Atezolizumab plus bevacizumab versus active surveillance in patients with resected or ablated high-risk hepatocellular carcinoma (IMbrave050): a randomised, open-label, multicentre, phase 3 trial.

BACKGROUND: No adjuvant treatment has been established for patients who remain at high risk for hepatocellular carcinoma recurrence after curative-intent resection or ablation. We aimed to assess the efficacy of adjuvant atezolizumab plus bevacizumab versus active surveillance in patients with high-risk hepatocellular carcinoma. METHODS: In the global, open-label, phase 3 IMbrave050 study, adult patients with high-risk surgically resected or ablated hepatocellular carcinoma were recruited from 134 hospitals and medical centres in 26 countries in four WHO regions (European region, region of the Americas, South-East Asia region, and Western Pacific region). Patients were randomly assigned in a 1:1 ratio via an interactive voice-web response system using permuted blocks, using a block size of 4, to receive intravenous 1200 mg atezolizumab plus 15 mg/kg bevacizumab every 3 weeks for 17 cycles (12 months) or to active surveillance. The primary endpoint was recurrence-free survival by independent review facility assessment in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT04102098. FINDINGS: The intention-to-treat population included 668 patients randomly assigned between Dec 31, 2019, and Nov 25, 2021, to either atezolizumab plus bevacizumab (n=334) or to active surveillance (n=334). At the prespecified interim analysis (Oct 21, 2022), median duration of follow-up was 17·4 months (IQR 13·9-22·1). Adjuvant atezolizumab plus bevacizumab was associated with significantly improved recurrence-free survival (median, not evaluable [NE]; [95% CI 22·1-NE]) compared with active surveillance (median, NE [21·4-NE]; hazard ratio, 0·72 [adjusted 95% CI 0·53-0·98]; p=0·012). Grade 3 or 4 adverse events occurred in 136 (41%) of 332 patients who received atezolizumab plus bevacizumab and 44 (13%) of 330 patients in the active surveillance group. Grade 5 adverse events occurred in six patients (2%, two of which were treatment related) in the atezolizumab plus bevacizumab group, and one patient (<1%) in the active surveillance group. Both atezolizumab and bevacizumab were discontinued because of adverse events in 29 patients (9%) who received atezolizumab plus bevacizumab. INTERPRETATION: Among patients at high risk of hepatocellular carcinoma recurrence following curative-intent resection or ablation, recurrence-free survival was improved in those who received atezolizumab plus bevacizumab versus active surveillance. To our knowledge, IMbrave050 is the first phase 3 study of adjuvant treatment for hepatocellular carcinoma to report positive results. However, longer follow-up for both recurrence-free and overall survival is needed to assess the benefit-risk profile more fully. FUNDING: F Hoffmann-La Roche/Genentech.

Meta-Analysis of 49 Roche Oncology Trials Comparing Blinded Independent Central Review (BICR) and Local Evaluation to Assess the Value of BICR.

BACKGROUND: Blinded independent central review (BICR) of radiographic images is frequently conducted in oncology trials to address the potential bias of local evaluation (LE) of endpoints such as progression-free survival (PFS) and objective response rate (ORR). Given that BICR is a complex and costly process, we evaluated the agreement between LE- and BICR-based treatment effect results and the impact of BICR on regulatory decision-making. MATERIALS AND METHODS: Meta-analyses were performed using hazard ratios (HRs) for PFS and odds ratios (ORs) for ORR from all randomized Roche-supported oncology clinical trials during 2006-2020 that had both LE and BICR results (49 studies with a total of over 32 000 patients). RESULTS: Overall, the evaluation bias of LE overestimating the treatment effect compared with BICR based on PFS was numerically small and not clinically meaningful, especially for double-blind studies (HR ratio between BICR and LE: 1.044). A larger bias is more likely to occur in studies with open-label design, smaller sample sizes, or an unequal randomization ratio. The majority (87%) of the PFS comparisons led to the same statistical inference by BICR and LE. For ORR, a high degree of agreement between BICR and LE results was also observed (OR ratio of 1.065), although the agreement was slightly lower than for PFS. CONCLUSION: BICR did not notably impact the study interpretation nor drive the sponsor's regulatory submission decisions. Hence, if bias can be diminished by appropriate means, LE is deemed as reliable as BICR for certain study settings.

