Tag: statistics

J Clin Oncol. 2024 Jun 4:JCO2302736. doi: 10.1200/JCO.23.02736. Online ahead of print.

ABSTRACT

PURPOSE: Treatment options are limited for patients with previously treated metastatic colorectal cancer (mCRC). In the LEAP-017 study, we evaluate whether lenvatinib in combination with pembrolizumab improves outcomes compared with standard of care (SOC) in previously treated mismatch repair proficient or not microsatellite instability high (pMMR or not MSI-H) mCRC.

METHODS: In this international, multicenter, randomized, controlled, open-label, phase III study, eligible patients age 18 years and older with unresectable, pMMR or not MSI-H mCRC, that had progressed on or after, or could not tolerate, standard treatment, were randomly assigned 1:1 to lenvatinib 20 mg orally once daily plus pembrolizumab 400 mg intravenously once every 6 weeks or investigator’s choice of regorafenib or trifluridine/tipiracil (SOC). Randomization was stratified by presence or absence of liver metastases. The primary end point was overall survival (OS). LEAP-017 is registered at ClinicalTrials.gov (NCT04776148), and has completed recruitment.

RESULTS: Between April 8, 2021, and December 21, 2021, 480 patients were randomly assigned to lenvatinib plus pembrolizumab (n = 241) or SOC (n = 239). At final analysis (median follow-up of 18.6 months [IQR, 3.9]), median OS with lenvatinib plus pembrolizumab versus SOC was 9.8 versus 9.3 months (hazard ratio [HR], 0.83 [95% CI, 0.68 to 1.02]; P = .0379; prespecified threshold P = .0214). Grade ≥3 treatment-related adverse events occurred in 58.4% (lenvatinib plus pembrolizumab) versus 42.1% (SOC) of patients. Two participants died due to treatment-related adverse events, both in the lenvatinib plus pembrolizumab arm.

CONCLUSION: In patients with pMMR or not MSI-H mCRC that had progressed on previous therapy, there was no statistically significant improvement in OS after lenvatinib plus pembrolizumab treatment versus SOC. No new safety signals were observed.

PMID:38833658 | DOI:10.1200/JCO.23.02736

Neurology. 2024 Jul 9;103(1):e209397. doi: 10.1212/WNL.0000000000209397. Epub 2024 Jun 4.

ABSTRACT

BACKGROUND AND OBJECTIVES: Individuals with epilepsy have increased risk of suicidal ideation (SI) and behaviors when compared with the general population. This relationship has remained largely unexplored in adolescents. We investigated the prevalence of suicidality in adolescents with newly diagnosed focal epilepsy within 4 months of treatment initiation and over the following 36 months.

METHODS: This was a post hoc analysis of the enrollment and follow-up data from the Human Epilepsy Project, an international, multi-institutional study that enrolled participants between 2012 and 2017. Participants enrolled were 11-17 years of age within 4 months of treatment initiation for focal epilepsy. We used data from the Columbia Suicide Severity Rating Scale (C-SSRS), administered at enrollment and over the 36-month follow-up period, along with data from medical records.

RESULTS: A total of 66 adolescent participants were enrolled and completed the C-SSRS. At enrollment, 14 (21%) had any lifetime SI and 5 (8%) had any lifetime suicidal behaviors (SBs). Over the following 36 months, 6 adolescents reported new onset SI and 5 adolescents reported new onset SB. Thus, the lifetime prevalence of SI within this population increased from 21% to 30% (14-20 adolescents), and the lifetime prevalence of SB increased from 8% to 15% (5-10).

DISCUSSION: The prevalence of suicidality in adolescents with newly diagnosed focal epilepsy reported in our study is consistent with previous findings of significant suicidality observed in epilepsy. We identify adolescents as an at-risk population at the time of epilepsy diagnosis and in the following years.

PMID:38833656 | DOI:10.1212/WNL.0000000000209397

Neurology. 2024 Jul 9;103(1):e209533. doi: 10.1212/WNL.0000000000209533. Epub 2024 Jun 4.

