Early Enrollees Research Articles

Medical care services interplay between individual and Medicaid managed care markets in expansion versus non‐expansion states

AbstractWe study enrollment, medical service utilization, and incurred expenses of individual comprehensive and Medicaid managed care plans in states with or without Medicaid expansion adopted at the Affordable Care Act (ACA) early stage 2014–2016. To make healthcare services more accessible, 27 states expanded Medicaid eligibility to cover nearly‐poor non‐elderly adults who have had incomes between 100% and 138% of federal poverty level in 2014. In non‐expansion states, early enrollees in this income cohort had to choose individual market plans rather than Medicaid. Early enrollees' enrollment choices and their health status have had a great impact on the individual market premiums and Medicaid spending. We examined health insurers' annual regulatory filings with the National Association of Insurance Commissioners for 2013–2016 and found that: First, individual comprehensive insurance enrollment grew much faster in states not expanding Medicaid eligibility. Second, after incorporating early enrollees, per member per month (PMPM) medical service utilization and expenses of individual comprehensive insurance grew much faster in non‐expansion states. Third, among major types of medical utilization and expense measures, PMPM hospital inpatient days and PMPM prescription drug expenses increased substantially since 2014. Finally, Medicaid beneficiaries generated more PMPM medical utilization and expenses in expansion states.

Characteristics, treatment, and outcomes of early vs. late enrollees of the STRONG-HF trial

The STRONG-HF trial showed that high-intensity care (HIC) consisting of rapid up-titration of guideline-directed medical therapy (GDMT) and close follow-up reduced all-cause death or heart failure (HF) readmission at 180 days compared to usual care (UC). We hypothesized that significant differences in patient characteristics, management, and outcomes over the enrolment period may exist. Two groups of the 1,078 patients enrolled in STRONG-HF were created according to the order of enrolment within center. The early group consisted of the first 10 patients enrolled at each center (N = 342) and the late group consisted of the following patients (N = 736). Late enrollees were younger, had more frequently reduced ejection fraction, slightly lower NT-proBNP and creatinine levels compared with early enrollees. The primary outcome occurred less frequently in early compared to late enrollees (15% vs. 21%, aHR 0.65, 95% CI 0.42-0.99, P = .044). No treatment-by-enrolment interaction was seen in respect to the average percentage of optimal dose of GDMT after randomization, which was consistently higher in early and late patients randomized to HIC compared to UC. The higher use of renin-angiotensin-inhibitors in the HIC arm was more pronounced in the late enrollees both after randomization (interaction-P = .013) and at 90 days (interaction-P < .001). No interaction was observed for safety events. Patients randomized late to UC displayed a trend toward more severe outcomes (26% vs. 16%, P = .10), but the efficacy of HIC showed no interaction with the enrolment group (aHR 0.77, 95% CI 0.35-1.67 in early and 0.58, 95% CI 0.40-0.83 in late enrollees, adjusted interaction-P = .51) with similar outcomes in the HIC arm in late and early enrollees (16% vs. 13%, P = .73). Late enrollees have different clinical characteristics and higher event rates compared to early enrollees. GDMT implementation in the HIC arm robustly achieved similar doses with consistent efficacy in early and late enrollees, mitigating the higher risk of adverse outcome in late enrollees. ClinicalTrials.gov Identifier: NCT03412201.

Social Information and Educational Investment—Nudging Remedial Math Course Participation

Abstract Using field experiments, I investigate if provision of (social) information can increase incoming university students' attendance in a voluntary remedial math course. In Intervention 1, treated students receive an invitation letter with or without information about a past sign-up rate for the course. In Intervention 2, among those who signed up for the course, treated students receive reminder letters including or excluding information on how helpful the course had been evaluated by previous students. On average, no treatment increases participation in the course, but further analyses reveal that the effects in Intervention 1 are heterogeneous along two dimensions: First, suggesting salience as a mechanism, both types of information raise attendance among students who enroll late in their study program, which in turn increases their first-year performance and closes the achievement gap to early enrollees. Second, the effect of the letter with information about the past sign-up rate depends on the predicted ex-ante sign-up probability. Students whose probability falls just short of the past sign-up rate increase sign-up and participation, while the opposite is true for students whose sign-up probability exceeds the social information. Along this dimension, however, the changes in attendance do not carry over to academic achievements.

