Original delayed-start ovarian stimulation protocol with a gonadotropin-releasing hormone antagonist, medroxyprogesterone acetate, and high-dose gonadotropin for poor responders and patients with poor-quality embryos.

Introduction: The delayed-start gonadotropin-releasing hormone antagonist protocol seems effective for patients who are poor ovarian responders, but there are insufficient data on whether it is also effective for patients with poor-quality embryos and low rates of good blastocyst formation. Specifically, the effectiveness of delayed-start gonadotropin-releasing hormone antagonists with progesterone has not been adequately investigated. Therefore, we compared the efficacy of the original delayed-start gonadotropin-releasing hormone antagonist protocol using medroxyprogesterone acetate (MPA) and high-dose gonadotropin in patients with poor ovarian response. Methods: Overall, 156 patients with recurrent assisted reproductive technology failure who underwent the original protocol were included. They received cetrorelix acetate (3 mg) and MPA (10 mg) on cycle day 3, and high-dose gonadotropin was initiated on day 11. When the leading follicle reached 14 mm, ganirelix acetate (0.25 mg) was administered until the trigger day. The number of oocytes retrieved, metaphase II (MII) oocytes, two pronuclear (2PN) zygotes, and good blastocysts and live birth rates were compared between the previous (Cycle A) and original (Cycle B) cycles in three groups (Group A, all patients; Group B, poor responders; and Group C, patients with poor-quality embryos). Results: In Group A (n=156), the number of MII oocytes (3.6 ± 3.3 versus 4.5 ± 3.6), 2PN zygotes (2.8 ± 2.9 versus 3.8 ± 3.1), good blastocysts (0.5 ± 0.9 versus 1.2 ± 1.6), and live birth rates (0.6 versus 24.4) significantly increased in Cycle B. Similar results were obtained in Group B (n=83; 2PN zygotes [1.7 ± 1.7 versus 2.3 ± 1.8], good blastocysts [0.4 ± 0.7 versus 0.9 ± 1.3], live birth rates [0 versus 18.1]) and Group C (n=73; MII oocytes [5.1 ± 3.8 versus 6.6 ± 4.0], 2PN zygotes [4.0 ± 3.4 versus 5.4 ± 3.4], good blastocysts [0.7 ± 1.1 versus 1.6 ± 1.9], and live birth rates [1.4 versus 31.5]). Conclusion: This original protocol increased the number of MII oocytes retrieved, 2PN zygotes, good blastocysts, and live birth rates in both poor responders and in patients with poor-quality embryos.

Solutions for surrogacy validation with longitudinal outcomes for a gene therapy.

Valid surrogate endpoints S can be used as a substitute for a true outcome of interest T to measure treatment efficacy in a clinical trial. We propose a causal inference approach to validate a surrogate by incorporating longitudinal measurements of the true outcomes using a mixed modeling approach, and we define models and quantities for validation that may vary across the study period using principal surrogacy criteria. We consider a surrogate-dependent treatment efficacy curve that allows us to validate the surrogate at different time points. We extend these methods to accommodate a delayed-start treatment design where all patients eventually receive the treatment. Not all parameters are identified in the general setting. We apply a Bayesian approach for estimation and inference, utilizing more informative prior distributions for selected parameters. We consider the sensitivity of these prior assumptions as well as assumptions of independence among certain counterfactual quantities conditional on pretreatment covariates to improve identifiability. We examine the frequentist properties (bias of point and variance estimates, credible interval coverage) of a Bayesian imputation method. Our work is motivated by a clinical trial of a gene therapy where the functional outcomes are measured repeatedly throughout the trial.

Neuroprotective Effects of Intermittent Theta Burst Stimulation in Parkinson's Disease (NET-PD): A Study Protocol for a Delayed-Start Randomized Double-Blind Sham-Controlled Trial.

