Analysis of survival outcomes using likelihood ratio test in trials incorporating patient's treatment choice.

Methods for designing and analyzing multiple arms survival trials that incorporate patient's treatment choice are needed. In these trials, patients are randomized into two groups, random and choice. Participants in the choice group choose their treatment, which is not a current standard practice in randomized clinical trials. In this paper, we propose a new method based on the likelihood function to design and analyze these trials with time to event outcomes in the presence of non-informative right censoring. We use simulations to evaluate the methods for Weibull outcomes, complete and censored. Finally, we provide an illustration for designing a study in which we discuss some design considerations and demonstrate the methods.

Impact of the Communities That HEAL Intervention on Buprenorphine-Waivered Practitioners and Buprenorphine Prescribing: A Prespecified Secondary Analysis of the HCS Randomized Clinical Trial.

Importance: Buprenorphine significantly reduces opioid-related overdose mortality. From 2002 to 2022, the Drug Addiction Treatment Act of 2000 (DATA 2000) required qualified practitioners to receive a waiver from the Drug Enforcement Agency to prescribe buprenorphine for treatment of opioid use disorder. During this period, waiver uptake among practitioners was modest; subsequent changes need to be examined. Objective: To determine whether the Communities That HEAL (CTH) intervention increased the rate of practitioners with DATA 2000 waivers and buprenorphine prescribing. Design, Setting, and Participants: This prespecified secondary analysis of the HEALing Communities Study, a multisite, 2-arm, parallel, community-level, cluster randomized, open, wait-list-controlled comparison clinical trial was designed to assess the effectiveness of the CTH intervention and was conducted between January 1, 2020, to December 31, 2023, in 67 communities in Kentucky, Massachusetts, New York, and Ohio, accounting for approximately 8.2 million adults. The participants in this trial were communities consisting of counties (n = 48) and municipalities (n = 19). Trial arm randomization was conducted using a covariate constrained randomization procedure stratified by state. Each state was balanced by community characteristics including urban/rural classification, fatal opioid overdose rate, and community population. Thirty-four communities were randomized to the intervention and 33 to wait-list control arms. Data analysis was conducted between March 20 and September 29, 2023, with a focus on the comparison period from July 1, 2021, to June 30, 2022. Intervention: Waiver trainings and other educational trainings were offered or supported by the HEALing Communities Study research sites in each state to help build practitioner capacity. Main Outcomes and Measures: The rate of practitioners with a DATA 2000 waiver (overall, and stratified by 30-, 100-, and 275-patient limits) per 100 000 adult residents aged 18 years or older during July 1, 2021, to June 30, 2022, were compared between the intervention and wait-list control communities. The rate of buprenorphine prescribing among those waivered practitioners was also compared between the intervention and wait-list control communities. Intention-to-treat and per-protocol analyses were performed. Results: A total of 8 166 963 individuals aged 18 years or older were residents of the 67 communities studied. There was no evidence of an effect of the CTH intervention on the adjusted rate of practitioners with a DATA 2000 waiver (adjusted relative rate [ARR], 1.04; 95% CI, 0.94-1.14) or the adjusted rate of practitioners with a DATA 2000 waiver who actively prescribed buprenorphine (ARR, 0.97; 95% CI, 0.86-1.10). Conclusions and Relevance: In this randomized clinical trial, the CTH intervention was not associated with increases in the rate of practitioners with a DATA 2000 waiver or buprenorphine prescribing among those waivered practitioners. Supporting practitioners to prescribe buprenorphine remains a critical yet challenging step in the continuum of care to treat opioid use disorder. Trial Registration: ClinicalTrials.gov Identifier: NCT04111939.

Late permissive hypercapnia and respiratory stability among very preterm infants: a pilot randomised trial.