A Feasibility and Safety Study of a Novel CD19-Directed Synthetic T-Cell Receptor and Antigen Receptor (STAR) T-Cell Therapy for Refractory and Relapsed (R/R) B Cell Acute Lymphoblastic Leukemia (B-ALL)

Introduction Chimeric antigen receptor (CAR) T -cell therapy has demonstrated high response rates among patients with B cell malignancies yet remission durability and safety could be improved. We have developed a novel double-chain chimeric receptor Synthetic T Cell Receptor and Antigen Receptor (STAR) consisting of 2 protein modules each containing an antibody light or heavy chain variable region, the T Cell Receptor (TCR) a or b chain constant region fused to the OX-40 co-stimulatory domain, with the 2 modules linked by a self-cleaving Furin-p2A sequence that allows the modules to be proteolytically separated and reconstituted (Fig. 1A). Here, we report pre-clinical and first-in-human phase I trial results of CD19 STAR-T cell therapy for CD19+ R/R B-ALL. Methods Peripheral blood (PB) mononuclear cells were obtained from healthy donors and patients for the pre-clinical and clinical studies, respectively. T-cells were transduced with the STAR lentiviral vector. A leukemia xenograft mouse model was used to assess the STAR T-cell antitumor function. For the clinical trial, from Dec. 2019 to Jun. 2020, 18 CD19+ R/R B-ALL patients (M/F 10:8) with a median age of 22.5 years (range: 6-68) were enrolled (NCT03953599). Patients received a conditioning regimen of IV fludarabine (25mg/m2/d) and cyclophosphamide (250mg/m2/d) for 3 days followed by a single STAR T-cell infusion. Once patients achieved complete remission (CR), they were given the option to proceed to consolidation allogeneic hematopoietic stem cell transplantation (allo-HSCT) or not. Results In preclinical studies, we found CD19 STAR T-cells to be superior to conventional CAR (BBz CAR) measured by the following parameters: 1) faster/stronger T-cell activation within 3 hours (76.67±2.621% vs 46.4±9.318%; p=0.0253); 2) higher cytokine production (4100.92±174.4 pg/ml vs 2556.78±563.39 pg/ml; p&amp;lt;0.05, Fig.1B) ;3) superior target killing ability (effector: target [E: T] ratio=1:1, 50.39±1.74% vs 60.85±1.52%, p&amp;lt;0.05. E:T ratio&amp;gt;1:1, p&amp;lt;0.01, Fig.1B); 4) robust elimination of B-ALL in a xenograft mouse model, where a lower E:T ratio was sufficient to eliminate an equal number of tumor cells (E:T ratio =1:1, STAR vs. BBz-CAR, p&amp;lt;0.01, Fig.1C). In the phase I trial, the median observation time was 69 (20-180) days. The median pre-treatment bone marrow (BM) blast level was 7.0% (0.1%-86.6%). All 18 patients received a single infusion of STAR T-cells at a median dose of 1×106/kg (5×105/kg-2.5×106/kg): low dose (5×105/kg) (n=3), medium dose (1×106/kg) (n=8) and high-dose (2-2.5×106/kg) (n=7). Three early enrollees subsequently received a second consolidation infusion of STAR T-cells at 1×106/kg (n=2) and 2×106/kg (n=1). The median STAR T-cell production time was 9 (7-13) days with a transduction efficacy of 57.4% (41.0%-78.2%). Two weeks post STAR T-cell infusion, 18/18 (100%) patients achieved CR with a negative minimal residual disease (MRD) status. After a median of 57 (43-66) days following STAR T-cell therapy, 8/18 patients made a choice to pursue consolidation allo-HSCT and all have remained in CR after a median follow-up of 110 (75-180) days. Of the 10 patients who did not undergo allo-HSCT, 1 relapsed on day 58 and died from relapse on day 63. This patient had a pre-CAR T-cell BM blast level of 86.6% with central nervous system leukemia. Another patient became MRD-positive with 0.09% blasts on day 30 per flow cytometry (FCM). The other 8 patients have remained in CR. Despite the achievement of a high CR rate, cytokine release syndrome (CRS) occurred only in 10/18 (55.6%) patients with 8 Grade I, and 2 Grade II CRS. Two patients developed Grade III neurotoxicity. After STAR T-cell infusion, CD19 STAR T-cells in PB were followed by qPCR and FCM. We saw high in vivo proliferation and persistence regardless of the infusion dose. The median peak level was reached on day 8.5 (day 4-10) with 4.9×104 (0.104-175×104) copy number/ug PB genomic DNA detectable at 6 months. Conclusion This study demonstrates the superiority of STAR T-cells compared to conventional CAR T-cells in terms of signaling capacity, cytokine production capability and anti-tumor potency in an animal model. The Phase I first-in-human study demonstrated technical feasibility, clinical safety and efficacy of STAR-T in treating CD19+ R/R B-ALL. A high CR could be achieved on day 14 with low toxicity. Longer-term observation of these patients and studies of larger patient cohorts are warranted. Disclosures No relevant conflicts of interest to declare.