BACKGROUND: As a typical high-disability neurodegenerative disease, Parkinson's disease (PD) progresses variably, and patients who are clinically insensitive to dopaminergic therapy and whose symptoms fail to improve are commonly observed. As a result, achieving early neuron protection is critical. METHODS/DESIGN: The NET-PD study is a 2-year prospective single-center, double-blind, multi-arm, delayed-start, sham-controlled clinical trial assessing the long-term neuroprotective effect of intermittent theta burst stimulation (iTBS) in PD patients. Patients diagnosed with PD, aged 50-80, Hoehn-Yahr stage ≤4, and who maintain medication stability during the study will be enrolled. Clinical assessment and multi-modal markers are used to clarify the clinical improvement and dynamic neuronal changes in PD patients. With a standard deviation of 2, a test level of 0.05, a dropout rate of 10%, and a degree of certainty of 0.9, 60 PD patients are required for this study. RESULTS: The NET-PD project was funded in March 2022, data collection began in July 2022, and is currently in the recruitment phase with two PD patients already enrolled. Data collection is expected to be completed in June 2024. The results are expected for publication in December 2024. DISCUSSION: Previous research has demonstrated a rudimentary method for assessing and delaying PD progression in clinical medication trials. The NET-PD study adopts a rigorous methodology and specific disease-modifying designs to demonstrate the neuroprotective effect of iTBS on PD and investigate the potential mechanism of iTBS in regulating brain and motor functions. We hope to provide supposition for the subsequent exploration of diverse neuroprotection methods.

Impacts of a delayed and slow-paced vaccination on cases and deaths during the COVID-19 pandemic: a modelling study.

In Brazil, vaccination has always cut across party political and ideological lines, which has delayed its start and brought the whole process into disrepute. Such divergences put the immunization of the population in the background and create additional hurdles beyond the pandemic, mistrust and scepticism over vaccines. We conduct a mathematical modelling study to analyse the impacts of late vaccination along with slowly increasing coverage, as well as how harmful it would be if part of the population refused to get vaccinated or missed the second dose. We analyse data from confirmed cases, deaths and vaccination in the state of Rio de Janeiro in the period between 10 March 2020 and 27 October 2021. We estimate that if the start of vaccination had been 30 days earlier, combined with efforts to drive vaccination rates up, about 31 657 deaths could have been avoided. In addition, the slow pace of vaccination and the low demand for the second dose could cause a resurgence of cases as early as 2022. Even when reaching the expected vaccination coverage for the first dose, it is still challenging to increase adherence to the second dose and maintain a high vaccination rate to avoid new outbreaks.

Alzheimer's Disease THErapy With NEuroaid (ATHENE): A Randomized Double-Blind Delayed-Start Trial.

OBJECTIVES: Preclinical and clinical studies indicate a role for MLC901 (NeuroAiD II) in Alzheimer's disease (AD). The primary aim was to investigate its safety as add-on therapy to standard treatment and the secondary aims its effect on cognition and slowing disease progression. DESIGN: Randomized double-blind placebo-controlled delayed-start study. SETTING AND PARTICIPANT: Patients with mild to moderate probable AD by NINCDS-ADRDA criteria, stable on acetylcholinesterase inhibitors or memantine (n = 125), were randomized to receive MLC901 (early starters) or placebo (delayed starters) for 6 months, followed by a further 6 months when all patients received MLC901, in a delayed-start design (clinical trial registration: ClinicalTrials.gov, NCT03038035). METHODS: The primary outcome measure was occurrence of serious adverse events (SAEs) at 6 months. Secondary outcomes included the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) and other assessment scales. RESULTS: There was no significant difference in the risk of SAEs between early and delayed starters at month (M) 6 (22.6% vs 27.0%, risk difference -4.4%, 90% CI -16.9% to 8.3%). Similarly, there was no significant difference in the risk of adverse events and the occurrence of stroke or vascular events between early and delayed starters throughout the 12-month study period. Early starters did not differ significantly on ADAS-Cog from delayed starters at M6 [mean difference (MD) -1.0, 95% CI -3.3 to 1.3] and M12 (MD -2.35, 95% CI -5.45 to 0.74) on intention-to-treat analysis. Other cognitive assessment scales did not show significant differences. CONCLUSIONS AND IMPLICATIONS: This study of 125 persons with dementia found no evidence of a significant increase in adverse events between MLC901 and placebo, thus providing support for further studies on both efficacy and safety. Analyses suggest the potential of MLC901 in slowing down AD progression, but this requires further confirmation in larger and longer studies using biomarkers for AD.

Exploring Reasons for Delayed Start-of-Care Nursing Visits in Home Health Care: Algorithm Development and Data Science Study.

