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Objective To build on the recently completed GRADE (Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study) randomised trial examining the comparative effectiveness of second line glucose lowering drugs in achieving and maintaining glycaemic control in adults with type 2 diabetes. Design Emulation of a target trial. Setting Medical and pharmacy claims data from the OptumLabs Data Warehouse, a de-identified US national dataset of beneficiaries of commercially insured and Medicare Advantage plans, 29 March 2013 to 30 June 2021. Participants Adults (≥18 years) with type 2 diabetes who first started taking glimepiride, sitagliptin, liraglutide, insulin glargine, or canagliflozin between 29 March 2013 and 30 June 2021. Participants were treatment naive or were receiving metformin monotherapy at the time of starting the study drug. Main outcome measures The main outcomes were time to primary and secondary metabolic failure of the assigned treatment, calculated as days to haemoglobin A1c levels of ≥7.0% and >7.5%, respectively. Secondary metabolic, cardiovascular, and microvascular outcomes were analysed as specified in the GRADE statistical analysis plan. Propensity scores were estimated with the gradient boosting method, and inverse propensity score weighting was used to emulate randomisation to the treatment groups, which were then compared with Cox proportional hazards regression. (Results The study cohort included participants starting treatment with glimepiride (n=20 511), liraglutide (n=5569), sitagliptin (n=13 039), insulin glargine (n=7262), and canagliflozin (n=5290). The insulin glargine arm was excluded because of insufficient control of confounding. Median times to primary metabolic failure were 439 (95% confidence interval 400 to 489) days in the canagliflozin arm, 439 (426 to 453) days in the glimepiride arm, 624 (567 to 731) days in the liraglutide arm, and 461 (442 to 482) days in the sitagliptin arm. Median time to secondary metabolic failure was also longest in the liraglutide arm. Adults receiving liraglutide had the lowest one year cumulative incidence rate of primary metabolic failure (0.37, 95% confidence interval 0.35 to 0.40) followed by sitagliptin (0.44, 0.43 to 0.45), glimepiride (0.45, 0.44 to 0.45), and canagliflozin (0.46, 0.44 to 0.48). Similarly, the one year cumulative incidence rate of secondary metabolic failure was 0.27 (0.25 to 0.29) in the canagliflozin arm, 0.28 (0.27 to 0.29) in the glimepiride arm, 0.23 (0.21 to 0.26) in the liraglutide arm, and 0.28 (0.27 to 0.29) in the sitagliptin arm. No differences were observed between the study arms in the rates of microvascular and macrovascular complications. Conclusions In this target trial emulation of an expanded GRADE study framework, liraglutide was more effective in achieving and maintaining glycaemic control as a second line glucose lowering drug than canagliflozin, sitagliptin, or glimepiride.

Observational medical data present unique opportunities for analysis of medical outcomes and treatment decision making. However, because these datasets do not contain the strict pairing of randomized control trials, matching techniques are to draw comparisons among patients. A key limitation to such techniques is verification that the variables used to model treatment decision making are also relevant in identifying the risk of major adverse events. This article explores a deep mixture of experts approach to jointly learn how to match patients and model the risk of major adverse events in patients. Although trained with information regarding treatment and outcomes, after training, the proposed model is decomposable into a network that clusters patients into phenotypes from information available before treatment. This model is validated on a dataset of patients with acute myocardial infarction complicated by cardiogenic shock. The mixture of experts approach can predict the outcome of mortality with an area under the receiver operating characteristic curve of 0.85 ± 0.01 while jointly discovering five potential phenotypes of interest. The technique and interpretation allow for identifying clinically relevant phenotypes that may be used both for outcomes modeling as well as potentially evaluating individualized treatment effects.

