Parent Trial Research Articles

Safety and Efficacy of Deucravacitinib in Moderate to Severe Plaque Psoriasis For Up to 3 Years

Safe and effective long-term treatments for moderate to severe plaque psoriasis are needed. To evaluate the long-term safety and efficacy of deucravacitinib through 3 years (week 148) in the randomized POETYK PSO-1, PSO-2, and nonrandomized long-term extension (LTE) trials. PSO-1/PSO-2 were global, 52-week, randomized, double-blinded phase 3 trials in patients with moderate to severe plaque psoriasis. After completing 52 weeks of treatment in PSO-1/PSO-2, patients could enroll in the prespecified, ongoing, nonrandomized LTE trial. The peak of the global COVID-19 pandemic coincided with the LTE trial. Patient enrollment in the LTE started August 12, 2019; safety and efficacy were assessed through June 15, 2022; and these data were analyzed through June 28, 2024. The PSO-1/PSO-2 trials randomized patients 1:2:1 to oral placebo, deucravacitinib, 6 mg once daily, or apremilast, 30 mg twice daily. Patients enrolling in the LTE trial received open-label deucravacitinib, 6 mg once daily. Safety outcomes were evaluated in patients who received 1 or more doses of deucravacitinib. Efficacy outcomes included 75% or greater or 90% or greater reduction from baseline in Psoriasis Area and Severity Index (PASI 75/90) and static Physician Global Assessment scores of 0 (clear) or 1 (almost clear) (sPGA 0/1) and were assessed in patients who received deucravacitinib treatment from day 1 of the parent trials who continued in the LTE trial. Of 1519 patients who received 1 or more doses of deucravacitinib, 513 received continuous deucravacitinib treatment from day 1 and entered the LTE trial. Exposure-adjusted incidence rates (EAIRs) per 100 person-years were decreased or similar in the 1-year vs 3-year cumulative periods, respectively, for adverse events (AEs) (229.2 vs 144.8; 95% CI, 215.4-243.9 vs 137.1-153.0), serious AEs (5.7 vs 5.5; 95% CI, 4.4-7.4 vs 4.7-6.4), discontinuations due to AEs (4.4 vs 2.4; 95% CI, 3.3-5.9 vs 2.0-3.0), and deaths (0.2 vs 0.3; 95% CI, 0.1-0.8 vs 0.2-0.6). Incidence rates of the most common AEs (EAIR per 100 person-years ≥5) during the 1-year and 3-year cumulative periods, respectively, were nasopharyngitis (26.1 vs 11.4; 95% CI, 23.0-29.8 vs 10.2-12.7), COVID-19 (0.5 vs 8.0; 95% CI, 0.2-1.2 vs 7.1-9.1), and upper respiratory tract infection (13.4 vs 6.2; 95% CI, 11.3-16.0 vs 5.4-7.2). EAIRs for AEs of interest, including herpes zoster, major adverse cardiovascular events, and malignant diseases, remained low and were decreased or comparable between the 1-year and 3-year cumulative periods. Clinical response rates were maintained through 3 years. The findings of this integrated analysis of the phase 3 POETYK PSO-1, PSO-2, and nonrandomized LTE trials demonstrate a consistent safety profile and durable clinical response of continuous treatment with deucravacitinib through 3 years of treatment in patients with psoriasis. ClinicalTrials.gov Identifiers: NCT03624127, NCT03611751, and NCT04036435.

Deucravacitinib in Plaque Psoriasis: 4-year Safety and Efficacy Results from the Phase 3 POETYK PSO-1, PSO-2, and LTE Trials

Introduction: Deucravacitinib, an oral, selective, allosteric TYK2 inhibitor, is approved in multiple countries for treatment of adults with moderate to severe plaque psoriasis who are candidates for systemic therapy. Deucravacitinib was superior to placebo and apremilast in the global, 52-week, phase 3 POETYK PSO-1 and PSO-2 parent trials in moderate to severe plaque psoriasis. Upon completion, patients could enroll in the ongoing POETYK long-term extension (LTE) trial. Here, deucravacitinib safety/efficacy are reported through 4 years. Methods: PSO-1/PSO-2 randomized patients 1:2:1 to oral placebo, deucravacitinib 6 mg once daily, or apremilast 30 mg twice daily. At Week 52, patients enrolled in the LTE received open-label deucravacitinib. Safety was evaluated in patients receiving ≥1 deucravacitinib dose. Exposure-adjusted incidence rate (EAIR) per 100 person-years (PY) was used to assess adverse events (AEs). Efficacy outcomes included PASI 75, PASI 90, and sPGA 0/1 and were analyzed using mNRI in LTE patients receiving continuous deucravacitinib from Day 1 of the parent trials. Results: 1519 patients received ≥1 deucravacitinib dose; cumulative exposure was 4392.8 PY. EAIRs/100 PY were decreased/comparable from the 1-year to 4-year cumulative period, respectively, for AEs (229.2, 131.7), serious AEs (5.7, 5.0), deaths (0.2, 0.3), discontinuation due to AEs (4.4, 2.2), herpes zoster (0.8, 0.6), malignancies (1.0, 0.9), major adverse cardiovascular events (0.3, 0.3), and venous thromboembolism (0.2, 0.1). Clinical response rates with continuous deucravacitinib (n=513) were maintained from Year 3 (PASI 75, 73.8% [95% CI, 69.6-78.0]; PASI 90, 49.0% [44.4-53.7]; sPGA 0/1, 55.2% [50.5-59.9]) to Year 4 (PASI 75, 71.7% [67.0-76.3]; PASI 90, 47.5% [42.6-52.4]; sPGA 0/1, 57.2% [52.1-62.2]) by mNRI. Conclusion: Deucravacitinib demonstrated a safety profile through 4 years consistent with 3 years with no emergence of new or long-term safety signals. Efficacy was maintained through 4 years in patients receiving continuous deucravacitinib from Day 1 in PSO-1/PSO-2.