ABSTRACT

BACKGROUND AND OBJECTIVES: Pivotal trials for neurologic drugs in clinical development are often initiated without a phase 2 trial (“bypass”) or despite a negative phase 2 efficacy result (“override”). Such practices may degrade the risk/benefit ratio of phase 3 trials. The aim of this study is to estimate the proportion of phase 3 trials for 10 neurologic diseases started without a positive phase 2 trial, to identify factors associated with this practice, and to investigate any association with unfavorable phase 3 trial outcomes.

METHODS: We searched ClinicalTrials.gov for phase 3 trials completed during 2011-2021, with at least 1 research site in the United States, Canada, the European Union, the United Kingdom, or Australia, and investigating drugs or biologics for treatment of 10 neurologic conditions. Our primary objective was to assess the prevalence of phase 2 bypass/override by searching for preceding phase 2 trials. We used Fisher exact tests to determine whether phase 3 trial characteristics and trial results were associated with phase 2 bypass/override.

RESULTS: Of the 1,188 phase 3 trials captured in our search, 113 met eligibility for inclusion. Of these, 46% were not preceded by a phase 2 trial that was positive on an efficacy endpoint (31% bypassed and 15% overrode phase 2 trial). Phase 2 bypass/override was not associated with industry funding (77% vs 89%, 95% CI 0.75-7.55, p = 0.13) or testing already approved interventions (23% vs 15%, 95% CI 0.60-5.14, p = 0.33). Overall, phase 3 trials based on phase 2 bypassed/override were statistically significantly less likely to be positive on their primary outcome (31% vs 57%, respectively, 95% CI 1.21-6.92, p = 0.01). This effect disappeared when indications characterized by nearly universal positive or negative results were excluded. Trials that bypassed/overrode phase 2 trials were not statistically significantly more likely to be terminated early because of safety or futility (29% vs 15%, respectively, 95% CI 0.15-1.18, p = 0.11) and did not show increased risk of adverse events in experimental arms (RR = 1.46, 95% CI 1.19-1.79, vs RR = 1.36, 95% CI 1.10-1.69, respectively, p = 0.65).

DISCUSSION: Almost half of the neurologic disease phase 3 trials were initiated without the support of a positive phase 2 trial. Although our analysis does not establish harm with bypass/override, its prevalence and the scientific rationale for phase 2 trial testing favor development of criteria defining when phase 2 bypass/override is justified.

PMID:38833654 | DOI:10.1212/WNL.0000000000209533

J Clin Oncol. 2024 Jun 4:JCO2302344. doi: 10.1200/JCO.23.02344. Online ahead of print.

ABSTRACT

PURPOSE: Phosphatidylinositol 3-kinase/AKT-serine threonine kinase/mammalian target of rapamycin (mTOR) pathway abnormalities contribute to endocrine resistance. Everolimus, an mTOR inhibitor, improved progression-free survival in hormone receptor-positive metastatic breast cancer (BC) when combined with endocrine therapy (ET). In this phase III randomized, placebo-controlled trial, we assessed the efficacy of everolimus + ET as adjuvant therapy in high-risk, hormone receptor-positive, human epidermal growth factor receptor 2-negative BC after adjuvant/neoadjuvant chemotherapy.

METHODS: Patients were randomly assigned 1:1 to physician’s choice ET and 1 year of everolimus (10 mg orally once daily) or placebo stratified by risk group. The primary end point was invasive disease-free survival (IDFS) evaluated by a stratified log-rank test with the hazard ratio (HR) estimated by Cox regression. Subset analyses included preplanned evaluation by risk group and exploratory analyses by menopausal status and age. Secondary end points included overall survival (OS) and safety. Everolimus did not improve IDFS/OS when added to ET in patients with early-stage high-risk, hormone receptor-positive BC.

RESULTS: One thousand and nine hundred thirty-nine patients were randomly assigned with 1,792 eligible for analysis. Overall, no benefit of everolimus was seen for IDFS (HR, 0.94 [95% CI, 0.77 to 1.14]) or OS (HR, 0.97 [95% CI, 0.75 to 1.26]). The assumption of proportional hazards was not met suggesting significant variability in the HR over time since the start of treatment. In an unplanned subgroup analysis among postmenopausal patients (N = 1,221), no difference in IDFS (HR, 1.08 [95% CI, 0.86 to 1.36]) or OS (HR, 1.19 [95% CI, 0.89 to 1.60]) was seen. In premenopausal patients (N = 571), everolimus improved both IDFS (HR, 0.64 [95% CI, 0.44 to 0.94]) and OS (HR, 0.49 [95% CI, 0.28 to 0.86]). Treatment completion rates were lower in the everolimus arm compared with placebo (48% v 73%) with higher grade 3 and 4 adverse events (35% v 7%).

