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BackgroundFibromyalgia is a chronic multidimensional pain disease with no curative treatment currently available. Its management relies on a multimodal approach involving pharmacologic and non-pharmacologic elements. Because a suggested factor in its etiology is a central sensitization phenomenon involving the N-methyl-D-aspartate receptor (NMDAR), NMDAR antagonists have been proposed as a treatment target. Ketamine and its levogyre form, S-ketamine, have been used to treat chronic pain for many years without consensus about their therapeutic efficiency. We aim to assess the efficacy of S-ketamine as a co-treatment for fibromyalgia.MethodsThis prospective, randomized, single-center, double-blind, parallel-group, dose-escalation trial will compare a co-treatment with S-ketamine (intervention) to a control treatment without S-ketamine (control). It will consist of two successive cohorts with 2:1 randomization ratio (S-ketamine at two different doses: control) with 105 participants in each cohort. The protocol follow-up time will be 12 weeks, including 3 visits for the treatment (week 0, week 2, and week 4) and 3 visits for follow-up (week 6, week 9, and week 12). Our primary outcome, pain relief and/or better patient function, will be assessed with the Brief Pain Inventory questionnaire. The statistical analysis will be performed on an intention-to-treat basis. If the primary outcome is reached at the end of follow-up in the first cohort with low-dose S-ketamine (0.2 mg/kg), the trial will end. If not, the trial will continue with the second cohort and high-dose S-ketamine (0.4 mg/kg).DiscussionThe challenge of our trial is the inclusion of a large number of participants in comparison to other trials involving ketamine or S-ketamine infusions for chronic pain management. The originality of our protocol is to include functionality in addition to pain relief as a primary outcome because these two endpoints are not linked in a linear way. For some patients, functional status is more important than pain relief.Trial registrationEudraCT reference: 2020-000473-25,ClinicalTrials.gov: NCT04436250, first posted June 18, 2020; last updated July 21, 2020. Protocol version 2.2 issued on September 30, 2020, after a revision by the ethics committee.https://clinicaltrials.gov/ct2/show/NCT04436250

Cluster randomized designs are frequently employed in pragmatic clinical trials which test interventions in the full spectrum of everyday clinical settings in order to maximize applicability and generalizability. In this study, we propose to directly incorporate pragmatic features into power analysis for cluster randomized trials with count outcomes. The pragmatic features considered include arbitrary randomization ratio, overdispersion, random variability in cluster size, and unequal lengths of follow-up over which the count outcome is measured. The proposed method is developed based on generalized estimating equation (GEE) and it is advantageous in that the sample size formula retains a closed form, facilitating its implementation in pragmatic trials. We theoretically explore the impact of various pragmatic features on sample size requirements. An efficient Jackknife algorithm is presented to address the problem of underestimated variance by the GEE sandwich estimator when the number of clusters is small. We assess the performance of the proposed sample size method through extensive simulation and an application example to a real clinical trial is presented.

Background Although autogenous venous grafts are preferable for below-the-knee bypass surgery in patients with critical limb ischemia, some 20% of patients will have no suitable vein for grafting, compelling a resort to artificial graft materials. Retrospective subgroup analyses within published studies comparing heparin-bonded polytetrafluoroethylene (PTFE) with crude PFTE graft in below-the-knee bypass suggest that heparin-bonded graft offers superior long-term patency rates, but this has not been prospectively verified in patients with critical limb ischemia. Methods A single-blind randomized controlled trial in 20 French centers has been designed. Patients assessed as having no suitable autologous vein for bypass grafting for critical lower limb ischemia will be randomized to receive either a heparin-bonded PTFE graft or a crude PTFE graft. A literature review suggested expected 1-year patency rates of 53% for the crude ePTFE arm and 74% for the heparin-bonded PTFE arm. On analyzing 1-year patency rate as a binary variable, for a significance level α = 0.05 and a randomization ratio of 1:1, a total of 176 patients (88 in each arm) will be required to obtain approximately 80% power to reject the null hypothesis. Assuming 10% dropout at 1 year and 20% mortality, 228 patients will be randomized (114 patients in each arm). Results The primary outcome variable will be patency at 1 year assessed by duplex ultrasound color-flow scan. Any intervention to open up or prevent a graft occlusion before 1 year will be classified as loss of patency. Technical success, deaths, complications, major adverse cardiovascular and limb events, length of hospitalization, and quality of life will also be recorded and analyzed as secondary outcome variables. Cost-utility and cost-effectiveness analyses based on standard tariffs in the French health insurance system will be performed. Conclusions The REPLACE trial is the first randomized controlled trial designed to determine if heparin-bonded PTFE graft is superior to crude PTFE graft in below-the-knee bypass surgery for critical limb ischemia.

Background Despite modern treatment techniques, radiotherapy (RT) in patients with head and neck cancer (HNC) may be associated with high rates of acute and late treatment-related toxicity. The most effective approach to reduce sequelae after RT is to avoid as best as possible healthy tissues and organs at risk from the radiation target volume. Even small geometric changes can lead to a significant dose reduction in normal tissue and better treatment tolerability. The major objective of the current study is to investigate 3D printed, tooth-borne tissue retraction devices (TRDs) compared to conventional dental splints for head and neck RT. Methods In the current two-arm randomized controlled phase II trial, a maximum of 34 patients with HNC will be enrolled. Patients will receive either TRDs or conventional dental splints (randomization ratio 1:1) for the RT. The definition of the target volume, modality, total dose, fractionation, and imaging guidance is not study-specific. The primary endpoint of the study is the rate of acute radiation-induced oral mucositis after RT. The quality of life, local control and overall survival 12 months after RT are the secondary endpoints. Also, patient-reported outcomes and dental status, as well as RT plan comparisons and robustness analyzes, will be assessed as exploratory endpoints. Finally, mesenchymal stem cells, derived from the patients’ gingiva, will be tested in vitro for regenerative and radioprotective properties. Discussion The preliminary clinical application of TRD showed a high potential for reducing acute and late toxicity of RT in patients with HNC. The current randomized study is the first to prospectively investigate the clinical tolerability and efficacy of TRDs for radiation treatment of head and neck tumors. Trial registration: ClinicalTrials.gov; NCT04454697; July 1st 2020; https://clinicaltrials.gov/ct2/show/record/NCT04454697.

