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Rationale & Objectives: Hyperglycemia is frequently observed early after transplantation and associated with development of post-transplant diabetes mellitus (PTDM). Here, we assessed continuous subcutaneous insulin infusion (CSII) targeting afternoon hyperglycemia. Study Design: Open-label randomized parallel 3-arm design. Settings & Participants: In total, 85 kidney transplant recipients without previous diabetes diagnosis were randomized to postoperative CSII therapy, basal insulin, or control. Interventions: Insulin was to be initiated at afternoon capillary blood glucose level of ≥140 mg/dL (7.8 mmol/L; CSII and basal insulin) or fasting plasma glucose level of ≥200 mg/dL (11.1 mmol/L; control). Outcomes: Hemoglobin A1c (HbA1c) levels at 3 months post-transplant (primary endpoint). PTDM assessed using oral glucose tolerance test at 12 and 24 months. Results: CSII therapy lasted until median day 18 and maximum day 88. The median HbA1c value at month 3 was 5.6% (38 mmol/mol) in the CSII group versus 5.7% (39 mmol/mol) in the control group (P = 0.70) and 5.4% (36 mmol/mol) in the basal insulin group (P = 0.02). At months 12 and 24, the odds for PTDM were similar compared with the control group (odds ratios [95% confidence intervals], 0.80 [0.18-3.49] and 0.71 [0.15-3.16], respectively) and the basal insulin group (0.96 [0.18-5.68] and 1.51 [0.24-12.84], respectively). Mild hypoglycemia events occurred in the CSII and the basal insulin groups. Limitations: This study is limited by outdated insulin pump technology, frequent discontinuations of CSII, a complex protocol, and concerns regarding reliability of HbA1c measurements. Conclusions: CSII therapy was not superior at reducing HbA1c levels at month 3 or PTDM prevalence at months 12 and 24 compared with the control or basal insulin group.

It has recently been suggested that precision oncology studies should be reanalysed using the intention-to-treat (ITT) methodology developed for randomized controlled clinical trials. This reanalysis dramatically decreases response rates in precision medicine studies. We contend that the ITT analysis of precision oncology trials is invalid. The ITT methodology was developed three decades ago to mitigate the problems of randomized trials, which try to ensure that both arms have an unselected patient population free from confounders. In contrast, precision oncology trials specifically select patients for confounders (that is biomarkers) that predict response. To demonstrate the issues inherent in an ITT reanalysis for precision cancer medicine studies, we take as an example the drug larotrectinib (TRK inhibitor) approved because of remarkable responses in malignancies harbouring NTRK fusions. Based on large-scale studies, NTRK fusions are found in ~0.31% of tumours. In a non-randomized pivotal study of larotrectinib, 75% of the 55 treated patients responded. Based upon the prevalence of NTRK fusions, ~18,000 patients would need to be screened to enrol the 55 treated patients. Utilizing the ITT methodology, the revised response rate to larotrectinib would be 0.23%. This is, of course, a dramatic underestimation of the efficacy of this now Food and Drug Administration (FDA)-approved drug. Similar issues can be shown for virtually any biomarker-based precision clinical trial. Therefore, retrofitting the ITT analysis developed for unselected patient populations in randomized trials yields misleading conclusions in precision medicine studies.

Under exceptional circumstances, including high rates of protocol non-compliance, per-protocol (PP) analysis can better indicate the real-world benefits of a medical intervention than intention-to-treat (ITT) analysis. Exemplifying this, the first randomized clinical trial (RCT) considered found that colonoscopy screenings were marginally beneficial, based upon ITT analysis, with only 42% of the intervention group actually undergoing the procedure. However, the study authors themselves concluded that the medical efficacy of that screening was a 50% reduction in colorectal cancer deaths among that 42% PP group. The second RCT found a ten-fold reduction in mortality for a COVID-19 treatment drug vs. placebo by PP analysis, but only a minor benefit by ITT analysis. The third RCT, conducted as an arm of the same platform trial as the second RCT, tested another COVID-19 treatment drug and reported no significant benefit by ITT analysis. Inconsistencies and irregularities in the reporting of protocol compliance for this study required consideration of PP outcomes for deaths and hospitalizations, yet the study coauthors refused to disclose them, instead directing inquiring scientists to a data repository which never held the study's data. These three RCTs illustrate conditions under which PP outcomes may differ significantly from ITT outcomes and the need for data transparency when these reported or indicated discrepancies arise. [ABSTRACT FROM AUTHOR]

