Safety and efficacy of a digital therapeutic for substance use disorder: Secondary analysis of data from a NIDA clinical trials network study.

Background: Traditional treatments for substance use disorders (SUDs) rely heavily on face-to-face interactions, which pose substantial limitations for patients. A clinical trial of a digital therapeutic (DT), delivering behavioral therapy demonstrated safety and efficacy in a population including patients with opioid use disorder (OUD) not treated with buprenorphine, which is not a guideline-recommended approach. This study re-analyzed the data excluding patients with OUD to more closely approximate real-world patient populations. Methods: Secondary analysis of patients with substance use disorders related to alcohol, cannabis, cocaine, or other stimulants (n = 399, patients with OUD excluded) from a previously-published randomized controlled trial. Patients received 12-weeks of outpatient treatment-as-usual (TAU; n = 193) or TAU with reduced counseling plus a DT (n = 206) providing computerized cognitive behavioral therapy and contingency management. Primary outcomes were abstinence in weeks 9-12 and retention in treatment. Results: The 399 patients in this analysis (206 in the DT group and 193 in the TAU group) reported substance use disorders related to alcohol, cannabis, cocaine, or other stimulants (e.g., methamphetamines). Demographic and baseline characteristics including age, sex, race, education, and reported primary substance use disorder were balanced between treatment groups. Abstinence was significantly higher in the DT group compared to TAU (40.3 vs. 17.6%; p < 0.001) as was retention in therapy (76.2 vs. 63.2%, p = 0.004). Intergroup adverse event rates were not significantly different (p = 0.68). Conclusions: The results demonstrate that use of a DT safely increased abstinence (reduced substance use) and retention in treatment among patients with substance use disorders related to alcohol, cannabis, cocaine, or other stimulants (including methamphetamines).

FDA regulations and prescription digital therapeutics: Evolving with the technologies they regulate.

Technological progress in digital therapeutics-and, in particular prescription digital therapeutics (PDTs)-has outpaced the processes that the Food and Drug Administration (FDA) uses to regulate such products. Digital therapeutics have entered the health care ecosystem so rapidly that substantial misunderstandings exist about how they are evaluated and regulated by the FDA. This review briefly explains the relevant regulatory history of software as medical devices (SaMDs) and reviews the current regulatory landscape in which prescription and non-prescription digital therapeutics are developed and approved for use. These are important issues because PDTs, and digital therapeutics in general, are an explosively growing field in medicine and offer many advantages over conventional face-to-face treatments for the behavioral dimensions of a wide range of conditions and disease states. By allowing access to evidence-based therapies remotely and privately, digital therapeutics can reduce existing disparities in care and improve health equity. But clinicians, payers, and other healthcare stakeholders must appreciate the rigor of the regulatory frameworks within which PDTs are approved for use.

Engagement patterns with a digital therapeutic for substance use disorders: Correlations with abstinence outcomes.

INTRODUCTION: Patient engagement may play a key role in the success or failure of treatments for substance use disorder (SUD). This exploratory analysis of data from a large, multisite effectiveness trial (NCT01104805) sought to determine how patient engagement with a digital therapeutic for SUD delivered at clinics was associated with abstinence outcomes. METHODS: The study evaluated engagement for 206 participants enrolled in a treatment program for SUDs related to cocaine, alcohol, cannabis, or other stimulants who were randomized to receive treatment as usual (TAU) or reduced TAU plus the digital Therapeutic Education System (TES) for 12 weeks. Participants were eligible for contingency management incentives for module completion (modules cover Community Reinforcement Approach topic areas) and negative urine drug screens. Analyses examined the association of module completion with end-of-treatment abstinence. RESULTS: Participants completed a mean of 38.8 (range 0-72) TES modules over 12 weeks of treatment. Study completers (n = 157) completed a mean of 45.5 (range 9-72) TES modules, whereas study noncompleters (n = 49) completed a mean of 17.4 (range 0-45) TES modules. The study observed a strong positive correlation between TES engagement (i.e., total number of modules completed) and the probability of abstinence during weeks 9-12 of treatment among 157 study completers (OR = 1.11; 95% CI 1.08-1.14). Each module completed increased the odds of abstinence during weeks 9-12 by approximately 11% for study completers and 9% for the full sample. The study observed a similar, but weaker, association between engagement and abstinence among 49 patients who did not complete the study (OR = 1.02; 95% CI 0.98-1.07). CONCLUSIONS: Greater engagement with a digital therapeutic for patients with SUD (i.e., number of modules completed over time) was strongly associated with the probability of abstinence in the last four weeks of treatment among those who completed the recommended 12-week treatment. TRIALS REGISTRATION: ClinicalTrials.gov Identifier: NCT01104805.

