Sleep-specific outcomes attributable to digitally delivered cognitive behavioral therapy for insomnia in adults with insomnia and depressive symptoms.

OBJECTIVE: Randomized controlled trials (RCTs) of digitally delivered Cognitive Behavioral Therapy for insomnia (CBT-I) have demonstrated reductions in insomnia severity, depression symptoms, anxiety symptoms, and suicidal ideation. The present study aimed to evaluate the effectiveness of self-guided, digital CBT-I to improve sleep-specific outcomes. METHOD: An RCT of Australian adults with insomnia and depressive symptoms (N = 1149) compared SHUTi, a digital CBT-I intervention, with HealthWatch, an attention-matched control internet program, at baseline, posttest (9 weeks) and at 6-, 12-, and 18-month follow-ups. Online sleep diaries were used to derive measures of sleep-onset latency (SOL), wake after sleep onset (WASO), sleep efficiency (SE), number of awakenings, sleep quality, and total sleep time (TST). RESULTS: Participants in the SHUTi condition had greater improvements at posttest compared with control for: SOL, WASO, SE, number of awakenings, and sleep quality. These improvements were sustained at every follow-up (p < .02 for all outcomes except TST, in which statistically significant increases were observed only at 12- and 18-months). CONCLUSIONS: Digitally delivered CBT-I produced lasting improvements in sleep outcomes among adults with insomnia and depressive symptoms. Findings provide further evidence of long-term improvements associated with a digital therapeutic for insomnia, compared to an attention-control condition.

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.

A Prescription Digital Therapeutic to Support Unsupervised Buprenorphine Initiation for Patients With Opioid Use Disorder: Protocol for a Proof-of-Concept Study.

BACKGROUND: Home-based (unsupervised) buprenorphine initiation is considered safe and effective, yet many patients report barriers to successful treatment initiation. Prescription digital therapeutics (PDTs) are software-based disease treatments regulated by the US Food and Drug Administration (FDA). The reSET-O PDT was authorized by the FDA in 2018 and delivers behavioral treatment for individuals receiving buprenorphine for opioid use disorder (OUD). A prototype PDT (PEAR-002b) designed for use with reSET-O was developed to assist in unsupervised buprenorphine initiation. OBJECTIVE: The primary objective of this pilot study is to evaluate the acceptability of PEAR-002b in individuals with OUD who use it to support buprenorphine initiation, their unsupervised buprenorphine initiation success rate, and their medication adherence. METHODS: Ten adults with OUD will be recruited for acceptability and feasibility testing. Outcomes will be assessed using week-1 visit attendance, participant interviews and satisfaction surveys, and urine drug screening (UDS). Three tools will be used in the study: PEAR-002b, reSET-O, and EmbracePlus. PEAR-002b includes a new set of features designed for use with reSET-O. The mechanism of action for the combined PEAR-002b and reSET-O treatment is a program of medication dosing support during week 1 of the initiation phase, cognitive behavioral therapy, and contingency management. During the medication initiation phase, participants are guided through a process to support proper medication use. PEAR-002b advises them when to take their buprenorphine based on provider inputs (eg, starting dose), self-reported substance use, and self-reported withdrawal symptoms. This study also administers the EmbracePlus device, a medical-grade smartwatch, to pilot methods for collecting physiologic data (eg, heart rate and skin conductance) and evaluate the device's potential for use along with PDTs that are designed to improve OUD treatment initiation. Home buprenorphine initiation success will be summarized as the proportion of participants attending the post-buprenorphine initiation visit (week 1) and the proportion of participants who experience buprenorphine initiation-related adverse events (eg, precipitated withdrawal). Acceptability of PEAR-002b will be evaluated based on individual participants' ratings of ease of use, satisfaction, perceived helpfulness, and likelihood of recommending PEAR-002b. Medication adherence will be evaluated by participant self-report data and confirmed by UDS. UDS data will be summarized as the mean of individual participants' proportion of total urine samples testing positive for buprenorphine or norbuprenorphine over the 4-week study. RESULTS: This project was funded in September 2019. As of September 2022, participant enrollment is ongoing. CONCLUSIONS: This is the first study to our knowledge to develop a PDT that assists with unsupervised buprenorphine initiation with the intent to better support patients and prescribers during this early phase of treatment. This pilot study will assess the acceptability and utility of a digital therapeutic to assist individuals with OUD with unsupervised buprenorphine initiation. TRIAL REGISTRATION: ClinicalTrials.gov NCT05412966; https://clinicaltrials.gov/ct2/show/NCT05412966. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/43122.

Evaluation of real-world outcomes associated with use of a prescription digital therapeutic to treat substance use disorders.