Accounting for post-randomization variables in meta-analysis: A joint meta-regression approach.

Meta-regression is widely used in systematic reviews to investigate sources of heterogeneity and the association of study-level covariates with treatment effectiveness. Existing meta-regression approaches are successful in adjusting for baseline covariates, which include real study-level covariates (e.g., publication year) that are invariant within a study and aggregated baseline covariates (e.g., mean age) that differ for each participant but are measured before randomization within a study. However, these methods have several limitations in adjusting for post-randomization variables. Although post-randomization variables share a handful of similarities with baseline covariates, they differ in several aspects. First, baseline covariates can be aggregated at the study level presumably because they are assumed to be balanced by the randomization, while post-randomization variables are not balanced across arms within a study and are commonly aggregated at the arm level. Second, post-randomization variables may interact dynamically with the primary outcome. Third, unlike baseline covariates, post-randomization variables are themselves often important outcomes under investigation. In light of these differences, we propose a Bayesian joint meta-regression approach adjusting for post-randomization variables. The proposed method simultaneously estimates the treatment effect on the primary outcome and on the post-randomization variables. It takes into consideration both between- and within-study variability in post-randomization variables. Studies with missing data in either the primary outcome or the post-randomization variables are included in the joint model to improve estimation. Our method is evaluated by simulations and a real meta-analysis of major depression disorder treatments.

Ipatasertib plus paclitaxel for PIK3CA/AKT1/PTEN-altered hormone receptor-positive HER2-negative advanced breast cancer: primary results from cohort B of the IPATunity130 randomized phase 3 trial.

PURPOSE: PI3K/AKT pathway alterations are frequent in hormone receptor-positive (HR+) breast cancers. IPATunity130 Cohort B investigated ipatasertib-paclitaxel in PI3K pathway-mutant HR+ unresectable locally advanced/metastatic breast cancer (aBC). METHODS: Cohort B of the randomized, double-blind, placebo-controlled, phase 3 IPATunity130 trial enrolled patients with HR+ HER2-negative PIK3CA/AKT1/PTEN-altered measurable aBC who were considered inappropriate for endocrine-based therapy (demonstrated insensitivity to endocrine therapy or visceral crisis) and were candidates for taxane monotherapy. Patients with prior chemotherapy for aBC or relapse < 1 year since (neo)adjuvant chemotherapy were ineligible. Patients were randomized 2:1 to ipatasertib (400 mg, days 1-21) or placebo, plus paclitaxel (80 mg/m2, days 1, 8, 15), every 28 days until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed progression-free survival (PFS). RESULTS: Overall, 146 patients were randomized to ipatasertib-paclitaxel and 76 to placebo-paclitaxel. In both arms, median investigator-assessed PFS was 9.3 months (hazard ratio, 1.00, 95% CI 0.71-1.40) and the objective response rate was 47%. Median paclitaxel duration was 6.9 versus 8.8 months in the ipatasertib-paclitaxel versus placebo-paclitaxel arms, respectively; median ipatasertib/placebo duration was 8.0 versus 9.1 months, respectively. The most common grade ≥ 3 adverse events were diarrhea (12% with ipatasertib-paclitaxel vs 1% with placebo-paclitaxel), neutrophil count decreased (9% vs 7%), neutropenia (8% vs 9%), peripheral neuropathy (7% vs 3%), peripheral sensory neuropathy (3% vs 5%) and hypertension (1% vs 5%). CONCLUSION: Adding ipatasertib to paclitaxel did not improve efficacy in PIK3CA/AKT1/PTEN-altered HR+ HER2-negative aBC. The ipatasertib-paclitaxel safety profile was consistent with each agent's known adverse effects. Trial registration NCT03337724.

