Pooled analyses of immune-related adverse events (irAEs) and efficacy from the phase 3 trials IMpower130, IMpower132, and IMpower150.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 9002-9002
Author(s):  
Mark A. Socinski ◽  
Robert M. Jotte ◽  
Federico Cappuzzo ◽  
Makoto Nishio ◽  
Tony S. K. Mok ◽  
...  
Keyword(s):  
Cox Model ◽  
Stage Iv ◽  
Pooled Analysis ◽  
Time Dependent ◽  
Pooled Data ◽  
Study Protocols ◽  
Improved Outcomes ◽  
Landmark Data ◽  
Landmark Analyses ◽  
And Control

9002 Background: PD-L1/PD-1 inhibitors have transformed the treatment (tx) of advanced NSCLC. Evidence suggests that the occurrence of irAEs with these agents may predict improved outcomes in cancers such as NSCLC. Atezolizumab (atezo; anti–PD-L1) has shown efficacy and tolerability in NSCLC and is currently approved in the 1L and 2L+ settings. The Ph 3 IMpower130, IMpower132 and IMpower150 trials evaluated atezo + chemo ± bevacizumab (bev) as 1L tx of NSCLC. We explore the association between irAEs and efficacy in these trials. Methods: Each trial enrolled tx-naive patients (pts) with nonsquamous stage IV NSCLC. Pts were randomized to: carboplatin (carbo) + nab-paclitaxel alone or with atezo in IMpower130; carbo or cisplatin alone or with atezo in IMpower132; atezo (A) + bev (B) + carbo + paclitaxel (CP), ACP or BCP in IMpower150. Data were pooled (data cutoffs: Mar 15 2018 [IMpower130]; May 22 2018 [IMpower132]; Sep 13 2019 [IMpower150]) and analyzed by tx (atezo-containing vs control) and irAE status. A time-dependent Cox model and landmark analyses at 1, 3, 6 and 12 mo were used to control for immortal bias. Study protocols required atezo tx interruption/discontinuation for grade (Gr) ≥3 irAEs. Results: 2503 pts were included in the analysis (atezo, n = 1577; control, n = 926). In both arms, baseline characteristics were generally balanced between pts with irAEs (atezo, n = 753; control, n = 289) and without irAEs (atezo, n = 824; control, n = 637). Any-Gr irAEs occurred in 48% (atezo) and 32% (control) of pts; Gr 3-5 irAEs occurred in 11% (atezo) and 5% (control). The most common irAEs (atezo vs control) were rash (28% vs 18%), hepatitis (lab abnormalities; 15% vs 10%) and hypothyroidism (12% vs 4%). Median time to onset of first irAE was 1.7 (atezo) vs 1.4 mo (control). OS HRs (95% CI) from the time-dependent Cox model between pts with vs without irAEs were 0.69 (0.60, 0.78) in the atezo arm and 0.82 (0.68, 0.99) in the control arm; after excluding rash (perceived as the least specific irAE), OS HRs (95% CI) were 0.75 (0.65, 0.87) and 0.90 (0.71, 1.12), respectively. OS landmark data are in the Table. Conclusions: In this exploratory pooled analysis, pts with irAEs had longer OS vs pts without irAEs in the atezo-containing and control arms per the time-dependent Cox model and landmark analyses; this trend remained for the atezo arm after excluding rash. Landmark analyses suggest that in the atezo arm, pts with Gr 1/2 irAEs had the longest OS and pts with Gr ≥3 irAEs had the shortest OS, potentially due to tx interruption/discontinuation. Clinical trial information: NCT02367781; NCT02657434; NCT02366143. [Table: see text]

Is it Worth CANVASing for CREDENCE? A Benefit-risk Analysis

2020 ◽  
Vol 16 (5) ◽  
pp. 509-514
Author(s):  
Binayak Sinha ◽  
Samit Ghosal
Keyword(s):  
Adverse Events ◽  
Fungal Infections ◽  
Absolute Risk ◽  
Pooled Analysis ◽  
Major Adverse Cardiovascular Events ◽  
Number Needed To Treat ◽  
Pooled Data ◽  
The Individual ◽  
Fracture Risks ◽  
Number Needed To Harm