Reduced Healthcare Resource Utilization in Patients with Opioid Use Disorder in the 12 Months After Initiation of a Prescription Digital Therapeutic.

BACKGROUND AND AIMS: reSET-O, an FDA-authorized prescription digital therapeutic (PDT) delivering cognitive behavioral therapy and contingency management to patients with opioid u®se disorder (OUD), may help improve clinical outcomes. One-year differences in healthcare resource utilization (HCRU) and costs post-PDT initiation were evaluated. METHODS: Retrospective analysis of healthcare claims data compared all-cause HCRU (across hospital facility encounters [sum of inpatient stays, treat-and-release emergency department [ED] visits, partial hospitalizations, and hospital outpatient department visits] and clinician services [procedure categories]) after PDT initiation (index) between reSET-O patients and controls. Overall and Medicaid-specific differences in HCRU, costs, and buprenorphine adherence were evaluated. FINDINGS: Cohorts included 901 reSET-O patients (median age 36 years, 62.4% female, 73.9% Medicaid) and 978 controls (median age 38 years, 51.1% female, 65.4% Medicaid). Compared to the control group, the reSET-O group experienced 12% fewer total unique hospital encounters (non-significant), driven by 28% fewer inpatient stays (IRR 0.72; 95% CI 0.55-0.96; P = 0.02), 56% fewer hospital readmissions [IRR 0.44; 95% CI 0.20-0.93; P = 0.033]), and 7% fewer ED visits (IRR 0.93; 95% CI 0.79-1.09; P = 0.386). Total clinician services increased by 1391 events versus controls. Differences were greater among the Medicaid patients. Adjustment for concomitant baseline substance use and mental health disorders resulted in similar HCRU incidence rate ratios. Changes in all-cause HCRU drove per-patient per-year cost differences of - $2791 versus controls (- $3832 versus Medicaid controls). Adjusted mean medication possession ratio was 0.848 (SE 0.0118) at 12 months for reSET-O patients, which was significantly higher than controls (0.761 [SE 0.0108]; P < 0.001). CONCLUSIONS: Use of reSET-O is associated with significant and durable real-world reductions in ED and inpatient (including readmissions) utilization, reduced net costs, and increased clinician services and buprenorphine adherence. Differences in costs versus controls were greatest among Medicaid patients. INFOGRAPHIC.

Real-World Evaluation of Clinical Response and Long-Term Healthcare Resource Utilization Patterns Following Treatment with a Digital Therapeutic for Chronic Insomnia.

Background and Objectives: This analysis evaluated insomnia severity and long-term impact on healthcare resource utilization (HCRU) and costs after treatment with Somryst® (previously called SHUTi), a digital therapeutic delivering cognitive behavioral therapy for insomnia (CBT-I). Methods: Change from baseline in insomnia severity index (ISI) score was assessed using last observed ISI score. A pre/post analysis of claims data was conducted, comparing HCRU in patients with self-identified sleep problems who successfully initiated the therapeutic (index date) between June 1, 2016 and December 31, 2018. Results: A total of 248 patients were analyzed (median age 56.5 years, 57.3% female, mean ISI score 19.13, 52.4% treated with sleep aid medications pre-index). After 9 weeks, mean ISI score declined by 37.2% from baseline (19.1 vs 12.0), 58.8% of patients achieved ISI responder status (ISI score improved by =>7; NNT: 1.7), and 26.6% of patients achieved insomnia remission (ISI score <8; NNT for remission: 3.8). After two-year follow-up, post-index events were reduced (compared to 2 years pre-index) for emergency department visits (-53%; IRR: 0.47; 95% CI 0.27, 0.82; P=0.008), hospiatizations (-21%; IRR: 0.79; 95% CI 0.46, 1.35; P=0.389) and hospital outpatient visits (-13%; IRR: 0.87; 95% CI 0.66, 1.14; P=0.315). Slightly increased rates were observed for ambulatory surgical center visits (2%; IRR: 1.02; 95% CI 0.73, 1.44; P=0.903) and office visits (2%; IRR: 1.02; 95% CI 0.92, 1.14; P=0.672). The number of patients treated with sleep aid medications dropped 18.5% (52.4% pre-index vs 42.7% post-index). Average number of prescriptions decreased from 3.98 pre-index to 3.73 post-index (P= 0.552). Total two-year cost reduction post-index vs pre-index was $510,678, or -$2059 per patient. Conclusion: In a real-world cohort of patients with chronic insomnia, treatment with a digital therapeutic delivering CBT-I was associated with reductions in insomnia severity, emergency department visits, and net costs.

