Telerehabilitation for chronic respiratory disease.

BACKGROUND: Pulmonary rehabilitation is a proven, effective intervention for people with chronic respiratory diseases including chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD) and bronchiectasis. However, relatively few people attend or complete a program, due to factors including a lack of programs, issues associated with travel and transport, and other health issues. Traditionally, pulmonary rehabilitation is delivered in-person on an outpatient basis at a hospital or other healthcare facility (referred to as centre-based pulmonary rehabilitation). Newer, alternative modes of pulmonary rehabilitation delivery include home-based models and the use of telehealth. Telerehabilitation is the delivery of rehabilitation services at a distance, using information and communication technology. To date, there has not been a comprehensive assessment of the clinical efficacy or safety of telerehabilitation, or its ability to improve uptake and access to rehabilitation services, for people with chronic respiratory disease. OBJECTIVES: To determine the effectiveness and safety of telerehabilitation for people with chronic respiratory disease. SEARCH METHODS: We searched the Cochrane Airways Trials Register, and the Cochrane Central Register of Controlled Trials; six databases including MEDLINE and Embase; and three trials registries, up to 30 November 2020. We checked reference lists of all included studies for additional references, and handsearched relevant respiratory journals and meeting abstracts. SELECTION CRITERIA: All randomised controlled trials and controlled clinical trials of telerehabilitation for the delivery of pulmonary rehabilitation were eligible for inclusion. The telerehabilitation intervention was required to include exercise training, with at least 50% of the rehabilitation intervention being delivered by telerehabilitation. DATA COLLECTION AND ANALYSIS: We used standard methods recommended by Cochrane. We assessed the risk of bias for all studies, and used the ROBINS-I tool to assess bias in non-randomised controlled clinical trials. We assessed the certainty of evidence with GRADE. Comparisons were telerehabilitation compared to traditional in-person (centre-based) pulmonary rehabilitation, and telerehabilitation compared to no rehabilitation. We analysed studies of telerehabilitation for maintenance rehabilitation separately from trials of telerehabilitation for initial primary pulmonary rehabilitation. MAIN RESULTS: We included a total of 15 studies (32 reports) with 1904 participants, using five different models of telerehabilitation. Almost all (99%) participants had chronic obstructive pulmonary disease (COPD). Three studies were controlled clinical trials. For primary pulmonary rehabilitation, there was probably little or no difference between telerehabilitation and in-person pulmonary rehabilitation for exercise capacity measured as 6-Minute Walking Distance (6MWD) (mean difference (MD) 0.06 metres (m), 95% confidence interval (CI) -10.82 m to 10.94 m; 556 participants; four studies; moderate-certainty evidence). There may also be little or no difference for quality of life measured with the St George's Respiratory Questionnaire (SGRQ) total score (MD -1.26, 95% CI -3.97 to 1.45; 274 participants; two studies; low-certainty evidence), or for breathlessness on the Chronic Respiratory Questionnaire (CRQ) dyspnoea domain score (MD 0.13, 95% CI -0.13 to 0.40; 426 participants; three studies; low-certainty evidence). Participants were more likely to complete a program of telerehabilitation, with a 93% completion rate (95% CI 90% to 96%), compared to a 70% completion rate for in-person rehabilitation. When compared to no rehabilitation control, trials of primary telerehabilitation may increase exercise capacity on 6MWD (MD 22.17 m, 95% CI -38.89 m to 83.23 m; 94 participants; two studies; low-certainty evidence) and may also increase 6MWD when delivered as maintenance rehabilitation (MD 78.1 m, 95% CI 49.6 m to 106.6 m; 209 participants; two studies; low-certainty evidence). No adverse effects of telerehabilitation were noted over and above any reported for in-person rehabilitation or no rehabilitation. AUTHORS' CONCLUSIONS: This review suggests that primary pulmonary rehabilitation, or maintenance rehabilitation, delivered via telerehabilitation for people with chronic respiratory disease achieves outcomes similar to those of traditional centre-based pulmonary rehabilitation, with no safety issues identified. However, the certainty of the evidence provided by this review is limited by the small number of studies, of varying telerehabilitation models, with relatively few participants. Future research should consider the clinical effect of telerehabilitation for individuals with chronic respiratory diseases other than COPD, the duration of benefit of telerehabilitation beyond the period of the intervention, and the economic cost of telerehabilitation.