Background/aims There has been growing interest in better understanding the potential of observational research methods in medical product evaluation and regulatory decision-making. Previously, we used linked claims and electronic health record data to emulate two ongoing randomized controlled trials, characterizing the populations and results of each randomized controlled trial prior to publication of its results. Here, our objective was to compare the populations and results from the emulated trials with those of the now-published randomized controlled trials. Methods This study compared participants’ demographic and clinical characteristics and study results between the emulated trials, which used structured data from OptumLabs Data Warehouse, and the published PRONOUNCE and GRADE trials. First, we examined the feasibility of implementing the baseline participant characteristics included in the published PRONOUNCE and GRADE trials’ using real-world data and classified each variable as ascertainable, partially ascertainable, or not ascertainable. Second, we compared the emulated trials and published randomized controlled trials for baseline patient characteristics (concordance determined using standardized mean differences <0.20) and results of the primary and secondary endpoints (concordance determined by direction of effect estimates and statistical significance). Results The PRONOUNCE trial enrolled 544 participants, and the emulated trial included 2226 propensity score-matched participants. In the PRONOUNCE trial publication, one of the 32 baseline participant characteristics was listed as an exclusion criterion on ClinicalTrials.gov but was ultimately not used. Among the remaining 31 characteristics, 9 (29.0%) were ascertainable, 11 (35.5%) were partially ascertainable, and 10 (32.2%) were not ascertainable using structured data from OptumLabs. For one additional variable, the PRONOUNCE trial did not provide sufficient detail to allow its ascertainment. Of the nine variables that were ascertainable, values in the emulated trial and published randomized controlled trial were discordant for 6 (66.7%). The primary endpoint of time from randomization to the first major adverse cardiovascular event and secondary endpoints of nonfatal myocardial infarction and stroke were concordant between the emulated trial and published randomized controlled trial. The GRADE trial enrolled 5047 participants, and the emulated trial included 7540 participants. In the GRADE trial publication, 8 of 34 (23.5%) baseline participant characteristics were ascertainable, 14 (41.2%) were partially ascertainable, and 11 (32.4%) were not ascertainable using structured data from OptumLabs. For one variable, the GRADE trial did not provide sufficient detail to allow for ascertainment. Of the eight variables that were ascertainable, values in the emulated trial and published randomized controlled trial were discordant for 4 (50.0%). The primary endpoint of time to hemoglobin A1c ≥7.0% was mostly concordant between the emulated trial and the published randomized controlled trial. Conclusion Despite challenges, observational methods and real-world data can be leveraged in certain important situations for a more timely evaluation of drug effectiveness and safety in more diverse and representative patient populations.

Abstract The objective of this study is to describe application of the Observational Medical Outcomes Partnership (OMOP) common data model (CDM) to support medical device real-world evaluation in a National Evaluation System for health Technology Coordinating Center (NESTcc) Test-Case involving 2 healthcare systems, Mercy Health and Mayo Clinic. CDM implementation was coordinated across 2 healthcare systems with multiple hospitals to aggregate both medical device data from supply chain databases and patient outcomes and covariates from electronic health record data. Several data quality assurance (QA) analyses were implemented on the OMOP CDM to validate the data extraction, transformation, and load (ETL) process. OMOP CDM-based data of relevant patient encounters were successfully established to support studies for FDA regulatory submissions. QA analyses verified that the data transformation was robust between data sources and OMOP CDM. Our efforts provided useful insights in real-world data integration using OMOP CDM for medical device evaluation coordinated across multiple healthcare systems.

Abstract Objective To emulate the GRADE (Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study) trial using real world data before its publication. GRADE directly compared second line glucose lowering drugs for their ability to lower glycated hemoglobin A 1c (HbA 1c ). Design Observational study. Setting OptumLabs® Data Warehouse (OLDW), a nationwide claims database in the US, 25 January 2010 to 30 June 2019. Participants Adults with type 2 diabetes and HbA 1c 6.8-8.5% while using metformin monotherapy, identified according to the GRADE trial specifications, who also used glimepiride, liraglutide, sitagliptin, or insulin glargine. Main outcome measures The primary outcome was time to HbA 1c ≥7.0%. Secondary outcomes were time to HbA 1c >7.5%, incident microvascular complications, incident macrovascular complications, adverse events, all cause hospital admissions, and all cause mortality. Propensity scores were estimated using the gradient boosting machine method, and inverse propensity score weighting was used to emulate randomization of the treatment groups, which were then compared using Cox proportional hazards regression. Results 8252 people were identified (19.7% of adults starting the study drugs in OLDW) who met eligibility criteria for the GRADE trial (glimepiride arm=4318, liraglutide arm=690, sitagliptin arm=2993, glargine arm=251). The glargine arm was excluded from analyses owing to small sample size. Median times to HbA 1c ≥7.0% were 442 days (95% confidence interval 394 to 480 days) for glimepiride, 764 (741 to not calculable) days for liraglutide, and 427 (380 to 483) days for sitagliptin. Liraglutide was associated with lower risk of reaching HbA 1c ≥7.0% compared with glimepiride (hazard ratio 0.57, 95% confidence interval 0.43 to 0.75) and sitagliptin (0.55, 0.41 to 0.73). Results were consistent for the secondary outcome of time to HbA 1c >7.5%. No significant differences were observed among treatment groups for the remaining secondary outcomes. Conclusions In this emulation of the GRADE trial, liraglutide was statistically significantly more effective at maintaining glycemic control than glimepiride or sitagliptin when added to metformin monotherapy. Generating timely evidence on medical treatments using real world data as a complement to prospective trials is of value.