Background Arterial hypertension is the most prevalent risk factor for cardiovascular disease in sub-Saharan Africa. Only a few and mostly small randomized trials have studied antihypertensive treatments in people of African descent living in sub-Saharan Africa. Methods In this open-label, three-arm, parallel randomized controlled trial conducted at two rural hospitals in Lesotho and Tanzania, we compare the efficacy and cost-effectiveness of three antihypertensive treatment strategies among participants aged ≥ 18 years. The study includes patients with untreated uncomplicated arterial hypertension diagnosed by a standardized office blood pressure ≥ 140/90 mmHg. The trial encompasses a superiority comparison between a triple low-dose antihypertensive drug combination versus the current standard of care (monotherapy followed by dual treatment), as well as a non-inferiority comparison for a dual drug combination versus standard of care with optional dose titration after 4 and 8 weeks for participants not reaching the target blood pressure. The sample size is 1268 participants with parallel allocation and a randomization ratio of 2:1:2 for the dual, triple and control arms, respectively. The primary endpoint is the proportion of participants reaching a target blood pressure at 12 weeks of ≤ 130/80 mmHg and ≤ 140/90 mmHg among those aged Discussion This trial will help to identify the most effective and cost-effective treatment strategies for uncomplicated arterial hypertension among people of African descent living in rural sub-Saharan Africa and inform future clinical guidelines on antihypertensive management in the region. Trial registration Clinicaltrials.govNCT04129840. Registered on 17 October 2019 (https://www.clinicaltrials.gov/).

Background/Purpose Current SLE treatment options have limited efficacy and potential toxicities that impede an individual’s ability to remain on therapy. AMG 570 is a bispecific antibody inhibiting both ICOSL and BAFF that engages ICOSL on antigen-presenting cells (dendritic cells and B cells) and reduces circulating naive B cells in healthy subjects. This phase 2 study will employ SLE drug screening and response-adaptive randomization (RAR) to optimize dose selection of AMG 570 in subjects with active SLE and inadequate response to standard of care (SOC) therapy (NCT04058028). Methods In this adaptive, phase 2, placebo-controlled, dose-ranging study, subjects (N∼300, age 18–75 years) will be randomized to receive placebo or 1 of 3 doses of AMG 570 Q2W for 52 weeks, followed by 16 weeks of safety follow-up. The primary objective is to evaluate efficacy of AMG 570 compared with placebo at week 24 using the SLE Responder Index (SRI-4). Key secondary endpoints include SRI-4 at week 52 with oral corticosteroid (OCS) reduction (≥10 mg/day at baseline to ≤7.5 mg/day in weeks 44–52) and SRI-4 and Lupus Low Disease Activity State at week 52. Subjects will undergo 2 screening visits to fulfill criteria for active SLE and demonstrate adherence to prior SLE treatment including OCS, immunosuppressants, and/or immunomodulators. Blood screening tests will confirm detectable serum drug levels of baseline SOC medications. RAR aims to allocate more subjects to more efficacious doses while maintaining the placebo allocation constant; the randomization ratio could be adapted after interim analyses based on clinical efficacy. The trial includes interim analyses for futility using the Bayesian approach. Results Study ongoing. Conclusion This study will provide safety and efficacy data for AMG 570 compared with placebo, and its adaptive trial design aims to optimize development of a novel therapy for SLE patients with inadequate response to current SOC. Acknowledgments Amgen Inc. sponsored this study.

Background The Enabling Reduction of Low-grade Inflammation in Seniors (ENRGISE) Pilot Study is a multicenter randomized clinical trial examining the feasibility of testing whether omega-3 fish oil (ω-3) and the angiotensin receptor blocker losartan alone or in combination can reduce inflammation and improve walking speed in older adults with mobility impairment. We describe recruitment methods and results. Methods Eligible participants were 70 years and older, had elevated interleukin-6 levels (2.5–30 pg/mL) and mobility impairment. Results Of those who responded to recruitment, 83% responded to mailings. A total of 5,424 telephone screens were completed; of these, 2,011 (37.1%) were eligible for further screening. The most common reasons for ineligibility at the telephone screens were lack of mobility impairment or use of angiotensin receptor blockers or angiotensin-converting enzyme inhibitors (n=1.789). Of the 1,305 initial screening visits, 1,087 participants had slow gait speed ( Conclusion Recruitment for ω-3 exceeded goals, but goals for the losartan and combination strata were not met due to the high proportion of participants taking angiotensin receptor blockers or angiotensin-converting enzyme inhibitors.

While recent Phase 3 glioblastoma (GBM) trials have failed to establish novel therapies, they potentially provide a high-quality source of external control patients treated with temozolomide. We consider hybrid two-stage adaptive designs that leverage these external controls to safely accelerate Phase 3 GBM trials. The basic strategy is that first patients are randomized 1:1 between the control and experimental arms, then an interim check measures similarity between the trial's control patients and potential external controls, and finally if this interim similarity is high the randomization ratio is changed accordingly and the external controls are used in the final analysis. An extensive simulation study is conducted to assess operating characteristics and we discuss when these hybrid designs can accelerate GBM therapy development while maintaining strict error control.