ASIED: a Bayesian adaptive subgroup-identification enrichment design.

Developing targeted therapies based on patients' baseline characteristics and genomic profiles such as biomarkers has gained growing interests in recent years. Depending on patients' clinical characteristics, the expression of specific biomarkers or their combinations, different patient subgroups could respond differently to the same treatment. An ideal design, especially at the proof of concept stage, should search for such subgroups and make dynamic adaptation as the trial goes on. When no prior knowledge is available on whether the treatment works on the all-comer population or only works on the subgroup defined by one biomarker or several biomarkers, it is necessary to incorporate the adaptive estimation of the heterogeneous treatment effect to the decision-making at interim analyses. To address this problem, we propose an Adaptive Subgroup-Identification Enrichment Design, ASIED, to simultaneously search for predictive biomarkers, identify the subgroups with differential treatment effects, and modify study entry criteria at interim analyses when justified. More importantly, we construct robust quantitative decision-making rules for population enrichment when the interim outcomes are heterogeneous in the context of a multilevel target product profile, which defines the minimal and targeted levels of treatment effect. Through extensive simulations, the ASIED is demonstrated to achieve desirable operating characteristics and compare favorably against alternatives.

Systematic review of controlled clinical studies using umbilical cord blood for regenerative therapy: Identifying barriers to assessing efficacy.

Clinical use of umbilical cord blood (UCB) for novel indications in regenerative therapy continues to rise, however, whether new indications are proven is less clear. An updated systematic search of the literature, focusing only on controlled clinical studies, is needed to properly assess potential efficacy. After updating our systematic search to April 1, 2018 (PROSPERO protocol CRD42016040157), a total of 16 studies were identified that addressed the treatment of cerebral palsy (four studies), type 1 diabetes (three studies), and nine other novel potential indications where only a single controlled study was identified. In the four controlled studies of patients with cerebral palsy, three used allogeneic cells and reported greater improvement in motor-related scores at 1, 3 and 6 months compared with controls. The results were mixed for other scores at other time points, including additional measures of mental and motor function. One study of autologous UCB treatment reported an improvement in motor function scores at 12 months compared with controls. In the three controlled studies of type 1 diabetes, two studies used autologous cells whereas one used allogeneic cord blood cells to "educate" autologous lymphocytes. Taken together, there was no clear difference in HbA1c levels or daily insulin requirements between treated patients and controls. For the nine published reports with a single controlled study, eight used allogeneic UCB cells and seven infused mesenchymal stromal cells derived from UCB. All but one study reported benefit. Many other published reports that lack a control group were not included in our analysis. More controlled studies are needed that use similar approaches regarding cell source and outcome measures at similar time points. Pooled estimates of results from multiple studies will be essential as published studies remain modest in size. Patients should continue to be enrolled in clinical trials because there are no novel potential indications remain unproven.

To add or not to add a new treatment arm to a multiarm study: A decision-theoretic framework.

Multiarm clinical trials, which compare several experimental treatments against control, are frequently recommended due to their efficiency gain. In practise, all potential treatments may not be ready to be tested in a phase II/III trial at the same time. It has become appealing to allow new treatment arms to be added into on-going clinical trials using a "platform" trial approach. To the best of our knowledge, many aspects of when to add arms to an existing trial have not been explored in the literature. Most works on adding arm(s) assume that a new arm is opened whenever a new treatment becomes available. This strategy may prolong the overall duration of a study or cause reduction in marginal power for each hypothesis if the adaptation is not well accommodated. Within a two-stage trial setting, we propose a decision-theoretic framework to investigate when to add or not to add a new treatment arm based on the observed stage one treatment responses. To account for different prospect of multiarm studies, we define utility in two different ways; one for a trial that aims to maximise the number of rejected hypotheses; the other for a trial that would declare a success when at least one hypothesis is rejected from the study. Our framework shows that it is not always optimal to add a new treatment arm to an existing trial. We illustrate a case study by considering a completed trial on knee osteoarthritis.

Does Self-Reported or Behavioral Impulsivity Predict Subjective Response to Low-Dose Alcohol?