CONCLUSION: One year of adjuvant everolimus + ET did not improve overall outcomes. Subset analysis suggests mTOR inhibition as a possible target for patients who remain premenopausal after chemotherapy.

PMID:38833643 | DOI:10.1200/JCO.23.02344

Cardiovasc Res. 2024 Jun 4:cvae123. doi: 10.1093/cvr/cvae123. Online ahead of print.

ABSTRACT

AIMS: Evaluate sex differences in cardiovascular disease (CVD) risk prediction, including use of i) optimal sex-specific risk predictors and ii) sex-specific risk thresholds.

METHODS AND RESULTS: Prospective cohort study using UK Biobank, including 121,724 and 182,632 healthy men and women, respectively, aged 38-73 years at baseline. There were 11,899 (men) and 9,110 (women) incident CVD cases (hospitalization or mortality) with median 12.1 years follow-up. We used recalibrated Pooled Cohort Equations (PCE, 7.5% 10-year risk threshold as per US guidelines), QRISK3 (10% 10-year risk threshold as per UK guidelines) and Cox survival models using sparse sex-specific variable sets (via LASSO stability selection) to predict CVD risk separately in men and women. LASSO stability selection included 12 variables in common between men and women, with three additional variables selected for men and one for women. C-statistics were slightly lower for PCE than QRISK3 and models using stably-selected variables, but were similar between men and women: 0.67 [0.66-0.68], 0.70 [0.69-0.71], and 0.71 [0.70-0.72] in men and 0.69 [0.68-0.70], 0.72 [0.71-0.73], and 0.72 [0.71-0.73] in women for PCE, QRISK3 and models using stably-selected variables, respectively. At current clinically implemented risk thresholds, test sensitivity was markedly lower in women than men for all models: at 7.5% 10-year risk, sensitivity was 65.1% and 68.2% in men and 24.0% and 33.4% in women for PCE and models using stably-selected variables, respectively; at 10% 10-year risk, sensitivity was 53.7% and 52.3% in men and 16.8% and 20.2% in women for QRISK3 and models using stably-selected variables, respectively. Specificity was correspondingly higher in women than men. However, the sensitivity in women at 5% 10-year risk threshold increased to 50.1%, 58.5% and 55.7% for PCE, QRISK3 and models using stably-selected variables, respectively.

CONCLUSIONS: Use of sparse sex-specific variables improved CVD risk prediction compared with PCE but not QRISK3. At current risk thresholds, PCE and QRISK3 work less well for women than men but sensitivity was improved in women using a 5% 10-year risk threshold. Use of sex-specific risk thresholds should be considered in any re-evaluation of CVD risk calculators.

TRANSLATIONAL PERSPECTIVE: Cardiovascular disease (CVD) risk prediction is an important component of clinical risk management and disease prevention. We find that at risk prediction thresholds used by currently applied risk prediction algorithms (PCE 7.5% 10-year risk threshold in the US and QRISK3 10% risk threshold in the UK), sensitivity of these risk prediction tools is markedly lower in women than in men. This sex inequality implies that women are proportionately less likely to receive appropriate clinical management including lipid-lowering therapy. If the risk prediction threshold is lowered to 5% 10-year risk in women, then sensitivity in women is substantially increased.

PMID:38833617 | DOI:10.1093/cvr/cvae123

Pain. 2024 Jun 4. doi: 10.1097/j.pain.0000000000003280. Online ahead of print.