Background and Aims: A number of significant positive and negative signals emerged from the CANVAS Program and CREDENCE trial with the use of canagliflozin. These signals are confusing. A Likelihood of being Helped of Harmed (LHH) analysis was conducted to determine the risk, benefit ratio associated with canagliflozin use and address the signals as a continuum. Materials &Methods: LHH was calculated from the number needed to treat (NNT) and number needed to harm (NNH) available from the absolute risk reductions reported with the outcomes of interest, in these two trials. Results: In the CANVAS Program, LHH for major adverse cardiovascular events (MACE) points at a significant benefit with canagliflozin use in comparison to amputation (1.65), fractures (1.65) and euglycaemic diabetic ketoacidosis (euDKA) (16.67) risks. Only genital fungal infections were significant more in both sexes (0.21-M and 0.1-F) when LHH was matched against the positive outcomes. In contrast, the hHF benefits were outweighed by amputation (0.95) and fracture risks (0.95). : In CREDENCE trial, the LHH for Primary composite, Renal composite and MACE, all supported the benefits in comparison to any adverse events encountered in the trial. : The LHH from pooled data (CANVAS Program and CREDENCE trial) was in favour of all the benefits (hHF and renal composites) except for MACE matched against amputation (0.66). Conclusion: The outcome benefits were in favour of canagliflozin in comparison to all reported adverse events, when hHF and renal composite were under consideration, in both the individual and pooled LHH analysis. However, the MACE benefits were overwhelmed by amputation risk in the pooled analysis.

School-based obesity interventions in the metropolitan area of Rio De Janeiro, Brazil: pooled analysis from five randomised studies

2021 ◽  
pp. 1-7
Author(s):  
Renata da R. M. Rodrigues ◽  
Bruna K. Hassan ◽  
Michele R. Sgambato ◽  
Bárbara da S. N. Souza ◽  
Diana B. Cunha ◽  
...  
Keyword(s):  
Eating Habits ◽  
Intervention Group ◽  
Pooled Analysis ◽  
Control Group ◽  
Intention To Treat ◽  
School Year ◽  
School Based ◽  
Obesity Interventions ◽  
The One ◽  
And Control

Abstract School-based studies, despite the large number of studies conducted, have reported inconclusive results on obesity prevention. The sample size is a major constraint in such studies by requiring large samples. This pooled analysis overcomes this problem by analysing 5926 students (mean age 11·5 years) from five randomised school-based interventions. These studies focused on encouraging students to change their drinking and eating habits, and physical activities over the one school year, with monthly 1-h sessions in the classroom; culinary class aimed at developing cooking skills to increase healthy eating and attempts to family engagement. Pooled intention-to-treat analysis using linear mixed models accounted for school clusters. Control and intervention groups were balanced at baseline. The overall result was a non-significant change in BMI after one school year of positive changes in behaviours associated with obesity. Estimated mean BMI changed from 19·02 to 19·22 kg/m2 in the control group and from 19·08 to 19·32 kg/m2 in the intervention group (P value of change over time = 0·09). Subgroup analyses among those overweight or with obesity at baseline also did not show differences between intervention and control groups. The percentage of fat measured by bioimpedance indicated a small reduction in the control compared with intervention (P = 0·05). This large pooled analysis showed no effect on obesity measures, although promising results were observed about modifying behaviours associated with obesity.

scholarly journals Times to Key Events in the Course of Zika Infection and their Implications for Surveillance: A Systematic Review and Pooled Analysis

2016 ◽  
Author(s):  
Justin Lessler ◽  
Cassandra T. Ott ◽  
Andrea C. Carcelen ◽  
Jacob M. Konikoff ◽  
Joe Williamson ◽  
...  
Keyword(s):  
Systematic Review ◽  
Blood Supply ◽  
Zika Virus ◽  
Blood Donation ◽  
Case Reports ◽  
Fold Increase ◽  
Pooled Analysis ◽  
Control Measures ◽  
History Of ◽  
And Control