AIMS: Subjective response to alcohol and impulsivity are both independent predictors of alcohol use and may be related risk factors for alcohol use disorders (AUDs). Recent findings suggest that more impulsive individuals may experience higher risk subjective response patterns at moderate-to-high doses of alcohol. However, whether these relationships are observable early in a drinking occasion remains an open question. This study examined multiple measures of impulsivity in relation to subjective response following low-dose alcohol. METHOD: Eighty-seven non-treatment-seeking heavy drinkers were enrolled in a placebo-controlled alcohol administration study testing the effects of NMDA receptor antagonist, Memantine. Baseline impulsivity assessments included the Cued Go/No-Go Task, Experiential Discounting Task, and Barratt Impulsiveness Scale, Version 11 (BIS-11). Following consumption of low-dose alcohol aimed to increase blood alcohol concentration (BAC) to 0.03%, subjective stimulation and sedation were measured using the Biphasic Alcohol Effects Scale. Models were tested to relate impulsivity measures to subjective response with a post hoc exploratory model exploring boredom as an alternate predictor. RESULTS: Increases in stimulation and sedation were observed following low-dose alcohol, but were not predicted significantly by impulsivity measures. Although greater impulsivity on the BIS-11 was a trend-level predictor of increased sedation, post hoc analyses suggested these results were an artifact of boredom. CONCLUSION: Although impulsivity did not predict subjective response to low-dose alcohol, the results suggest that small amounts of alcohol can produce a range of subjective effects, even among heavy drinkers. Future studies would benefit by examining subjective response across a range of BACs among both light and heavy drinkers.

Approaches for testing noninferiority in two-arm trials for risk ratio and odds ratio.

For an existing established drug regimen, active control trials are defacto standard due to ethical reason as well as for clinical equipoise. However, when superiority claim of a new drug against the active control is unlikely to be successful, researchers often address the issue in terms of noninferiority (NI), provided the experimental drug demonstrates the evidence of other benefits beyond efficacy. Such trials aim to demonstrate that an experimental treatment is non-inferior to an existing comparator by not more than a pre-specified margin. The issue of choosing such a margin is complex. In this article, two-arm NI trials with binary outcomes are considered when margin is defined in terms of relative risk or odds ratio. A Frequentist test based on proposed NI margin is developed first. Since two-arm NI trials without placebo arm are dependent upon historical information, in order to make accurate and meaningful interpretation of their results, a Bayesian approach is developed next. Bayesian approach is flexible to incorporate the available information from the historical trial. The operating characteristics of the proposed methods are studied in terms of power and sample size for varying design factors. A clinical trial data is reanalyzed to study the properties of the proposed approach.

Effect of low-carbohydrate diet on markers of renal function in patients with type 2 diabetes: A meta-analysis.

Meta-analysis was conducted to clarify the effect of low-carbohydrate diet (LCD) on renal function in patients with type 2 diabetes. An extensive literature search was conducted on scientific databases including PubMed, Scopus, and Cochrane Library until September 2017. Only controlled trials on human subjects written in English were included in this meta-analysis. Several markers of renal function were compared between subjects who adopted an LCD or control diet, including estimated glomerular filtration rate, creatinine clearance, urinary albumin, serum creatinine, and serum uric acid. Random effect model was used in the analysis of each marker. In this meta-analysis, 12 controlled trials were selected, which involved 942 participants (500 received LCD and 442 received a control diet). The pooled standardized mean difference (SMD) of estimated glomerular filtration rate from LCD vs control diet was not different (pooled SMD: 0.26; 95% CI, -0.03 to 0.55; P = .08). Investigation on creatinine clearance also showed no significant difference (pooled SMD: 0.51; 95% CI, -0.38 to 1.40; P = .26). Other comparisons from urinary albumin (pooled SMD: -0.04; 95% CI, -0.75 to 0.67; P = .90), serum creatinine (pooled SMD: -0.57; 95% CI, -1.51 to 0.38; P = .24), and serum uric acid (pooled SMD: -0.86; 95% CI, -4.00 to 2.28; P = .59) also showed no significant difference in the results. In the present meta-analysis, no effect on markers of renal function was found after provision of a LCD compared with a control diet in patients with type 2 diabetes.

Improving likelihood-based inference in control rate regression.