Deucravacitinib in Plaque Psoriasis: Laboratory Parameters Through 4 Years of Treatment in the Phase 3 POETYK PSO-1, PSO-2, and LTE Trials

Introduction: Deucravacitinib, an oral, selective, allosteric tyrosine kinase 2 inhibitor, is approved in multiple countries for treatment of adults with moderate to severe plaque psoriasis who are candidates for systemic therapy. Deucravacitinib was efficacious versus placebo and apremilast and was well tolerated in the global, 52-week, phase 3 POETYK PSO-1 (NCT03624127) and POETYK PSO-2 (NCT03611751) parent trials. At Week 52, patients could enroll in the ongoing POETYK long-term extension (LTE) (NCT04036435) trial and receive open-label deucravacitinib. Changes in blood laboratory parameters known to be associated with Janus kinase (JAK) 1,2,3 inhibitors were evaluated through 4 years of deucravacitinib treatment. Methods: Changes from baseline in lipid (cholesterol, triglycerides), chemistry (alanine aminotransferase [ALT], aspartate aminotransferase [AST], creatinine, creatine phosphokinase [CPK]), and hematology (hemoglobin, lymphocytes, neutrophils, platelets) parameters in the blood known to be affected by JAK1,2,3 inhibitors in clinical trials were evaluated through Week 208 (4 years; data cutoff, November 1, 2023). Treatment discontinuations due to laboratory abnormalities were assessed. Results: A total of 1519 patients received ≥1 deucravacitinib dose (total exposure, 4392.8 person-years); 1203 (79.2%) had ≥52 weeks and 542 (35.7%) had ≥208 weeks of continuous deucravacitinib exposure (median, 185 weeks). No trends or clinically meaningful mean changes from baseline were observed in any of the above laboratory parameters. In total, 3 patients discontinued treatment due to increased CPK, and 1 patient each discontinued due to lymphopenia, abnormal hepatic function, increased ALT, and increased AST. Discontinuations due to triglyceride elevations were not observed. Conclusion: In PSO-1/PSO-2/LTE, no trends or clinically meaningful mean changes from baseline were observed in lipid, chemistry, or hematology parameters, in contrast to signature changes (eg, increased cholesterol, creatinine, serum transaminases, CPK, cytopenias) observed with JAK1,2,3 inhibitors. Discontinuations due to laboratory abnormalities noted above were rare (n=7 events) through 4 years of deucravacitinib treatment. Results suggest deucravacitinib treatment does not warrant routine laboratory testing for all patients, in contrast with the requirements for JAK1,2,3 inhibitors, reflecting its selectivity for TYK2.

Promoting Race and Ethnic Diversity in a Hospital-Based Randomized Clinical Trial to Address Untreated Alcohol Use Disorder: Initial Lessons Learned.

This study aimed to describe initial experiences and lessons learned conducting a trial focused on recruiting racially and ethnically diverse hospitalized patients with untreated alcohol use disorder (AUD). The parent trial is comparing the effectiveness of strategies including Brief Negotiation Interview (BNI), facilitated initiation of medications for AUD, and computer-based training for cognitive behavioral therapy (CBT4CBT) on AUD treatment engagement post-hospitalization. Guided by the Framework for Reporting Adaptations and Modifications-Enhanced, we catalogued protocol changes and evaluated outcomes using study and electronic medical record data during the first 18 months of recruitment. Recipients: (1) Selected entry criterion to intentionally include individuals most likely impacted by structural racism, (2) developed multipronged recruitment approaches, and (3) selected bilingual, multicultural, and ethnically diverse research staff. Intervention: (1) Added scripts in the BNI to consider how cultural factors influence and how racism may impact, alcohol use, and AUD treatment engagement, (2) offered tablets as a compensation alternative with support for CBT4CBT initiation (as relevant), and (3) anticipate and troubleshoot internet access challenges. Setting: (1) Identified community-based AUD treatment options with Spanish-speaking services and (2) identified resources to address social determinants of health. Study: (1) Audited data to monitor whether diverse enrollment is occurring. Among n = 132 randomized as of March 1, 2024, 25% endorsed Black, 24% endorsed Latine, 58% endorsed White, 1% endorsed Indigenous, and 15% endorsed race not listed or declined to disclose. We observed no difference by race or ethnicity in recruitment or retention experiences. Multilevel practices within a hospital-based AUD-focused trial can promote recruitment and retention of a racially and ethnically diverse sample.