Culturally adapted and lay-delivered cognitive behaviour therapy for older adults with depressive symptoms in rural China: a pilot trial.

BACKGROUND: Late-life depression issues in developing countries are challenging because of understaffing in mental health. Cognitive behavioural therapy (CBT) is effective for treating depression. AIM: This pilot trial examined the adherence and effectiveness of an eight-session adapted CBT delivered by trained lay health workers for older adults with depressive symptoms living in rural areas of China, compared with the usual care. METHOD: Fifty with screen-positive depression were randomly assigned to the CBT arm or the care as usual (CAU) arm. The primary outcomes were the session completion of older adults and changes in depressive symptoms, assessed using the Geriatric Depression Scale (GDS). RESULTS: The majority (19/24) of participants in the CBT arm completed all sessions. Mixed-effect linear regression showed that the CBT reduced more GDS scores over time compared with CAU. CONCLUSION: Lay-delivered culturally adapted CBT is potentially effective for screen-positive late-life depression.

Safety, Tolerability, and Pharmacokinetics of Crenezumab in Patients with Mild-to-Moderate Alzheimer's Disease Treated with Escalating Doses for up to 133 Weeks.

BACKGROUND: Crenezumab is a fully humanized, monoclonal anti-amyloid-ß immunoglobulin G4 antibody. OBJECTIVE: This Phase Ib study (NCT02353598) evaluated the safety, tolerability, and pharmacokinetics of crenezumabat doses of ≤120 mg/kg administered intravenously every 4 weeks (q4w). Immunogenicity and exploratory biomarkers were also evaluated. METHODS: In this multicenter, double-blind study, participants (aged 50-90 years) with mild-to-moderate Alzheimer's disease (AD) and amyloid-positive positron emission tomography (PET) scan were randomized to receive crenezumab 30 or 45 mg/kg (Cohort 1, n = 21), 60 mg/kg (Cohort 2, n = 21), or 120 mg/kg (Cohort 3, n = 19) or corresponding placebo (n = 14) intravenously q4w for 13 weeks. Seventy-one participants were subsequently enrolled in an optional open-label extension (OLE) and received crenezumab at the originally assigned dose level, except for Cohort 3 (crenezumab 60 mg/kg during OLE). Participants received regular brain MRIs to assess amyloid-related imaging abnormalities (ARIA). Results up to Week 133 are reported. RESULTS: Approximately 94% of participants experienced ≥1 adverse event (AE). Most AEs were mild or moderate; 15.5% experienced a Grade ≥3 AE. No ARIA-edema/effusion (ARIA-E) events were observed. New ARIA-micro hemorrhages and hemosiderosis (ARIA-H) were reported in 4.9% (double-blind treatment period) and 9.9% (combined double-blind treatment and OLE periods) of participants. Steady-state trough concentrations of crenezumab were dose-proportional and maintained for each dose level. CONCLUSION: Crenezumab doses of ≤120 mg/kg intravenously q4w were well tolerated. The observed safety profile for ≤133 weeks of treatment in a mild-to-moderate AD population was similar to that seen in previous trials.

Bayesian Network Meta-analysis of Multiple Outcomes in Dental Research.

OBJECTIVES: Dental research typically targets multiple outcomes. Interdental cleaning devices such as interdental brushes (IB) and water jet devices (WJ) share a sizable portion of the medical device market. However, recommendations for device selection are limited by the conflicting evidence from multiple outcomes in available studies and the lack of an appropriate synthesis approach to summarize evidences taken from multiple outcomes. In particular, both pairwise meta-analyses and single-outcome network meta-analyses can give discordant results. The purpose of this multioutcome, Bayesian network meta-analysis is to introduce this innovative method to the dental research community using data from interdental cleaning device studies for illustrative purposes. METHODS: We reanalyzed a network meta-analysis of interproximal oral hygiene methods in the reduction of clinical indices of inflammation, which included 22 trials assessing 10 interproximal oral hygiene aids. We focused on the primary outcome of gingival inflammation, which was measured by 2 correlated outcome variables, the Gingival Index (GI) and bleeding on probing (BOP). RESULTS: In our previous single-outcome analysis, we concluded that IB and WJ rank high for reducing gingival inflammation while toothpick and flossing rank last. In this multioutcome Bayesian network meta-analysis with equal weight on GI and BOP, the surface under the cumulative ranking curve was 0.87 for WJ and 0.85 for IB. WJ and IB remained ranked as the 2 best devices across different sets of weightings for the GI and BOP. CONCLUSION: In conclusion, multioutcome Bayesian network meta-analysis naturally takes the correlations among multiple outcomes into account, which in turn can provide more comprehensive evidence.

