scholarly journals TREATMENT SWITCHING: STATISTICAL AND DECISION-MAKING CHALLENGES AND APPROACHES

2016 ◽  
Vol 32 (3) ◽  
pp. 160-166 ◽  
Author(s):  
Nicholas R. Latimer ◽  
Chris Henshall ◽  
Uwe Siebert ◽  
Helen Bell
Keyword(s):  
Statistical Methods ◽  
Failure Time ◽  
Controlled Trial ◽  
International Workshop ◽  
Experimental Treatment ◽  
Decision Makers ◽  
Control Group ◽  
Intention To Treat ◽  
Treatment Switching ◽  
New Treatment

Objectives: Treatment switching refers to the situation in a randomized controlled trial where patients switch from their randomly assigned treatment onto an alternative. Often, switching is from the control group onto the experimental treatment. In this instance, a standard intention-to-treat analysis does not identify the true comparative effectiveness of the treatments under investigation. We aim to describe statistical methods for adjusting for treatment switching in a comprehensible way for nonstatisticians, and to summarize views on these methods expressed by stakeholders at the 2014 Adelaide International Workshop on Treatment Switching in Clinical Trials.Methods: We describe three statistical methods used to adjust for treatment switching: marginal structural models, two-stage adjustment, and rank preserving structural failure time models. We draw upon discussion heard at the Adelaide International Workshop to explore the views of stakeholders on the acceptability of these methods.Results: Stakeholders noted that adjustment methods are based on assumptions, the validity of which may often be questionable. There was disagreement on the acceptability of adjustment methods, but consensus that when these are used, they should be justified rigorously. The utility of adjustment methods depends upon the decision being made and the processes used by the decision-maker.Conclusions: Treatment switching makes estimating the true comparative effect of a new treatment challenging. However, many decision-makers have reservations with adjustment methods. These, and how they affect the utility of adjustment methods, require further exploration. Further technical work is required to develop adjustment methods to meet real world needs, to enhance their acceptability to decision-makers.

scholarly journals Causal inference for long-term survival in randomised trials with treatment switching: Should re-censoring be applied when estimating counterfactual survival times?

2018 ◽  
Vol 28 (8) ◽  
pp. 2475-2493 ◽  
Author(s):  
NR Latimer ◽  
IR White ◽  
KR Abrams ◽  
U Siebert
Keyword(s):  
Treatment Effect ◽  
Failure Time ◽  
Survival Function ◽  
Experimental Treatment ◽  
Control Group ◽  
Survival Times ◽  
Term Survival ◽  
Long Term Survival ◽  
Treatment Switching

Treatment switching often has a crucial impact on estimates of effectiveness and cost-effectiveness of new oncology treatments. Rank preserving structural failure time models (RPSFTM) and two-stage estimation (TSE) methods estimate ‘counterfactual’ (i.e. had there been no switching) survival times and incorporate re-censoring to guard against informative censoring in the counterfactual dataset. However, re-censoring causes a loss of longer term survival information which is problematic when estimates of long-term survival effects are required, as is often the case for health technology assessment decision making. We present a simulation study designed to investigate applications of the RPSFTM and TSE with and without re-censoring, to determine whether re-censoring should always be recommended within adjustment analyses. We investigate a context where switching is from the control group onto the experimental treatment in scenarios with varying switch proportions, treatment effect sizes, treatment effect changes over time, survival function shapes, disease severity and switcher prognosis. Methods were assessed according to their estimation of control group restricted mean survival that would be observed in the absence of switching, up to the end of trial follow-up. We found that analyses which re-censored usually produced negative bias (i.e. underestimating control group restricted mean survival and overestimating the treatment effect), whereas analyses that did not re-censor consistently produced positive bias which was often smaller in magnitude than the bias associated with re-censored analyses, particularly when the treatment effect was high and the switching proportion was low. The RPSFTM with re-censoring generally resulted in increased bias compared to the other methods. We believe that analyses should be conducted with and without re-censoring, as this may provide decision-makers with useful information on where the true treatment effect is likely to lie. Incorporating re-censoring should not always represent the default approach when the objective is to estimate long-term survival times and treatment effects.