Retention in care among clinically stable antiretroviral therapy patients following a six-monthly clinical consultation schedule: findings from a cohort study in rural Malawi.

IntroductionLonger intervals between clinic consultations for clinically stable antiretroviral therapy (ART) patients may improve retention in care and reduce facility workload. We assessed long‐term retention among clinically stable ART patients attending six‐monthly clinical consultations (SMCC) with three‐monthly fast‐track drug refills, and estimated the number of consultations “saved” by this model of ART delivery in rural Malawi.MethodsStable patients (aged ≥18 years, on first‐line ART ≥12 months, CD4 count ≥300 cells/mL 3, without opportunistic infections, not pregnant/breastfeeding) were eligible for SMCC, with three‐monthly drug refills from community health workers. Early enrollees were those starting SMCC within six months of eligibility, while late enrollees started at least 6 months after first eligibility. Kaplan–Meier methods were used to calculate cumulative probabilities of retention, stratified by timing of their enrolment and from first six‐monthly clinical consultation. Cox regression was used to measure attrition hazards from the first six‐monthly clinical consultation and risk factors for attrition, accounting for the time‐varying nature of their eligibility and enrolment in this model of care.ResultsFrom 2008 to 2015, 22,633 clinically stable patients from 11 facilities were eligible for SMCC for at least three months, contributing 74,264 person‐years of observation, and 18,363 persons (81%) initiated this model of care. The median time from eligibility to enrolment was 12 months and the median cumulative time on SMCC was 14.5 months. Five years after first SMCC eligibility, cumulative probabilities of retention were 85.5% (95% CI: 84.0% to 86.9%) among early enrollees and 93% (95% CI: 92.8% to 94.0%) among late enrollees. The cumulative probability of retention from first SMCC was 97.0% (95% CI: 96.7% to 97.3%) and 86% (95% CI: 85% to 87%) at one and five years respectively. Among eligible patients initiating SMCC, the adjusted hazards of attrition were 2.4 (95% CI: 2.0 to 2.8) times higher during periods of SMCC discontinuation compared to periods on SMCC. Male sex, younger age, more recent SMCC eligibility and WHO Stage 3/4 conditions in the past year were also independently associated with attrition from SMCC. Approximately 26,000 consultations were “saved” during 2014.ConclusionAfter five years, retention among patients attending SMCC was high, especially among women and older patients, and its scale‐up could facilitate universal access to ART.

SA12. Baseline Demographics and Clinical Characteristics From a Prospective, Randomized, Open-Label Study of Paliperidone Palmitate Long-Acting Injection in Subjects With Recent-Onset Schizophrenia or Schizophreniform Disorder

Abstract Background: The early, effective treatment of schizophrenia may slow disease progression and improve overall patient outcomes. The DREaM study (NCT02431702) is a doubly randomized, matched-control, open-label, flexible-dose study designed to compare the efficacy of treatment with paliperidone palmitate (PP) once monthly or once-every-3-months long-acting injection (LAI) versus treatment with oral antipsychotics in subjects with recent-onset schizophrenia or schizophreniform disorder. This abstract reports the baseline demographics and clinical characteristics of early enrollees to the study. Methods: DREaM includes 3 treatment phases. Part 1 consists of subjects who meet the inclusion/exclusion criteria and are entered into a 2-month, run-in phase to establish the tolerability of oral paliperidone prior to the next phase of study. The primary objectives of Part 2 and 3 are to examine whether PP LAI can slow disease progression and modify the course of schizophrenia when compared to oral antipsychotics. Baseline demographics and clinical characteristics have been evaluated using descriptive statistics. Results: As of September 2016, the study had enrolled 59 subjects with a mean age (± SD) of 22.5 ± 3.88 years (range, 18–35). The population is predominantly male (91.5%, 54/59); 51.7% of subjects are white and 37.9% are black. The population has a diagnosis of either schizophrenia (83.1%) or schizophreniform disorder (16.9%). Mean ± SD number of psychiatric hospitalizations within the prior 24 months is 1.2 ± 0.99, ranging from 0 to 4 hospitalizations across the population. Histories of antipsychotic exposure, categorized as 12 months of use, are 60.3%, 13.8%, and 25.9% of the population, respectively. Cumulative substance history, categorized as 0 years, ≤2 years, and >2 years, is 42.5%, 15.0%, and 42.5%, respectively. Mean ± SD MATRICS Consensus Cognitive Battery score is 27.8 ± 14.99; 40.4% of subjects had a score of <25. The screening mean ± SD Personal and Social Performance scale score is 47.7 ± 15.15 (range, 5–80); the majority of these subjects had a score of 31–70 (86.4%). Conclusion: This study population’s baseline characteristics and clinical data are representative of recently diagnosed patients with schizophrenia and will be used to match subjects in anticipation of randomization for Parts 2 and 3 of the study.