Introduction Cognitive behavioural therapy for insomnia (CBT-I) is effective at treating chronic insomnia, yet in-person CBT-I can often be challenging to access. Prior studies have used technology to bridge barriers but have been unable to extensively assess the impact of the digital therapeutic on real-world patient experience and multidimensional outcomes. Among patients with insomnia, our aim is to determine the impact of a prescription digital therapeutic (PDT) (PEAR-003b, FDA-authorised as Somryst; herein called PDT) that provides mobile-delivered CBT-I on patient-reported outcomes (PROs) and healthcare utilisation. Methods and analysis We are conducting a pragmatically designed, prospective, multicentre randomised controlled trial that leverages Hugo, a unique patient-centred health data-aggregating platform for data collection and patient follow-up from Hugo Health. A total of 100 participants with insomnia from two health centres will be enrolled onto the Hugo Health platform, provided with a linked Fitbit (Inspire 2) to track activity and then randomised 1:1 to receive (or not) the PDT for mobile-delivered CBT-I (Somryst). The primary outcome is a change in the insomnia severity index score from baseline to 9-week postrandomisation. Secondary outcomes include healthcare utilisation, health utility scores and clinical outcomes; change in sleep outcomes as measured with sleep diaries and a change in individual PROs including depressive symptoms, daytime sleepiness, health status, stress and anxiety. For those allocated to the PDT, we will also assess engagement with the PDT. Ethics and dissemination The Institutional Review Boards at Yale University and the Mayo Clinic have approved the trial protocol. This trial will provide important data to patients, clinicians and policymakers about the impact of the PDT device delivering CBT-I on PROs, clinical outcomes and healthcare utilisation. Findings will be disseminated to participants, presented at professional meetings and published in peer-reviewed journals. Trial registration number NCT04909229 .

Introduction Opioid analgesics are often used to treat moderate-to-severe acute non-cancer pain; however, there is little high-quality evidence to guide clinician prescribing. An essential element to developing evidence-based guidelines is a better understanding of pain management and pain control among individuals experiencing acute pain for various common diagnoses. Methods and analysis This multicentre prospective observational study will recruit 1550 opioid-naïve participants with acute pain seen in diverse clinical settings including primary/urgent care, emergency departments and dental clinics. Participants will be followed for 6 months with the aid of a patient-centred health data aggregating platform that consolidates data from study questionnaires, electronic health record data on healthcare services received, prescription fill data from pharmacies, and activity and sleep data from a Fitbit activity tracker. Participants will be enrolled to represent diverse races and ethnicities and pain conditions, as well as geographical diversity. Data analysis will focus on assessing patients’ patterns of pain and opioid analgesic use, along with other pain treatments; associations between patient and condition characteristics and patient-centred outcomes including resolution of pain, satisfaction with care and long-term use of opioid analgesics; and descriptive analyses of patient management of leftover opioids. Ethics and dissemination This study has received approval from IRBs at each site. Results will be made available to participants, funders, the research community and the public. Trial registration number NCT04509115 .

Background: While lack of insurance is known to be associated with worse outcomes after myocardial infarction (MI), it is unknown whether health insurance status is associated with rates of non-elective hospitalizations after MI. Methods: Using data on 3571 U.S. MI patients enrolled between April 2005 to December 2008 in the 24-center, prospective TRIUMPH registry, we examined the association between being insured (reference), underinsured, and uninsured on rates of non-elective readmissions (all-cause) in the 1 st year following MI. Insurance status was obtained from medical records, and underinsurance was defined as those patients with insurance but with financial concerns about accessing care from patient interviews. Multivariable modified Poisson regression models were used to adjust for site, demographics, MI severity, risk factors, socio-economic, and psychological factors. Results: A total of 2269 (63.5%) patients were insured; 650 (18.2%) were underinsured; and 652 (18.3%) were uninsured. Emergency readmissions were highest for uninsured patients (25.0%), followed by the underinsured (21.8%), and lowest in insured patients (19.5%) (P<.001). After multivariable adjustment, uninsured patients had significantly higher rates of emergency readmission (adjusted RR, 1.52 [95% CI: 1.22-1.90] while underinsured patients did not (adjusted RR, 0.99 [95% CI: 0.81-1.21]) (Figure). Conclusions: Uninsured patients had a significantly higher adjusted risk of non-elective readmissions after MI, while underinsured patients did not. Future studies are needed to determine if providing even modest insurance coverage to the uninsured can minimize readmission rates.