Real-world evidence from users of a behavioral digital therapeutic for chronic insomnia.

BACKGROUND: There have been many research trials of various digital therapeutics, but few real world evaluations of their efficacy. This type of data, however, can provide a more rounded understanding of their impact, utility, reach, and adoption. Findings presented here focus on outcome and patient engagement data of SHUTi (Sleep Health Using the Internet), a digital therapeutic delivering Cognitive Behavioral Therapy for insomnia (CBT-I), in a large real-world dataset of adults with insomnia. METHODS: 7216 adults who purchased access to SHUTi between December 2015 and February 2019 are included in the analysis. The Insomnia Severity Index (ISI) was administered at the beginning of each of six treatment Cores of the intervention. Users entered sleep diaries between Cores to track changes in sleep over time and obtain tailored sleep recommendations. Number of Cores completed and sleep diaries entered indicate program usage. RESULTS: Users showed a reduction in mean ISI scores and a corresponding increase in effect size at the start of each subsequent Core (compared to Core 1) (range: d = 0.3-1.9). Effect sizes at the last Core relative to the first were moderate-to-large for diary-derived sleep onset latency and wake after sleep onset. A reduction in number of medicated nights was also found, with those with severe insomnia showing the largest reduction from last-to-first week of treatment (d = 0.3). At the last Core, 61% met criteria for meaningful treatment response (reduction of >7 points on ISI) and 40% met criteria for remission (ISI<8). Engagement was comparable to SHUTi research trials. CONCLUSION: Consistent with controlled trials, real-world data suggest that digital therapeutics can result in relatively high levels of engagement and clinically meaningful sleep improvements.

Comparison of Healthcare Resource Utilization Between Patients Who Engaged or Did Not Engage With a Prescription Digital Therapeutic for Opioid Use Disorder.

BACKGROUND: A prescription digital therapeutic (PDT) (reSET-O®) may expand access to behavioral treatment for patients with opioid use disorder (OUD) treated with buprenorphine, but long-term data on effectiveness are lacking. OBJECTIVE: To compare real-world healthcare resource utilization (HCRU) among patients who engaged with reSET-O and buprenorphine compared to similar patients in recovery treated with buprenorphine who did not fill their reSET-O script or engage with the PDT beyond week one. METHODS: A retrospective analysis of facility and clinical service claims data was conducted in adults with PDT initiation and between 12 weeks and 9 months of continuous enrollment in a health plan after initiation. Patients who filled their prescription and engaged with the therapeutic were compared to patients who filled the prescription but did not engage beyond week one (NE), and patients who did not fill the prescription (NR) (the latter two groups combined into one group hereafter referred to as "non-engagers"). Comparisons were analyzed using a repeated-measures negative binomial model of encounters/procedures, adjusted for number of days in each period. Associated cost trends assessed using current Medicare reimbursement rates. RESULTS: A total of 444 patients redeemed a prescription and engaged with the PDT (mean age 37.5 years, 63.1% female, 84% Medicaid), and 64 patients did not engage with the PDT (mean age 39.5 years, 32.8% female, 73.4% Medicaid). Total cost of hospital facility encounters was $2693 for engaged patients vs $6130 for non-engaged patients. Engaged patients had somewhat higher rates of certain clinician services. Total facility and clinician services costs for engaged vs non-engaged patients were $8733 vs $11,441, for a net cost savings over 9 months of $2708 per patient who engaged with reSET-O. CONCLUSION: Patients who engaged with an OUD-specific PDT had a net cost reduction for inpatient and outpatient services of $2708 per patient over 9 months compared to patients who did not engage with the PDT, despite similar levels of buprenorphine adherence.