scholarly journals Improved two-stage estimation to adjust for treatment switching in randomised trials: g-estimation to address time-dependent confounding

2020 ◽  
Vol 29 (10) ◽  
pp. 2900-2918
Author(s):  
NR Latimer ◽  
IR White ◽  
K Tilling ◽  
U Siebert
Keyword(s):  
Disease Progression ◽  
Failure Time ◽  
Experimental Treatment ◽  
Time Dependent ◽  
Control Group ◽  
Two Stage ◽  
Inverse Probability ◽  
Nested Models ◽  
Treatment Switching ◽  
Stage Estimation

In oncology trials, control group patients often switch onto the experimental treatment during follow-up, usually after disease progression. In this case, an intention-to-treat analysis will not address the policy question of interest – that of whether the new treatment represents an effective and cost-effective use of health care resources, compared to the standard treatment. Rank preserving structural failure time models (RPSFTM), inverse probability of censoring weights (IPCW) and two-stage estimation (TSE) have often been used to adjust for switching to inform treatment reimbursement policy decisions. TSE has been applied using a simple approach (TSEsimp), assuming no time-dependent confounding between the time of disease progression and the time of switch. This is problematic if there is a delay between progression and switch. In this paper we introduce TSEgest, which uses structural nested models and g-estimation to account for time-dependent confounding, and compare it to TSEsimp, RPSFTM and IPCW. We simulated scenarios where control group patients could switch onto the experimental treatment with and without time-dependent confounding being present. We varied switching proportions, treatment effects and censoring proportions. We assessed adjustment methods according to their estimation of control group restricted mean survival times that would have been observed in the absence of switching. All methods performed well in scenarios with no time-dependent confounding. TSEgest and RPSFTM continued to perform well in scenarios with time-dependent confounding, but TSEsimp resulted in substantial bias. IPCW also performed well in scenarios with time-dependent confounding, except when inverse probability weights were high in relation to the size of the group being subjected to weighting, which occurred when there was a combination of modest sample size and high switching proportions. TSEgest represents a useful addition to the collection of methods that may be used to adjust for treatment switching in trials in order to address policy-relevant questions.

scholarly journals Assessing methods for dealing with treatment switching in clinical trials: A follow-up simulation study

2016 ◽  
Vol 27 (3) ◽  
pp. 765-784 ◽  
Author(s):  
Nicholas R Latimer ◽  
Keith R Abrams ◽  
Paul C Lambert ◽  
James P Morden ◽  
Michael J Crowther
Keyword(s):  
Sample Size ◽  
Treatment Effect ◽  
Failure Time ◽  
Control Group ◽  
Structural Failure ◽  
Inverse Probability ◽  
Intention To Treat ◽  
Treatment Switching ◽  
Randomised Controlled ◽  
The Impact

When patients randomised to the control group of a randomised controlled trial are allowed to switch onto the experimental treatment, intention-to-treat analyses of the treatment effect are confounded because the separation of randomised groups is lost. Previous research has investigated statistical methods that aim to estimate the treatment effect that would have been observed had this treatment switching not occurred and has demonstrated their performance in a limited set of scenarios. Here, we investigate these methods in a new range of realistic scenarios, allowing conclusions to be made based upon a broader evidence base. We simulated randomised controlled trials incorporating prognosis-related treatment switching and investigated the impact of sample size, reduced switching proportions, disease severity, and alternative data-generating models on the performance of adjustment methods, assessed through a comparison of bias, mean squared error, and coverage, related to the estimation of true restricted mean survival in the absence of switching in the control group. Rank preserving structural failure time models, inverse probability of censoring weights, and two-stage methods consistently produced less bias than the intention-to-treat analysis. The switching proportion was confirmed to be a key determinant of bias: sample size and censoring proportion were relatively less important. It is critical to determine the size of the treatment effect in terms of an acceleration factor (rather than a hazard ratio) to provide information on the likely bias associated with rank-preserving structural failure time model adjustments. In general, inverse probability of censoring weight methods are more volatile than other adjustment methods.