Baseline demographic, clinical, and cognitive characteristics of the Alzheimer's Prevention Initiative (API) Autosomal-Dominant Alzheimer's Disease Colombia Trial.

INTRODUCTION: The API AutosomalDominant AD (ADAD) Colombia Trial is a placebo-controlled clinical trial of crenezumab in 252 cognitively unimpaired 30 to 60-year-old Presenilin 1 (PSEN1) E280A kindred members, including mutation carriers randomized to active treatment or placebo and non-carriers who receive placebo. METHODS: Of the 252 enrolled, we present data on a total of 242 mutation carriers and non-carriers matched by age range, excluding data on 10 participants to protect participant confidentiality, genetic status, and trial integrity. RESULTS: We summarize demographic, clinical, cognitive, and behavioral data from 167 mutation carriers and 75 non-carriers, 30 to 53 years of age. Carriers were significantly younger than non-carriers ((mean age ± SD) 37 ± 5 vs 42 ± 6), had significantly lower Mini Mental Status Exam (MMSE) scores (28.8 ± 1.4 vs 29.2 ± 1.0), and had consistently lower memory scores. DISCUSSION: Although PSEN1 E280A mutation carriers in the Trial are cognitively unimpaired, they have slightly lower MMSE and memory scores than non-carriers. Their demographic characteristics are representative of the local population.

A Bayesian Hierarchical Summary Receiver Operating Characteristic Model for Network Meta-analysis of Diagnostic Tests.

In studies evaluating the accuracy of diagnostic tests, three designs are commonly used, crossover, randomized, and non-comparative. Existing methods for meta-analysis of diagnostic tests mainly consider the simple cases in which the reference test in all or none of the studies can be considered a gold standard test, and in which all studies use either a randomized or non-comparative design. The proliferation of diagnostic instruments and the diversity of study designs create a need for more general methods to combine studies that include or do not include a gold standard test and that use various designs. This paper extends the Bayesian hierarchical summary receiver operating characteristic model to network meta-analysis of diagnostic tests to simultaneously compare multiple tests within a missing data framework. The method accounts for correlations between multiple tests and for heterogeneity between studies. It also allows different studies to include different subsets of diagnostic tests and provides flexibility in the choice of summary statistics. The model is evaluated using simulations and illustrated using real data on tests for deep vein thrombosis, with sensitivity analyses.

A win ratio approach to the re-analysis of Multiple Risk Factor Intervention Trial.