Real-world use and clinical outcomes after 24 weeks of treatment with a prescription digital therapeutic for opioid use disorder.

PURPOSE: To evaluate real-world prescription digital therapeutic (PDT) use and associated clinical outcomes among patients with opioid use disorder (OUD). PATIENTS AND METHODS: A real-world observational evaluation of patients who filled either a 12- or 24-week (refill) prescription for the reSET-O® PDT. The PDT content consists of 67 interactive lessons unlocked in sequence during use as well as the chance to earn rewards for progress and/or negative urine screens. Engagement/retention data (ongoing engagement in weeks 9-12, or 21-24) were collected via the PDT and analyzed with descriptive statistics. Substance use was evaluated as a composite of patient self-reports and urine drug screens (UDS). Missing UDS data were assumed to be positive. A regression analyses of hospital encounters for 12- vs. 24-week prescriptions controlling for covariates was conducted. RESULTS: In a cohort of 3,817 individuals with OUD who completed a 12-week PDT prescription, a cohort of 643 was prescribed a second 12-week 'refill' prescription, for a total treatment time of 24 weeks. Mean age of the 24-week cohort was 39 years, 56.7% female. At 24 weeks of total treatment: abstinence in the last 4 weeks of treatment was 86% in an analysis in which patients with no data are assumed to be positive for illicit opioids. Over 91% of patients were retained in treatment. An analysis of matched insurance claims showed that those treated for 24 weeks had a 27% decrease in unique hospital encounters compared to those who got the first 12-week prescription only. CONCLUSIONS: These data present real-world evidence that a second prescription (24 weeks) of a PDT for OUD is associated with improved outcomes, high levels of retention, and fewer hospital encounters compared to a single prescription for a PDT.PLAIN LANGUAGE SUMMARYPrescription digital therapeutics (PDTs) are software-based treatments that are FDA-authorized to improve clinical outcomes for serious diseases and conditions. The reSET-O PDT consists of 67 interactive lessons unlocked in sequence during use as well as the chance to earn rewards for progress and/or negative urine screens. Multiple studies show that a single 12-week PDT prescription for opioid use disorder (OUD) helps patients engage in treatment, reduces substance use, and helps patients remain in treatment, but to date there has been no evaluation of how patients who receive a 'refill' second prescription engage with the therapeutic and whether the positive effects on substance use and retention are durable across a second 12 weeks (total of 24 weeks) of treatment.This real-world analysis evaluated 643 patients from 12 U.S. states who were prescribed a second PDT prescription. 93% of this cohort completed 8 or more core lesson modules in the second prescription period, 85% completed at least half of core modules, and 64% completed all 32 core modules. Patients used the PDT outside of clinic hours about 40% of the time. 94.4% of patients had 80% or greater negative reports of opioid use across the second 12 weeks of treatment. A 27% decrease in unique hospital encounters was observed in patients who completed a second prescription vs. patients who completed only one prescription.These data show that a second prescription of a PDT for OUD is associated with postive patient outcomes. Patients showed durable and high levels of engagement with the PDT, reduced substance use, and improved treatment retention through 24 weeks of treatment.

Protocol for Digital Real-world Evidence trial for Adults with insomnia treated via Mobile (DREAM): an open-label trial of a prescription digital therapeutic for treating patients with chronic insomnia.

Background: Cognitive behavioral therapy for insomnia (CBT-I) is underused in healthcare settings and is challenging for people with insomnia to access because of uneven geographical distribution of behavioral sleep medicine providers. Prescription digital therapeutics can overcome these barriers. This study evaluates the effectiveness of a specific digital CBT-I therapeutic. Materials & methods:Digital Real-world Evidence trial for Adults with insomnia treated via Mobile (DREAM) is a 9-week, open-label, decentralized clinical trial to collect real-world evidence for a digital therapeutic (Somryst™) delivering CBT-I to patients with chronic insomnia. The primary objective is to examine the effectiveness of Somryst to reduce self-reported insomnia symptoms and severity in a real-world population (n = 350). Conclusion: This pragmatic study seeks to assess the potential benefits of treating insomnia with an asynchronous, mobile, tailored prescription digital therapeutic. Clinical trial registration: NCT04325464 (ClinicalTrials.gov).