Improvement in depressive symptoms is associated with sustained improvement in fatigue impact in adults with multiple sclerosis

BackgroundFatigue is one of the most common and disabling symptoms of multiple sclerosis (MS). Behavioral interventions that target one or more behaviors such as sleep hygiene, exercise, energy management, cognitive processes, as well as mood have been shown to reduce fatigue in people with MS. Yet, little is known about mechanisms of intervention effects on MS fatigue. Research suggests that depressive symptoms may be an important intervention target for improving MS fatigue. This study examined the association between pre- to post-intervention improvement in depressive symptoms and improvement in MS fatigue impact from pre-intervention through six months post-intervention. MethodsThis study is a secondary analysis of data from a randomized controlled trial comparing a fatigue self-management intervention to general MS education for improving fatigue in people with MS. Adults with MS (N = 218) were recruited for the parent trial from the Portland, Seattle, Baltimore, and North Florida/South Georgia VA Medical Centers, affiliated academic medical centers, and surrounding communities. Both study interventions showed similar efficacy, so participants were combined into one sample for this secondary analysis. Structural equation modeling was used to examine whether clinically significant change in depressive symptoms (a 17.5 % reduction in the total Beck Depression Inventory-II score) from pre- to post-intervention, was associated with improvement in fatigue impact on the physical, cognitive, and psychosocial subscales of the Modified Fatigue Impact Scale from pre-intervention through six-month follow-up. ResultsParticipants were predominantly female (72 %), middle-aged (M = 53.7 ± 10.1), and White (76 %) with a disease duration of 12.5 ± 8.4 years. Over half of the sample (58 %) had relapsing-remitting MS. Clinically significant improvement in depressive symptoms was associated with reduction in physical fatigue impact (β = -0.17, p = .004, 95 % CI [-0.28, -0.05]), cognitive fatigue impact (β = -0.20, p = .000, 95 % CI [-0.31, -0.10]), and psychosocial fatigue impact (β = -0.13, p = .03, 95 % CI [-0.25, -0.01]) through the six-month follow-up controlling for baseline depressive symptoms and fatigue impact, MS subtype (RRMS or Progressive MS), and income level. The model demonstrated adequate fit, χ2(6) = 12.747, p = .047, RMSEA = 0.072, CFI = 0.986, SRMR = 0.016, and accounted for 32 %, 39 %, and 28 % of the variance in physical, cognitive, and psychosocial fatigue impact respectively, which corresponded with large effect sizes. ConclusionThese findings, building on previous research, support the importance of reducing depressive symptoms for improving fatigue impact in people with MS. Future research should examine whether explicit focus on reducing depressive symptoms or related cognitive behavioral factors reduces fatigue in people with MS.

The effects of neighborhood disadvantage and adverse childhood experiences on conditioned pain modulation in adults with chronic low back pain

Chronic low back pain (cLBP) remains a major health crisis worldwide. Current conceptualizations of cLBP utilize the biopsychosocial model, yet research on social factors remains limited. Adverse childhood experiences (ACEs) are a risk factor for a variety of chronic health problems, including cLBP. However, the extent to which socioeconomic context might influence associations between ACEs and cLBP remains unclear. Socioeconomic factors such as healthcare access and living conditions, which cluster at the neighborhood level, may affect how ACEs relate to cLBP in adulthood. This study examined (1) the relationship between ACEs and conditioned pain modulation (CPM), and (2) the moderating effect of area-level deprivation index (ADI) in a sample of community-dwelling adults with cLBP. 183 adults with cLBP (53% female, 62.8% non-Hispanic Black) reported on ACEs, ADI, sociodemographics, and completed experimental testing of conditioned pain modulation (CPM). Greater ACEs were associated with a less efficient CPM response for individuals residing in low neighborhood deprivation (p < 0.01). ACEs were not significantly associated with CPM for those residing in average (p = 0.31) or high deprivation (p = 0.15). Our findings suggest that a history of ACEs is associated with diminished ability to inhibit pain, especially among individuals living in less deprived neighborhoods. The association between ACEs and CPM was weakest for the portion of our sample residing in neighborhoods with the most deprivation. People from disadvantaged backgrounds may experience numerous psychosocial stressors that hinder CPM, making it difficult to assess the specific impact of ACEs on CPM. Trial registrationThis study utilized baseline data collected as part of a parent trial titled “Examining Racial and SocioEconomic Disparities in Chronic Low Back Pain” (ERASED - ClinicalTrials.gov ID: NCT03338192). PerspectiveThis study demonstrates that early life adversity is associated with abnormal endogenous pain modulation, particularly for participants who live in neighborhoods characterized by less deprivation.

Vasopressor or advanced airway first in cardiac arrest?

BackgroundWhile resuscitation guidelines emphasize early vasopressor administration and advanced airway management, their optimal sequence remains unclear. We sought to determine the associations between vasopressor-airway resuscitation sequence and out-of-hospital cardiac arrest (OHCA) outcomes in the Pragmatic Airway Resuscitation Trial (PART). MethodsWe analyzed data from the PART trial. For each patient we determined times of first vasopressor administration (epinephrine or vasopressin), and successful advanced airway insertion (laryngeal tube or endotracheal tube). We classified each case as vasopressor-first or advanced airway-first. We used Generalized Estimating Equations to determine associations between vasopressor-airway sequence and outcomes (72-hour survival, return of spontaneous circulation (ROSC) on emergency department arrival, survival to hospital discharge, hospital survival with favorable neurologic status) and CPR outside of recommended parameters (chest compression fraction <0.8, chest compression rate <100 or >120 per min, or ventilation rate <8 or >12 breaths/min), adjusting for confounders. ResultsOf 3,004 patients in the parent trial, we analyzed 2,404, including 1,821 vasopressor-first and 583 advanced airway-first. Median intervention times: ALS arrival-to-vasopressor 8 min (IQR 6–11) and ALS arrival-to-airway 11 min (8–15). Compared with airway-first, vasopressor-first sequence was not associated with 72-hour survival (adjusted OR 0.96; 95% CI: 0.71–1.31), ROSC (0.83; 0.66–1.06), hospital survival (1.09; 0.68–1.73), or hospital survival with favorable neurologic status (0.97; 0.53–1.78). Vasopressor-first sequence was not associated with non-compliance with recommended CPR performance parameters. ConclusionsVasopressor-airway resuscitation sequence was not associated with OHCA outcomes or CPR quality.