BACKGROUND: Composite outcomes, which combine multiple types of clinical events into a single outcome, are common in clinical trials. The usual analysis considers the time to first occurrence of any event in the composite. The major criticisms of such an approach are (1) this implicitly treats the outcomes as if they were of equal importance, but they often vary in terms of clinical relevance and severity, (2) study participants often experience more than one type of event, and (3) often less severe events occur before more severe ones, but the usual analysis disregards any information beyond that first event. METHODS: A novel approach, referred to as the win ratio, which addresses the aforementioned criticisms of composite outcomes, is illustrated with a re-analysis of data on fatal and non-fatal cardiovascular disease time-to-event outcomes reported for the Multiple Risk Factor Intervention Trial. In this trial, 12,866 participants were randomized to a special intervention group (n = 6428) or a usual care (n = 6438) group. Non-fatal outcomes were ranked by risk of cardiovascular disease death up to 20 years after trial. In one approach, participants in the special intervention and usual care groups were first matched on coronary heart disease risk at baseline and time of enrollment. Each matched pair was categorized as a winner or loser depending on which one experienced a cardiovascular disease death first. If neither died of cardiovascular disease causes, they were evaluated on the most severe non-fatal outcome. This process continued for all the non-fatal outcomes. A second win ratio statistic, obtained from Cox partial likelihood, was also estimated. This statistic provides a valid estimate of the win ratio using multiple events if the marginal and conditional survivor functions of each outcome satisfy proportional hazards. Loss ratio statistics (inverse of win ratios) are compared to hazard ratios from the usual first event analysis. A larger 11-event composite was also considered. RESULTS: For the 7-event cardiovascular disease composite, the previously reported first event analysis based on 581 events in the special intervention group and 652 events in the usual care group yielded a hazard ratio (95% confidence interval) of 0.89 (0.79-0.99), compared to 0.86 (0.77-0.97) and 0.91 (0.81-1.02) for the severity ranked estimates. Results for the 11-event composite also confirmed the findings of the first event analysis. CONCLUSION: The win ratio analysis was able to leverage information collected past the first experienced event and rank events by severity. The results were similar to and confirmed previously reported traditional first event analysis. The win ratio statistic is a useful adjunct to the traditional first event analysis for trials with composite outcomes.

Real-world Performance of Meta-analysis Methods for Double-Zero-Event Studies with Dichotomous Outcomes Using the Cochrane Database of Systematic Reviews.

BACKGROUND: Meta-analysis combines multiple independent studies, which can increase power and provide better estimates. However, it is unclear how best to deal with studies with zero events; such studies are also known as double-zero-event studies (DZS). Several statistical methods have been proposed, but the agreement among different approaches has not been systematically assessed using real-world published systematic reviews. METHODS: The agreement of five commonly used methods (i.e., the inverse-variance, Mantel-Haenszel, Peto, Bayesian, and exact methods) was assessed using the Cohen's κ coefficients using 368 meta-analyses with rare events selected from the Cochrane Database of Systematic Reviews. Three continuity corrections, including the correction of a constant 0.5, the treatment arm continuity correction (TACC), and the empirical (EMP) correction, were used to handle DZS when applying inverse-variance and Mantel-Haenszel methods. RESULTS: When the proportion of DZS studies was lower than 50% in a meta-analysis, different methods had moderately high agreement. However, when this proportion was increased to be over 50%, the agreement among the methods decreased to different extents. For the Bayesian, exact, and Peto methods and the inverse-variance and Mantel-Haenszel methods using the EMP correction, their agreement coefficients with the inverse-variance and Mantel-Haenszel methods using a constant 0.5 and TACC decreased from larger than 0.70 to smaller than 0.30. In contrast, the agreement coefficients only decreased slightly among the Bayesian, exact, and Peto methods and the inverse-variance and Mantel-Haenszel methods using the EMP correction. CONCLUSIONS: To utilize all available information and reduce research waste and avoid overestimating the effect, meta-analysts should incorporate DZS, rather than simply removing them. The Peto and other conventional methods with continuity correction should be avoided when the proportion of DZS is extremely high. The exact and Bayesian methods are highly recommended, except when none of the included studies have an event in one or both treatment arms.

A Bayesian approach for correcting exposure misclassification in meta-analysis.

In observational studies, misclassification of exposure is ubiquitous and can substantially bias the estimated association between an outcome and an exposure. Although misclassification in a single observational study has been well studied, few papers have considered it in a meta-analysis. Meta-analyses of observational studies provide important evidence for health policy decisions, especially when large randomized controlled trials are unethical or unavailable. It is imperative to account properly for misclassification in a meta-analysis to obtain valid point and interval estimates. In this paper, we propose a novel Bayesian approach to filling this methodological gap. We simultaneously synthesize two (or more) meta-analyses, with one on the association between a misclassified exposure and an outcome (main studies), and the other on the association between the misclassified exposure and the true exposure (validation studies). We extend the current scope for using external validation data by relaxing the "transportability" assumption by means of random effects models. Our model accounts for heterogeneity between studies and can be extended to allow different studies to have different exposure measurements. The proposed model is evaluated through simulations and illustrated using real data from a meta-analysis of the effect of cigarette smoking on diabetic peripheral neuropathy.