Control rate regression is a diffuse approach to account for heterogeneity among studies in meta-analysis by including information about the outcome risk of patients in the control condition. Correcting for the presence of measurement error affecting risk information in the treated and in the control group has been recognized as a necessary step to derive reliable inferential conclusions. Within this framework, the paper considers the problem of small sample size as an additional source of misleading inference about the slope of the control rate regression. Likelihood procedures relying on first-order approximations are shown to be substantially inaccurate, especially when dealing with increasing heterogeneity and correlated measurement errors. We suggest to address the problem by relying on higher-order asymptotics. In particular, we derive Skovgaard's statistic as an instrument to improve the accuracy of the approximation of the signed profile log-likelihood ratio statistic to the standard normal distribution. The proposal is shown to provide much more accurate results than standard likelihood solutions, with no appreciable computational effort. The advantages of Skovgaard's statistic in control rate regression are shown in a series of simulation experiments and illustrated in a real data example. R code for applying first- and second-order statistic for inference on the slope on the control rate regression is provided.

Full publication of results initially presented in abstracts.

BACKGROUND: Abstracts of presentations at scientific meetings are usually available only in conference proceedings. If subsequent full publication of results reported in these abstracts is based on the magnitude or direction of the results, publication bias may result. Publication bias creates problems for those conducting systematic reviews or relying on the published literature for evidence about health and social care. OBJECTIVES: To systematically review reports of studies that have examined the proportion of meeting abstracts and other summaries that are subsequently published in full, the time between meeting presentation and full publication, and factors associated with full publication. SEARCH METHODS: We searched MEDLINE, Embase, the Cochrane Library, Science Citation Index, reference lists, and author files. The most recent search was done in February 2016 for this substantial update to our earlier Cochrane Methodology Review (published in 2007). SELECTION CRITERIA: We included reports of methodology research that examined the proportion of biomedical results initially presented as abstracts or in summary form that were subsequently published. Searches for full publications had to be at least two years after meeting presentation. DATA COLLECTION AND ANALYSIS: Two review authors extracted data and assessed risk of bias. We calculated the proportion of abstracts published in full using a random-effects model. Dichotomous variables were analyzed using risk ratio (RR), with multivariable models taking into account various characteristics of the reports. We assessed time to publication using Kaplan-Meier survival analyses. MAIN RESULTS: Combining data from 425 reports (307,028 abstracts) resulted in an overall full publication proportion of 37.3% (95% confidence interval (CI), 35.3% to 39.3%) with varying lengths of follow-up. This is significantly lower than that found in our 2007 review (44.5%. 95% CI, 43.9% to 45.1%). Using a survival analyses to estimate the proportion of abstracts that would be published in full by 10 years produced proportions of 46.4% for all studies; 68.7% for randomized and controlled trials and 44.9% for other studies. Three hundred and fifty-three reports were at high risk of bias on one or more items, but only 32 reports were considered at high risk of bias overall.Forty-five reports (15,783 abstracts) with 'positive' results (defined as any 'significant' result) showed an association with full publication (RR = 1.31; 95% CI 1.23 to 1.40), as did 'positive' results defined as a result favoring the experimental treatment (RR =1.17; 95% CI 1.07 to 1.28) in 34 reports (8794 abstracts). Results emanating from randomized or controlled trials showed the same pattern for both definitions (RR = 1.21; 95% CI 1.10 to 1.32 (15 reports and 2616 abstracts) and RR = 1.17; 95% CI, 1.04 to 1.32 (13 reports and 2307 abstracts), respectively.Other factors associated with full publication include oral presentation (RR = 1.46; 95% CI 1.40 to 1.52; studied in 143 reports with 115,910 abstracts); acceptance for meeting presentation (RR = 1.65; 95% CI 1.48 to 1.85; 22 reports with 22,319 abstracts); randomized trial design (RR = 1.51; 95% CI 1.36 to 1.67; 47 reports with 28,928 abstracts); and basic research (RR = 0.78; 95% CI 0.74 to 0.82; 92 reports with 97,372 abstracts). Abstracts originating at an academic setting were associated with full publication (RR = 1.60; 95% CI 1.34 to 1.92; 34 reports with 16,913 abstracts), as were those considered to be of higher quality (RR = 1.46; 95% CI 1.23 to 1.73; 12 reports with 3364 abstracts), or having high impact (RR = 1.60; 95% CI 1.41 to 1.82; 11 reports with 6982 abstracts). Sensitivity analyses excluding reports that were abstracts themselves or classified as having a high risk of bias did not change these findings in any important way.In considering the reports of the methodology research that we included in this review, we found that reports published in English or from a native English-speaking country found significantly higher proportions of studies published in full, but that there was no association with year of report publication. The findings correspond to a proportion of abstracts published in full of 31.9% for all reports, 40.5% for reports in English, 42.9% for reports from native English-speaking countries, and 52.2% for both these covariates combined. AUTHORS' CONCLUSIONS: More than half of results from abstracts, and almost a third of randomized trial results initially presented as abstracts fail to be published in full and this problem does not appear to be decreasing over time. Publication bias is present in that 'positive' results were more frequently published than 'not positive' results. Reports of methodology research written in English showed that a higher proportion of abstracts had been published in full, as did those from native English-speaking countries, suggesting that studies from non-native English-speaking countries may be underrepresented in the scientific literature. After the considerable work involved in adding in the more than 300 additional studies found by the February 2016 searches, we chose not to update the search again because additional searches are unlikely to change these overall conclusions in any important way.