Background Evidence suggests that Zika virus has driven a 10-fold increase in babies born with microcephaly in Brazil, prompting the WHO to declare a Public Health Emergency of International Concern. However, little is known about the natural history of infection. These data are critical for implementation of surveillance and control measures such as protecting the blood supply. Methods We conducted a systematic review and pooled analysis to estimate the distribution of times from Zika infection to symptom onset, seroconversion, and viral clearance, and analyzed their implications for surveillance and blood supply safety. Results Based on 25 case reports, we estimate the median incubation period of Zika virus infection is 5.9 days (95% CI: 4.4-7.6), and that 95% of cases will develop symptoms by 11.1 days post-infection (95% CI: 7.6-18.0). On average seroconversion occurs 9.0 days (95% CI, 7.0-11.6) after infection, and virus is detectable in blood for 9.9 days (95% CI: 6.8-21.4). In 5% of cases detectable virus persists for over 18.9 days (95% CI: 12.6-79.5). The baseline (no screening) risk of a blood donation being infected with Zika increases by approximately 1 in 10,000 for every 1 per 100,000 person-days increase in Zika incidence. Symptom based screening reduces this by 7% (RR 0.93, 93% CI 0.86-0.99), and antibody screening by 29% (RR 0.71, 95% CI: 0.28-0.88). Conclusions Symptom or antibody-based surveillance can do little to reduce the risk of Zika contaminated blood donations. High incidence areas may consider PCR testing to identify lots safe for use in pregnant women.

Social care

2020 ◽  
pp. 361-370
Author(s):  
Jo Moriarty
Keyword(s):  
Mental Health ◽  
Social Care ◽  
Mental Health Problems ◽  
Health Problems ◽  
Term Care ◽  
Improved Outcomes ◽  
Broad Term ◽  
Key Policy ◽  
And Control

Social care is the broad term for the support provided to people living at home and in care homes. Major changes have taken place to this sector in the past few years and this chapter describes the key policy developments that have impacted upon the kind of support provided to older people with mental health problems and how that support is funded. The policy of personalization is intended to increase choice and control, but as yet it is unclear whether this will lead to improved outcomes in terms of quality of life or independence. Some long-standing issues, such as the high prevalence of people with unidentified mental health problems in long-term care, continue to provide challenges for organizations providing social care support.

scholarly journals A Personalized Approach to Guide Allogeneic Stem Cell Transplantation in Younger Adults with Acute Myeloid Leukemia.

Blood ◽  
2020 ◽  
Author(s):  
Laurène Fenwarth ◽  
Xavier Thomas ◽  
Stéphane de Botton ◽  
Nicolas Duployez ◽  
Jean-Henri Bourhis ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Good Prognosis ◽  
Time Dependent ◽  
Similar Time ◽  
Hematopoietic Stem ◽  
Multistage Model ◽  
Landmark Analyses ◽  
Personalized Approach

A multistage model instructed by a large dataset (knowledge bank [KB] algorithm) has recently been developed to improve outcome prediction and tailor therapeutic decision, including hematopoietic stem cell transplantation (HSCT) in AML. We assessed the performance of the KB in guiding HSCT decision in first complete remission (CR1) in 656 AML patients younger than 60 years from the ALFA-0702 trial (NCT00932412). KB predictions of Overall Survival (OS) were superior to those of European LeukemiaNet (ELN) 2017 risk stratification (C-index 68.9 versus 63.0). Among patients reaching CR1, HSCT in CR1, as a time-dependent covariate was detrimental in those with favorable ELN 2017 risk and those with negative NPM1 MRD (interaction tests P=0.01 and P=0.02, respectively). Using KB simulations of survival at 5 years in a scenario without HSCT in CR1 (KB score), we identified in a similar time-dependent analysis a significant interaction between the KB score and HSCT, with HSCT in CR1 being detrimental only in patients with a good prognosis based on KB simulations (KB score ≥40, interaction test P=0.01). We could finally integrate ELN 2017, NPM1 MRD and KB scores to sort 545 CR1 patients into 278 (51.0%) HSCT candidates and 267 (49.0%) chemo-only candidates. In both time-dependent and 6-month landmark analyses, HSCT significantly improved OS in HSCT candidates while it significantly shortened OS in chemo-only candidates. Integrating KB predictions with ELN 2017 and MRD may thus represent a promising approach to optimize HSCT timing in younger AML patients.