Early Enrollees and Peer Age Effect: First Evidence from INVALSI Data

This paper estimates peer age effect on educational outcomes of Italian pupils attending primary school by exploiting changes in enrollment rules over the last few years. The empirical procedure allows to understand if there is selection in classroom formation, arguing that in the absence of pupils sorting by early age at school entry, it is possible to estimate the “true” peer age effect. Results suggest that the proportion of youngest students “in advance” in the classroom has a positive impact on child’s achievements measured by Normalized and Rasch test scores both in Reading and Mathematics. Additional empirical evidence shows that the effect on individual scores of sharing the classroom with pupils “in advance” differs by students’ age group and it is higher for youngest pupils. Findings do not seem to be invalidated by “cheating” phenomena that may occur during the implementation and evaluation of tests.

Safety of Early Enrollment into Outpatient Cardiac Rehabilitation After Open Heart Surgery

The safety of early enrollment (<2 weeks after hospital discharge) into cardiac rehabilitation (CR) after recent coronary artery bypass graft (CABG) surgery or heart valve surgery (HVS) has not previously been assessed and has important policy implications. Consequently, we performed a detailed review of all clinical adverse events within 6 months of hospital discharge. We compared early and late attendees for patients undergoing CABG surgery or HVS and included patients with myocardial infarction (MI) as an additional control group. We analyzed 112 patients undergoing CABG surgery, 69 patients undergoing HVS, and 59 patients with MI. Median time (interquartile range) from hospital discharge to CR enrollment was 10.5 (8 to 15), 12 (8.5 to 21), and 9 days (7 to 14), respectively. There was no difference in major event rates between early and late enrollees (17% vs 17%, respectively, log-rank p = 0.98) or by diagnosis (15%, 16%, and 22% for CABG surgery, HVS, and MI, respectively; log-rank p = 0.50). Sternal instability and wound infection rates were similar. CR-related adverse events trended toward increased event rates in surgical and early enrollees, but of 44 events, only 3 were exercise related, none resulted in permanent harm, and 41 (93%) were managed in CR without need for emergency services. In conclusion, it appears that a policy of encouraging early enrollment into CR in patients with a recent open heart surgery seems unlikely to harm patients when careful individualized assessment and exercise prescription take place within the bounds of an established CR program.

Implementation of Massachusetts Health Insurance Reform with Vulnerable Populations in a Safety-Net Setting

This qualitative study examines the experience of racial and ethnic minorities receiving behavioral health care in a safety net setting during the early process of health insurance reform in Massachusetts. Three rounds of interviews were conducted between August 2007 and May 2009, collecting information from patients (n=65) on the experience of health reform and delivery of mental health care. Four categories of enrollees transitioning into health reform emerged over the course of the study that grouped into a typology of experiences with reform: early enrollees, middle enrollees, late enrollees, and multiple switchers. With support, a majority of the sample transitioned smoothly to the new health insurance mechanisms. However, some experienced administrative confusion and disruption in mental health care during the transition. Administrative policies providing special accommodations for individuals with mental health disorders and other vulnerable populations may be important to consider during the transition to health insurance reform.