BACKGROUND Early rehabilitation has been shown to enhance functional outcomes. Whether the addition of virtual reality (VR) training could further improve muscle strength, mood state, and functional status for patients with acute stroke is unknown. AIMS To investigate the effectiveness of VR training on muscle strength, mood state (depression, anxiety), and functional status in patients following acute stroke. METHODS A randomized controlled trial was conducted. Patients with acute ischemic stroke (N = 152) were selected and randomly assigned with a 1:3 randomization ratio to either experimental group (EG) or comparison group (CG). Both groups received early rehabilitation. The EG received an extra 5 days of VR training (15 min of time, two times a day), started 24 hr to 3 days poststroke. Muscle strength, mood state, and functional status were collected at admission and at the day of discharge. Generalized estimating equations were applied to examine the intervention effects. RESULTS A total of 143 participants (94%) completed the study, and 145 were included in the intention-to-treat analysis. Participants in the EG reported increased muscle strength of upper and lower limbs in both affected and unaffected sides, decreased depression and anxiety, and increased functional status at discharge. When the group-time interaction was examined, the EG had greater increased upper limb muscle strength of the unaffected side (s = 0.34, p

Background Co-occurring parental substance use and child maltreatment has increased in recent years and is associated with poor child welfare outcomes. The Sobriety Treatment and Recovery Teams (START) program was developed to meet the needs of these families. Objective A randomized controlled trial was implemented to compare START to usual child welfare services on three outcomes: out-of-home care (OOHC) placements; reunification; and subsequent child maltreatment. Participants and setting Families reported to child welfare services in Jefferson County, Kentucky, were eligible if they had a current finding of child maltreatment or services needed, substance use as a primary risk factor, a child under six years of age, and no other open child welfare cases. Methods Biased coin randomization was used for a control: treatment randomization ratio of 1:2. Analyses were conducted using intent-to-treat (ITT), though a subsample of families receiving services was also analyzed. Differences were assessed using t-tests, chi-square, and risk ratios. Results A total of 348 families including 526 children were randomized to START (n = 346) and usual services (n = 180). There were no significant differences between groups on the three outcomes in the ITT sample or the subsample that received services, though the START OOHC rate was 7 percentage points lower (relative difference: 21.6 %) and the reunification rate was 13 percentage points higher (relative difference: 27.6 %) in the subsample. Conclusions Although differences between groups were not significantly different, the relative differences were meaningful and this is the third study showing lower rates of OOHC among START relative to usual services. Additionally, the START reunification rate is higher than the overall U.S. average in spite of notable risk factors.

Objective: To assess the short-term efficacy of transregional interferential current therapy on pain perception and disability level in chronic non-specific low back pain. Design: A randomized, single-blinded (the assessor collecting the outcome data was blinded), controlled trial. Setting: A private physiotherapy research clinic. Subjects: A total of 64 individuals, 20 men and 44 women, mean (SD) age was 51 years (11.93), with low back pain of more than three months, with or without pain radiating to the lower extremities above the knee, were distributed into a control ( n = 20) or an experimental group ( n = 44). A 2:1 randomization ratio was used in favour of the latter. Interventions: A transregional interferential current electrotherapy protocol was performed for participants in the experimental group, while the control group underwent a ‘usual care’ treatment (massage, mobilization and soft-tissue techniques). All subjects received up to 10 treatment sessions of 25 minutes over a two-week period, and completed the intervention and follow-up evaluations. Outcome measures: Self-perceived pain was assessed with a Visual Analogue Scale. Secondary measure included the Oswestry Low Back Disability Index. Evaluations were collected at baseline and after the intervention protocol. Results: Significant between-group differences were found for interferential current therapy on pain perception ( p = 0.032) and disability level ( p = 0.002). The observed differences in the between-group mean changes were of 11.34 mm (1.77/20.91) and 13.38 points (4.97/21.78), respectively. Conclusions: A two-week transregional interferential current treatment has shown significant short-term efficacy, when compared with a ‘usual care’ protocol, on self-perceived pain and functionality in subjects with chronic low back pain.

Designing optimal, Bayesian decision-theoretic trials has traditionally required the use of computationally-intensive backward induction. While methods for addressing this barrier have been put forward, few are both computationally tractable and non-myopic, with applications of the Gittins index being one notable example. Here we explore the look-ahead approach with adaptive-randomization, with designs ranging from the fully myopic to the fully informed. We compare the operating characteristics of the look-ahead designed trials, in which decision rules are based on a fixed number of future blocks, with those of trials designed using traditional backward induction. The less-myopic designs performed well. As the designs become more myopic or the trials longer, there were disparities in regions of the decision space that are transition zones between continuation and stopping decisions. The more myopic trials generally suffered from early stopping as compared to the less myopic and backward induction trials. Myopic trials with adaptive randomization also saw as many as 28 % of their continuation decisions change to a different randomization ratio as compared to the backward induction designs. Finally, early stages of myopic-designed trials may have disproportionate effect on trial characteristics.

Mixed-effects models for repeated measures (MMRM) analyses using the Kenward-Roger method for adjusting standard errors and degrees of freedom in an "unstructured" (UN) covariance structure are increasingly becoming common in primary analyses for group comparisons in longitudinal clinical trials. We evaluate the performance of an MMRM-UN analysis using the Kenward-Roger method when the variance of outcome between treatment groups is unequal. In addition, we provide alternative approaches for valid inferences in the MMRM analysis framework. Two simulations are conducted in cases with (1) unequal variance but equal correlation between the treatment groups and (2) unequal variance and unequal correlation between the groups. Our results in the first simulation indicate that MMRM-UN analysis using the Kenward-Roger method based on a common covariance matrix for the groups yields notably poor coverage probability (CP) with confidence intervals for the treatment effect when both the variance and the sample size between the groups are disparate. In addition, even when the randomization ratio is 1:1, the CP will fall seriously below the nominal confidence level if a treatment group with a large dropout proportion has a larger variance. Mixed-effects models for repeated measures analysis with the Mancl and DeRouen covariance estimator shows relatively better performance than the traditional MMRM-UN analysis method. In the second simulation, the traditional MMRM-UN analysis leads to bias of the treatment effect and yields notably poor CP. Mixed-effects models for repeated measures analysis fitting separate UN covariance structures for each group provides an unbiased estimate of the treatment effect and an acceptable CP. We do not recommend MMRM-UN analysis using the Kenward-Roger method based on a common covariance matrix for treatment groups, although it is frequently seen in applications, when heteroscedasticity between the groups is apparent in incomplete longitudinal data.

