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Objective To test the effectiveness of a 32-week, stepped-care intervention on disease remission rates in overweight and obese patients with medial tibiofemoral osteoarthritis (OA) compared to controls. Methods In this randomized controlled trial, eligible participants were ≥50 years of age with a body mass index of ≥28 kg/m2 and radiographic evidence of medial tibiofemoral OA. Participants were randomized to stepped-care (n = 87) or control group (n = 84). The stepped-care group received a 2-step intervention. The first step consisted of an 18-week diet and exercise program. The second step consisted of 4 treatment subgroups: 1) diet and exercise maintenance; 2) cognitive-behavioral therapy; 3) unloader knee brace; and 4) muscle strengthening exercises. Allocation into subgroups was based on disease remission state and clinical characteristics. The primary end point was the disease remission rate (yes/no) at 32 weeks, which was reached when participants achieved the Patient Acceptable Symptom State cutoff value for pain and for the patient global assessment of disease activity and/or functional impairment. Results Disease remission at 32 weeks was achieved by 18 of 68 (26%) in the control group and 32 of 82 (39%) in the stepped-care group (difference 12.6% [95% confidence interval -2.3, 27.4], P = 0.10). The stepped-care group showed an improvement in pain and function between baseline and 20 weeks. While functional improvement was maintained at 32 weeks, pain levels tended to get worse between weeks 20 and 32. Conclusion The proposed intervention did not promote a significant difference in the rate of disease remission in comparison to the control group for overweight or obese patients with medial tibiofemoral OA.

The main objective of a confirmatory multiregional clinical trial (MRCT) is to demonstrate the overall efficacy of test drugs in all participating regions as well as to evaluate the possibility of extrapolating the overall results to each region. With the emergence of the demands of biosimilar drugs development, some guidelines recommended using equivalence design to demonstrate the comparability of efficacy between biosimilar and reference drugs. Previous discussions about assessing regional consistency in MRCT are mainly focused on superiority or non-inferiority designs, while the extensions to equivalence designs were limited. In this work, we proposed a flexible regional consistency criterion for the MRCT with equivalence design. Based on this criterion, sample size determination and sample allocation were also discussed.

ObjectiveTo evaluate Telephone-Delivered Cognitive Behavioural Therapy (T-CBT) compared to CBT face to face treatment as usual (TAU-CBT), in cancer patients with high psychological needs, in terms of mental health and coping. MethodA prospective randomised equivalence trial with Patient Reported Outcome (PRO's), measured pre- and post-therapy including; Hospital Anxiety and Depression Scale (HADS), Mental Adjustment to Cancer Scale: Helpless/Hopeless subscale only (MAC H/H), Checklist of Cancer Concerns (CLCC) and the Cancer Coping Questionnaire (CCQ). A study-specific Service Evaluation Questionnaire (SEQ) was include. ResultsAssessment of change scores, in n=118 randomised patients referred for psychological care, indicate significant improvements (P

With the increasing globalization of drug development, the multiregional clinical trial (MRCT) has gained extensive use. The data from MRCTs could be accepted by regulatory authorities across regions and countries as the primary sources of evidence to support global marketing drug approval simultaneously. The MRCT can speed up patient enrollment and drug approval, and it makes the effective therapies available to patients all over the world simultaneously. However, there are many challenges both operationally and scientifically in conducting a drug development globally. One of many important questions to answer for the design of a multiregional study is how to partition sample size into each individual region. In this paper, two systematic approaches are proposed for the sample size allocation in a multiregional equivalence trial. A numerical evaluation and a biosimilar trial are used to illustrate the characteristics of the proposed approaches.