Use of web-based decision support to improve informed choice for chemoprevention: a qualitative analysis of pre-implementation interviews (SWOG S1904)

BackgroundWomen with high-risk breast lesions, such as atypical hyperplasia (AH) or lobular carcinoma in situ (LCIS), have a 4- to tenfold increased risk of breast cancer compared to women with non-proliferative breast disease. Despite high-quality data supporting chemoprevention, uptake remains low. Interventions are needed to break down barriers.MethodsThe parent trial, MiCHOICE, is a cluster randomized controlled trial evaluating the effectiveness and implementation of patient and provider decision support tools to improve informed choice about chemoprevention among women with AH or LCIS. For this pre-implementation analysis, 25 providers participated in semi-structured interviews prior to accessing decision support tools. Interviews sought to understand attitudes/beliefs and barriers/facilitators to chemoprevention.ResultsInterviews with 25 providers (18 physicians and 7 advanced practice providers) were included. Providers were predominantly female (84%), white (72%), and non-Hispanic (88%). Nearly all providers (96%) had prescribed chemoprevention for eligible patients. Three themes emerged in qualitative analysis. The first theme describes providers’ confidence in chemoprevention and the utility of decision support tools. The second theme elucidates barriers to chemoprevention, including time constraints, risk communication and perceptions of patients’ fear of side effects and anxiety. The third theme is the need for early implementation of decision support tools.ConclusionsThis qualitative study suggests that providers were interested in the early inclusion of decision aids (DA) in their chemoprevention discussion workflow. The DAs may help overcome certain barriers which were elucidated in these interviews, including patient level concerns about side effects, clinic time constraints and difficulty communicating risk. A multi-faceted intervention with a DA as one active component may be needed.Trial registrationThis trial was registered with the NIH clinical trial registry, clinicaltrials.gov, NCT04496739.

Examining changes in pain interference via pandemic-induced isolation among patients receiving medication for opioid use disorder: a secondary data analysis

BackgroundEarly in the pandemic, the United States population experienced a sharp rise in the prevalence rates of opioid use, social isolation, and pain interference. Given the high rates of pain reported by patients on medication for opioid use disorder (MOUD), the pandemic presented a unique opportunity to disentangle the relationship between opioid use, pain, and social isolation in this high-risk population. We tested the hypothesis that pandemic-induced isolation would partially mediate change in pain interference levels experienced by patients on MOUD, even when controlling for baseline opioid use. Such work can inform the development of targeted interventions for a vulnerable, underserved population.MethodsAnalyses used data from a cluster randomized trial (N = 188) of patients on MOUD across eight opioid treatment programs. As part of the parent trial, participants provided pre-pandemic data on pain interference, opioid use, and socio-demographic variables. Research staff re-contacted participants between May and June 2020 and 133 participants (71% response rate) consented to complete a supplemental survey that assessed pandemic-induced isolation. Participants then completed a follow-up interview during the pandemic that again assessed pain interference and opioid use. A path model assessed whether pre-pandemic pain interference had an indirect effect on pain interference during the pandemic via pandemic-induced isolation.ResultsConsistent with hypotheses, we found evidence that pandemic-induced isolation partially mediated change in pain interference levels among MOUD patients during the pandemic. Higher levels of pre-pandemic pain interference and opioid use were both significantly associated with higher levels of pandemic-induced isolation. In addition, pre-pandemic pain interference was significantly related to levels of pain interference during the pandemic, and these pain levels were partially explained by the level of pandemic-induced isolation reported.ConclusionsPatients on MOUD with higher use of opioids and higher rates of pain pre-pandemic were more likely to report feeling isolated during COVID-related social distancing and this, in turn, partially explained changes in levels of pain interference. These results highlight social isolation as a key risk factor for patients on MOUD and suggest that interventions promoting social connection could be associated with reduced pain interference, which in turn could improve patient quality of life.Trial registrationNCT03931174 (Registered 04/30/2019).

Reliability of Uroflowmetry Pattern Interpretation in Adult Women.

Uroflowmetry is often used to assess lower urinary tract symptoms (LUTS). Criteria for characterization of flow patterns are not well established, and subjective interpretation is the most common approach for flow curve classification. We assessed the reliability of uroflowmetry curve interpretation in adult women. Uroflowmetry studies were obtained in 296 women who participated in an observational cohort study. Four investigators with expertise in female LUTS and urodynamics reviewed and categorized each tracing for interrater reliability. A random subset of 50 tracings was re-reviewed by each investigator for intrarater reliability. The uroflowmetry tracings were rated using categories of continuous, continuous fluctuating, interrupted, and prolonged. Other parameters included flow rate, voided volume, time to maximum flow, and voiding time. Agreement between raters is summarized with kappa (k) statistics and percentage where at least three raters agreed. The mean age of participants was 44.8 ± 18.3 years. Participant age categories were 18-24 years: 20%; 25-34 years: 17%; 35-64 years: 42%; 65+ years: 18%. Nine percent described their race as Asian, 31% Black, 62% White, and 89% were of non-Hispanic ethnicity. The interrater reliability was highest for the continuous flow category (k = 0.65), 0.47 for prolonged, 0.41 for continuous fluctuating, and 0.39 for interrupted flow curves. Agreement among at least three raters occurred in 74.3% of uroflow curves (69% for continuous, 33% for continuous fluctuating, 23% for interrupted, and 25% for prolonged). For intrarater reliability, the mean k was 0.72 with a range of 0.57-0.85. Currently accepted uroflowmetry pattern categories have fair to moderate interrater reliability, which is lower for flow curves that do not meet "continuous" criteria. Given the subjective nature of interpreting uroflowmetry data, more consistent and clear parameters may enhance reliability for use in research and as a screening tool for LUTS and voiding dysfunction. Parent trial: Validation of Bladder Health Instrument for Evaluation in Women (VIEW); ClinicalTrials.gov ID: NCT04016298.