The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) E9 (R1) addendum will have an important impact on the design and analysis of randomized controlled clinical trials, which represent crucial sources of evidence in health technology assessments, and on the intention-to-treat (ITT) principle in particular. This article brings together a task force of health economists and statisticians in academic institutes and the pharmaceutical industry, to examine the implications of the addendum from the perspective of the National Institute for Health and Care Excellence (NICE) and the Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen (IQWiG) and to address the question of whether the ITT principle should be considered the gold standard for estimating treatment effects. We review the ITT principle, as introduced in the ICH E9 guideline. We then present an overview of the ICH E9 (R1) addendum and its estimand framework, highlighting its premise and the proposed strategies for handling intercurrent events, and examine some cases among submissions to IQWiG and NICE. IQWiG and NICE appear to have diverging perspectives around the relevance of the ITT principle and, in particular, the acceptance of hypothetical strategies for estimating treatment effects, as suggested by examples where the sponsor proposed an alternative approach to the ITT principle when accounting for treatment switching for interventional oncology trials. The ICH E9 (R1) addendum supports the use of methods that depart from the ITT principle. The relevance of estimands using these methods depends on the perspectives and objectives of payers. It is challenging to design a study that meets all stakeholders' research questions. Different estimands may serve to answer different relevant questions or decision problems. • The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use E9 (R1) addendum, through the estimand framework, has affirmed the desirability, in certain circumstances, of estimating treatment effects in randomized controlled trials on the basis of strategies that depart from the intention-to-treat principle. • To the best of our knowledge, there have been limited attempts to date to assess the implications of the addendum for health technology assessment decision making. • To help with this shortfall, we discuss the perspectives of 2 agencies, the Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen and the National Institute for Health and Care Excellence, on the intention-to-treat principle, building on our understanding of published methods guidance, publicly available agency documents, and our experience of working with these agencies. [ABSTRACT FROM AUTHOR]

Donnie Funch,1 Kathleen Mortimer,1 Najat J Ziyadeh,1 John D Seeger,1 Li Zhou,1 Eva Ng,1 Douglas Ross,2,3 Atheline Major-Pedersen,4 Heidrun Bosch-Traberg,5 Helge Gydesen,6 David D Dore1,7 1Optum Epidemiology, Boston, MA, USA; 2Massachusetts General Hospital, Thyroid Associates, Boston, MA, USA; 3Harvard Medical School, Department of Medicine, Boston, MA, USA; 4Global Safety, Novo Nordisk A/S, Copenhagen, Denmark; 5Global Development, Novo Nordisk A/S, Copenhagen, Denmark; 6Epidemiology, Novo Nordisk A/S, Copenhagen, Denmark; 7Department of Health Services, Policy & Practice, Brown University School of Public Health, Providence, RI, USACorrespondence: Najat J ZiyadehOptum Epidemiology, 1325 Boylston Street, 11th Floor, Boston, MA, 02215, USAEmail najat.ziyadeh@optum.comBackground: Quantify association between the glucagon-like peptide-1 receptor agonist liraglutide and risk of thyroid cancer (TC) compared to other antidiabetics.Patients and Methods: Initiators of liraglutide, exenatide, metformin, pioglitazone or groups of dipeptidyl peptidase-4 inhibitors or sulfonylureas were identified in a US health plan (2010– 2014) and followed for a median of 17 months. Thyroid cancer cases during follow-up were identified via a validated algorithm. Incidence rates of TC among liraglutide and comparators were assessed using relative risks estimated within propensity score-matched cohorts using intention to treat (ITT) and time on drug analyses. Latency effects and potential surveillance bias were evaluated.Results: Relative risks from ITT analyses ranged from 1.00 (95% confidence interval (CI) 0.56– 1.79) versus metformin to 1.70 (95% CI 1.03– 2.81) versus all comparators excluding exenatide. Effect estimates from latency analyses were slightly attenuated. Time on drug analyses suggested no increased risk for either longer duration or higher cumulative dose of liraglutide. Medical record review found 85% were papillary or a follicular variant of papillary or both; 46% were microcarcinomas (≤ 10 millimeters), which were more prevalent in the liraglutide cohort (67% versus 43% in all comparators).Conclusion: Relative risks were elevated for several comparisons, which should be interpreted cautiously because of potential residual confounding and surveillance bias. Liraglutide cases had smaller thyroid nodules and shorter time-to-diagnosis, suggesting increased surveillance for TC among liraglutide initiators, especially shortly after the drug´s approval. After adjusting the primary analyses (ITT) for latency, no significant elevated risk of TC was observed among liraglutide initiators.Keywords: glucagon-like peptide-1 receptor agonist, type 2 diabetes, administrative claims, intention-to-treat, time-on-drug