Imputing missing time-dependent covariate values for the discrete time Cox model

2019 ◽  
Vol 29 (8) ◽  
pp. 2074-2086
Author(s):  
Havi Murad ◽  
Rachel Dankner ◽  
Alla Berlin ◽  
Liraz Olmer ◽  
Laurence S Freedman
Keyword(s):  
Discrete Time ◽  
Missing Values ◽  
Cox Regression ◽  
Cox Model ◽  
Missing At Random ◽  
Time Dependent ◽  
Outcome Variable ◽  
Sequential Approach ◽  
Random Patterns ◽  
Event Times

We describe a procedure for imputing missing values of time-dependent covariates in a discrete time Cox model using the chained equations method. The procedure multiply imputes the missing values for each time-period in a time-sequential manner, using covariates from the current and previous time-periods as well as the survival outcome. The form of the outcome variable used in the imputation model depends on the functional form of the time-dependent covariate(s) and differs from the case of Cox regression with only baseline covariates. This time-sequential approach provides an approximation to a fully conditional approach. We illustrate the procedure with data on diabetics, evaluating the association of their glucose control with the risk of selected cancers. Using simulations we show that the suggested estimator performed well (in terms of bias and coverage) for completely missing at random, missing at random and moderate non-missing-at-random patterns. However, for very strong non-missing-at-random patterns, the estimator was seriously biased and the coverage was too low. The procedure can be implemented using multiple imputation with the Fully conditional Specification (FCS) method (MI procedure in SAS with FCS statement or similar packages in other software, e.g. MICE in R). For use with event times on a continuous scale, the events would need to be grouped into time-intervals.

scholarly journals Secukinumab efficacy on resolution of enthesitis in psoriatic arthritis: pooled analysis of two phase 3 studies

2019 ◽  
Vol 21 (1) ◽  
Author(s):  
Laura C. Coates ◽  
Johan K. Wallman ◽  
Dennis McGonagle ◽  
Georg A. Schett ◽  
Iain B. McInnes ◽  
...  
Keyword(s):  
Psoriatic Arthritis ◽  
Pooled Analysis ◽  
Search Query ◽  
Two Phase ◽  
Pooled Data ◽  
Link Type ◽  
Full Resolution ◽  
Shift Analysis ◽  
Post Hoc ◽  
Future 2

Abstract Background Enthesitis is one of the psoriatic arthritis (PsA) domains. Patients with enthesitis are associated with worse outcomes than those without enthesitis. The effect of secukinumab on the resolution of enthesitis in patients with PsA was explored using pooled data from the FUTURE 2 and 3 studies. Method Assessments of enthesitis through week 104 used the Leeds Enthesitis Index. These post hoc analyses included resolution of enthesitis count (EC = 0), median time to first resolution of enthesitis (Kaplan-Meϊer estimate), and shift analysis (as observed) of baseline EC (1, 2, or 3–6) to full resolution (FR), stable (similar or reduction of EC), or worse (EC > baseline). Efficacy outcomes (ACR, PASI, HAQ-DI, SF-36 PCS, and DAS28-CRP) were assessed in patients with or without baseline enthesitis. Results are reported for secukinumab 300 and 150 mg in the overall population and by prior TNFi treatment. Results A total of 65% (466/712) of patients had baseline enthesitis. In the overall population, FR was achieved as early as week 16 in 65% (300 mg) and 56% (150 mg) versus 44% (placebo) patients, with further improvements to 91% (300 mg) and 88% (150 mg) at week 104. The majority (89%) of patients without enthesitis at baseline maintained this status at week 104. Median days to resolution of EC were shorter with secukinumab 300 and 150 mg versus placebo (57 and 85 vs 167 days, respectively). In patients with EC of 1 or 2, shift analysis from baseline to week 24 showed that more patients achieved FR with secukinumab 300 mg and 150 mg versus placebo, whereas no difference between secukinumab and placebo was shown in the more severe patients with EC of 3–6. Increases in proportions of patients with FR were observed with secukinumab irrespective of the severity of EC from baseline to week 104. Improvements in efficacy outcomes were similar in patients with or without enthesitis treated with secukinumab 300 mg. Conclusion Secukinumab provided early and sustained resolution of enthesitis in patients with PsA over 2 years. Secukinumab 300 mg provided higher resolution than 150 mg in patients with more severe baseline EC and showed similar overall efficacy in patients with or without enthesitis. Trial registration FUTURE 2: ClinicalTrials.gov, NCT01752634 (date of study registration: December 19, 2012), and EudraCT, 2012-004439-22 (date of study registration: December 12, 2012) FUTURE 3: ClinicalTrials.gov, NCT01989468 (date of study registration: November 21, 2013), and EudraCT, 2013-004002-25 (date of study registration: December 17, 2013)

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