"So Many Other Things Improve" with Transdiagnostic Treatment for Sleep and Circadian Problems: Interviews with Community Providers on Treating Clients with Serious Mental Illness.

Community mental health centers (CMHCs) offer invaluable, publicly-funded treatment for serious mental illness (SMI). Unfortunately, evidence-based psychological treatments are often not delivered at CMHCs, in part due to implementation barriers, such as limited time, high caseloads, and complex clinical presentations. Transdiagnostic treatments may help address these barriers, because they allow providers to treat symptoms across multiple disorders concurrently. However, little research has investigated CMHC providers' experiences of delivering transdiagnostic treatments "on the ground," particularly for adults with SMI. Thus, the aim of the present study was to assess CMHC providers' perspectives on delivering a transdiagnostic treatment - the Transdiagnostic Intervention for Sleep and Circadian Dysfunction (TranS-C) - to adults diagnosed with SMI. In the context of a larger parent trial, providers were randomized to deliver a standard version of TranS-C (Standard TranS-C) or a version adapted to the CMHC context (Adapted TranS-C). Twenty-five providers from the parent trial participated in a semi-structured interview (n = 10 Standard TranS-C; n = 15 from Adapted TranS-C). Responses were deductively and inductively coded to identify themes related to Proctor's taxonomy of implementation outcomes. Four novel "transdiagnostic take homes" were identified: (1) transdiagnostic targets, such as sleep, can be perceived as motivating and appropriate when treating SMI, (2) strategies to bolster client motivation/adherence and address a wider range of symptom severity may improve transdiagnostic treatments, (3) balancing feasibility with offering in-depth resources is an important challenge for transdiagnostic treatment development, and (4) adapting transdiagnostic treatments to the CMHC context may improve provider perceptions of implementation outcomes.

Effects of a 6-Week Treadmill Training With and Without Virtual Reality on Frailty in People With Multiple Sclerosis

ObjectiveTo examine the effects of a cognitive-motor rehabilitation program consisting of treadmill training (TT) augmented by virtual reality (TT+VR) on frailty in people with multiple sclerosis (pwMS). DesignSecondary analysis from a multicenter randomized controlled trial investigating the effects of TT+VR, compared with TT only, on measures of mobility and cognitive function in pwMS. SettingFour university research laboratories in 3 countries. ParticipantsA total of 124 pwMS were randomized into the parent trial. Here, we studied a subset of n = 83 participants (mean age, 49.4±9.3y; 73.5% female; expanded disability status scale range, 2.0-6.0), who completed the intervention and had complete preintervention and postintervention frailty data. InterventionsParticipants were randomly allocated to TT+VR (n=44) or TT (n=39). Both groups trained 3 times a week for 6 weeks. Main Outcome MeasuresFrailty was assessed using a 40-item frailty index (FI) through standard validated procedures and represented the primary study outcome. Two exploratory frailty indices were also computed by isolating health-related deficits involving the cognitive (FI-physical) or physical (FI-cognitive) domains from the main FI. The assessments were performed at baseline and after 6 weeks, upon intervention completion. ResultsThe mean FI of study participants at baseline was 0.33±0.13, indicating a moderate average level of frailty. FI scores improved in both TT+VR and TT groups participants (pooled mean ΔFI, 0.024; 95% CI, 0.010-0.038; F=10.49; P=.002; ηp2=0.115), without any group-by-time interaction (F=0.82; P=.367; ηp2=0.010). However, a significant group-by-time interaction was found for pretraining and posttraining changes in FI-cognitive (F=5.74; P=.019; ηp2=0.066), suggesting a greater improvement for TT+VR group participants than for TT group participants. ConclusionsTT with or without virtual reality can reduce frailty levels in pwMS. While both TT and TT+VR had a positive effect on overall frailty, only TT+VR improved cognitive aspects of frailty and may represent an appropriate strategy for counteracting frailty in pwMS.

Is a very brief web-based intervention with focus on protective behavioral strategies efficacious in reducing impaired control over alcohol in undergraduates?

Impaired control (i.e., difficulty adhering to limits on alcohol use) prospectively predicts self-reported alcohol-related problems in undergraduates yet remains understudied. In particular, there is little evidence regarding whether brief interventions can reduce impaired control. An efficacious, very brief, web-based intervention focused on protective behavioral strategy (PBS) use may be well suited to reducing impaired control, but there is also little evidence regarding relationships between impaired control and PBS use. Data were analyzed from a randomized controlled trial of U.S. Tertiary Health Research Intervention via Email (Leeman et al., 2016) that yielded evidence of reduced weekly and peak alcohol use among undergraduates who drink heavily (N = 208). Multilevel models were tested to determine efficacy in reducing impaired control over alcohol use. The parent trial tested variants providing both direct (e.g., avoiding drinking games) and indirect (e.g., securing a designated driver) PBS, direct only or indirect only. Given this focus of the parent trial, self-reported PBS use was included in the model. U.S. Tertiary Health Research Intervention via Email did not significantly reduce impaired control over alcohol use compared to a control condition (p = .15-.96), and there was no significant main effect of time or interactions with time. However, direct and indirect PBS use was significantly inversely related to impaired control. An efficacious, very brief web-based intervention associated with decreased alcohol use did not decrease impaired control over alcohol significantly. More intensive, or longer, interventions may be needed to reduce impaired control. Greater PBS use was associated with less impaired control; thus, interventions that increase PBS use may decrease impaired control. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Breast Cancer Index in Premenopausal Women With Early-Stage Hormone Receptor–Positive Breast Cancer