BACKGROUND AND OBJECTIVES: Digital therapeutics can expand the reach and fidelity of behavioral treatment for substance use disorders (SUDs). This analysis evaluated real-world engagement and clinical outcomes in patients diagnosed with SUD who were prescribed reSET®, an FDA-authorized prescription digital therapeutic (PDT). METHODS: Patients were prescribed a 12-week PDT comprising 61 therapy lessons (31 "core" and 30 "keep learning" lessons) and contingency management rewards (positive reinforcement message or monetary gift cards) based on lesson completion and negative urine drug screens. Engagement (defined as any activity in the PDT), retention (any activity in Weeks 9-12), and substance use data were collected automatically by the PDT and analyzed descriptively. Associations between early lesson completion and end-of-treatment outcomes were assessed. RESULTS: Six hundred and fifty-eight patients filled their prescription. Evaluated were 602 patients who were exposed to therapeutic content by completing at least one lesson (median age 37 years, 33% female, 41% male, 26% unreported sex). Median lessons completed was 33 (out of 61 possible), and 52% of patients completed all core modules. Retention in treatment during the last 4 weeks of treatment was 74%, and 62% were abstinent (missing data considered positive). [Correction added on 13 December 2022, after first online publication: In the preceding sentence, the treatment percentage values were revised from 74.6% to 74%.] DISCUSSION AND CONCLUSIONS: Patients with SUD exhibited robust engagement with a PDT, high rates of retention through 12 weeks, and substantial rates of abstinence at end of treatment when the therapeutic was used in a real-world setting. PDT's hold promise as a new way to access effective SUD treatment. SCIENTIFIC SIGNIFICANCE: This study is the first to report real-world PDT engagement and clinical outcomes data from a large, geographically diverse population of patients with SUDs.

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 Reductions in Healthcare Resource Utilization over 6 Months in Patients with Substance Use Disorders Treated with a Prescription Digital Therapeutic.

BACKGROUND AND AIMS: Substance use disorders (SUDs) affect approximately 40.3 million people in the USA, yet only approximately 19% receive evidence-based treatment each year. reSET® is a prescription digital therapeutic (PDT) and the only FDA-authorized treatment for patients with cocaine, cannabis, and stimulant use disorders. This study evaluated real-world healthcare resource utilization (HCRU) and associated costs 6 months after initiation of reSET in patients with SUD. METHODS: A retrospective analysis of HealthVerity PrivateSource20 data compared the 6-month incidence of all-cause hospital facility encounters and clinician services in patients treated with reSET (re-SET cohort) before (pre-index period) and after (post-index period) reSET initiation (index). Incidence was compared using incidence rate ratios (IRR). HCRU-related costs were also assessed. RESULTS: The sample included 101 patients (median age 37 years, 50.5% female, 54.5% Medicaid-insured). A statistically significant decrease of 50% was observed in overall hospital encounters from pre-index to post-index (IRR 0.50; 95% CI 0.37-0.67; P < 0.001), which included inpatient stays (56% decrease; IRR 0.44; 95% CI 0.26-0.76; P = 0.003), partial hospitalizations (57% decrease; IRR 0.43; 95% CI 0.21-0.88; P = 0.021), and emergency department visits (45% decrease; IRR 0.55; 95% CI 0.38-0.80; P < 0.004). Additionally, some clinician services declined significantly including pathology and laboratory services: other (54% decrease; IRR 0.46; 95% CI 0.28-0.76; P = 0.003); pathology and laboratory services: drug assays prior to opioid medication prescription (37% decrease; IRR 0.63; 95% CI 0.41-0.96; P = 0.031); and alcohol and drug abuse: medication services (46% decrease; IRR 0.54; 95% CI 0.41-0.70; P < 0.001). Reductions in facility-encounters drove 6-month reSET per-patient cost reductions of $3591 post-index compared to pre-index. CONCLUSIONS: Use of reSET by patients with SUD is associated with durable reductions in HCRU and lower healthcare costs over 6 months compared to the 6 months before PDT treatment, after adjusting for covariates, providing an economic benefit to the healthcare system.

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 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.

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).

Patient Engagement With a Game-Based Digital Therapeutic for the Treatment of Opioid Use Disorder: Protocol for a Randomized Controlled Open-Label, Decentralized Trial.