BACKGROUND: Delayed start-of-care nursing visits in home health care (HHC) can result in negative outcomes, such as hospitalization. No previous studies have investigated why start-of-care HHC nursing visits are delayed, in part because most reasons for delayed visits are documented in free-text HHC nursing notes. OBJECTIVE: The aims of this study were to (1) develop and test a natural language processing (NLP) algorithm that automatically identifies reasons for delayed visits in HHC free-text clinical notes and (2) describe reasons for delayed visits in a large patient sample. METHODS: This study was conducted at the Visiting Nurse Service of New York (VNSNY). We examined data available at the VNSNY on all new episodes of care started in 2019 (N=48,497). An NLP algorithm was developed and tested to automatically identify and classify reasons for delayed visits. RESULTS: The performance of the NLP algorithm was 0.8, 0.75, and 0.77 for precision, recall, and F-score, respectively. A total of one-third of HHC episodes (n=16,244) had delayed start-of-care HHC nursing visits. The most prevalent identified category of reasons for delayed start-of-care nursing visits was no answer at the door or phone (3728/8051, 46.3%), followed by patient/family request to postpone or refuse some HHC services (n=2858, 35.5%), and administrative or scheduling issues (n=1465, 18.2%). In 40% (n=16,244) of HHC episodes, 2 or more reasons were documented. CONCLUSIONS: To avoid critical delays in start-of-care nursing visits, HHC organizations might examine and improve ways to effectively address the reasons for delayed visits, using effective interventions, such as educating patients or caregivers on the importance of a timely nursing visit and improving patients' intake procedures.

Comparison of chronic kidney disease trial designs and analysis strategies.

BACKGROUND: Despite the large burden of chronic kidney disease (CKD), it is challenging to conduct adequately powered clinical trials in this setting. Sound and efficient trials are needed to advance treatment. Various analysis strategies can be used to compare the efficacy of a parallel trial design with that of three two period trial designs. METHODS: The type 1 error rates and powers of various trial designs were calculated using simulated data from models fit to two recent CKD trials. In addition, we assessed the influences of a variety of analysis strategies and of the presence of a carryover effect. RESULTS: The parallel and crossover designs (with analysis of change from baseline to the off treatment value) maintained the target type 1 error rate in all scenarios. In some scenarios, an open label design yielded inflated type 1 error rates. In many scenarios, the open label and delayed start designs had unacceptably low power and high type 1 error rates. Overall, the crossover design had the highest power by far, and always controlled the type 1 error rate. CONCLUSION: The recommended approach to a CKD trial is a two period design with an endpoint that is the rate of change in estimated glomerular filtration rate from pretreatment to off treatment. As compared to a parallel trial, a crossover study involves a considerably smaller sample size and shorter total follow-up duration. A crossover design may also be preferable for patients, and facilitates recruitment of a sufficient number of subjects.

Efficacy of the delayed start antagonist protocol for controlled ovarian stimulation in Bologna poor ovarian responders: a systematic review and meta-analysis.

BACKGROUND: Patients with a poor ovarian response (POR) represent the most difficult group of population to deal with in the clinical fertility practice. Bologna criteria are the first uniform definition of POR. Choosing a suitable controlled ovarian stimulation (COS) protocol which could give adequate oocytes to maximize the chance of obtaining at least one euploid blastocyst is crucial in the management for such patients. The delayed start antagonist protocol is a novel COS protocol designed for POR patients, however, its real efficacy is controversial compared to conventional protocols. The present study aims to summarize all available studies on this topic and perform a meta-analysis to explore the real treatment effect of this novel protocol in terms of reproductive outcomes. STUDY DESIGN: PubMed, EMBASE, Google Scholar, and the Cochrane Library from database establishment to June 2019 were searched. Randomized controlled trials (RCTs), which compared delayed start antagonist protocol (Del) to conventional controlled ovarian stimulation (COS) protocols (Con) in terms of reproductive outcomes, were included. The RevMan 5.3 was used to perform statistical analysis. The primary outcomes were the cycle cancellation rate, the clinical pregnancy rate and the miscarriage rate. RESULTS: 5 RCTs yielding 514 patients were eligible, of which 5, 5, 4 studies were included in analyzing the cycle cancellation rate, the clinical pregnancy rate, and the miscarriage rate respectively. Synthesized data of meta-analysis showed: delayed start antagonist protocol introduced a lower risk of cycle cancellation [risk ratio (RR) = 0.63, 95% confidence interval (CI) (0.45, 0.90), P = 0.01; 5 RCTs, 514 women (Del:Con = 256:258); I2 = 0%; with rates of 16.02% (Del) vs. 26.36% (Con)], an increased chance to get clinical pregnancy [RR = 2.30, 95% CI (1.38, 3.82), P = 0.001; 5 RCTs, 514 women (Del:Con = 256:258); I2 = 0%; with rates of 16.80% (Del) vs. 7.36% (Con)], and a comparable miscarriage rate [RR = 0.55, 95% CI (0.24, 1.23), P = 0.15; 4 RCTs, 58 women (Del:Con = 41:17) I2 = 17%; with rates of 19.51% (Del) vs. 35.29% (Con)] compared to conventional COS protocols. CONCLUSIONS: Delayed start antagonist protocol was a potentially valuable alternation for poor ovarian responders. However, future RCTs with large sample size and more scientific design are needed to verify its validity and draw a sound conclusion.