ABSTRACT

This trial assessed the efficacy of naproxen in patients with sciatica in outpatient clinics across 4 Norwegian hospitals. A total of 123 adults with radiating pain below the knee (≥4 on a 0-10 numeric rating scale) and signs consistent with nerve root involvement were included. Participants were randomized to receive either naproxen 500 mg or a placebo twice daily for 10 days. The primary outcome, daily leg pain intensity measured on a 0 to 10 numeric rating scale throughout the treatment period, revealed a statistically significant difference in favor of naproxen, with an adjusted mean difference of -0.5 (95% CI -0.8 to -0.1, P = 0.015). In the naproxen group, the treatment effect was significantly related to time, and over the whole 10-day period, the average adjusted difference was -0.6 (95% CI -0.8 to -0.5). Mean numbers needed to treat for 30% and 50% improvement were 9.9 (95% CI 4.7-15.0) and 20.7 (8.7-32.7), respectively. The adjusted mean difference for back pain was -0.4 (95% CI -0.8 to 0.0), and for Roland Morris Disability Questionnaire for Sciatica, it was -1.5 (95% CI -3.0 to 0.0). No differences were found for sciatica bothersomeness or consumption of rescue medication or opioids. Participants in the naproxen group exhibited an adjusted odds ratio of 4.7 (95% CI 1.3-16.2) for improvement by 1 level on the global perceived change scale. In conclusion, naproxen treatment showed small, likely clinically unimportant benefits compared with placebo in patients with moderate-to-severe sciatica.

PMID:38833590 | DOI:10.1097/j.pain.0000000000003280

J Perinat Neonatal Nurs. 2024 Jan 10. doi: 10.1097/JPN.0000000000000746. Online ahead of print.

ABSTRACT

BACKGROUND: Gastric tube insertion is necessary to support early enteral feeding of newborns during their neonatal intensive care stay. This frequent and invasive procedure is known to be painful. Very few analgesic techniques (sweet solutions, sucking, swaddling, and skin-to-skin contact) are available to reduce the pain caused by orogastric tube insertion procedure.

OBJECTIVE: To determine whether a new orogastric tube insertion technique modifies the pain response in newborns, we hypothesize that inserting an orogastric tube through the nipple of a bottle reduces pain caused by this procedure.

DESIGN: Prospective, controlled, randomized, multicentered and open label study.

SETTINGS: Three neonatal intensive care units in France (2 level 3 units and 1 level 2B).

PARTICIPANTS: Full-term or premature newborns at 32 weeks of gestation or more, postnatal age between 48 hours and 21 days, not ventilated and requiring enteral feeding, were randomized into 2 groups: usual technique (n = 36) and experimental technique (n = 35).

METHODS: Our experimental technique was to insert the orogastric tube through a modified nipple of a bottle. This method was compared with the usual technique of inserting the tube directly into the newborn’s mouth without a support to guide it accompanied by a nipple encouraging sucking with a nonnutritive solution. An association of nonnutritive sucking and orally administered 30% glucose was given to all children for analgesic purposes. Pain during the orogastric tube insertion was assessed on video recordings by 2 independent experts, using a heteroassessment behavioral scale for pain (DAN-Douleur Aiguë du Nouveau-né; APN-Acute Pain in Newborns). The primary outcome was an Acute Pain in Newborns score of less than 3 at the time of the procedure. Comparisons were made using Fisher exact test or Mann-Whitney U test. Factors associated with an Acute Pain in Newborns score of 3 and greater were explored using univariable and multivariable regression models.

RESULTS: All but 1 video recording in each group were analyzed. Among the 34 neonates in the experimental group, 71.4% (95% CI: [53.7-85.4]) had an Acute Pain in Newborns score of less than 3 during orogastric tube insertion versus 41% (95% CI: [27.9-61.9]) in the control group (P = .031). Gagging was frequent and nonsignificantly different between the 2 groups (69% in the control group, 51% in the experimental group, P = .13). In multivariable analysis, the experimental technique was an independent factor of pain prevention compared with the usual technique (odds ratio = 0.21 [0.06-0.71], P = .015).

CONCLUSIONS: This study suggests that a simple, inexpensive, and feasible technique of orogastric tube insertion through the nipple of a bottle limits pain associated with this procedure in newborns.

PMID:38833575 | DOI:10.1097/JPN.0000000000000746

J Healthc Qual. 2024 Jun 4. doi: 10.1097/JHQ.0000000000000432. Online ahead of print.