Abstract Background In non-inferiority trials, there is a concern that intention-to-treat (ITT) analysis, by including participants who did not receive the planned interventions, may bias towards making the treatment and control arms look similar and lead to mistaken claims of non-inferiority. In contrast, per protocol (PP) analysis is viewed as less likely to make this mistake and therefore preferable in non-inferiority trials. In a systematic review of antibiotic non-inferiority trials, we compared ITT and PP analyses to determine which analysis was more conservative. Methods In a secondary analysis of a systematic review, we included non-inferiority trials that compared different antibiotic regimens, used absolute risk reduction (ARR) as the main outcome and reported both ITT and PP analyses. All estimates and confidence intervals (CIs) were oriented so that a negative ARR favored the control arm, and a positive ARR favored the treatment arm. We compared ITT to PP analyses results. The more conservative analysis between ITT and PP analyses was defined as the one having a more negative lower CI limit. Results The analysis included 164 comparisons from 154 studies. In terms of the ARR, ITT analysis yielded the more conservative point estimate and lower CI limit in 83 (50.6%) and 92 (56.1%) comparisons respectively. The lower CI limits in ITT analysis favored the control arm more than in PP analysis (median of − 7.5% vs. -6.9%, p = 0.0402). CIs were slightly wider in ITT analyses than in PP analyses (median of 13.3% vs. 12.4%, p

Abstract Background Neoadjuvant therapy has several potential advantages over upfront surgery in patients with localized pancreatic cancer; more patients receive systemic treatment, fewer patients undergo futile surgery, and R0 resection rates are higher, thereby possibly improving overall survival (OS). Two recent randomized trials have suggested benefit of neoadjuvant chemoradiotherapy over upfront surgery, both including single-agent chemotherapy regimens. Potentially, the multi-agent FOLFIRINOX regimen (5-fluorouracil with leucovorin, irinotecan, and oxaliplatin) may further improve outcomes in the neoadjuvant setting for localized pancreatic cancer, but randomized studies are needed. The PREOPANC-2 trial investigates whether neoadjuvant FOLFIRINOX improves OS compared with neoadjuvant gemcitabine-based chemoradiotherapy and adjuvant gemcitabine in resectable and borderline resectable pancreatic cancer patients. Methods This nationwide multicenter phase III randomized controlled trial includes patients with pathologically confirmed resectable and borderline resectable pancreatic cancer with a WHO performance score of 0 or 1. Resectable pancreatic cancer is defined as no arterial and ≤ 90 degrees venous involvement; borderline resectable pancreatic cancer is defined as ≤90 degrees arterial and ≤ 270 degrees venous involvement without occlusion. Patients receive 8 cycles of neoadjuvant FOLFIRINOX chemotherapy followed by surgery without adjuvant treatment (arm A), or 3 cycles of neoadjuvant gemcitabine with hypofractionated radiotherapy (36 Gy in 15 fractions) during the second cycle, followed by surgery and 4 cycles of adjuvant gemcitabine (arm B). The primary endpoint is OS by intention-to-treat. Secondary endpoints include progression-free survival, quality of life, resection rate, and R0 resection rate. To detect a hazard ratio of 0.70 with 80% power, 252 events are needed. The number of events is expected to be reached after inclusion of 368 eligible patients assuming an accrual period of 3 years and 1.5 years follow-up. Discussion The PREOPANC-2 trial directly compares two neoadjuvant regimens for patients with resectable and borderline resectable pancreatic cancer. Our study will provide evidence on the neoadjuvant treatment of choice for patients with resectable and borderline resectable pancreatic cancer. Trial registration Primary registry and trial identifying number: EudraCT: 2017–002036-17 . Date of registration: March 6, 2018. Secondary identifying numbers: The Netherlands National Trial Register – NL7094 , NL61961.078.17, MEC-2018-004.