Cost-utility analysis of hearing aid device for older adults in the community: a delayed start study.

BACKGROUND: Hearing aids (HA) is the primary medical intervention aimed to reduce hearing handicap. This study assessed the cost-effectiveness of HA for older adults who were volunteered to be screened for hearing loss in a community-based mobile hearing clinic (MHC). METHODS: Participants with (1) at least moderate hearing loss (≥40 dB HL) in at least one ear, (2) no prior usage of HA, (3) no ear related medical complications, and (4) had a Mini-Mental State Examination score ≥ 18 were eligible for this study. Using a delayed-start study design, participants were randomized into the immediate-start (Fitted) group where HA was fitted immediately or the delayed-start (Not Fitted) group where HA fitting was delayed for three months. Cost utility analysis was used to compare the cost-effectiveness of being fitted with HA combined with short-term, aural rehabilitation with the routine care group who were not fitted with HA. Incremental cost effectiveness ration (ICER) was computed. Health Utility Index (HUI-3) was used to measure utility gain, a component required to derive the quality adjusted life years (QALY). Total costs included direct healthcare costs, direct non-healthcare costs and indirect costs (productivity loss of participant and caregiver). Demographic data was collected during the index visit to MHC. Cost and utility data were collected three months after index visit and projected to five years. RESULTS: There were 264 participants in the Fitted group and 163 participants in the Not Fitted group. No between-group differences in age, gender, ethnicity, housing type and degree of hearing loss were observed at baseline. At 3 months, HA fitting led to a mean utility increase of 0.12 and an ICER gain of S$42,790/QALY (95% CI: S$32, 793/QALY to S$62,221/QALY). At five years, the ICER was estimated to be at S$11,964/QALY (95% CI: S$8996/QALY to S$17,080/QALY) assuming 70% of the participants continued using the HA. As fewer individuals continued using their fitted HA, the ICER increased. CONCLUSIONS: HA fitting can be cost-effective and could improve the quality of life of hearing-impaired older individuals within a brief period of device fitting. Long term cost-effectiveness of HA fitting is dependent on its continued usage.

Disease Modification in Alzheimer's Disease: Current Thinking.

Alzheimer's disease (AD) has increasingly been recognized as a huge unmet medical need. Currently, there is no approved drug to cure, prevent, or even slow down the disease. It is imperative to develop disease-modifying treatments for AD to alter the underlying disease progression. This paper reviews the most up-to-date regulatory guidance on how to demonstrate disease modification and provides an overview of available methodologies and applications to clinical trials. The intent is to assist the field with future clinical trials designed to demonstrate disease-modifying effect in AD. The methodologies may be generalizable to broader neurodegenerative diseases.

"Delayed start" gonadotropin-releasing hormone antagonist protocol in Bologna poor-responders: A systematic review and meta-analysis of randomized controlled trials.