scholarly journals A modified weighted log-rank test for confirmatory trials with a high proportion of treatment switching

PLoS ONE ◽  
2021 ◽  
Vol 16 (11) ◽  
pp. e0259178
Author(s):  
José L. Jiménez ◽  
Julia Niewczas ◽  
Alexander Bore ◽  
Carl-Fredrik Burman
Keyword(s):  
Statistical Power ◽  
Experimental Treatment ◽  
Hazard Ratio ◽  
Rank Test ◽  
Control Group ◽  
Potential Hazard ◽  
Intention To Treat ◽  
Treatment Switching ◽  
Log Rank Test ◽  
The Impact

In confirmatory cancer clinical trials, overall survival (OS) is normally a primary endpoint in the intention-to-treat (ITT) analysis under regulatory standards. After the tumor progresses, it is common that patients allocated to the control group switch to the experimental treatment, or another drug in the same class. Such treatment switching may dilute the relative efficacy of the new drug compared to the control group, leading to lower statistical power. It would be possible to decrease the estimation bias by shortening the follow-up period but this may lead to a loss of information and power. Instead we propose a modified weighted log-rank test (mWLR) that aims at balancing these factors by down-weighting events occurring when many patients have switched treatment. As the weighting should be pre-specified and the impact of treatment switching is unknown, we predict the hazard ratio function and use it to compute the weights of the mWLR. The method may incorporate information from previous trials regarding the potential hazard ratio function over time. We are motivated by the RECORD-1 trial of everolimus against placebo in patients with metastatic renal-cell carcinoma where almost 80% of the patients in the placebo group received everolimus after disease progression. Extensive simulations show that the new test gives considerably higher efficiency than the standard log-rank test in realistic scenarios.

Do Nutrition Education Approaches With Preschoolers and Their Caregivers Influence Retention of Biofortified Orange-Fleshed Sweetpotato on Farms?: Evidence From Homa Bay County, Kenya

2021 ◽  
pp. 037957212110254
Author(s):  
Sylvester O. Ojwang ◽  
David J. Otieno ◽  
Julius J. Okello ◽  
Penina Muoki ◽  
Rose A. Nyikal
Keyword(s):  
Nutrition Education ◽  
Early Childhood Development ◽  
Controlled Trial ◽  
Text Messages ◽  
Sub Saharan Africa ◽  
Childhood Development ◽  
Control Group ◽  
Micronutrient Deficiencies ◽  
Household Level ◽  
Intention To Treat

Background: Biofortified staples have been promoted widely in sub-Saharan Africa to combat micronutrient deficiencies. Contemporary projects are increasingly using elementary schools to target households with these foods. Objective: This study assessed the effects of integrated nutrition education approaches, targeting preschoolers and their caregivers, on retention of orange-fleshed sweetpotato (OFSP) on farms in the second season after lapse of free vine dissemination initiatives. Methods: Rural farming households, with preschoolers and no prior engagement with OFSP, were targeted. A multistage sample of 431 preschooler–caregiver pairs was recruited for a cluster-randomized controlled trial. After issuing routine OFSP promotion activities, 15 village-level clusters of the pairs were randomized into 1 control group (3 villages) and 3 treatment arms (4 villages each) for the interventions. Baseline and follow-up household-level survey data were collected from the caregivers. The interventions included: (1) OFSP-branded exercise books, posters, and a poem to preschoolers only; (2) OFSP-oriented mobile phone-mediated text messages to caregivers only; and (3) both 1 and 2 provided to individual households concurrently. Interventions 1 and 2 were single-channeled, while 3 was multichanneled. We estimated the intention-to-treat (ITT) and treatment-on-the-treated (TOT) effects using a binary logit model and a special regressor method, respectively. Results: Only the multichanneled nutrition education approach had significant effects (ITT = 0.167, P = .001; TOT = .243, P = .007) on the caregivers’ likelihood to retain OFSP on their farms. Conclusions: The finding implies that multichanneled agriculture-nutrition education interventions through Early Childhood Development institutions can be effective in ensuring sustainable adoption of OFSP.