Adjuvant ovarian function suppression (OFS) with oral endocrine therapy improves outcomes for premenopausal patients with hormone receptor-positive (HR+) breast cancer but adds adverse effects. A genomic biomarker for selecting patients most likely to benefit from OFS-based treatment is lacking. To assess the predictive and prognostic performance of the Breast Cancer Index (BCI) for OFS benefit in premenopausal women with HR+ breast cancer. This prospective-retrospective translational study used all available tumor tissue samples from female patients from the Suppression of Ovarian Function Trial (SOFT). These individuals were randomized to receive 5 years of adjuvant tamoxifen alone, tamoxifen plus OFS, or exemestane plus OFS. BCI testing was performed blinded to clinical data and outcome. The a priori hypothesis was that BCI HOXB13/IL17BR ratio (BCI[H/I])-high tumors would benefit more from OFS and high BCI portended poorer prognosis in this population. Settings spanned multiple centers internationally. Participants included premenopausal female patients with HR+ early breast cancer with specimens in the International Breast Cancer Study Group tumor repository available for RNA extraction. Data were collected from December 2003 to April 2021 and were analyzed from May 2022 to October 2022. Primary end points were breast cancer-free interval (BCFI) for the predictive analysis and distant recurrence-free interval (DRFI) for the prognostic analyses. Tumor specimens were available for 1718 of the 3047 female patients in the SOFT intention-to-treat population. The 1687 patients (98.2%) who had specimens that yielded sufficient RNA for BCI testing represented the parent trial population. The median (IQR) follow-up time was 12 (10.5-13.4) years, and 512 patients (30.3%) were younger than 40 years. Tumors were BCI(H/I)-low for 972 patients (57.6%) and BCI(H/I)-high for 715 patients (42.4%). Patients with tumors classified as BCI(H/I)-low exhibited a 12-year absolute benefit in BCFI of 11.6% from exemestane plus OFS (hazard ratio [HR], 0.48 [95% CI, 0.33-0.71]) and an absolute benefit of 7.3% from tamoxifen plus OFS (HR, 0.69 [95% CI, 0.48-0.97]) relative to tamoxifen alone. In contrast, patients with BCI(H/I)-high tumors did not benefit from either exemestane plus OFS (absolute benefit, -0.4%; HR, 1.03 [95% CI, 0.70-1.53]; P for interaction = .006) or tamoxifen plus OFS (absolute benefit, -1.2%; HR, 1.05 [95% CI, 0.72-1.54]; P for interaction = .11) compared with tamoxifen alone. BCI continuous index was significantly prognostic in the N0 subgroup for DRFI (n = 1110; P = .004), with 12-year DRFI of 95.9%, 90.8%, and 86.3% in BCI low-risk, intermediate-risk, and high-risk N0 cancers, respectively. In this prospective-retrospective translational study of patients enrolled in SOFT, BCI was confirmed as prognostic in premenopausal women with HR+ breast cancer. The benefit from OFS-containing adjuvant endocrine therapy was greater for patients with BCI(H/I)-low tumors than BCI(H/I)-high tumors. BCI(H/I)-low status may identify premenopausal patients who are likely to benefit from this more intensive endocrine therapy.

Exploring the association between adherence to home-based exercise recommendations and recovery of nonspecific low back pain: a prospective cohort study

BackgroundAdherence to home-based exercise (HBE) recommendations is critical in physiotherapy for patients with low back pain (LBP). However, limited research has explored its connection with clinical outcomes. This study examined how adherence to HBE relates to changes in physical function, pain intensity, and recovery from LBP in patients undergoing physiotherapy treatment.MethodsData from a multicenter cluster randomized controlled trial in the Netherlands involving patients with LBP from 58 primary care physiotherapy practices were used. Adherence to HBE was assessed with the Exercise Adherence Scale (EXAS) at each treatment session. Previously identified adherence trajectories served as a longitudinal measure of adherence and included the classes “declining adherence” (12% of participants), “stable adherence” (45%), and “increasing adherence” (43%). The main outcomes included disability (Oswestry Disability Index), pain (Numeric Pain Rating Scale), and recovery (pain-free for > 4 weeks), which were measured at baseline and after three months. Linear and binomial logistic regression analyses adjusted for confounders were used to examine adherence–outcome relationships.ResultsIn the parent trial, 208 participants were included. EXAS scores were available for 173 participants, collected over a median of 4.0 treatment sessions (IQR 3.0 to 6.0). Forty-five (28.5%) patients considered themselves to have recovered after three months. The median changes in the Oswestry Disability Index and Numeric Pain Rating Scale were − 8 (IQR − 1 to -20) and − 2 (IQR − 0.5 to -4), respectively. The mean EXAS scores varied among patient classes: “declining adherence” (46.0, SD 19.4), “stable adherence” (81.0, SD 12.4), and “increasing adherence” (39.9, SD 25.3), with an overall mean of 59.2 (SD 25.3). No associations between adherence and changes in physical functioning or pain were found in the regression analyses.ConclusionsNo association between adherence to HBE recommendations and changes in clinical outcomes in patients with LBP was found. These findings suggest that the relationship between adherence to HBE recommendations and treatment outcomes may be more complex than initially assumed. Further research using detailed longitudinal data combined with qualitative methods to investigate patient motivation and beliefs may lead to a deeper understanding of the relationship between adherence and clinical outcomes in patients with LBP.

