key: cord-0952911-c5j09epq authors: Röhr, Susanne; Arai, Hidenori; Mangialasche, Francesca; Matsumoto, Nanae; Peltonen, Markku; Raman, Rema; Riedel‐Heller, Steffi G.; Sakurai, Takashi; Snyder, Heather M.; Sugimoto, Taiki; Carrillo, Maria; Kivipelto, Miia; Espeland, Mark A. title: Impact of the COVID‐19 pandemic on statistical design and analysis plans for multidomain intervention clinical trials: Experience from World‐Wide FINGERS date: 2021-03-11 journal: Alzheimers Dement (N Y) DOI: 10.1002/trc2.12143 sha: e17ad74c56feb9f7698c7efb04d66073e8f45a5f doc_id: 952911 cord_uid: c5j09epq INTRODUCTION: The coronavirus disease‐19 (COVID‐19) pandemic presents challenges to the conduct of randomized clinical trials of lifestyle interventions. METHODS: World‐Wide FINGERS is an international network of clinical trials to assess the impact of multidomain lifestyle intervention on cognitive decline in at‐risk adults. Individual trials are tailoring successful approaches from the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) to local cultures and environments. The network convened a forum for researchers to discuss statistical design and analysis issues they faced during the pandemic. We report on experiences of three trials that, at various stages of conduct, altered designs and analysis plans to navigate these issues. We provide recommendations for future trials to consider as they develop and launch behavioral intervention trials. RESULTS: The pandemic led researchers to change recruitment plans, interrupt timelines for assessments and intervention delivery, and move to remote intervention and assessment protocols. The necessity of these changes add emphasis to the importance, in study design and analysis, of intention to treat approaches, flexibility, within‐site stratification, interim power projections, and sensitivity analyses. DISCUSSION: Robust approaches to study design and analysis are critical to negotiate issues related to the intervention. The world‐wide network of similarly oriented clinical trials will allow us to evaluate the effectiveness of responses to the pandemic across cultures, local environments, and phases of the pandemic. The coronavirus disease-19 (COVID-19) pandemic has taken a staggering toll on public health. As of mid-November 2020, more than 54 millions cases and almost 1. Many of these consequences have necessitated changes and adjustments in study protocols, to accommodate suspension of in-person data collection, alterations in approaches to recruitment, and changes in intervention delivery. [2] [3] [4] Common concerns expressed by study teams are barriers to participant enrollment, health concerns of study staff, and financial concerns related to study suspensions and cancellations. 5 Further, in some studies ethical concerns have been raised regarding the conduct of trials related to participant safety and the potential that interventions may adversely interact with COVID-19 infection. 6 Even trial monitoring is affected, with the imperative of streamlining how protocols are evaluated and safety data are collected. 7 Lifestyle intervention trials may be particularly susceptible to disruption from the pandemic. Traditionally, many of these have focused on developing strong bonds between interventionists and participants through group and individual face-to-face sessions, and past work has highlighted that these interactions are important for sustaining high levels of adherence, retention, and well-being. Often, they are delivered in the community. Pandemic control measures may present additional challenges to maintain participant safety and to comply with local regulations. Lifestyle behaviors may be adversely affected by social isolation imposed by self-distancing, in part due to challenges related to the comorbidities of increased anxiety and depression. [8] [9] [10] Trials focused on interventions to prevent cognitive decline often recruit individuals for whom COVID-19 poses greater risks due to their older age and greater burden of age-related chronic diseases. The focus we bring to the discussion is the impact of the pandemic on the statistical design and analysis plans for ongoing clinical trials. This article highlights experience from the World-Wide FIN-GERS (WW-FINGERS), a network of clinical trials to assess the relative impact of multidomain lifestyle intervention on cognitive function, 11 and the discussion below focuses on how such trials face challenges in different environments and different stages in the trial, that is, during recruitment, intervention delivery, and longer term follow-up. The WW-FINGERS network provides a forum for studies to share and learn from one another. In particular, the global response and different regional responses have enriched the context of this sharing and conversation throughout 2020. How ongoing studies have responded to local environments, making adjustments to protocols at different stages of trial conduct, informs our discussion. WW-FINGERS is the first network of multidomain lifestyle-based intervention trials for risk reduction and prevention of cognitive impairment and dementia in older adults. 