To evaluate the effectiveness of delay start protocol in improving the success of in vitro fertilization (IVF) in poor responders according to Bologna's criteria. Only randomized controlled trial (RCT) of infertile women undergoing a single IVF/ICSI cycle with ovarian stimulation protocol based on daily injections with delay start protocol or a conventional antagonist protocol were included in this systematic review and meta-analysis. The review protocol was registered in PROSPERO before starting the data extraction (CRD42019128284). Primary outcome was clinical pregnancy rate. Ongoing pregnancy rate, miscarriage rate, number of oocytes, number of MII oocytes, stimulation length, gonadotropin amount and cancellation rate were considered as secondary outcomes. Four randomized controlled trials were included with a total number of 380 participants. 189 patients were included in the delayed start protocol and 191 were allocated to the comparison group. The results showed a significant higher clinical pregnancy rate (CPR) in patients allocated to the intervention. Data from all studies failed to detect a statistical difference between groups in terms of ongoing pregnancy rate (OPR), miscarriage rate (MR), Total-Oocyte, MII-Oocyte and Total-Embryos. Gonadotropin amount (GA) was significantly lower in the intervention group in comparison to controls, with no difference in stimulation length (SL) and cancelled cycle (CC). Delayed start GnRH-antagonist protocol may reduce GA and improve CPR in poor ovarian responder according to Bologna criteria.

Statistical considerations in a delayed-start design to demonstrate disease modification effect in neurodegenerative disorders.

There has been a paradigm shift in diagnostic conceptualization of Alzheimer's disease (AD) based on the current evidence suggesting that structure and biology changes start to occur before clinical symptoms emerge. Consequently, therapeutic drug development is also shifting to treat early AD patients using biomarkers for enrichment in clinical trials. A similar paradigm shift is occurring for Parkinson disease. In the absence of acceptable biomarkers that could be combined with a clinical endpoint to demonstrate a disease modification (DM) effect in neurodegenerative disorders, a delayed-start design can be applied to demonstrate a lasting effect on the disease course. The delayed-start design includes two treatment periods, where in period 1, patients are randomized to receive an active treatment or placebo, and in period 2, placebo patients are switched to the active treatment while patients in the active treatment arm will continue the same treatment. The hypothesis is that patients who start the active treatment later will fail to catch up to the treatment benefit achieved by patients who receive the active treatment in both periods. A usual analytical approach has sought to demonstrate the divergence of slope during period 1 and the parallelism of slopes during period 2 as the DM effect. However, due to heterogeneity in timing and the magnitude of maximal effect among patients, nonlinear response over time could be observed within the two treatment arms in both periods. We propose an approach to evaluate the DM effect with the linearity assumption for treatment differences, but not for each arm separately.

Application of Bayesian analyses to doubly randomized delayed start, matched control designs to demonstrate disease modification.

Disease modification is a primary therapeutic aim when developing treatments for most chronic progressive diseases. The best treatments do not simply affect disease symptoms but fundamentally improve disease course by slowing, halting, or reversing disease progression. One of many challenges for establishing disease modification relates to the identification of adequate analytic tools to show differences in a disease course following intervention. Traditional approaches rely on the comparisons of slopes or noninferiority margins. However, it has proven difficult to conclusively demonstrate disease modification using such approaches. To address these challenges, we propose a novel adaptation of the delayed start study design that incorporates posterior probabilities identified by hierarchical Bayesian inference approaches to establish evidence for disease modification. Our models compare the size of treatment differences at the end of the delayed start period with those at the end of the early start period. Simulations that compare several models are provided. These include general linear models, repeated measures models, spline models, and model averaging. Our work supports the superiority of model averaging for accurately characterizing complex data that arise in real world applications. This novel approach has been applied to the design of an ongoing, doubly randomized, matched control study that aims to show disease modification in young persons with schizophrenia (the Disease Recovery Evaluation and Modification (DREaM) study). The application of this Bayesian methodology to the DREaM study highlights the value of this approach and demonstrates many practical challenges that must be addressed when implementing this methodology in a real world trial.

Does the "delayed start" protocol with gonadotropin-releasing hormone antagonist improve the pregnancy outcome in Bologna poor responders? a randomized clinical trial.