A network meta-analysis of interproximal oral hygiene methods in the reduction of clinical indices of inflammation.

BACKGROUND: A wide selection of Interdental Oral Hygiene (IOH) aids is available to consumers. Recommendations for selection are, however, limited by the lack of direct comparisons in available studies. We aimed to assess the comparative efficacy of IOH aids using Bayesian Network Meta-Analysis (BNMA). METHODS: Two independent reviewers performed a systematic literature review of randomized clinical trials assessing IOH aids, based on a focused question. Gingival inflammation (Gingival Index (GI), Bleeding-on-probing (BOP)) was the primary outcome and plaque and probing depth were secondary outcomes A random-effects arm-based BNMA model was run for each outcome; posterior medians and 95% credible-intervals (CIs) summarized marginal distributions of parameters. RESULTS: A two-phase selection process identified 22 trials assessing 10 IOH aids as brushing adjuncts. Interdental brushes (IB) yielded the largest reduction in GI (0.23 [95% CI: 0.09, 0.37]) as toothbrushing adjuncts, followed by water-jet (WJ) (0.19 [95% CI: 0.14, 0.24]). Rankings based on posterior probabilities revealed that IB and WJ had the highest probability of being "best" (64.7% and 27.4%, respectively) for GI reduction, whereas the probability for toothpick and floss being the "best" IOH aids was near zero. Notably, except for toothpicks, all IOH aids were better at reducing GI as compared with control. CONCLUSIONS: BNMA enabled us to quantitatively evaluate IOH aids and provide a global ranking of their efficacy. Interdental brushes and water-jets ranked high for reducing gingival bleeding, whereas toothpicks and floss ranked last. The patient-perceived benefit of IOH aids is not clear because gingival inflammation measures are physical indicators of periodontal health.

Prescription opioids are associated with higher mortality in patients diagnosed with sepsis: A retrospective cohort study using electronic health records.

Sepsis continues to be a major problem for hospitalized patients. Opioids are widely used medications for pain management despite recent evidence revealing their adverse effects. The present study evaluates survival differences between opioid-treated patients and non-opioid-treated patients hospitalized with a diagnosis of sepsis. Clinical data was extracted from the University of Minnesota's Clinical Data Repository, which includes Electronic Health Records (EHRs) of the patients seen at 8 hospitals. Among 5,994 patients diagnosed with sepsis, 4,540 opioid-treated patients and 1,454 non-opioid patients were included based on whether they are exposed to prescription opioids during their hospitalization. Cox proportional hazards regression showed that after adjustments for demographics, clinical comorbidities, severity of illness, and types of infection, opioid-treated patients had a significantly higher risk of death at 28 days.

A Bayesian hierarchical model for network meta-analysis of multiple diagnostic tests.

To compare the accuracy of multiple diagnostic tests in a single study, three designs are commonly used (i) the multiple test comparison design; (ii) the randomized design, and (iii) the non-comparative design. Existing meta-analysis methods of diagnostic tests (MA-DT) have been focused on evaluating the performance of a single test by comparing it with a reference test. The increasing number of available diagnostic instruments for a disease condition and the different study designs being used have generated the need to develop efficient and flexible meta-analysis framework to combine all designs for simultaneous inference. In this article, we develop a missing data framework and a Bayesian hierarchical model for network MA-DT (NMA-DT) and offer important promises over traditional MA-DT: (i) It combines studies using all three designs; (ii) It pools both studies with or without a gold standard; (iii) it combines studies with different sets of candidate tests; and (iv) it accounts for heterogeneity across studies and complex correlation structure among multiple tests. We illustrate our method through a case study: network meta-analysis of deep vein thrombosis tests.