In clinical trials, sample size reestimation is a useful strategy for mitigating the risk of uncertainty in design assumptions and ensuring sufficient power for the final analysis. In particular, sample size reestimation based on unblinded interim effect size can often lead to sample size increase, and statistical adjustment is usually needed for the final analysis to ensure that type I error rate is appropriately controlled. In current literature, sample size reestimation and corresponding type I error control are discussed in the context of maintaining the original randomization ratio across treatment groups, which we refer to as "proportional increase." In practice, not all studies are designed based on an optimal randomization ratio due to practical reasons. In such cases, when sample size is to be increased, it is more efficient to allocate the additional subjects such that the randomization ratio is brought closer to an optimal ratio. In this research, we propose an adaptive randomization ratio change when sample size increase is warranted. We refer to this strategy as "nonproportional increase," as the number of subjects increased in each treatment group is no longer proportional to the original randomization ratio. The proposed method boosts power not only through the increase of the sample size, but also via efficient allocation of the additional subjects. The control of type I error rate is shown analytically. Simulations are performed to illustrate the theoretical results.

The outbreak of Ebola virus disease in West Africa is the largest ever recorded. Numerous treatment alternatives for Ebola have been considered, including widely available repurposed drugs, but initiation of enrollment into clinical trials has been limited. The proposed trial is an adaptive platform design. Multiple agents and combinations will be investigated simultaneously. Additionally, new agents may enter the trial as they become available, and failing agents may be removed. In order to accommodate the many possible agents and combinations, a critical feature of this design is the use of response adaptive randomization to assign treatment regimens. As the trial progresses, the randomization ratio evolves to favor the arms that are performing better, making the design also suitable for all-cause pandemic preparedness planning. The study was approved by US and Sierra Leone ethics committees, and reviewed by the US Food and Drug Administration. Additionally, data management, drug supply lines, and local sites were prepared. However, in response to the declining epidemic seen in February 2015, the trial was not initiated. Sierra Leone remains ready to rapidly activate the protocol as an emergency response trial in the event of a resurgence of Ebola. (ClinicalTrials.gov Identifier: NCT02380625.) In summary, we have designed a single controlled trial capable of efficiently identifying highly effective or failing regimens among a rapidly evolving list of proposed therapeutic alternatives for Ebola virus disease and to treat the patients within the trial effectively based on accruing data. Provision of these regimens, if found safe and effective, would have a major impact on future epidemics by providing effective treatment options.

A large number of analgesics have failed to prove superiority over placebo in randomized controlled trials (RCTs), and as this has been related to increasing placebo responses, there is currently an interest in specifying predictors of the placebo response. The literature on placebo mechanisms suggests that factors related to patients' expectations of treatment efficacy are pivotal for the placebo response. Also, general characteristics of RCTs have been suggested to influence the placebo response. Yet, only few meta-analyses have directly tested these hypotheses. Placebo data from 9 industrially sponsored, randomized, double-blind, placebo-controlled, multicenter phase III trials in 2017 adult patients suffering from chronic painful osteoarthritis (hip or knee) or low back pain were included. The primary outcome was pain intensity. Based on previous studies, we chose 3 expectancy-related primary predictors: type of active medication, randomization ratio, and number of planned face-to-face visits. In addition, explorative analyses tested whether RCT and patients' characteristics predicted the placebo response. Opioid trials, a high number of planned face-to-face visits, and randomization ratio predicted the magnitude of the placebo response, thereby supporting the expectancy hypothesis. Exploratory models with baseline pain intensity, age, washout length, and discontinuation because of adverse events accounted for approximately 10% of the variability in the placebo response. Based on these results and previous mechanisms studies, we think that patients' perception of treatment allocation and expectations toward treatment efficacy could potently predict outcomes of RCTs.

Prospective randomized clinical trials addressing biomarkers are time consuming and costly, but are necessary for regulatory agencies to approve new therapies with predictive biomarkers. For this reason, recently, there have been many discussions and proposals of various trial designs and comparisons of their efficiency in the literature. We compare statistical efficiencies between the marker-stratified design and the marker-based precision medicine design regarding testing/estimating 4 hypotheses/parameters of clinical interest, namely, treatment effects in each marker-positive and marker-negative cohorts, marker-by-treatment interaction, and the marker's clinical utility. As may be expected, the stratified design is more efficient than the precision medicine design. However, it is perhaps surprising to find out how low the relative efficiency can be for the precision medicine design. We quantify the relative efficiency as a function of design factors including the marker-positive prevalence rate, marker assay and classification sensitivity and specificity, and the treatment randomization ratio. It is interesting to examine the trends of the relative efficiency with these design parameters in testing different hypotheses. We advocate to use the stratified design over the precision medicine design in clinical trials with predictive biomarkers.