Background and Aims: Morphometric features such as the Milan criteria serve as standard criteria for liver transplantation (LT) in patients with hepatocellular carcinoma (HCC). Since it has been recognized that these criteria are too restrictive and do not adequately display the tumor biology, additional selection parameters are emerging. Methods: Concise review of the current literature on patient selection for downstaging and LT for HCC outside the Milan criteria. Results: The major task in patients outside the Milan criteria is the need for higher granularity with patient selection, since the benefit through LT is not uniform. The recent literature clearly shows that beneath tumor size and number, additional selection parameters are useful in the process of patient selection for and during downstaging. For initial patient selection, the alpha fetoprotein (AFP) level adds additional information to the size and number of HCC nodules concerning the chance of successful downstaging and LT. This effect is quantifiable using newer selection tools like the WE (West-Eastern) downstaging criteria or the Metroticket 2.0 criteria. Also an initial PET-scan and/or tumor biopsy can be helpful, especially in the high risk group of patients outside the University of California San Francisco (UCSF) criteria. After this entry selection, the clinical course during downstaging procedures concerning the tumor and the AFP response is of paramount importance and serves as an additional final selection tool. Conclusion: Selection criteria for liver transplantation in HCC patients are becoming more and more sophisticated, but are still imperfect. The implementation of molecular knowledge will hopefully support a more specific risk prediction for HCC patients in the future, but do not provide a profound basis for clinical decision-making at present. [ABSTRACT FROM AUTHOR]

Abstract Background An estimand defines the target of estimation for a clinical trial through specification of the treatment, target population, variable, population-level summary and of the strategies for intercurrent events. A carefully defined estimand aligns the clinical trial design and analysis with the scientific question of interest and adequately accounts for so-called intercurrent events. The ICH E9(R1) addendum suggests five estimand strategies. We evaluated to what extent current practice in drug development and regulatory assessment fits in the estimand framework. Methods We systematically evaluated what estimands, especially what strategies for intercurrent events are advised in European Medicines Agency disease guidelines, used in sponsors’ trials and additionally requested by the European Medicines Agency in assessment dossiers. We selected four therapeutic areas: nervous system, oncology, cardiovascular diseases and respiratory diseases. For each, we evaluated all disease guidelines with approved drugs, the dossiers of the most recently approved drugs matching the guidelines and corresponding regulatory questions. Results Strategies for intercurrent events were present in 18 (53%) of 34 guidelines, in all 34 sponsor documentations and in 15 (44%) of 34 sets of regulatory questions. Treatment policy was advised in 13 (38%) guidelines and was applied in 9 corresponding sponsor documentations. Of these 9, it was the sole strategy in 4 cases and accompanied by another strategy in 5 cases. Hypothetical strategy was not advised in guidelines. However, it was the leading strategy applied in 25 (74%) sponsor documentations. Composite strategy was advised in 3 (9%) guidelines and applied accompanied by another strategy in 2 corresponding sponsor documentations. While on treatment strategy was not advised in guidelines, but was applied in 2 sponsor documentations. Principal stratum strategy was advised in 2 guidelines but not applied in corresponding sponsor documentations. Of the regulatory questions, treatment policy was present in 2 cases (6%), hypothetical in 6 cases (18%), composite in 6 cases (18%) and while on treatment in 1 case (3%). Conclusions Estimand attributes are present in guidelines, sponsor documentations and regulatory questions, but not described as estimands. Treatment policy was most often advised in guidelines, but hypothetical was the leading strategy applied in sponsor documentations. Thus, results indicate not a full concordance between the regulatory target of estimation and what is actually estimated. The lack of concordance was mostly due to limitations in collection of intercurrent events data to enable a treatment policy strategy. There is, therefore, a need to better define estimands at the design stage and throughout the applications dossiers and assessment reports.