scholarly journals Effect of Inquiry-Based Stress Reduction (IBSR) Intervention on Well-Being, Resilience and Burnout of Teachers during the COVID-19 Pandemic

2021 ◽  
Vol 18 (7) ◽  
pp. 3689
Author(s):  
Tzofnat Zadok-Gurman ◽  
Ronit Jakobovich ◽  
Eti Dvash ◽  
Keren Zafrani ◽  
Benjamin Rolnik ◽  
...  
Keyword(s):  
Stress Reduction ◽  
Controlled Trial ◽  
Intervention Group ◽  
Well Being ◽  
Stressful Events ◽  
Control Group ◽  
Subjective Well Being ◽  
Intention To Treat ◽  
School Year ◽  
Blended Intervention

Objective: The COVID-19 pandemic has had a major impact on teachers professional and personal lives. Our primary aim was to assess the effect of a blended Inquiry-Based Stress Reduction (IBSR), an emerging mindfulness and cognitive reframing intervention on teacher’s well-being. Our secondary aims were to assess the effect of IBSR on resilience, burnout, mindfulness, and stress among teachers during the COVID-19 pandemic. Methods: The study was a prospective controlled trial with an intervention group (N = 35) and a comparison control group (N = 32). The intervention took place in the Jerusalem District throughout the school year from November 2019 to May 2020. The sessions were conducted in blended learning that included traditional learning (face-to-face) and online learning. Data was analyzed on an intention-to-treat basis. Results: IBSR blended intervention enhanced the resilience and improved the subjective and psychological well-being of teachers in spite of the breakout of the COVID-19 pandemic and the first lockdown in Israel. Simultaneously the control group suffered from enhanced burnout levels and a decline in psychological and subjective well-being. Conclusions: Implementation of IBSR blended intervention during the school year may benefit teachers’ well-being and ability to flourish, even during stressful events such as the COVID-19 pandemic.

Statistical methods for unidirectional switch designs: Past, present, and future

2017 ◽  
Vol 27 (9) ◽  
pp. 2872-2882 ◽  
Author(s):  
Zhuozhao Zhan ◽  
Geertruida H de Bock ◽  
Edwin R van den Heuvel
Keyword(s):  
Statistical Methods ◽  
Large Scale ◽  
Sample Size Calculation ◽  
Complex Interventions ◽  
New Drugs ◽  
Control Treatment ◽  
Future Research ◽  
Control Group ◽  
Unified Framework ◽  
New Treatment

Clinical trials may apply or use a sequential introduction of a new treatment to determine its efficacy or effectiveness with respect to a control treatment. The reasons for choosing a particular switch design have different origins. For instance, they may be implemented for ethical or logistic reasons or for studying disease-modifying effects. Large-scale pragmatic trials with complex interventions often use stepped wedge designs (SWDs), where all participants start at the control group, and during the trial, the control treatment is switched to the new intervention at different moments. They typically use cross-sectional data and cluster randomization. On the other hand, new drugs for inhibition of cognitive decline in Alzheimer’s or Parkinson’s disease typically use delayed start designs (DSDs). Here, participants start in a parallel group design and at a certain moment in the trial, (part of) the control group switches to the new treatment. The studies are longitudinal in nature, and individuals are being randomized. Statistical methods for these unidirectional switch designs (USD) are quite complex and incomparable, and they have been developed by various authors under different terminologies, model specifications, and assumptions. This imposes unnecessary barriers for researchers to compare results or choose the most appropriate method for their own needs. This paper provides an overview of past and current statistical developments for the USDs (SWD and DSD). All designs are formulated in a unified framework of treatment patterns to make comparisons between switch designs easier. The focus is primarily on statistical models, methods of estimation, sample size calculation, and optimal designs for estimation of the treatment effect. Other relevant open issues are being discussed as well to provide suggestions for future research in USDs.