To reduce a clinical trial's cost and ethical risk to its enrollees, some oncology trial designers have suggested borrowing information from similar but already completed trials to reduce the number of patients needed for the current study. Motivated by competing drug therapies for lymphoma, we propose a Bayesian adaptive "platform" trial design that uses commensurate prior methods at interim analyses to borrow adaptively from the control group of an earlier-starting trial. The design adjusts the trial's randomization ratio in favor of the novel treatment when the interim posterior indicates commensurability of the two control groups. In this setting, our design can supplement a control arm with historical data, and randomize more new patients to the novel treatments. This design is both ethical and economical, since it shortens the process of introducing new treatments into the market, and any additional costs introduced by this design will be compensated by the savings in control arm sizes. Our approach performs well via simulation across settings with varying degrees of commensurability and true treatment effects, and compares favorably to an adaptive "all-or-nothing" approach in which the decision to pool or discard historical controls is based on a simple ad-hoc frequentist test at interim analysis. We also consider a three drug extension where a new imaginary intervention joins the platform, and show again that our procedure performs well via simulation.

Early recovery after surgery concepts have gained wide acceptance in various surgical specialties. However, limited data are available for radical cystectomy. A new early recovery after surgery concept was compared to a more conservative regimen in patients undergoing radical cystectomy for bladder cancer.A total of 101 consecutive patients were prospectively randomized to early recovery after surgery (62) or a conservative regimen (39) (intended randomization ratio was 2 early recovery after surgery-to-1 conservative regimen). Primary end points were differences in quality of life, and secondary end points included postoperative morbidity, demand for analgesics, time spent in the intermediate care unit, mobility and number of gastrointestinal events during hospital stay.Quality of life parameters, as measured by the EORTC (European Organization for the Research and Treatment of Cancer) Quality of Life questionnaire QLQ-30 did not change significantly between postoperative days 3 and 7 and at discharge from hospital in the conservative regimen group, whereas a significant improvement was observed in the early recovery after surgery group. Postoperative morbidity was lower in the early recovery after surgery group in terms of wound healing disorders (p = 0.006), fever (p = 0.004) and thrombosis (p = 0.027). The demand for analgesics was significantly lower in the early recovery after surgery group. The amount of food consumed in relation to the amount of food offered was significantly higher for the early recovery after surgery group as early as day 3 (p = 0.02). Time spent in the intermediate care unit was significantly shorter for the early recovery after surgery group (p0.001). There were no significant differences between the groups with respect to gastrointestinal events. The main limitations of this study were the lack of long-term data as well as the single center approach.Early recovery after surgery of patients who underwent radical cystectomy appears to have significant benefits compared to a conservative regimen in terms of postoperative morbidity, quality of life, use of analgesics and time spent in the intermediate care unit.

Background: This is the first multicenter clinical and experimental study of the anti wrinkle efficacy of Argireline in Chinese subjects. Objective: To evaluate the safety and efficacy of Argireline in the treatment of periorbital lines in Chinese subjects, and to observe the effect of Argireline on microstructural changes of the skin in the aged mice induced by D-galactose. Methods: The study was comprised of two parts: i) Clinical study: A total of 60 subjects received a single treatment in a 3:1 randomization ratio of Argireline: placebo. Argireline or placebo was applied to their periorbital wrinkles twice daily for 4 weeks, evaluations were made for the improvements in wrinkles. ii) Animal study: Argireline was applied to the aged mice twice daily for 6 weeks and the histopathological changes of skin tissue were evaluated. Results: In humans, the total anti wrinkle efficiency in the Argireline group was 48.9%, the depth of the wrinkles was notably reduced(P

Background Although disease management programs have been shown to provide a number of clinical benefits to patients with heart failure (HF), the incremental impact of an automated home monitoring (AHM) system on health-related quality of life (HRQL) is unknown. Methods and Results We performed a prospective randomized investigation, examining the additive value of AHM to a previously described nurse-directed HF disease management program (SPAN-CHF), with attention to HRQL, in patients with a recent history of decompensated HF. A total of 188 patients were randomized to receive the SPAN-CHF intervention for 90 days, either with (AHM group) or without (NAHM, standard-care group) AHM, with a 1:1 randomization ratio after HF-related hospitalization. HRQL, measured by the Minnesota Living With Heart Failure Questionnaire (MLHFQ) (Physical, Emotional, and Total scores on MLHFQ) was assessed at 3 time points: baseline, 45 days, and 90 days. Although both treatments (AHM and NAHM) improved HRQL at 45 and 90 days compared with baseline with respect to Physical, Emotional, and Total domain scales, no significant difference emerged between AHM and NAHM groups. Conclusions AHM and NAHM treatments demonstrated improved HRQL scores at 45 and 90 days after baseline assessment. When comparing 2 state-of the-art disease management programs regarding HRQL outcomes, our results did not support the added value of AHM.

Background Mitral valve surgery is the standard of care for patients with symptomatic mitral regurgitation (MR) or asymptomatic MR with evidence of left ventricular dysfunction or dilation. Whether an endovascular approach to repair can offer comparable effectiveness with improved safety remains to be determined in randomized trials. Study Design The EVEREST II Trial is a multicenter, randomized controlled trial to evaluate the benefits and risks of endovascular mitral valve repair using the MitraClip device compared with open mitral valve surgery (control) in patients with moderate or severe MR. Using a 2:1 randomization ratio, the trial is enrolling up to 186 MitraClip-treated subjects and 93 control subjects. Trial end points include a primary efficacy end point: the proportion of patients free from death, surgery for valve dysfunction, and with moderate-severe (3+) or severe (4+) MR at 12 months; the primary safety end point includes the proportion of patients with death, myocardial infarction, reoperation, nonelective cardiovascular surgery, stroke, renal failure, deep would infection, ventilation >48 hours, gastrointestinal complication, new permanent atrial fibrillation, septicemia, or transfusion of ≥2 U at 30 days or hospital discharge, whichever is longer. Conclusions This randomized controlled trial is designed to evaluate the performance of endovascular mitral repair in comparison to open mitral valve surgery in patients with significant MR.