Efficacy of Desvenlafaxine Compared With Placebo in Major Depressive Disorder Patients by Age Group and Severity of Depression at Baseline.

PURPOSE: This post hoc meta-analysis evaluated the efficacy and safety of desvenlafaxine 50 and 100 mg versus placebo across age groups and severity of depression at baseline in patients with major depressive disorder. METHODS: Data from placebo and desvenlafaxine 50-mg and 100-mg dose arms were pooled from 9 short-term, placebo-controlled, major depressive disorder studies (N = 4279). Effects of age (18-40 years, >40 to <55 years, 55-<65 years, and ≥65 years) and baseline depression severity (mild, 17-item Hamilton Rating Scale for Depression total score [HAM-D17] ≤18; moderate, HAM-D17 >18 to <25; severe, HAM-D17 ≥25) on desvenlafaxine efficacy were assessed using analysis of covariance for continuous end points and logistic regression for categorical end points. FINDINGS: Desvenlafaxine-treated (50 or 100 mg/d) patients had significantly (P < 0.05, 2-sided) greater improvement in most measures of depression and function compared with placebo for patients 18 to 40 years, older than 40 to younger than 55 years, and 55 to younger than 65 years, with no significant evidence of an effect of age. Desvenlafaxine significantly improved most measures of depression and function in moderately and severely depressed patients. There was a significant baseline severity by treatment interaction for HAM-D17 total score only (P = 0.027), with a larger treatment effect for the severely depressed group. IMPLICATIONS: Desvenlafaxine significantly improved depressive symptoms in patients younger than 65 years and in patients with moderate or severe baseline depression. Sample sizes were not adequate to assess desvenlafaxine efficacy in patients 65 years or older or with mild baseline depression.

Estimation in multi-arm two-stage trials with treatment selection and time-to-event endpoint.

We consider estimation of treatment effects in two-stage adaptive multi-arm trials with a common control. The best treatment is selected at interim, and the primary endpoint is modeled via a Cox proportional hazards model. The maximum partial-likelihood estimator of the log hazard ratio of the selected treatment will overestimate the true treatment effect in this case. Several methods for reducing the selection bias have been proposed for normal endpoints, including an iterative method based on the estimated conditional selection biases and a shrinkage approach based on empirical Bayes theory. We adapt these methods to time-to-event data and compare the bias and mean squared error of all methods in an extensive simulation study and apply the proposed methods to reconstructed data from the FOCUS trial. We find that all methods tend to overcorrect the bias, and only the shrinkage methods can reduce the mean squared error. © 2017 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd.

Effectiveness of mild ovarian stimulation versus GnRH agonist protocol in women undergoing assisted reproductive technology: a meta-analysis.