Aim To develop and test a format of delivery of diabetes self-management education by paired professional and lay educators. Methods We conducted an equivalence trial with non-randomized participant allocation to a Diabetes Education and Self Management for Ongoing and Newly Diagnosed Type 2 diabetes (DESMOND) course, delivered in the standard format by two trained healthcare professional educators (to the control group) or by one trained lay educator and one professional educator (to the intervention group). A total of 260 people with Type 2 diabetes diagnosed within the previous 12 months were referred for self-management education as part of routine care and attended either a control or intervention format DESMOND course. The primary outcome measure was change in illness coherence score (derived from the Diabetes Illness Perception Questionnaire-Revised) between baseline and 4 months after attending education sessions. Secondary outcome measures included change in HbA1c level. The trial was conducted in four primary care organizations across England and Scotland. Results The 95% CI for the between-group difference in positive change in coherence scores was within the pre-set limits of equivalence (difference = 0.22, 95% CI 1.07 to 1.52). Equivalent changes related to secondary outcome measures were also observed, including equivalent reductions in HbA1c levels. Conclusion Diabetes education delivered jointly by a trained lay person and a healthcare professional educator with the same educator role can provide equivalent patient benefits. This could provide a method that increases capacity, maintains quality and is cost-effective, while increasing access to self-management education.

Objective To compare the efficacy of non-nutritive sweetened beverages (NNS) or water for weight loss during a 12-week behavioral weight loss treatment program. Methods An equivalence trial design with water or NNS beverages as the main factor in a prospective randomized trial among 303 men and women was employed. All participants participated in a behavioral weight loss treatment program. The results of the weight loss phase (12 weeks) of an ongoing trial (1 year) that is also evaluating the effects of these two treatments on weight loss maintenance were reported. Results The two treatments were not equivalent with the NNS beverage treatment group losing significantly more weight compared to the water group (5.95 kg versus 4.09 kg; P < 0.0001) after 12 weeks. Participants in the NNS beverage group reported significantly greater reductions in subjective feelings of hunger than those in the water group during 12 weeks. Conclusion These results show that water is not superior to NNS beverages for weight loss during a comprehensive behavioral weight loss program.

Context The optimal learner to simulator ratio for procedural skills training is not known. Research in motor learning suggests observational training in pairs, termed ‘dyad training’, may be as effective as directed self-regulated learning (DSRL). Objectives This study was conducted to compare the relative effectiveness and efficiency of dyad versus DSRL training of simulation-based lumbar puncture (LP). Methods We conducted a two-group randomised equivalence trial. First-year internal medicine residents (n = 50) were randomly assigned to learn LP either in dyads or as individual learners on a simulator, using a directed self-regulated approach (i.e. the learning sequence was defined for them, but they defined the pace of learning). Participants were videotaped performing a simulated LP on a pre-test, an immediate post-test, and a 6-week delayed retention test. In duplicate, blinded raters independently evaluated all trainee performances using a previously validated 5-point global rating scale (GRS) and 35-item checklist. Results Our analyses showed no significant differences (p = 0.69) on pre-test, post-test or retention test GRS scores between the dyad (mean ± standard deviation [SD] scores by test: 2.39 ± 0.57, 3.48 ± 0.62, 3.12 ± 0.85, respectively) and DSRL (mean ± SD scores by test: 2.67 ± 0.50, 3.34 ± 0.77, 3.21 ± 0.79, respectively) groups. Both groups improved significantly from pre-test to post-test (p

Development of biosimilars to innovative therapeutic biologics promises reduction of healthcare cost and therefore will provide patients worldwide greater access to effective treatments. Because of the differences in raw materials or manufacturing processes, 'equivalence' of bioavailability between a biosimilar and the reference biologic is generally regarded as insufficient, and thus, clinical trials providing efficacy and safety data are often required by regulatory agencies. The traditional non-inferiority trial design may not be accepted for establishing biosimilarity in order to avoid superior efficacy with additional safety (e.g., immunogenicity) risks. On the other hand, the bioequivalence trial design, which is used in the generic paradigm for the evaluation of bioavailability of generic chemical drugs, is not appropriate for evaluating clinical efficacy because the equivalence margins are generally too wide and not justified on statistical or clinical grounds. Motivated by the World Health Organization guideline and the newly released Food and Drug Administration draft guideline on biosimilars, we propose a biosimilarity trial design for evaluating clinical efficacy. The design uses a non-inferiority margin and an asymmetrical non-superiority margin for statistical inference. The independent choice of both margins provides the scientific foundation for drawing clinical efficacy conclusions while maintaining the logical consistency of the inference. The design also has a higher statistical power than a naïve equivalence trial design.