BACKGROUND: Recently, a novel approach with delaying the start of controlled ovarian stimulation along with gonadotropin-releasing hormone (GnRH) antagonist pretreatment for 7 days after estrogen priming for further suppression of endogenous follicle stimulating hormone (FSH) during the early follicular phase, resulting in more FSH-responsive follicles and thus improving synchronous follicular development was introduced. Two clinical trials have examined this strategy and reported controversial results. This study aimed to compare the effect of delayed-start GnRH antagonist protocol and standard GnRH antagonist in patients with poor ovarian response (POR) undergoing in vitro fertilization (IVF)/ intracytoplasmic sperm injection (ICSI). METHODS: This randomized clinical trial was conducted at infertility department of Royan Institute from January 2017 to June 2018. Poor ovarian response was defined according to the Bologna criteria. The eligible women were randomly allocated into an experimental and control groups. In experimental group, patients received delayed-start GnRH antagonist protocol with estrogen priming followed by early follicular-phase GnRH antagonist treatment for 7 days before ovarian stimulation with gonadotropin and in control group, patients treated with estrogen priming antagonist protocol. IVF/ICSI outcomes were compared between groups. RESULTS: Among all the 250 patients examined 156 women were eligible for study and finally 120 patients were allocated to intervention (n = 60) and control (n = 60) groups. Demographic characteristics and hormonal profiles of the patients did not differ between groups. The statistical analysis showed that there were significant differences between groups regarding the total dose of used gonadotropins (P < 0.001), stimulation duration (P < 0.001), number of retrieved oocytes (P = 0.01) and top quality embryo (P < 0.001) and also cancellation (P = 0.002) and fertilization rates (P = 0.002). CONCLUSION: On the basis of present results the delayed-start protocol in poor responders can improve the fertilization rate and quality of embryos and reduce the cycle cancellation but have no significant effect on clinical pregnancy rate; however, larger randomized clinical trials are required to compare it with other protocols. TRIAL REGISTRATION: NCT, NCT03134690. Registered 1 May 2017 - Retrospectively registered, http://www.clinicaltrial.gov / NCT03134690.

Optimal unidirectional switch designs.

Stepped wedge designs and delayed start designs can all be considered as special cases of the so-called unidirectional switch design. This paper provides optimal proportions of clusters that are allocated to switch patterns in a unidirectional switch design to minimize the asymptotic variance of the treatment effect estimator. This unique optimal design applies to certain cross-sectional and longitudinal variance component models. When the intraclass correlation coefficient is zero, the optimal unidirectional switch design coincides with the classic (cluster) parallel group design. The optimal unidirectional switch design is more efficient than the optimal stepped wedge design and delayed start designs. Compared with the uniform unidirectional switch design, the efficiency gain of the optimal unidirectional switch design can be substantial, but it depends on the intraclass correlation and the cluster size. We also showed that augmenting the optimal stepped wedge design with pure control pattern is more efficient than the optimal stepped wedge design. In addition, robust minimax design for unidirectional switch design, delayed start design, and stepped wedge design are provided.

Deep Brain Stimulation Targeting the Fornix for Mild Alzheimer Dementia (the ADvance Trial): A Two Year Follow-up Including Results of Delayed Activation.

BACKGROUND: Given recent challenges in developing new treatments for Alzheimer dementia (AD), it is vital to explore alternate treatment targets, such as neuromodulation for circuit dysfunction. We previously reported an exploratory Phase IIb double-blind trial of deep brain stimulation targeting the fornix (DBS-f) in mild AD (the ADvance trial). We reported safety but no clinical benefits of DBS-f versus the delayed-on (sham) treatment in 42 participants after one year. However, secondary post hoc analyses of the one-year data suggested a possible DBS-f benefit for participants≥65 years. OBJECTIVE: To examine the long-term safety and clinical effects of sustained and delayed-on DBS-f treatment of mild AD after two years. METHODS: 42 participants underwent implantation of DBS-f electrodes, with half randomized to active DBS-f stimulation (early on) for two years and half to delayed-on (sham) stimulation after 1 year to provide 1 year of active DBS-f stimulation (delayed on). We evaluated safety and clinical outcomes over the two years of the trial. RESULTS: DBS-f had a favorable safety profile with similar rates of adverse events across both trial phases (years 1 and 2) and between treatment arms. There were no differences between treatment arms on any primary clinical outcomes. However, post-hoc age group analyses suggested a possible benefit among older (>65) participants. CONCLUSION: DBS-f was safe. Additional study of mechanisms of action and methods for titrating stimulation parameters will be needed to determine if DBS has potential as an AD treatment. Future efficacy studies should focus on patients over age 65.