OBJECTIVE: our meta-analysis was conducted to evaluate the effectiveness of the mild ovulation induction protocol using CC/gonadotropin/GnRH antagonist compared to the conventional GnRH agonist protocol in women undergoing ART. METHOD: Six electronic databases were searched from their date of establishment until August 2016. Outcomes in our analysis were calculated in terms of relative risk (RR) and weighted mean differences (WMD) and standard mean differences (SMD) with 95% confidence intervals (CI) using random effect models or fixed effect models. RESULTS: Six prospective controlled clinical trials with 1543 women comparing the clinical impacts of the two protocols were included. The synthesized results suggested a significant reduction in the quantity of gonadotropins (SMD: -1.96, 95% CI: -2.28 to 1.64, I2 = 78.5%), the incidence of OHSS (RR: 0.16, 95% CI 0.03-0.86, I2 = 0%) and an increase in the cycle cancelation rate (RR: 1.46, 95% CI 1.05-2.03, I2 = 89.4%). While no evidence of statistically significant differences between the groups existed in the other clinical outcomes. CONCLUSION: This study suggested that the probable benefits of the mild protocol, including its less costs and safer process without reducing the overall IVF treatment success rates, seemed to make it a better treatment option. Larger sample prospective trials evaluating live birth, clinical pregnancy, OHSS, multiple pregnancy incidence and so on were desired to establish.

[Placebo effect in clinical trials with allergen-specific immunotherapy with inhalant allergens]. / Placeboeffekt in Studien zur allergenspezifischen Immuntherapie mit Inhalationsallergenen.

Placebo effects play an important role in the treatment of allergic diseases. Therefore, in this study, we analysed the described effects of placebo in all double-blind placebo-controlled clinical trials of allergen-specific immunotherapy (ASIT) with inhalant allergens (birch, grass, house dust mites) listed in the tables (updated July 2016) attached to the German S2k guideline on allergen-specific immunotherapy in IgE-mediated allergic diseases. The most common placebo consisted of verum without allergen, but when the subcutaneous route was used, histamine was sometimes added. From the 33 studies analysed no conclusions could be drawn regarding the pure placebo effect. The symptom medication score (SMS) from an adequate baseline period was described in one single study. An untreated population was not included in any study. Indirect evidence points to substantial placebo effects in up to 77% of the subjects with respect to retrospective, subjective parameters. Well-known factors influencing the placebo effect such as age, gender, application route/composition of the placebo, individual and cultural differences, severity of symptoms at the beginning and the probability of receiving verum have not been addressed regarding ASIT and could not be estimated from available data. Taken together regarding ASIT the placebo effect has been investigated inadequately. In spite of significant expenditure of time and costs future ASIT studies should include assessment of the SMS in an adequate baseline period and preferably include an untreated trial arm. A better understanding of placebo effects in ASIT trials will improve the design of clinical trials and the assessment of therapeutic effects.

Avoiding ambiguity with the Type I error rate in noninferiority trials.

This review article sets out to examine the Type I error rates used in noninferiority trials. Most papers regarding noninferiority trials only state Type I error rate without mentioning clearly which Type I error rate is evaluated. Therefore, the Type I error rate in one paper is often different from the Type I error rate in another paper, which can confuse readers and makes it difficult to understand papers. Which Type I error rate should be evaluated is related directly to which paradigm is employed in the analysis of noninferiority trial, and to how the historical data are treated. This article reviews the characteristics of the within-trial Type I error rate and the unconditional across-trial Type I error rate which have frequently been examined in noninferiority trials. The conditional across-trial Type I error rate is also briefly discussed. In noninferiority trials comparing a new treatment with an active control without a placebo arm, it is argued that the within-trial Type I error rate should be controlled in order to obtain approval of the new treatment from the regulatory agencies. I hope that this article can help readers understand the difference between two paradigms employed in noninferiority trials.

Sample size calculation based on efficient unconditional tests for clinical trials with historical controls.

In historical clinical trials, the sample size and the number of success in the control group are often considered as given. The traditional method for sample size calculation is based on an asymptotic approach developed by Makuch and Simon (1980). Exact unconditional approaches may be considered as alternative to control for the type I error rate where the asymptotic approach may fail to do so. We provide the sample size calculation using an efficient exact unconditional testing procedure based on estimation and maximization. The sample size using the exact unconditional approach based on estimation and maximization is generally smaller than those based on the other approaches.

SIDE EFFECTS OF TUBERCULOSIS TREATMENT WITH FIXED-DOSE COMBINATIONS.