BACKGROUND: Prescription digital therapeutics are software-based disease treatments that are regulated by the US Food and Drug Administration; the reSET-O prescription digital therapeutic was authorized in 2018 and delivers behavioral treatment for individuals receiving buprenorphine for opioid use disorder. Although reSET-O improves outcomes for individuals with opioid use disorder, most of the therapeutic content is delivered as narrative text. PEAR-008 is an investigational device based on reSET-O that uses an interactive, game-based platform to deliver similar therapeutic content designed to enhance patient engagement, which may further improve treatment outcomes. OBJECTIVE: We aim to investigate how participants interact with the prescription digital therapeutic's new content delivery format. Secondary objectives include evaluating treatment success, symptoms of co-occurring mental health disorders, recovery capital, and skill development. METHODS: Due to the COVID-19 pandemic, this study was redesigned using a decentralized model because it was not possible to conduct medication initiation and study visits in person, as initially intended. A decentralized, randomized controlled trial design will be utilized to compare patient engagement with PEAR-008 and that with reSET-O using both subjective and objective assessments. The study population will consist of approximately 130 individuals with opioid use disorder (based on Diagnostic and Statistical Manual of Mental Disorders 5 criteria) who have recently started buprenorphine treatment for opioid use disorder. Participants will be virtually recruited and randomly assigned to receive either PEAR-008 or reSET-O. All study sessions will be virtual, and the duration of the study is 12 weeks. The primary outcome measure of engagement is operationalized as the number of active sessions per week with either PEAR-008 or reSET-O. (An active session is any session that contains some active participation in the app, such as navigating to a different screen, engaging with a learning module, or responding to a notification.) Subjective dimensions of engagement will be assessed with participant surveys. The hypothesis is that PEAR-008 will have significantly greater participant engagement than reSET-O. RESULTS: As of February 2021, participant enrollment is ongoing. CONCLUSIONS: This randomized controlled trial will investigate if changing the delivery format and enhancing the content of a prescription digital therapeutic for opioid use disorder will affect how participants use and interact with the prescription digital therapeutic. The study design may serve as a useful model for conducting decentralized studies in this patient population. TRIAL REGISTRATION: ClinicalTrials.gov NCT04542642; https://clinicaltrials.gov/ct2/show/NCT04542642. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/32759.

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.

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.

Reversal of Bortezomib-Induced Neurotoxicity by Suvecaltamide, a Selective T-Type Ca-Channel Modulator, in Preclinical Models.

This study evaluated suvecaltamide, a selective T-type calcium channel modulator, on chemotherapy-induced peripheral neurotoxicity (CIPN) and anti-cancer activity associated with bortezomib (BTZ). Rats received BTZ (0.2 mg/kg thrice weekly) for 4 weeks, then BTZ alone (n = 8) or BTZ+suvecaltamide (3, 10, or 30 mg/kg once daily; each n = 12) for 4 weeks. Nerve conduction velocity (NCV), mechanical threshold, ß-tubulin polymerization, and intraepidermal nerve fiber (IENF) density were assessed. Proteasome inhibition was evaluated in peripheral blood mononuclear cells. Cytotoxicity was assessed in human multiple myeloma cell lines (MCLs) exposed to BTZ alone (IC50 concentration), BTZ+suvecaltamide (10, 30, 100, 300, or 1000 nM), suvecaltamide alone, or vehicle. Tumor volume was estimated in athymic nude mice bearing MCL xenografts receiving vehicle, BTZ alone (1 mg/kg twice weekly), or BTZ+suvecaltamide (30 mg/kg once daily) for 28 days, or no treatment (each n = 8). After 4 weeks, suvecaltamide 10 or 30 mg/kg reversed BTZ-induced reduction in NCV, and suvecaltamide 30 mg/kg reversed BTZ-induced reduction in IENF density. Proteasome inhibition and cytotoxicity were similar between BTZ alone and BTZ+suvecaltamide. BTZ alone and BTZ+suvecaltamide reduced tumor volume versus the control (day 18), and BTZ+suvecaltamide reduced tumor volume versus BTZ alone (day 28). Suvecaltamide reversed CIPN without affecting BTZ anti-cancer activity in preclinical models.

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.

Real-world changes in US health system hospital-based services following treatment with a prescription digital therapeutic for opioid use disorder.

Outcomes associated with buprenorphine therapy for the treatment of opioid use disorder (OUD) are suboptimal. reSET-O is an FDA-authorized prescription digital therapeutic (PDT) delivering neurobehavioral therapy via mobile devices to patients with OUD treated with buprenorphine. This analysis evaluated the net impact of reSET-O on medical costs among actively-engaged reSET-O patients using real-world observations. This real-world retrospective analysis of health care claims between October 2018 and October 2019 evaluated health care resource utilization up to 6 months before and 6 months after the initiation of a reSET-O prescription after accounting for the subset of patients not continuing on therapy after week 1 (non-engaged patients). Repeated-measures negative binomial models compared incidences of hospital-based encounters/procedures adjusted for days in each period as well as associated costs. The number needed to treat (NNT) to avoid an inpatient visit was calculated. Of the 351 patients who were prescribed reSET-O, 321 met the criteria of active engagement. Treatment with reSET-O was associated with a substantial reduction in medical costs of -$765,450 (-$2,385/patient, $235/patient greater than a previous analysis in which non-engaged patients were included) in the 6-month period after initiation. The gross reSET-O prescription cost of $584,415 ($1,665/patient) was substantially offset by $49,950 ($142.31/patient) in refunds to payers. The medical cost reduction in engaged patients offset the cost of the therapeutic resulting in an overall cost reduction of -$230,985 in this cohort (net savings of -$720 per patient). The number needed to treat to avoid an inpatient visit was 4.8. Engagement and continued treatment with reSET-O in patients with OUD treated with buprenorphine is associated with substantial real-world reductions in medical costs in the 6-month period following the initiation of the reSET-O prescription.

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.