scholarly journals Effectiveness of Measures to Eradicate Staphylococcus aureus Carriage in Patients with Community-Associated Skin and Soft-Tissue Infections: A Randomized Trial

2011 ◽  
Vol 32 (9) ◽  
pp. 872-880 ◽  
Author(s):  
Stephanie A. Fritz ◽  
Bernard C. Camins ◽  
Kimberly A. Eisenstein ◽  
Joseph M. Fritz ◽  
Emma K. Epplin ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Soft Tissue ◽  
Controlled Trial ◽  
Control Group ◽  
Open Label ◽  
Intention To Treat ◽  
Intranasal Mupirocin ◽  
Mupirocin Ointment ◽  
Hygiene Education ◽  
To Receive

Background.Despite a paucity of evidence, decolonization measures are prescribed for outpatients with recurrent Staphylococcus aureus skin and soft-tissue infection (SSTI).Objective.Compare the effectiveness of 4 regimens for eradicating S. aureus carriage.Design.Open-label, randomized controlled trial. Colonization status and recurrent SSTI were ascertained at 1 and 4 months.Setting.Barnes-Jewish and St. Louis Children's Hospitals, St. Louis, Missouri, 2007–2009.Participants.Three hundred patients with community-onset SSTI and S. aureus colonization in the nares, axilla, or inguinal folds.Interventions.Participants were randomized to receive no therapeutic intervention (control subjects) or one of three 5-day regimens: 2% mupirocin ointment applied to the nares twice daily, intranasal mupirocin plus daily 4% chlorhexidine body washes, or intranasal mupirocin plus daily dilute bleach water baths.Results.Among 244 participants with 1-month colonization data, modified intention-to-treat analysis revealed S. aureus eradication in 38% of participants in the education only (control) group, 56% of those in the mupirocin group (P = .03 vs controls), 55% of those in the mupirocin and chlorhexidine group (P = .05), and 63% off those in the mupirocin and bleach group (P = .006). Of 229 participants with 4-month colonization data, eradication rates were 48% in the control group, 56% in the mupirocin only group (P = .40 vs controls), 54% in the mupirocin and chlorhexidine group (P = .51), and 71% in the mupirocin and bleach group (P = .02). At 1 and 4 months, recurrent SSTIs were reported by 20% and 36% of participants, respectively.Conclusions.An inexpensive regimen of dilute bleach baths, intranasal mupirocin, and hygiene education effectively eradicated S. aureus over a 4-month period. High rates of recurrent SSTI suggest that factors other than endogenous colonization are important determinants of infection.Trial Registration.ClinicalTrials.gov identifier: NCT00513799.

scholarly journals Effectiveness of a psychological online training to promote physical activity among students: protocol of a randomized-controlled trial

Trials ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Lena Violetta Krämer ◽  
Nadine Eschrig ◽  
Lena Keinhorst ◽  
Luisa Schöchlin ◽  
Lisa Stephan ◽  
...  
Keyword(s):  
Physical Activity ◽  
Randomized Controlled Trial ◽  
Mixed Model ◽  
Controlled Trial ◽  
Control Group ◽  
Web Based ◽  
Intention To Treat ◽  
Randomized Controlled ◽  
Link Type