Background In the GLOBAL LEADERS trial, ticagrelor monotherapy beyond 1 month compared with standard antiplatelet regimens after coronary stent implantation did not improve outcomes at intention‐to‐treat analysis. Considerable differences in treatment adherence between the experimental and control groups may have affected the intention‐to‐treat results. In this reanalysis of the GLOBAL LEADERS trial, we compared the experimental and control treatment strategies in a per‐protocol analysis of patients who did not deviate from the study protocol. Methods and Results Baseline and postrandomization information were used to classify whether and when patients were deviating from the study protocol. With logistic regressions, we derived time‐varying inverse probabilities of nondeviation from protocol to reconstruct the trial population without protocol deviation. The primary end point was a composite of all‐cause mortality or nonfatal Q‐wave myocardial infarction at 2 years. At 2‐year follow‐up, 1103 (13.8%) of 7980 patients in the experimental group and 785 (9.8%) of 7988 patients in the control group qualified as protocol deviators. At per‐protocol analysis, the rate ratio for the primary end point was 0.88 (95% CI, 0.75–1.03; P=0.10) on the basis of 274 versus 325 events in the experimental versus control group. The rate ratio for the key safety end point of major bleeding was 1.00 (95% CI, 0.79–1.26; P=0.99). The per‐protocol and intention‐to‐treat effect estimates were overall consistent. Conclusions Among patients who complied with the study protocol in the GLOBAL LEADERS trial, ticagrelor plus aspirin for 1 month followed by ticagrelor monotherapy was not superior to 1‐year standard dual antiplatelet therapy followed by aspirin alone at 2 years after coronary stenting. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01813435.

Purpose of reviewWe discuss selected statistical issues in the design and analysis of preexposure prophylaxis (PrEP) trials. The general principles may inform thinking for other interventions in HIV prevention.Recent findingsTo date, four different designs have been used to determine the effectiveness of PrEP: randomized, double-blind, placebo-controlled; randomized, open-label, immediate or delayed access; nonrandomized comparison of HIV incidence according to the level of drug detected; comparison of the observed HIV incidence to the expected rate using historical control data. Open-label trials of PrEP, which assess public health effectiveness, complement the placebo-controlled trials which established the biological efficacy of TDF/FTC. Future trials of PrEP will be highly challenging to design since a no PrEP group is difficult to justify and the natural control regimen, TDF/FTC, is highly efficacious.SummaryStandard statistical paradigms for noninferiority trials should be reconsidered for evaluating alternative PrEP regimens.

Abstract Background Cluster randomized trials (CRTs) are a design used to test interventions where individual randomization is not appropriate. The mixed model for repeated measures (MMRM) is a popular choice for individually randomized trials with longitudinal continuous outcomes. This model’s appeal is due to avoidance of model misspecification and its unbiasedness for data missing completely at random or at random. Methods We extended the MMRM to cluster randomized trials by adding a random intercept for the cluster and undertook a simulation experiment to investigate statistical properties when data are missing at random. We simulated cluster randomized trial data where the outcome was continuous and measured at baseline and three post-intervention time points. We varied the number of clusters, the cluster size, the intra-cluster correlation, missingness and the data-generation models. We demonstrate the MMRM-CRT with an example of a cluster randomized trial on cardiovascular disease prevention among diabetics. Results When simulating a treatment effect at the final time point we found that estimates were unbiased when data were complete and when data were missing at random. Variance components were also largely unbiased. When simulating under the null, we found that type I error was largely nominal, although for a few specific cases it was as high as 0.081. Conclusions Although there have been assertions that this model is inappropriate when there are more than two repeated measures on subjects, we found evidence to the contrary. We conclude that the MMRM for CRTs is a good analytic choice for cluster randomized trials with a continuous outcome measured longitudinally. Trial registration ClinicalTrials.gov, ID: NCT02804698.