Sample size formulas are functions of two categories of quantities. The first category does not depend on the analysis variables and contains randomization ratio, Type I error rate, and power. The second category depends on the analysis variables and includes means and standard deviations for the two-sample t-test, competing probabilities for the Wilcoxon–Mann–Whitney test, and median survival times for the logrank test. Quantities in the second category depend on subject matter knowledge and are much harder to specify than those in the first category. In addition, these quantities have different interpretations. In this article we propose using the competing probability as the only second category quantity when calculating sample sizes for the aforementioned three commonly used tests in clinical trials. Doing so unifies the interpretation of and sheds new light on the two-sample t-tests and the logrank tests in terms of sample size calculations.

Background Long-term adherence to prescription medications for the treatment of chronic disease remains low. While there are many contributors to suboptimal medication use, simple forgetfulness is widely believed to be central. Relatively simple devices may be a particularly cost-efficient and scalable way to promote adherence, however limited data exists about their ability to improve adherence in real-world settings. Methods/design The REMIND trial is a prospective, intent-to-treat randomized control trial to evaluate the impact on medication adherence of three simple, low-cost devices (Take-N-Slide™, the RxTimerCap™, and a standard pillbox). In March 2014, we enrolled 53,480 individuals 18 to 64 years old taking one to three medications to treat chronic disease whose prescription drug benefits were administered by CVS Caremark. The study's primary outcome is optimal adherence over the 12-month period after randomization. Using a randomization ratio of 1:2 between control and each intervention arm, the study has more than 80% power with an alpha of 5% to detect a 1% difference in the rate of optimal adherence between intervention and control groups and across intervention arms. Discussion The REMIND trial is the first randomized study to rigorously evaluate the impact of simple, low-cost reminder devices on medication adherence. The results will inform comparative cost effectiveness studies of reminder systems in improving medication adherence and clinical outcomes.

Introduction Clinical equipoise (i.e., uncertainty within the expert clinical community) is considered as a prerequisite for a randomized controlled trial (RCT). Indeed, a RCT must start with an “honest null hypothesis”, which indicates controversy in the clinical expert community about the superiority of one of the 2 compared interventions. At the planning stage, randomization may reflect the clinical uncertainty, namely, by the randomization ratio. A 1:1 ratio appears to best fit this state of uncertainty. Objective We aimed to assess whether the clinical equipoise principle is satisfied in unbalanced RCTs (i.e., with an unequal probability of subjects being allocated to one group than another). Method Observational and comparative study between unbalanced and balanced RCTs. We searched the “core clinical journals” of MEDLINE to identify reports of two-parallel–group superiority unbalanced RCTs published between January 2009 and December 2010. For each unbalanced RCT, we identified a maximum of 4 reports (to maximize power) of matched balanced RCTs dealing with the same population. Our primary outcome was the proportion of positive RCTs (i.e., with statistically significant results for the primary outcome [P Results We selected 46 reports of unbalanced RCTs and 164 of balanced RCTs; 65.2% unbalanced RCTs and 43.9% of balanced RCTs were positive [odds ratio 2.38; 95% confidence interval: 1.23, 4.63]. As compared with balanced RCTs, unbalanced RCTs were more often industry-funded and their control treatments were more often inactive. Adjusting for these latter variables did not modify the results. Conclusion This result questions the respect of clinical equipoise in unbalanced RCTs.

In developing targeted therapy, the marker-strategy design (MSD) provides an important approach to evaluate the predictive marker effect. This design first randomizes patients into non-marker-based or marker-based strategies. Patients allocated to the non-marker-based strategy are then further randomized to receive either the standard or targeted treatments, while patients allocated to the marker-based strategy receive treatments based on their marker statuses. Little research has been done on the statistical properties of the MSD, which has led to some widespread misconceptions and placed clinical researchers at high risk of using inefficient designs. In this article, we show that the commonly used between-strategy comparison has low power to detect the predictive effect and is valid only under a restrictive condition that the randomization ratio within the non-marker-based strategy matches the marker prevalence. We propose a Wald test that is generally valid and also uniformly more powerful than the between-strategy comparison. Based on that, we derive an optimal MSD that maximizes the power to detect the predictive marker effect by choosing the optimal randomization ratios between the two strategies and treatments. Our numerical study shows that using the proposed optimal designs can substantially improve the power of the MSD to detect the predictive marker effect. We use a lung cancer trial to illustrate the proposed optimal designs.

Fixed design confirmatory trials rely on emerging and reliable prior data and knowledge to provide necessary assumptions about the key design parameters including nuisance parameters. Traditionally, a fixed design has been the gold standard for its simplicity, validity, and ability to provide an unbiased estimate of the treatment effect. To allow for pre-specified flexibility in an ongoing trial, a simple two-arm controlled trial with a single primary efficacy endpoint, the repeated significance testing involving multiplicity adjustment becomes more complex than a fixed design approach. The repeated significance testing recognized in group sequential design and analysis was proposed as early as the randomization ratio adaptation in late 1960s (Zelen 1969), e.g., Armitage et al. (1969).

Cause-specific proportional hazards models are commonly used for analyzing competing risks data in clinical studies. Motivated by the objective to assess differential vaccine protection against distinct pathogen types in randomized preventive vaccine efficacy trials, we present an alternative case-only method to standard maximum partial likelihood estimation that applies to a rare failure event, e.g. acquisition of HIV infection. A logistic regression model is fit to the counts of cause-specific events (infecting pathogen type) within study arms, with an offset adjusting for the randomization ratio. This formulation of cause-specific hazard ratio estimation permits immediate incorporation of host-genetic factors to be assessed as effect modifiers, an important area of vaccine research for identifying immune correlates of protection, thus inheriting the estimation efficiency, and cost benefits of the case-only estimator commonly used for assessing gene–treatment interactions. The method is used to reassess HIV genotype-specific vaccine efficacy in the RV144 trial, providing nearly identical results to standard Cox methods, and to assess if and how this vaccine efficacy depends on Fc-γ receptor genes.