Abstract Background Many students in Germany do not meet recommended amounts of physical activity. In order to promote physical activity in students, web-based interventions are increasingly implemented. Yet, data on effectiveness of web-based interventions in university students is low. Our study aims at investigating a web-based intervention for students. The intervention is based on the Health Action Process Approach (HAPA), which discriminates between processes of intention formation (motivational processes) and processes of intention implementation (volitional processes). Primary outcome is change in physical activity; secondary outcomes are motivational and volitional variables as proposed by the HAPA as well as quality of life and depressive symptoms. Methods A two-armed randomized controlled trial (RCT) of parallel design is conducted. Participants are recruited via the internet platform StudiCare (www.studicare.com). After the baseline assessment (t1), participants are randomized to either intervention group (immediate access to web-based intervention) or control group (access only after follow-up assessment). Four weeks later, post-assessment (t2) is performed in both groups followed by a follow-up assessment (t3) 3 months later. Assessments take place online. Main outcome analyses will follow an intention-to-treat principle by including all randomized participants into the analyses. Outcomes will be analysed using a linear mixed model, assuming data are missing at random. The mixed model will include group, time, and the interaction of group and time as fixed effects and participant and university as random effect. Discussion This study is a high-quality RCT with three assessment points and intention-to-treat analysis meeting the state-of-the-art of effectiveness studies. Recruitment covers almost 20 universities in three countries, leading to high external validity. The results of this study will be of great relevance for student health campaigns, as they reflect the effectiveness of self-help interventions for young adults with regard to behaviour change as well as motivational and volitional determinants. From a lifespan perspective, it is important to help students find their way into regular physical activity. Trial registration The German clinical trials register (DRKS) DRKS00016889. Registered on 28 February 2019

scholarly journals Title: Application of a physiotherapy protocol to women during the active phase of labour improves obstetric outcomes: a randomized clinical trial.

2021 ◽  
Author(s):  
LICIA SANTANA ◽  
Rubneide Gallo ◽  
Silvana Quintana ◽  
Geraldo Duarte ◽  
Cristine Homsi Ferreira ◽  
...  
Keyword(s):  
Controlled Trial ◽  
Perinatal Outcomes ◽  
Active Phase ◽  
Labour Pain ◽  
Obstetric Outcomes ◽  
Control Group ◽  
Phase Duration ◽  
Intention To Treat ◽  
Reference Centre ◽  
Care Protocol

Objective: To evaluate the effectiveness of a non-pharmacological childbirth care protocol in women in the active phase of labour in improving obstetric and perinatal outcomes. Design: Randomized trial with concealed allocation, assessor blinding, and intention-to-treat analysis. Setting: Reference Centre of Women’s Health of Ribeirão Preto–MATER, São Paulo, Brazil. Methods: Eighty low-risk primiparous women at the end of pregnancy and beginning of the active phase of labour were randomized to experimental group (EG) (n=40) or control group (CG) (n=40). Women in EG received four interventions: ambulation at 4 to 6 cm of cervical dilation; alternative maternal positions associated with TENS at 6 to 7 cm, and a warm shower bath at >7 cm. The CG received only routine obstetric. Main outcome measures: The length of the active phase of labour, the expulsive phase duration, and the prevalence of labour dystocia assessed by the partograph. Results: The parturients who received the sequential non-pharmacological protocol had a shorter length of the active phase of labour (CG=444 minutes; EG=373 minutes; p=0,02), presented rupture of membranes later in labour (CG=7cm; EG=8cm; p<0,01), requested pharmacological analgesia with more significant cervical dilatation (CG=5cm; EG=8cm; p<0,01) and had lower labour dystocia rates than the patients in the CG. Conclusion: The implementation of a sequential non-pharmacological protocol has the potential in decreased and delayed use of pharmacological analgesia, duration of the active phase of labour and dystocia rates. Keywords: length of labour, labour pain, dystocia, randomized controlled trial, non-pharmacological resources, pharmacological analgesia. Trial registration: NCT01601860 Link: https://clinicaltrials.gov/ct2/show/NCT01601860

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