Does it matter how meditation feels? An experience sampling study.

Meditation apps are the most widely used mental health apps. The precise mechanisms underlying their effects remain unclear. In particular, the degree to which affect experienced during meditation is associated with outcomes has not been established. We used the meditation app arm of a recently completed randomized controlled trial comparing a self-guided meditation app (Healthy Minds Program) to a waitlist control. Predominantly distressed public school employees (n = 243, 80.9% with clinically elevated depression and/or anxiety) reported positive and negative affect during meditation practice. Data were analyzed using two-level multivariate latent growth curve models (observations nested within participants) that simultaneously attended to both positive and negative affect. We examined whether positive and negative affect during meditation changed over time and whether these changes were associated with changes in psychological distress (parent trial's preregistered primary outcome) at posttest or 3-month follow-up. On average, participants reported decreased negative affect but no change in positive affect during meditation over time. Increased positive affect and decreased negative affect during meditation were associated with improvements in distress at posttest and follow-up. Change in positive affect was a stronger predictor of distress at follow-up than change in negative affect. Despite notions embedded within mainstream mindfulness meditation training that deemphasize the importance of the affective experience of practice (i.e., nonjudgmental awareness of present moment experience, regardless of valence), results indicate that these experiences contain signals associated with outcomes. Monitoring affect during meditation may be worthwhile to guide intervention delivery (i.e., measurement-based care, precision medicine). (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Long-Term Efficacy and Safety of Stapokibart in Adults with Moderate-to-Severe Atopic Dermatitis: An Open-Label Extension, Nonrandomized Clinical Trial.

Stapokibart/CM310, a humanized monoclonal antibody targeting the interleukin-4 receptor α chain, has shown promising treatment benefits in patients with moderate-to-severe atopic dermatitis in previous phase II clinical trials. We aimed to evaluate the long-term efficacy and safety of stapokibart in adults with moderate-to-severe atopic dermatitis. Enrolled patients who previously completed parent trials of stapokibart received a subcutaneous stapokibart 600-mg loading dose, then 300mg every 2weeks up to 52weeks. Efficacy outcomes included the proportions of patients with ≥50%/75%/90% improvements from baseline of parent trials in the Eczema Area and Severity Index, Investigator's Global Assessment, and weekly average of the daily Peak Pruritus Numerical Rating Scale. In total, 127 patients were enrolled, and 110 (86.6%) completed the study. At week52, the Eczema Area and Severity Index-50/75/90 response rates were 96.3%, 87.9%, and 71.0%, respectively. An Investigator's Global Assessment 0/1 with a ≥2-point reduction was achieved in 39.3% of patients at week16, increasing to 58.9% at week52. The proportions of patients with ≥3-point and ≥4-point reductions in the weekly average of daily Peak Pruritus Numerical Rating Scale scores were 80.2% and 62.2%, respectively, at week52. Improvement in patients' quality of life was sustained over a 52-week treatment period. Treatment-emergent adverse events occurred in 88.2% of patients, with an exposure-adjusted event rate of 299.2 events/100 patient-years. Coronavirus disease 2019, upper respiratory tract infection, and conjunctivitis were the most common treatment-emergent adverse events. Long-term treatment with stapokibart for 52weeks showed high efficacy and good safety profiles, supporting its use as a continuous long-term treatment option for atopic dermatitis. ClinicalTrials.gov identifier: NCT04893707 (15 May, 2021).

Deucravacitinib Long-Term Efficacy Through 4 years in Week 16 Placebo Crossover Patients in the Phase 3 POETYK PSO-1, PSO-2, and LTE Program

Introduction: Deucravacitinib, an oral, selective, allosteric tyrosine kinase 2 inhibitor, is approved in the US, EU, and other countries for treatment of adults with moderate to severe plaque psoriasis who are candidates for systemic therapy. Deucravacitinib was efficacious and well tolerated in two global, 52-week, phase 3 POETYK PSO-1 (NCT03624127) and POETYK PSO-2 (NCT03611751) parent trials, and through 2 additional years in the POETYK long-term extension (LTE) (NCT04036435) trial in patients treated with deucravacitinib from Day 1 of PSO-1/PSO-2. Here, long-term efficacy was assessed through 4 years in patients who crossed over from placebo to deucravacitinib at Week 16 in PSO-1 or PSO-2 and entered the LTE trial. Methods: PSO-1 and PSO-2 randomized patients 1:2:1 to oral placebo, deucravacitinib 6 mg once daily, or apremilast 30 mg twice daily. At Week 16, patients randomized to placebo crossed over to deucravacitinib. At Week 52, patients could enroll in the LTE and receive open-label deucravacitinib. Efficacy was evaluated in patients who crossed over from placebo to deucravacitinib at Week 16 of the parent trial and received continuous deucravacitinib through 4 years (Week 208; data cutoff, November 1, 2023). Outcomes included ≥75%/≥90% reduction from baseline in Psoriasis Area and Severity Index (PASI 75/90) and static Physician Global Assessment score of 0 (clear) or 1 (almost clear) (sPGA 0/1). Efficacy is reported using modified nonresponder imputation (mNRI) in patients who reached the Week 208 assessment or discontinued before Week 208. Results: Of 421 patients originally randomized to placebo, 348 crossed over to deucravacitinib at Week 16; 298 completed the parent trials and entered the LTE, with 291 meeting mNRI criteria. Efficacy response rates improved from Week 16 on placebo (PASI 75, 12.0% [95% CI, 8.5%-16.3%]; PASI 90, 3.4% [1.7%-6.2%]; sPGA 0/1, 10.0% [6.8%-14.0%]) through Week 52 on deucravacitinib (PASI 75, 75.2% [70.2%-80.2%]; PASI 90, 47.4% [41.6%-53.1%]; sPGA 0/1, 60.1% [54.5%-65.7%]). Response rates were maintained well through Week 208 (PASI 75, 75.6% [70.0%-81.2%]; PASI 90, 46.6% [40.4%-52.7%]; sPGA 0/1, 55.1% [48.8%-61.4%]). Conclusion: These findings support the long-term efficacy profile of once-daily oral deucravacitinib for treatment of patients with moderate to severe plaque psoriasis.