We aim to establish whether it is ever appropriate to conduct cost-minimisation analysis (CMA) rather than cost-effectiveness analysis.We perform a literature review to examine how the use of CMA has changed since Briggs & O'Brien announced its death in 2001. Examples of simulated and trial data are presented: firstly to illustrate the advantages and disadvantages of CMA in the context of non-inferiority trials and those finding no significant difference in efficacy and secondly to assess whether CMA gives biased results.We show that CMA is still used and will bias measures of uncertainty, causing overestimation or underestimation of the value of information and the probability that treatment is cost-effective. Although bias will be negligible for non-inferiority studies comparing treatments that differ enormously in cost, it is generally necessary to collect and analyse data on costs and efficacy (including utilities) to assess this bias. Cost-effectiveness analysis (including evaluation of the joint distribution of costs and benefits) is almost always required to avoid biased estimation of uncertainty. The remit of CMA in trial-based economic evaluation is therefore even narrower than previously thought, suggesting that CMA is not only dead but should also be buried.

Non-inferiority (NI) trials enable a direct comparison of the relative benefit-to-risk profiles of an experimental intervention and a standard-of-care regimen. When the standard has clinical efficacy of substantial magnitude that is precisely estimated ideally using data from multiple adequate and well-controlled trials, with such estimates being relevant to the setting of the NI trial, then the NI trial can provide the scientific and regulatory evidence required to reliably assess the efficacy of the new intervention. In clinical practice, considerable uncertainty remains regarding when such trials should be conducted, how they should be designed, what standards for quality of trial conduct must be achieved, and how results should be interpreted. Recent examples will be considered to provide important insights and to highlight some of the challenges that remain to be adequately addressed regarding the use of the NI approach for the evaluation of new interventions. 'Imputed placebo' and 'margin'-based approaches to NI trial design will be considered, as well as the risk of 'bio-creep' with repeated NI trials, use of NI trials when determining whether excess safety risks can be ruled out, higher standards regarding quality of study conduct required with NI trials, and the myth that NI trials always require huge sample sizes.

In randomized trials comparing a new therapy to standard therapy, the sharp null hypothesis of equivalent therapeutic efficacy does not imply the intent-to-treat null hypothesis of equal outcome distributions in the two-treatment arm if non-compliance is present. As a consequence, the development of analytic methods that adjust for non-compliance is of particular importance in equivalence trials comparing a new therapy to standard therapy. This paper provides, in the context of equivalence trial, a unified overview of various analytic approaches to correct for non-compliance in randomized trials. The overview focuses on comparing and contrasting the plausibility, robustness, and strength of assumptions required by each method and their programming and computational burdens. In addition, several new structural (causal) models are introduced: the coarse structural nested models, the non-nested marginal structural models and the continuous-time structural nested models, and their properties are compared with those of previously proposed structural nested models. The fundamental assumption that allows us to correct for non-compliance is that the decision whether or not to continue to comply with assigned therapy at time t is random (that is, ignorable or explainable) conditional on the history up to t of measured pre- and time-dependent post-randomization prognostic factors. In the final sections of the paper, we consider how the consequences of violations of our assumption of conditionally ignorable non-compliance can be explored through a sensitivity analysis. Finally, the analytic methods described in this paper can also be used to estimate the causal effect of a time-varying treatment from observational data.

The design of a clinical trial to establish the equivalence of two treatments differs from that of an efficacy trial. The conventional null hypothesis of equivalent treatment efficacy is replaced by a null hypothesis of inequivalence which must be tested by appropriate statistics. In addition, the maximum allowable value of the true difference between the efficacy of two equivalent treatments must be specified. In oncology, such a trial is necessary when a standard treatment is replaced by a new less toxic one of equivalent efficacy. The statistical formulation is one-sided. A trial comparing two pre-operative treatments in childhood nephroblastoma is presented here and analysed according to this methodology.