This paper aimed to explore the therapeutic effect and safety of Fixed-dose Combinations (FDCs) on tuberculosis. A computer search was carried out to review the literature related to clinical randomized controlled trials (RCTs) and clinical controlled trails (CCTs) on the curative effect and safety of treating pulmonary tuberculosis with FDCs. The results demonstrated that, in the 22 studies examined, comparison of sputum negative conservation rate of treating smear-positive pulmonary tuberculosis with FDCs and single drug, the relative risk (RR) value and 95% confidence interval (CI) were 1.02 (1.01, 1.03) and 1.01 (1.00, 1.02), respectively, at the end of the 2nd month and 6th month (P<0.05), while comparison of the relapse rate within six months showed that RR value and 95% CI was 1.72 (0.98, 3.02) (P>0.05). No statistically significant differences were found between the two groups in total occurrence of the rates of side effects pertaining to skin reaction, gastrointestinal tract side reaction, occurrence rate of liver and gall side reaction or occurrence rate of drug withdrawal because of side effects (P>0.05). After sensitivity analysis, it was found that occurrence rate of gastrointestinal tract side effects and occurrence rate of liver and gall side effects were unstable. All the findings suggest that the curative effect of treating tuberculosis with FDCs is better than that of a single drug. More reliable evidence is required since the safety evaluation results are not stable.

Sample size calculation for count data in comparative clinical trials with nonuniform patient accrual and early dropout.

In clinical trials with counts of recurrent event data, it is often of particular interest to test whether the experimental treatment reduces the event rate in comparison with a control. The sample size calculation for such a trial often assumes fixed follow-up time for each patient. In many trials, however, we follow all patients for a predetermined follow-up time after the end of the accrual period, in which case the follow-up time is variable. This article provides methods for sample size calculation for clinical trials with ordinary Poisson count data and variable follow-up time allowing for nonuniform accrual and early dropouts. We also generalize the sample size formula to count data with overdispersion.

Declining efficacy in controlled trials of antidepressants: effects of placebo dropout.

Drug-placebo differences (effect-sizes) in controlled trials of antidepressants for major depressive episodes have declined for several decades, in association with selectively increasing clinical improvement associated with placebo-treatment. As these trends require adequate explanation, we tested the hypothesis that decreasing trial-dropout rates may be an important contributor. We gathered reports of peer-reviewed, placebo-controlled trials of antidepressants (1980-2011) by computerized literature searching, and applied meta-analysis, meta-regression and multiple linear regression methods to evaluate associations of dropout rates and other factors of interest, to reporting year and reported efficacy [standardized mean drug-placebo difference (SMD) as Hedges' g-statistic]. In 56 trials meeting inclusion and exclusion criteria, we confirmed significant overall efficacy of antidepressants but declining drug-placebo contrasts over the past three decades. Among other changes, there was a corresponding increase in placebo-associated improvement with a decline in placebo-dropout rate, mainly for lack of efficacy. These effects were found only when last-observation-carried-forward (LOCF) analyses were used. Other trial-design and subject factors, including drug-responses and drug-dropout rates, were much less associated with efficacy. We propose that declining placebo-dropout rates ascribed to inefficacy combined with use of LOCF analyses led to increasing improvement in placebo-arms that contributed to declining antidepressant-placebo contrasts in controlled treatment trials since the 1980s.

Flexible sequential designs for multi-arm clinical trials.

Adaptive designs that are based on group-sequential approaches have the benefit of being efficient as stopping boundaries can be found that lead to good operating characteristics with test decisions based solely on sufficient statistics. The drawback of these so called 'pre-planned adaptive' designs is that unexpected design changes are not possible without impacting the error rates. 'Flexible adaptive designs' on the other hand can cope with a large number of contingencies at the cost of reduced efficiency. In this work, we focus on two different approaches for multi-arm multi-stage trials, which are based on group-sequential ideas, and discuss how these 'pre-planned adaptive designs' can be modified to allow for flexibility. We then show how the added flexibility can be used for treatment selection and sample size reassessment and evaluate the impact on the error rates in a simulation study. The results show that an impressive overall procedure can be found by combining a well chosen pre-planned design with an application of the conditional error principle to allow flexible treatment selection.

A modest proposal for dropping poor arms in clinical trials.

This paper presents a simple procedure for clinical trials comparing several arms with control. Demand for streamlining the evaluation of new treatments has led to phase III clinical trials with more arms than would have been used in the past. In such a setting, it is reasonable that some arms may not perform as well as an active control. We introduce a simple procedure that takes advantage of negative results in some comparisons to lessen the required strength of evidence for other comparisons. We evaluate properties analytically and use them to support claims made about multi-arm multi-stage designs.