Deucravacitinib in Plaque Psoriasis: Maintenance of Response Over 4 Years in the Phase 3 POETYK PSO-1, PSO-2, and LTE Trials

Introduction: Deucravacitinib, an oral, selective, allosteric TYK2 inhibitor, was superior to placebo and apremilast in two global, phase 3 trials (POETYK PSO-1 and PSO-2) in moderate to severe plaque psoriasis. At Week 52, patients could enter the POETYK long-term extension (LTE) trial and receive open-label deucravacitinib. Long-term efficacy was maintained through 3 total years of continuous treatment with no new safety signals in the ongoing LTE. Methods: Efficacy was further evaluated through Week 208 (4 years; data cutoff, November 1, 2023) in patients from the pooled PSO-1/PSO-2 populations who received continuous deucravacitinib from Day 1, achieved ≥75% reduction from baseline in Psoriasis Area and Severity Index (PASI 75) at Week 16 (primary endpoint) or Week 24 (peak response), and entered the LTE. Maintenance of response assessments included PASI 75, PASI 90, and sPGA 0/1 (static Physician Global Assessment score of 0 [clear]/1 [almost clear]). Efficacy is reported using modified nonresponder imputation in patients who reached or discontinued before Week 208. Results: Of 513 patients who received continuous deucravacitinib from Day 1 and entered the LTE, PASI 75 was achieved by 313 (61.0%) and 336 (65.5%) patients at Week 16 and Week 24. Among Week 16 PASI 75 responders, response rates were maintained well from Week 16 to Week 208 (PASI 75: 100%, 84.4%; PASI 90: 55.7%, 57.4%; sPGA 0/1: 82.8%, 65.4%). Among Week 24 PASI 75 responders, response rates were also maintained from Week 24 to Week 208 (PASI 75: 100%, 84.6%; PASI 90: 62.7%, 58.2%; sPGA 0/1: 82.5%, 66.0%). Conclusion: Clinical efficacy was generally maintained with continuous deucravacitinib in the vast majority of Week 16 and Week 24 PASI 75 responders from the parent trials through 4 years, supporting the long-term effectiveness and treatment durability of once-daily oral deucravacitinib for moderate to severe plaque psoriasis.

Deucravacitinib in Plaque Psoriasis: 4-Year Safety and Efficacy Results From the Phase 3 POETYK PSO-1, PSO-2, and LTE Trials

Introduction: Deucravacitinib, an oral, selective, allosteric TYK2 inhibitor, is approved in the US, EU, and other countries for treatment of adults with moderate to severe plaque psoriasis who are candidates for systemic therapy. Deucravacitinib was superior to placebo and apremilast in the phase 3 POETYK PSO-1 and PSO-2 trials in moderate to severe plaque psoriasis. Upon trial completion, patients could enroll in the ongoing POETYK long-term extension (LTE) trial. Here, deucravacitinib safety and efficacy are reported through 4 years. Methods: PSO-1/PSO-2 randomized patients 1:2:1 to placebo, deucravacitinib 6 mg QD, or apremilast 30 mg BID. At Week 52, patients in the LTE received open-label deucravacitinib 6 mg QD. Safety was evaluated in patients receiving ≥1 deucravacitinib dose. Exposure-adjusted incidence rate (EAIR) per 100 person-years (PY) was used to assess adverse events (AEs). Efficacy outcomes included PASI 75, PASI 90, and sPGA 0/1 and were analyzed using mNRI in LTE patients receiving continuous deucravacitinib from Day 1 of the parent trials. Results: 1519 patients received ≥1 deucravacitinib dose; cumulative exposure was 4392.8 PY. EAIRs/100 PY were decreased/comparable from the 1- to 4-year cumulative period, respectively: AEs (229.2, 131.7), serious AEs (5.7, 5.0), deaths (0.2, 0.3), discontinuation due to AEs (4.4, 2.2), herpes zoster (0.8, 0.6), malignancies (1.0, 0.9), MACE (0.3, 0.3), and venous thromboembolism (0.2, 0.1). With continuous deucravacitinib treatment (n = 513), clinical response rates were maintained from Year 3 (PASI 75, 73.8% [95% CI, 69.6, 78.0]; PASI 90, 49.0% [95% CI, 44.4, 53.7]; sPGA 0/1, 55.2% [95% CI, 50.5, 59.9]) to Year 4 (PASI 75, 71.7% [95% CI, 67.0, 76.3]; PASI 90, 47.5% [95% CI, 42.6, 52.4]; sPGA 0/1, 57.2% [95% CI, 52.1, 62.2]) by mNRI. Conclusion: Deucravacitinib demonstrated durable efficacy with continuous treatment and a safety profile through 4 years consistent with that at 3 years, without new or long-term safety signals.