ABSTRACT

INTRODUCTION: Studies have demonstrated the efficacy of intravenous (IV) iron when administered to patients with congestive heart failure (CHF) and iron deficiency (ID). We aimed to better understand the adherence of treatment for ID among a population with CHF, with particular interest in high-risk groups not often studied due to inadequate recruitment.

METHODS: A retrospective chart review at our institution was conducted from January 1, 2012, to July 7, 2021. Analysis included hospitalized patients with CHF and ID and dividing these patients into two time periods based on changes in iron treatment patterns and treatment between sexes.

RESULTS: Four thousand eight hundred thirteen patients were included in this study. During the “early era,” 7.0% of patients with CHF and ID received IV iron compared with 20.9% of “late-era” patients. Female patients with ID were statistically less likely to receive IV iron when compared with male patients, both unadjusted (0.66, confidence interval [CI] 0.55-0.79, p < .0001) and adjusted (0.72, CI 0.59-0.87, p < .0001) for covariates.

CONCLUSION: This study illustrates improved adherence to treatment for ID among hospitalized population with CHF and ID over time but persistent undertreatment remains. Future studies will need to identify the barriers to treating female patients with CHF and ID to reduce these disparities.

PMID:38833574 | DOI:10.1097/JHQ.0000000000000432

J Addict Med. 2024 May-Jun 01;18(3):335-338. doi: 10.1097/ADM.0000000000001287.

ABSTRACT

OBJECTIVES: Overdose mortality has risen most rapidly among racial and ethnic minority groups while buprenorphine prescribing has increased disproportionately in predominantly non-Hispanic White urban areas. To identify whether buprenorphine availability equitably meets the needs of diverse populations, we examined the differential geographic availability of buprenorphine in areas with greater concentrations of racial and ethnic minority groups.

METHODS: Using IQVIA longitudinal prescription data, IQVIA OneKey data, and Microsoft Bing Maps, we calculated 2 outcome measures across the continental United States: the number of buprenorphine prescribers per 1000 residents within a 30-minute drive of a ZIP code, and the number of buprenorphine prescriptions dispensed per capita at retail pharmacies among nearby buprenorphine prescribers. We then estimated differences in these outcomes by ZIP codes’ racial and ethnic minority composition and rurality with t tests.

RESULTS: Buprenorphine prescribers per 1000 residents within a 30-minute drive decreased by 3.8 prescribers per 1000 residents in urban ZIP codes (95% confidence interval = -4.9 to -2.7) and 2.6 in rural ZIP codes (95% confidence interval = -3.0 to -2.2) whose populations consisted of ≥5% racial and ethnic minority groups. There were 45% to 55% fewer prescribers in urban areas and 62% to 79% fewer prescribers in rural areas as minority composition increased. Differences in dispensed buprenorphine per capita were similar but larger in magnitude.

CONCLUSIONS: Achieving more equitable buprenorphine access requires not only increasing the number of buprenorphine-prescribing clinicians; in urban areas with higher racial and ethnic minority group populations, it also requires efforts to promote greater buprenorphine prescribing among already prescribing clinicians.

PMID:38833558 | DOI:10.1097/ADM.0000000000001287

Sex Health. 2024 Jun;21:SH24033. doi: 10.1071/SH24033.

ABSTRACT

Background In mid-2022 Australia’s National Cervical Screening Program made self-collection of a vaginal sample an option for screening for young women or people with a cervix aged 25 to 29 years for the first time. This study explored what young women thought about, and wanted to know about, self-collection, and what their future screening preferences are. Methods Young women (n =21), aged 24-29years, were recruited through social media. Semi-structured interviews explored screening history, screening preferences and thoughts about self-collection. Data were analysed using an a priori coding framework informed by the Theoretical Framework of Acceptability. Results Young women valued the addition of self-collection to the national cervical screening program, believing it to be less invasive and more convenient. However, they also valued the choice to opt for a clinician-collected specimen if preferred. Conclusions Self-collection is a valuable addition to the National Cervical Screening Program. This study suggests that continued efforts are needed to raise awareness of its availability, and improve understanding about its accuracy, the ease of collection, that you still need to engage with a primary healthcare service to access it and that you can still opt for a clinician-collected test.

PMID:38833543 | DOI:10.1071/SH24033