OBJECTIVE: Determine if targeting higher transcutaneous carbon dioxide improves respiratory stability among very preterm infants on ventilatory support. DESIGN: Single-centre pilot randomised clinical trial. SETTING: The University of Alabama at Birmingham. PATIENTS: Very preterm infants on ventilatory support after postnatal day 7. INTERVENTIONS: Infants were randomised to two different transcutaneous carbon dioxide levels targeting 5 mm Hg (0.67 kPa) changes with four sessions each lasting 24 hours for 96 hours: baseline-increase-baseline-increase or baseline-decrease-baseline-decrease. MAIN OUTCOME MEASURES: We collected cardiorespiratory data evaluating episodes of intermittent hypoxaemia (oxygen saturations (SpO2)<85% for ≥10 s), bradycardia (<100 bpm for ≥10 s), and cerebral and abdominal hypoxaemia on near-infrared spectroscopy. RESULTS: We enrolled 25 infants with a gestational age of 24 w 6 d±11 d (mean±SD) and birth weight 645±142 g on postnatal day 14±3. Continuous transcutaneous carbon dioxide values (56.8±6.9 in the higher group vs 54.5±7.8 in the lower group; p=0.36) did not differ significantly between groups during the intervention days. There were no differences in intermittent hypoxaemia (126±64 vs 105±61 per 24 hours; p=0.30) or bradycardia (11±16 vs 15±23 per hour; p=0.89) episodes between groups. The proportion of time with SpO2<85%, SpO2<80%, cerebral hypoxaemia or abdominal hypoxaemia did not differ (all p>0.05). There was moderate negative correlation between mean transcutaneous carbon dioxide and bradycardia episodes (r=-0.56; p<0.001). CONCLUSION: Targeting 5 mm Hg (0.67 kPa) changes in transcutaneous carbon dioxide did not improve respiratory stability among very preterm infants on ventilatory support but the intended carbon dioxide separation was difficult to achieve and maintain. TRIAL REGISTRATION NUMBER: NCT03333161.

Childhood-Onset Lupus Nephritis in the Childhood Arthritis and Rheumatology Research Alliance Registry: Short-Term Kidney Status and Variation in Care.

OBJECTIVE: The goal was to characterize short-term kidney status and describe variation in early care utilization in a multicenter cohort of patients with childhood-onset systemic lupus erythematosus (cSLE) and nephritis. METHODS: We analyzed previously collected prospective data from North American patients with cSLE with kidney biopsy-proven nephritis enrolled in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry from March 2017 through December 2019. We determined the proportion of patients with abnormal kidney status at the most recent registry visit and applied generalized linear mixed models to identify associated factors. We also calculated frequency of medication use, both during induction and ever recorded. RESULTS: We identified 222 patients with kidney biopsy-proven nephritis, with 64% class III/IV nephritis on initial biopsy. At the most recent registry visit at median (interquartile range) of 17 (8-29) months from initial kidney biopsy, 58 of 106 patients (55%) with available data had abnormal kidney status. This finding was associated with male sex (odds ratio [OR] 3.88, 95% confidence interval [95% CI] 1.21-12.46) and age at cSLE diagnosis (OR 1.23, 95% CI 1.01-1.49). Patients with class IV nephritis were more likely than class III to receive cyclophosphamide and rituximab during induction. There was substantial variation in mycophenolate, cyclophosphamide, and rituximab ever use patterns across rheumatology centers. CONCLUSION: In this cohort with predominately class III/IV nephritis, male sex and older age at cSLE diagnosis were associated with abnormal short-term kidney status. We also observed substantial variation in contemporary medication use for pediatric lupus nephritis between pediatric rheumatology centers. Additional studies are needed to better understand the impact of this variation on long-term kidney outcomes.

Patient-Reported Outcomes Among Transition-Age Young Adults With Juvenile Idiopathic Arthritis in the Childhood Arthritis and Rheumatology Research Alliance Registry.

OBJECTIVE: To evaluate patient-reported care utilization and outcomes among young adults with juvenile idiopathic arthritis (JIA), including factors associated with complete transfer to adult rheumatology. METHODS: We included young adults with JIA enrolled in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry from 2015 to 2019 with age ≥ 18 years at their last clinical site visit. We used data from the CARRA Registry Long-term Follow-up program, which follows inactive CARRA Registry patients and collects patient-reported information through phone surveys. We compared the characteristics of respondents with complete and incomplete transfer to adult rheumatology care at their first Long-term Follow-up phone survey. RESULTS: We identified 540 young adults with JIA; 187 (35%) responded to the Long-term Follow-up phone survey. The 54% of respondents with complete transfer to adult rheumatology were slightly older and reported more self-assessed disease activity, morning stiffness, and pain compared to those with incomplete transfer. Biologic use was high at both timepoints and did not differ by transfer status. Patients who completed the transfer were more likely to have private insurance and be actively pursuing postsecondary education compared to those with an incomplete transfer. Across the cohort, 65% reported problems with pain or discomfort and 45% with anxiety or depression. CONCLUSION: Young adult respondents with JIA in the CARRA Registry commonly report persistent medication use, but still report more problems with pain as compared to population norms. Additional work is needed to understand how best to address comorbid pain around the period of transition to adult care.