Background: Stress fractures are a common and potentially debilitating overuse injury to bone and occur frequently among military recruits and athletes. Recovery from a lower body stress fracture typically requires several weeks of physical rehabilitation. Teriparatide, a recombinant form of the bioactive portion of parathyroid hormone (1-34 amino acids), is used to treat osteoporosis, prevent osteoporotic fractures, and enhance fracture healing due to its net anabolic effect on bone. The study aim is to investigate the effect of teriparatide on stress fracture healing in young, otherwise healthy adults undergoing military training.Methods: In a two-arm, parallel, prospective, randomised controlled, intention-to-treat trial, Army recruits (n = 136 men and women, 18-40 years) with a magnetic resonance imaging (MRI) diagnosed lower body stress fracture (pelvic girdle, sacrum, coccyx, or lower limb) will be randomised to receive either usual Army standard care, or teriparatide and usual Army standard care. Teriparatide will be self-administered by subcutaneous injections (20 μg/day) for 16 weeks, continuing to 24 weeks where a fracture remains unhealed at week 16. The primary outcome will be the improvement in radiological healing by two grades or more, or reduction to grade zero, 8 weeks after randomisation, assessed using Fredericson grading of MRI by radiologists blind to the randomisation. Secondary outcomes will be time to radiological healing, assessed by MRI at 8, 10, 12, 14, 16, 20 and 24 weeks, until healed; time to clinical healing, assessed using a clinical severity score of injury signs and symptoms; time to discharge from Army physical rehabilitation; pain, assessed by visual analogue scale; health-related quality of life, using the Short Form (36) Health Survey; and adverse events. Exploratory outcomes will include blood and urine biochemistry; bone density and morphology assessed using dual-energy X-ray absorptiometry, peripheral quantitative computed tomography (pQCT), and high-resolution pQCT; physical activity measured using accelerometers; and long-term future fracture rate.Discussion: This study will evaluate whether teriparatide, in addition to standard care, is more effective for stress fracture healing than standard care alone in Army recruits who have sustained a lower body stress fracture.Trial Registration: ClinicalTrials.gov NCT04196855 . Registered on 12 December 2019. [ABSTRACT FROM AUTHOR]

Background: In non-inferiority trials, there is a concern that intention-to-treat (ITT) analysis, by including participants who did not receive the planned interventions, may bias towards making the treatment and control arms look similar and lead to mistaken claims of non-inferiority. In contrast, per protocol (PP) analysis is viewed as less likely to make this mistake and therefore preferable in non-inferiority trials. In a systematic review of antibiotic non-inferiority trials, we compared ITT and PP analyses to determine which analysis was more conservative.Methods: In a secondary analysis of a systematic review, we included non-inferiority trials that compared different antibiotic regimens, used absolute risk reduction (ARR) as the main outcome and reported both ITT and PP analyses. All estimates and confidence intervals (CIs) were oriented so that a negative ARR favored the control arm, and a positive ARR favored the treatment arm. We compared ITT to PP analyses results. The more conservative analysis between ITT and PP analyses was defined as the one having a more negative lower CI limit.Results: The analysis included 164 comparisons from 154 studies. In terms of the ARR, ITT analysis yielded the more conservative point estimate and lower CI limit in 83 (50.6%) and 92 (56.1%) comparisons respectively. The lower CI limits in ITT analysis favored the control arm more than in PP analysis (median of - 7.5% vs. -6.9%, p = 0.0402). CIs were slightly wider in ITT analyses than in PP analyses (median of 13.3% vs. 12.4%, p < 0.0001). The median success rate was 89% (interquartile range IQR 82 to 93%) in the PP population and 44% (IQR 23 to 60%) in the patients who were included in the ITT population but excluded from the PP population (p < 0.0001).Conclusions: Contrary to common belief, ITT analysis was more conservative than PP analysis in the majority of antibiotic non-inferiority trials. The lower treatment success rate in the ITT analysis led to a larger variance and wider CI, resulting in a more conservative lower CI limit. ITT analysis should be mandatory and considered as either the primary or co-primary analysis for non-inferiority trials.Trial Registration: PROSPERO registration number CRD42020165040 . [ABSTRACT FROM AUTHOR]