Background Prospective trial design often occurs in the presence of ‘acceptable’ historical control data. Typically, these data are only utilized for treatment comparison in a posteriori retrospective analysis to estimate population-averaged effects in a random-effects meta-analysis. Purpose We propose and investigate an adaptive trial design in the context of an actual randomized controlled colorectal cancer trial. This trial, originally reported by Goldberg et al., succeeded a similar trial reported by Saltz et al., and used a control therapy identical to that tested (and found beneficial) in the Saltz trial. Methods The proposed trial implements an adaptive randomization procedure for allocating patients aimed at balancing total information (concurrent and historical) among the study arms. This is accomplished by assigning more patients to receive the novel therapy in the absence of strong evidence for heterogeneity among the concurrent and historical controls. Allocation probabilities adapt as a function of the effective historical sample size (EHSS), characterizing relative informativeness defined in the context of a piecewise exponential model for evaluating time to disease progression. Commensurate priors are utilized to assess historical and concurrent heterogeneity at interim analyses and to borrow strength from the historical data in the final analysis. The adaptive trial’s frequentist properties are simulated using the actual patient-level historical control data from the Saltz trial and the actual enrollment dates for patients enrolled into the Goldberg trial. Results Assessing concurrent and historical heterogeneity at interim analyses and balancing total information with the adaptive randomization procedure lead to trials that on average assign more new patients to the novel treatment when the historical controls are unbiased or slightly biased compared to the concurrent controls. Large magnitudes of bias lead to approximately equal allocation of patients among the treatment arms. Using the proposed commensurate prior model to borrow strength from the historical data, after balancing total information with the adaptive randomization procedure, provides admissible estimators of the novel treatment effect with desirable bias-variance trade-offs. Limitations Adaptive randomization methods in general are sensitive to population drift and more suitable for trials that initiate with gradual enrollment. Balancing information among study arms in time-to-event analyses is difficult in the presence of informative right-censoring. Conclusions The proposed design could prove important in trials that follow recent evaluations of a control therapy. Efficient use of the historical controls is especially important in contexts where reliance on preexisting information is unavoidable because the control therapy is exceptionally hazardous, expensive, or the disease is rare.

The study's purpose was to analyze the effects of exercise training on exercise tolerance and left ventricular systolic function and structure in heart failure patients with preserved, mild, and moderate to severe reduction of left ventricular ejection fraction (LVEF).Ninety-eight patients with moderate to severe (n = 34), mild (n = 33), and preserved (n = 31) LVEF were randomly assigned to exercise training plus usual care (n = 65) or usual care alone (n = 33) in a randomization ratio of 2:1. Left ventricular function, left ventricular dimensions, and exercise tolerance were assessed before and after each intervention.Exercise tolerance and LVEF increased with exercise training in all patient groups, whereas they remained unchanged after usual care alone. Exercise training increased the mean ratio of early to late mitral inflow velocities (E/A ratio) and decreased deceleration time (DT) of early filling in patients with mild and preserved LVEF. In patients with moderate to severe systolic dysfunction and advanced diastolic dysfunction (DT160 ms), exercise training decreased E/A ratio and increased DT, both of which were unchanged after usual care alone. In the remaining patients (DT160 ms), exercise training also improved mitral inflow patterns. Exercise training decreased left ventricular dimensions in patients with mild and moderate to severe reduction of LVEF but not in patients with preserved LVEF.These results indicate that exercise training can improve the course of heart failure independent of the degree of baseline left ventricular dysfunction.

Forty eight hospitalized patients, due to Chronic Obstructive Pulmonary Disease (COPD) exacerbation, were included in this study with a randomization ratio 1:1. The study group patients were early discharged and monitored at home through the wearable “Healthwear” system, while control group patients underwent conventional care. Patients' intensive monitoring included ECG, heart and respiratory rate, oxygen saturation, activity and body position, combined with 3G mobile video sessions. There was a significant reduction in study group patients' hospital length of stay, outpatient clinic and emergency room visits, as well as in readmission rates.

BACKGROUND This is the first well-controlled study of the use of botulinum toxin type A (BoNTA) for glabellar lines in China. OBJECTIVES To evaluate the safety and efficacy of BoNTA in the treatment of glabellar lines in Chinese subjects. MATERIALS AND METHODS A total of 227 subjects received a single treatment in a 3:1 randomization ratio of BoNTA (20 U):placebo and were observed for 120 days after injection. Effective outcome measures included investigator's rating of wrinkle severity at maximum frown and rest and subjects' global assessment and self-perception of age. RESULTS A significantly higher responder rate at maximum frown, ranging from 94.1% at day 30 to 52.9% at day 120, was noted in the BoNTA group. The proportion of subjects with none or mild glabellar lines at rest was 66.7% in the BoNTA group at day 30. Most (95.3%) of the subjects treated with BoNTA reported better than 50% improvement at day 30, and self-perception of age was less than chronological age. There were no statistically significant differences in adverse events reported between the two groups (p=.06). CONCLUSION A single treatment of 20 U of BoNTA was effective and safe in reducing glabellar lines in Chinese subjects.

Study design factors are partly to blame for the high failure rate in trials with antidepressant drugs. Clinical trial simulation (CTS) allows the investigation of the influence of design characteristics on important aspects of clinical trials such as power and type I error. Using CTS scenarios, we evaluated the impact of population size, randomization ratio, frequency of assessments, dropout mechanisms, clinical end point, and statistical method on the outcome of clinical trials with antidepressant drugs. The results reveal that (i) an increase in the frequency of visits does not increase statistical power, (ii) a skewed randomization for a placebo or comparator arm may decrease statistical power, and (iii) analysis of the percentage of responders should be avoided. CTS should become best practice in the optimization of study design. To date, no other statistical approach has enabled such comprehensive evaluation of the factors contributing to study failure in depression.