11 The 2-year lifestyle intervention, compared to general health advice, resulted in improved global cognition, the primary outcome of the study. It also showed positive effects in several secondary outcomes, including cognitive subdomains, mobility and functional status, development of chronic disease, and health-related quality of life. [14] [15] [16] [17] Extended follow-up of study participants is ongoing to monitor long-term effects of the intervention: 5-and 7-year follow-up assessments have been completed in 2016 and 2018, respectively, and a 10- year follow-up assessment was planned for 2020, but has been postponed to 2021 due to the COVID-19 pandemic. For each RCT, we summarize main aspects of the study design and the major statistical and design issues associated with the pandemic interference. We then discuss lessons learned and a way forward to address methodological challenges and identify new opportunities. The COVID-19 had a significant impact on the study design of J-MINT and caused a potential statistical problem. The intervention was originally planned to start in April 2020, but was delayed for 2 months. Therefore, there is no effect of the first waves of the pandemic on the inter- The first COVID-19 case in North Carolina was announced in early March 2020. Later that month, the state governor released a "stayat-home" order, urging citizens to avoid non-essential travel. This was The 4-month pause in face-to-face contact with U.S. POINTER participants interrupted the collection of outcome data, which was originally scheduled to occur at 6-month intervals after "intervention initiation" when intervention groups (consisting of approximately 10-15 members assigned to the same arm) held their first "team meeting." While some data were accumulated continuously during the pause (e.g., safety, health-care use, objective measures of physical activity, and cognitive training for the multidomain intervention group), others (cognitive and physical function, risk factors) were postponed relative to the timing of planned assessments and rescheduled to resume at the end of the pause. During the pause, adherence to intervention goals continued to be monitored and participants received encouragement toward meeting these goals even though some activities (e.g., group meeting attendance) were suspended. After the pause, intervention meetings were held remotely and full adherence monitoring was resumed. The major statistical and design considerations arising from the pandemic-related changes in procedures relate to alterations in how interventions were delivered and assessment schedules, and the potential that outcomes and adherence may be differentially affected depending on the temporal influences of the pandemic. AgeWell.de is a pragmatic cluster-randomized, controlled lifestyle trial against cognitive decline, conducted in Germany across five study sites. In Germany, the first COVID-19 case was reported January 28, 2020, Institute, the German public health institute responsible for disease control. Therefore, face-to-face assessments were feasible as long as infection levels did not require strict infection control measures, such as further lockdowns. Lockdowns during follow-up may introduce regional differences and cluster effects between study sites as well as individual variance in follow-up duration. In fact, a second nationwide lockdown imposed from early November, expected to last a month, led to pausing face-to-face assessments. Varying follow-up duration is a minor issue that will be handled by statistical modeling. Cluster effects may be more difficult in that they may reduce statistical power: these need to be thoroughly investigated by assessing potential biases and intra-cluster correlations. If study participants are not willing to participate in face-to-face assessments, they are offered a telephone interview that will allow for comprehensive nonresponse analyses. It is unclear the extent that the COVID-19 pandemic and the associated public health measures to curb the spread of the virus impact participants' behavior and everyday routines. As long as the pandemic per- sists, adaptations to accommodate extra safety precautions must be taken in protocols of lifestyle RCTs. It may be important to add measures, for example, to assess well-being, mental and social health, virus exposure, health-care access, and intervention adherence/motivation. This may further our understanding of how the COVID-19 pandemic has impacted trial results. WW-FINGERS is currently developing a COVID-19 survey to identify special challenges to inform how interventions might best be tailored to address these issues. Prospective studies may consider alternatives to face-to-face assessments, such as computerized and/or remote (telephone, video) assessments. Studies with in-person assessments will need to adopt safety and hygiene protocols that allow for continued face-to-face assessments to avoid a change in assessment modes: consistency is key for pre-post comparisons. Without this consistency, bias may be introduced in trial outcomes. The need for consistency, however, must be balanced against risk of infection: safety is the greatest priority, and safety and hygiene protocols need to be up to-date. The impact of the pandemic on the conduct of trials adds emphasis to the importance of study hypotheses being independent of postintervention events. Hypotheses based on intention-to-treat remain as initially framed, that is, to compare cohorts by random assignment to different intervention programs. While the intervention goals have remained unchanged, protocols for intervention delivery have changed. Particularly for trials of behavioral interventions, it is often the case that the details behind intervention delivery may change over time. This may result from accrued experience in finding ways to opti-mize adherence or from changes in the nature of the study cohort as it is recruited over time. Examples include the Lifestyle Interventions for Independence for Elders, which revised intervention protocols to include guidelines for the temporary suspensions of its physical activity interventions to address hospitalizations that occurred at high rates in its older cohort, 27 and the Action for Health in Diabetes trial, which mid-trial ceased providing weight loss medications to individuals assigned to its behavioral intervention who were unsuccessful in losing weight when the drugs were found to be ineffective. 