Lay abstract Chronic insomnia is linked to a range of health problems, including heart disease, chronic pain, high blood pressure and depression. A behavioral treatment called cognitive behavioral therapy for insomnia (CBT-I) is considered the first choice for helping patients overcome insomnia and reduce their risks of insomnia-related problems. Although the benefits of CBT-I have been established, it can be difficult for patients to access trained CBT-I therapists. One possible solution is to use digital forms of CBT-I, which patients can access on mobile devices. Somryst™ is a prescription digital therapeutic, which means it is authorized by the US FDA and has been proven effective in carefully-controlled clinical trials. Less is known, however, about how well the prescription digital therapeutic works in real-world settings. The Digital Real-world Evidence trial for Adults with insomnia treated via Mobile study (DREAM) will explore this question by evaluating a range of symptoms and outcomes in at least 350 patients with chronic insomnia who will use Somryst and be followed for 1 year.

Real-world evidence for a prescription digital therapeutic to treat opioid use disorder.

OBJECTIVES: To evaluate patient engagement and usage of a prescription digital therapeutic (PDT) and associated outcomes of opioid use and treatment retention in a large real-world dataset of patients with opioid use disorder (OUD) treated with buprenorphine medication for opioid use disorder (MOUD). PDTs are software-based disease treatments evaluated for safety and effectiveness in randomized clinical trials (RCTs), and authorized by the U.S. Food and Drug Administration (FDA) to treat disease with approved directions for use (label). METHODS: A real-world observational evaluation of an all-comer population of patients who redeemed a 12-week prescription for the reSET-O PDT. Engagement and therapeutic use data were collected and analysed on a population level. Substance use was evaluated as a composite of self-reports recorded with reSET-O and urine drug screens (UDS). RESULTS: Data from 3144 individuals with OUD were evaluated. 45.5% were between ages 30 and 39 years. 80% completed at least 8 of the 67 possible therapeutic modules, 66% completed half of all modules, and 49% completed all modules. Abstinence during the last 4 weeks of treatment was calculated with two imputation methodologies: 66% abstinent using "missing data excluded (patients with no data as positive)", and 91% abstinent with "missing data removed (patients with no data excluded)". 91% of patients met the responder definition of ≥80% of self-report or UDS negative. 74.2% of patients were retained through the last 4 weeks of treatment. Subgroup analysis of patients using reSET-O appropriately (4 or more modules per week for the first 4 weeks) showed 88.1% abstinence using "missing data excluded (patients with no data as positive)", and retention at weeks 9-12 of 85.8%. CONCLUSIONS: Results demonstrate that reSET-O is readily and broadly used by patients with OUD and that high real-world engagement with the therapeutic is positively associated with abstinence and retention in treatment. ReSET-O is a potentially valuable adjunct to buprenorphine MOUD therapy for patients with OUD.

Safety and efficacy of a prescription digital therapeutic as an adjunct to buprenorphine for treatment of opioid use disorder.

OBJECTIVES: To evaluate the safety and efficacy of a digital therapeutic in treatment-seeking individuals with opioid use disorder (OUD) in an analysis of randomized clinical trial (RCT) data (ClinicalTrials.gov identifier: NCT00929253). METHODS: Secondary analysis of an RCT including 170 adults meeting DSM-IV criteria for OUD. Participants were randomized to 12-weeks of treatment-as-usual (TAU) or TAU plus a digital therapeutic providing 67 digital, interactive educational modules based on the Community Reinforcement Approach. TAU consisted of buprenorphine maintenance therapy, 30 min biweekly clinician interaction, and abstinence-based contingency management. Primary endpoints were treatment retention and abstinence (negative urine drug screen) during weeks 9-12 of treatment. Safety was assessed by evaluating adverse events. RESULTS: Participants randomized to TAU plus a digital therapeutic had significantly greater odds of opioid abstinence during weeks 9-12 compared to TAU: 77.3 versus 62.1%, respectively (p=.02), OR 2.08, 95% CI 1.10-3.95. The risk of patients leaving treatment was significantly lower in the digital therapeutic group (HR 0.49, 95% CI 0.26-0.92). No significant difference was observed in the rate of adverse events between groups (p=.42). CONCLUSIONS: A prescription digital therapeutic (PDT) in combination with buprenorphine therapy improves clinically significant patient outcomes including abstinence from illicit opioids and retention in treatment compared with treatment as usual.