Objectives: To investigate the effectiveness of a long established intervention, occupational therapy for people with psychotic conditions, and to inform future research designs. Design: A pilot randomized controlled trial. Setting: Two community mental health teams in a UK city. Participants: Forty-four adults with schizophrenia or other psychotic conditions, and functional problems. Interventions: Twelve months of individualized occupational therapy in community settings, as an adjunct to usual care and compared to treatment as usual. A two to one randomization ratio was used in favour of occupational therapy. Outcome measures: Social Functioning Scale, Scale for the Assessment of Negative Symptoms and employment. Results: Both groups' scores on Social Functioning Scale and Scale for the Assessment of Negative Symptoms showed significant improvement over 12 months. The Social Functioning Scale overall mean difference for occupational therapy was 2.33, P=0.020 and for treatment as usual was 6.17, P=0.023. The Scale for the Assessment of Negative Symptoms total mean difference for occupational therapy was -16.25, P Conclusion: This pilot study suggested that individualized occupational therapy may contribute to recovery but more focus is recommended on people's cognitive abilities and employment.

This paper provides explicit sample size determination formulas for planning a long-term trial in patients with chronic disease by using available results from existing short-term studies that may predict long-term disease progression patterns. The sample size calculation formulas are flexible to incorporate different nonlinear disease progression patterns. Various within-patient correlation structures are considered. By using the proposed formulas, sample size sensitivity can be easily explored for possible choices of study duration, assumed nonlinear disease progression patterns, randomization ratio, and expected clinical meaningful difference in the end of study. In addition, sample size calculation formulas are provided when the primary endpoint is change from baseline. Discussions on the relationship among required sample size, study duration, randomization ratio are also included.

discogenic pain due to one-level degenerative disc disease unresponsive to nonoperative treatment. The randomization ratio is 2:1. PATIENT SAMPLE: 75 patients (49 artificial discs and 26 controls) randomized in a 2:1 ratio. 43 patients have achieved 1-year follow-up (30 artificial discs and 13 controls). 6 patients have been evaluated at the 2-year mark (4 artificial discs and 2 controls). OUTCOME MEASURES: Oswestry Disability Index (ODI) back pain, visual analog pain score (VAS) METHODS: Prospective data were collected preoperatively and at defined intervals postoperatively. RESULTS: Oswestry Disability Index (ODI) preoperatively was 61 (Flexicore) and 59 (control). At 6-week follow-up Flexicore-36, control-50; at 3 months Flexicore-31, control-30; at 6 months Flexicore-25, control-27; at 12 months Flexicore-19 control-26; at 24 months Flexicore-3 control-4. Visual analog pain score (VAS) preoperatively was 86 (Flexicore) and 83 (control). At 6-week follow-up Flexicore-30, control-45; at 3 months Flexicore-39 control-33; at 6 months Flexicore-32, control-28; at 12 months Flexicore-22, control-40. Range of motion in flexion/extension preoperatively was an average of 8 degrees; the Flexicore group postoperatively was 5 degrees. Lateral bending averaged 4 degrees preoperatively and 3 degrees after Flexicore disc replacement. CONCLUSIONS: These initial results demonstrate the Flexicore artificial disc to compare very favorably with circumferential fusion for the treatment of lumbar degenerative disc disease unresponsive to nonoperative treatment at the 1-year follow-up period. FDA DEVICE/DRUG STATUS: Flexicore artificial disc: Investigational/ not approved. CONFLICT OF INTEREST: Author (RS) Grant/Research Support: Stryker.

Background Although even randomization (that is, approximately 1:1 randomization ratio in study arms) provides the greatest statistical power, designed uneven randomization (DUR), (for example, 1:2 or 1:3) is used to increase participation rates. Until now, no convincing data exists addressing the impact of DUR on participation rates in trials. The objective of this study is to evaluate the epidemiology and to explore factors associated with DUR. Methods We will search for reports of RCTs published within two years in 25 general medical journals with the highest impact factor according to the Journal Citation Report (JCR)-2010. Teams of two reviewers will determine eligibility and extract relevant information from eligible RCTs in duplicate and using standardized forms. We will report the prevalence of DUR trials, the reported reasons for using DUR, and perform a linear regression analysis to estimate the association between the randomization ratio and the associated factors, including participation rate, type of informed consent, clinical area, and so on. Discussion A clearer understanding of RCTs with DUR and its association with factors in trials, for example, participation rate, can optimize trial design and may have important implications for both researchers and users of the medical literature.

Institutional review boards must guarantee the ethical acceptability of a randomized controlled trial before it is conducted. However, some may regard an unbalanced randomization ratio as reflecting an absence of uncertainty between the groups being compared. The objective was to assess institutional review board members’ perceptions of whether unbalanced randomization in randomized controlled trials is justified and ethically acceptable. Institutional review board members worldwide completed a survey involving clinical vignettes modeling situations classically advocated to explain the use of unbalanced randomization. Institutional review board members were asked whether unbalanced randomization was justified and ethically sound. Answers were collected by using visual analog scales. Data were analyzed by principal component analysis, and a hierarchical ascending classification was created. Verbatim answers were assessed by qualitative content analysis. We analyzed responses from 148 institutional review board members. Three classes of respondents were identified: class 1 (n = 58; 39.2%), mostly skeptics who disagreed with unbalanced randomization, whatever the justification; class 2 (n = 46; 31.1%), believers who considered that unbalanced randomization was acceptable whatever the justification, except cost; and class 3 (n = 44; 29.7%), circumstantial believers for whom unbalanced randomization may be justified for methodological and safety issues but not cost or ethical issues. When institutional review board members were asked whether unbalanced randomization respected the equipoise principle, the mean quotation was low (4.5 ± 3.3 out of 10), especially for class 1 members. Institutional review board members perceive unbalanced randomization heterogeneously in terms of its justification and its ethical validity.