helped with designing and running 2 pivotal, phase III studies that ultimately formed the basis of the successful FDA submission.

Can you provide an overview of the STARS Adjunct Trial and the main objectives of the study?

We conducted a very traditional randomized clinical trial as the first phase III study to test out this treatment for kids. Children with ADHD already on medication were not included because we wanted an unconfounded comparison of the effects of Akili's treatment versus a control condition. We only included kids with demonstrated deficits in their attentional functioning as measured by the Test of Variables of Attention.

While the results of that 4 week study were positive, from a practical perspective we knew kids in the real world are usually treated with medication. Our next objective became studying if the treatment provided any incremental benefit to kids that are also receiving medication. Since many children with ADHD do not receive a test to measure their levels of function, we also removed that pre-requisite for inclusion in the study. Since ADHD is a chronic condition, we also extended the duration of treatment to see if there is continued improvement over time. 

The adjunct study was designed specifically to answer those three objectives. About a third of the kids in the study didn't receive medication and two-thirds of them were on stimulants. Under the new study design, kids were treated for a month, taken off treatment for a month, and then treated again for another month. 

What led to exploring digital therapeutics as a form of ADHD treatment, and how did these digital therapeutics differ from traditional pharmacological interventions?

In order to be the most practical and applicable to real-world experiences of people with ADHD, the primary outcome in this study was something we called the Impairment Rating Scale. It is specifically designed to measure how ADHD impacts day-to-day functioning in individual people measuring impairment across a range of domains, including school functioning, peer functioning, and home functioning. And we thought that that would be a really good metric to understand, "Is this really improving people's lives and is it improving their functioning?" 

The secondary outcome of that foundational adjunct study was collecting data on ADHD symptoms. Symptom rating scales are typically used in almost every medication clinical trial, but they don't correlate as strongly as you would think with day-to-day functioning. And so from a clinical perspective, we felt, "Yeah, the day-to-day functioning is really what matters, because at the end of the day, if your symptoms get better, but you're still not turning your homework in or your grades are suffering or you're not getting along with peers, it doesn't really matter." That's really where the rubber meets the road so that's why we wanted to measure impairment as our primary outcome. Symptoms are important and so we still measured those as a secondary outcome.

Ultimately, we found improvements. We saw significant changes from baseline to the end of the first month, in both the Impairment Rating Scale as well as ADHD symptoms. An exciting confirmation of our hypothesis is that when we stopped treatment, we didn't see a bounce back to where they were in terms of functioning at the beginning of the study. This meant that in contrast with a medication where ADHD symptoms are going to bounce back up to somewhere around where they were at the start, there was maintained improvement that leveled off in the second month of treatment by all measures. That was really exciting for us because it suggested that our hypothesis here is that this is a treatment impacting brain function. 

The study mentions improvements in ADHD-related impairment. Could you explain the significance of these improvements and how they relate to the overall management of ADHD?

We found an improvement in brain functioning regardless of whether or not a kid was on stimulant medication. This means if a kid was on medication, there was still room for improvement with our treatment. Results were exactly the same in the medicated and the unmedicated groups and suggests that there's incremental benefit available for all people with ADHD. Our digital therapeutic is not a competing treatment, it is complementary.

Treating ADHD with digital therapeutics differs from other pharmacological interventions in many ways. First of all, they're easily accessible. Right now in the United States we are experiencing a massive stimulant medication shortage that's affecting millions of people with ADHD. In contrast, we have a digital therapeutic that is is an app in the App Store. We don't have supply chain issues to worry about like medication. Access to other forms of treatment, such as quality behavior therapy, can also be challenging, too.

Safety is also important. In both of our pivotal studies, as well as in a lot of other clinical studies we've done, our digital therapeutic is an extremely safe treatment. The rate of adverse events in medication clinical trials usually result in between 50% and 70% of all participants experiencing some kind of adverse event. Even when they are not severe, it can be an inconvenience and they can impact who is able to access traditional treatments.

And another big difference from a patient and caregiver perspective is that digital therapeutics provide another treatment option. I've seen hundreds, probably thousands of patients over the years, and I know there's a lot of reticence in taking medicine or giving medicine to your child for ADHD, as well as a lot of questions. Digital therapeutics provide an alternative, that prior to our product coming along, just hadn't been out there. This is a safe, easily accessible treatment that just adds another arrow in the quiver for how to tackle and how to optimally manage ADHD.

What research has been conducted since these foundational studies to expand on the use of digital therapeutics for treating ADHD? 

After these initial, pivotal studies were successful as part of a regulatory submission, the product was approved in June of 2020. However that is oftentimes just the start of data collection and research. Since then we have completed 2 additional studies in older age groups. Our initial research was in kids age 8 to 12, and our label from the FDA is for that age group. By conducting research in older age groups, we hope to expand our treatment use with the FDA. 

We also have a product we shared promising research findings on in May from an adult study. In this study, adults experienced even more benefit than adolescents. Due to that study, we decided to launch a non-prescription, over-the-counter version of our product for adults called Endeavor OTC. We are working to submit that product for regulatory approval sometime later this year and we will continue to market it as a non-prescription option for adults.

We are also excited from a research perspective that for our adolescent patients, and soon our adult patients, will be a part of a research registry. Everybody using our products will have an opportunity to consent and participate in an ongoing research study so that we can understand the long-term impact of these treatments outside of the confines of a tightly controlled clinical trial. We've enrolled nearly a hundred kids in our pediatric registry and excited to launch this alongside our adult over-the-counter products for the continual improvement of these digital therapeutics.