28 While the influence of the COVID-19 pandemic may be more disruptive than these examples, the importance of adhering to an intention-to-treat protocol remains consistent and important for considerations in data analysis plans. Randomization stratification by site is designed to ensure balanced intervention assignment and avoid confounding attributable to local differences in cohorts and environments. 29 As noted above, the dynamic influence of the pandemic on trial operations varied by site and country. Stratification promotes fair comparisons within each site. An advantage of multi-site trials and networks is that differences in the disruption of trial operations and possibly outcomes among sites provides additional opportunity to study and contrast how environments may influence findings. While unknown, it is possible that the COVID-19 pandemic may adversely impact adherence, attenuate the effect sizes of trial interventions, and increase attrition. It may also be that alterations in the assessment of study outcomes, for example transitioning from clinic-based to telephone-based assessment, may increase variance. Each of these may lower statistical power. Study groups may consider altering designs (e.g., increasing enrollment or extending follow-up) in response. Other trials have navigated issues associated with changes in how outcomes are assessed. [30] [31] [32] It is important that any decisions on protocol changes be made by experts who are masked to outcome data by arm to preserve type 1 error. If interventions are altered during the course of trial enrollment, post hoc stratification may be considered, in which participants enrolled prior to the alteration constitute one strata and those enrolled later constituting a second strata. This permits a formal comparison of relative intervention effects as interventions change and may be considered a sensitivity analysis. Alterations in assessment schedules and differences in assessment time frames among participants pose thorny analytical issues. These confound assessments with secular trends in health and behavior associated with the pandemic. Sensitivity analyses may be required to gauge the potential impact of these factors on results from planned analyses. Prior to unmasking the study, statistical analysis plans should be reviewed and updated to include all planned modifications and additional analysis to assess the impact of the pandemic disruption on the efficacy analyses. The COVID-19 pandemic has profoundly altered the landscape for the design and conduct of RCTs of multidomain lifestyle interventions. Older individuals with comorbid health conditions, many of whom are ideal candidates for WW-FINGERS interventions, have the greatest health risks. The WW-FINGERS was originally initiated to support adaptation of a multidomain intervention model to prevent cognitive decline and to harmonize study protocols. The existing network with ongoing studies at different phases now also presents opportunities to evaluate approaches to intervention and data collection that may be more feasible in the context of a pandemic. It has gathered international teams with expertise to address, almost in real time, the methodological challenges that cut across its linked RCTs. It provides an opportunity to synergize and collaborate on solutions that support the overall aims of the network, including successful conduct of each RCT and a way forward to data sharing and joint analyses. This allows studies at earlier stages in their implementation to adjust and pivot to address these potential challenges in study design and analytics, while others that are more advanced will be able to leverage other sites' expertise to develop and adjust statistical plans to most appropriately manage their specific circumstances. The lessons from the WW-FINGERS to adapt and cope with the challenges due to COVID-19 might be helpful also for other existing and planned lifestyle intervention studies. The authors thank Emily S. A. Meyers (Alzheimer's Association) and Kristal Morales Perez (Karolinska Institute) for their exceptional work in coordinating the development of this proposal. We also thank the World-Wide FINGERS study participants whose contributions make its research possible. AgeWell.de: The study "AgeWell.de -a multi-centric cluster- WHO Scientific and Technical Advisory Group for Infectious Hazards, COVID-19: what is next for public health COVID-19 and readjusting clinical trials Transition from physical to virtual visit format for a longitudinal brain aging study, in response to the Covid-19 pandemic. 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The Lanceet Digit Health The effect of intervening hospitalizations on the benefit of structured physical activity in promoting independent mobility among community-living older persons: secondary analysis of a randomized controlled trial Four-year weight losses in the Look AHEAD study: factors associated with long-term success Fundamentals of Clinical Trials 5th Edition When and how can endpoints be changed after initiation of a randomized clinical trial Measuring the incidence, causes, and repercussions of protocol amendments Dementia outcomes after addition of proxy-based assessments for deceased or proxydependent participants Impact of the COVID-19 pandemic on statistical design and analysis plans for multidomain intervention clinical trials: Experience from World-Wide FINGERS Additional support was provided by the Wake Forest Alzheimer's Disease Core Center (P30AG049638-01A1). There are no conflicts to report beyond listed funding for World-Wide FINGERS studies.