Surgical Removal vs Observation for Subfoveal Choroidal Neovascularization,Either Associated With the Ocular Histoplasmosis Syndrome or Idiopathic

To report findings regarding health-related quality-of-life outcomes by treatment arm, both overall and within subgroups defined by selected baseline characteristics, among patients who participated in the Submacular Surgery Trials (SST) randomized trial of observation vs surgical removal of subfoveal choroidal neovascular lesions that were either idiopathic or associated with ocular histoplasmosis (SST Group H Trial). Eligible patients were 18 years or older and had subfoveal choroidal neovascularization (including a classic component on fluorescein angiography) and visual acuity of 20/50 to 20/800 inclusive in the eye randomly assigned to surgery or observation. Trained interviewers, who were masked to treatment assignment, administered the National Eye Institute Visual Function Questionnaire (NEI-VFQ), the 36-Item Short-Form Health Survey (SF-36), and the Hospital Anxiety and Depression Scale (HADS) by telephone before enrollment and at 6, 12, and 24 months after enrollment; early enrollees also had interviews at 36 and 48 months. Baseline clinical examinations provided data regarding visual acuity, other aspects of vision, and presence of unilateral or bilateral choroidal neovascularization. Of 225 patients interviewed at baseline and enrolled, 201, 190, and 161 patients (respectively, 89%, 85%, and 88% of those eligible to be interviewed) were interviewed 12, 24, and 36 months later. The NEI-VFQ scores in both treatment arms improved from baseline (median score, 75) to the 24-month interview. Patients in the surgery arm had 4-point larger improvements, on average, than patients in the observation arm (95% confidence interval, 1-8 points). The largest differences between treatment arms for mean 24-month improvements from baseline were in the role difficulties subscale (9 points) and dependency subscale (8 points), with larger mean improvements in the surgery arm. Scores on the SF-36 worsened by approximately 1 point on the physical component summary and improved by 2 points or more on the mental component summary in both treatment arms by 24 months in comparison to baseline. The percentage of HADS-defined "definite cases" of both anxiety and depression declined from baseline in each treatment arm. Vision-targeted quality of life improved more after submacular surgery than with observation, supporting a possible small overall benefit of surgery suggested by the ophthalmic outcomes reported elsewhere. Ophthalmologists and patients similar to those who participated in the SST Group H Trial should be aware of the effects of submacular surgery on specific aspects of vision-targeted quality of life as well as on ophthalmic outcomes when considering this treatment approach.

Randomized clinical trials: Alternatives to conventional randomization

The randomized allocation format remains an exceedingly powerful tool for clinical research. Because humans are the subjects in clinical research, this area of scientific study must operate within the limits dictated by such basic principles as individual autonomy, justice, and beneficence. As randomized studies have become more common in clinical research, it has become apparent that there is often need for modification of the basic randomized format or for alternatives. The most widespread modification is the use of sequential analyses to monitor the progress of a trial and ensure early identification of either unanticipated adverse effects or more pronounced differences than expected. Although this modification does not affect the basic randomized allocation format, it does provide a protection that is lacking in the conventional trial and should be utilized whenever feasible. Modifications that do affect the basic structure of the randomized trial include adaptive allocation and pre-randomization. The former is attractive and useful but limited to studies in which results from early enrollees are known before late enrollees are allocated. The greater the linkage between preceding subject results and subsequent assignments, the greater is the protection afforded by such a format. Pre-randomization, more universally applicable than adaptive allocation, suffers from pronounced cross-over potential and has been criticized on ethical grounds, a combination of weaknesses that raises questions of whether pre-randomization truly offers advantages to conventional randomized formats. True alternatives to the randomized format include the self-controlled study and the historical control design. Both possess significant ethical advantages over the simple randomized study. Unfortunately, both are at some methodological disadvantage when the same comparison is made. The self-controlled study is limited to the study of conditions sufficiently stable or recurrent that they permit two or more treatment courses in a single patient. In emergency medicine and critical care, this description fits only a small proportion of the illness spectrum. This design is underutilized in clinical research focused on less severe problems of the type seen in ambulatory and primary-care settings. Such problems can be suitable topics for research by emergency medicine specialists. Historical control studies are eminently applicable in the emergency and critical-care setting. Indeed, in such clinical venues, many of the major weaknesses of the historical control design may be mitigated because the delivery of care is more standardized and there may be less difficulty in determining the comparability of subject populations. The historical control design must be used carefully and interpreted cautiously, but it can validly be applied to the study of emergency medical problems. In all cases, the best strategy for clinical research is a strategy that has been chosen after consideration of the unique requirements and demands of the research situation.