Delayed-Start Analyses in the Phase 3 Solanezumab EXPEDITION3 Study in Mild Alzheimer's Disease.

OBJECTIVE: A delayed-start design has been proposed to assess a potential disease-modifying effect in investigational drugs for Alzheimer's disease that target the underlying disease process. We extended this methodology to recently obtained data from the EXPEDITION3. METHODS: EXPEDITION3 was a Phase 3, double-blind study with participants randomized to solanezumab (400 mg) or placebo every 4 weeks for 80 weeks, with an optional extension of active treatment. The delayed-start analysis was designed to determine if a statistically significant treatment difference established during the placebo-controlled period is maintained (at predefined level) during the delayed-start period, which would suggest the active drug has a disease-modifying effect. The delayed-start analysis was assessed across multiple efficacy measures, and includes data from baseline in the placebo-controlled period and up to 9 months in the delayed-start period. RESULTS: No significant difference was observed between the placebo and solanezumab treatment groups at the end of the placebo-controlled period for the Alzheimer's Disease Assessment Scale-Cognitive 14-item subscale. A significant treatment difference was observed at the end of the placebo-controlled period for the Alzheimer's Disease Cooperative Study-Activities of Daily Living instrumental items, an effect also seen at 6 months in the delayed-start period, and the noninferiority criterion was met. No other efficacy measures met these criteria. CONCLUSIONS: Delayed-start statistical methodology was used to understand the longitudinal outcomes in EXPEDITION3 and its extension. The small treatment differences observed at the end of the placebo-controlled phase prevented adequate assessment of any putative disease modifying effect.

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

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.

Critical appraisal of arguments for the delayed-start design proposed as alternative to the parallel-group randomized clinical trial design in the field of rare disease.

BACKGROUND: A number of papers have proposed or evaluated the delayed-start design as an alternative to the standard two-arm parallel group randomized clinical trial (RCT) design in the field of rare disease. However the discussion is felt to lack a sufficient degree of consideration devoted to the true virtues of the delayed start design and the implications either in terms of required sample-size, overall information, or interpretation of the estimate in the context of small populations. OBJECTIVES: To evaluate whether there are real advantages of the delayed-start design particularly in terms of overall efficacy and sample size requirements as a proposed alternative to the standard parallel group RCT in the field of rare disease. METHODS: We used a real-life example to compare the delayed-start design with the standard RCT in terms of sample size requirements. Then, based on three scenarios regarding the development of the treatment effect over time, the advantages, limitations and potential costs of the delayed-start design are discussed. RESULTS: We clarify that delayed-start design is not suitable for drugs that establish an immediate treatment effect, but for drugs with effects developing over time, instead. In addition, the sample size will always increase as an implication for a reduced time on placebo resulting in a decreased treatment effect. CONCLUSIONS: A number of papers have repeated well-known arguments to justify the delayed-start design as appropriate alternative to the standard parallel group RCT in the field of rare disease and do not discuss the specific needs of research methodology in this field. The main point is that a limited time on placebo will result in an underestimated treatment effect and, in consequence, in larger sample size requirements compared to those expected under a standard parallel-group design. This also impacts on benefit-risk assessment.

A stepped wedge design for testing an effect of intranasal insulin on cognitive development of children with Phelan-McDermid syndrome: A comparison of different designs.

This paper compares the power of the parallel group design, the matched-pairs design, and several options for the stepped wedge and delayed start designs for testing a possible effect of intranasal insulin with respect to placebo on developmental growth of children with a rare disorder like Phelan-McDermid syndrome. A subject-specific linear mixed effects model for the primary outcome developmental age in a longitudinal setting with five time points was assumed. Monte Carlo simulation studies with small sample sizes were applied since the rare disorder prohibits large trials. The stepped wedge designs, which were initially preferred for ethical reasons, appear to be competitive in power to other designs and were in some settings even the best. The assumed statistical model also demonstrates that all of the designs can be viewed as a stepped wedge or delayed treatment design. Our results show that the stepped wedge design is an appropriate alternative for randomized controlled trials on developmental growth with small numbers of participants under the formulated statistical conditions.