Predicting High-Flow Nasal Cannula Therapy Outcomes Using the ROX-HR Index in the Pediatric ICU.

BACKGROUND: High-flow nasal cannula (HFNC) use is increasing in pediatric patients. Objective measures that predict HFNC outcomes are lacking. The respiratory rate-oxygenation (ROX) and ROX heart rate (ROX-HR) indices are validated to predict HFNC therapy failure in adults. This study examined the performance of both indices in predicting HFNC therapy failure in children admitted to the pediatric ICU (PICU). METHODS: This retrospective, longitudinal, observational cohort study was completed in a 24-bed PICU in a quaternary care children's hospital. All subjects ≤ 24 months of age initiated on HFNC in the PICU from January 1, 2018-August 31, 2020, were included. The ROX and ROX-HR indices were collected at standardized time points during HFNC therapy. Performance in predicting HFNC failure was evaluated using area under the receiver operating characteristic curve (AUROC) and Kaplan-Meier survival analysis. Failure was defined as escalation of respiratory support to either noninvasive ventilation or endotracheal intubation. RESULTS: Among 446 subject encounters, 111 (24.9%) failed HFNC therapy. HFNC failure was associated with lower ROX and ROX-HR indices at termination compared to HFNC liberation (P < .001). A ROX-HR index < 3 was significantly associated with a higher risk of HFNC failure at 1 (AUROC 0.76, P = .01) and 6 (AUROC 0.81, P = .02) h. CONCLUSIONS: ROX-HR may be a useful tool for early identification of patients ≤ 24 months at risk for HFNC failure and allow for earlier intervention. Larger prospective studies are necessary to validate the utility of the ROX-HR index in pediatric patients.

Evaluation of a web-based fall prevention program among people with multiple sclerosis.

BACKGROUND: Falls are common and impactful in people with multiple sclerosis (MS) but currently there is no accepted standard of care for fall prevention in MS. Evidence supports that the in-person, group-based, Free from Falls (FFF) program is associated with both immediate and six-month sustained improvements in mobility and balance and a reduction in falls, but program attendance is limited by access to the class at a given time and location and by the cost and availability of trained facilitators. Therefore, we developed and evaluated an online, web-based version of FFF, Free from Falls Online (FFFO). METHODS: Thirty people with MS who reported falling at least twice in the previous two months were randomized to FFFO or to a control group. FFFO consists of eight weekly sessions, each with an instructional and exercise component. Subjects in the control group were given a brochure on minimizing fall risk, a letter was sent to their treating physician informing them that the subject reported falling, and these subjects were invited to use the FFFO program at study completion. Outcomes included baseline demographics, falls prospectively reported for the eight weeks of intervention and the following three months, and a program satisfaction survey for the active group. Regression models were used to test for associations between treatment group and fall incidence. RESULTS: Subjects' mean age was 55.8 years, 70% were female, 73% had progressive MS, median Expanded Disability Status Scale (EDSS) score was 6.0, and subjects reported a median of two falls in the month prior to study enrollment. Although, in general, regression models demonstrated trends that those in the intervention group were less likely to fall than those in the control group, statistical significance was only achieved (p = 0.0038) with a post hoc model evaluating the relationship between the square of days and the probability of not falling. This model supported that those in the intervention group were slightly less likely to fall than those in the control group. This difference was most prominent in the first month of the study, less prominent in the following month, and not sustained three months following the intervention. User experience with FFFO was overall positive, with over 75% reporting the web-based program easy to learn and to use, 85% reporting the program was easy to follow, 62% reporting the material to be useful, and 77% finding the exercises to be a useful component of the program. CONCLUSION: This study supports the viability of online delivery of self-management strategies in MS, suggests that FFFO may help prevent falls in people with MS, and provides the preliminary data needed to verify the findings of this pilot study of FFFO with a fully powered randomized controlled trial in people with MS.