Background: Neoadjuvant therapy has several potential advantages over upfront surgery in patients with localized pancreatic cancer; more patients receive systemic treatment, fewer patients undergo futile surgery, and R0 resection rates are higher, thereby possibly improving overall survival (OS). Two recent randomized trials have suggested benefit of neoadjuvant chemoradiotherapy over upfront surgery, both including single-agent chemotherapy regimens. Potentially, the multi-agent FOLFIRINOX regimen (5-fluorouracil with leucovorin, irinotecan, and oxaliplatin) may further improve outcomes in the neoadjuvant setting for localized pancreatic cancer, but randomized studies are needed. The PREOPANC-2 trial investigates whether neoadjuvant FOLFIRINOX improves OS compared with neoadjuvant gemcitabine-based chemoradiotherapy and adjuvant gemcitabine in resectable and borderline resectable pancreatic cancer patients.Methods: This nationwide multicenter phase III randomized controlled trial includes patients with pathologically confirmed resectable and borderline resectable pancreatic cancer with a WHO performance score of 0 or 1. Resectable pancreatic cancer is defined as no arterial and ≤ 90 degrees venous involvement; borderline resectable pancreatic cancer is defined as ≤90 degrees arterial and ≤ 270 degrees venous involvement without occlusion. Patients receive 8 cycles of neoadjuvant FOLFIRINOX chemotherapy followed by surgery without adjuvant treatment (arm A), or 3 cycles of neoadjuvant gemcitabine with hypofractionated radiotherapy (36 Gy in 15 fractions) during the second cycle, followed by surgery and 4 cycles of adjuvant gemcitabine (arm B). The primary endpoint is OS by intention-to-treat. Secondary endpoints include progression-free survival, quality of life, resection rate, and R0 resection rate. To detect a hazard ratio of 0.70 with 80% power, 252 events are needed. The number of events is expected to be reached after inclusion of 368 eligible patients assuming an accrual period of 3 years and 1.5 years follow-up.Discussion: The PREOPANC-2 trial directly compares two neoadjuvant regimens for patients with resectable and borderline resectable pancreatic cancer. Our study will provide evidence on the neoadjuvant treatment of choice for patients with resectable and borderline resectable pancreatic cancer.Trial Registration: Primary registry and trial identifying number: EudraCT: 2017-002036-17 . Date of registration: March 6, 2018. Secondary identifying numbers: The Netherlands National Trial Register - NL7094 , NL61961.078.17, MEC-2018-004. [ABSTRACT FROM AUTHOR]

Donnie Funch,1 Kathleen Mortimer,1 Ling Li,1 Heather Norman,1 Atheline Major-Pedersen,2 Anne Helene Olsen,3 Margit S Kaltoft,4 David D Dore1,5 1Optum Epidemiology, Boston, MA, USA; 2Global Safety, Novo Nordisk A/S, Copenhagen, Denmark; 3Epidemiology, Novo Nordisk A/S, Copenhagen, Denmark; 4Global Development, Novo Nordisk A/S, Copenhagen, Denmark; 5Department of Health Services, Policy & Practice, Brown University School of Public Health, Providence, RI, USA Background: Liraglutide is a human glucagon-like peptide-1 receptor agonist approved for treatment of adults with type 2 diabetes mellitus at a maximum dose of 1.8 mg/day (Victoza®) and more recently at 3.0 mg/day for weight management (Saxenda®). During the evaluation of liraglutide for approval in weight management, a minor imbalance in the numbers of reported breast neoplasms was observed, motivating the present study. Our objective was to quantify the association between liraglutide and incidence of breast cancer (BC) among women in a real-world setting. Patients and methods: Women initiating liraglutide or other antidiabetic therapies and who were enrolled in a large US health plan (2010–2014) were included. Comparisons of BC incidence rates were made between matched cohorts of initiators of liraglutide and cohorts of initiators of exenatide, metformin, pioglitazone, sulfonylureas, and dipeptidyl peptidase-4 inhibitors separately and as two “all comparators” groupings: with or without exenatide. Women with two or more claims with BC diagnosis codes within 61days of each other were identified as possible cases, with additional confirmation by clinician review of comprehensive claims listings. Propensity score matched intention-to-treat (ITT) and time-on-drug (TOD) analyses were completed via Poisson regression. A latency analysis was performed. Results: Relative risks for BC for liraglutide vs comparators from the ITT analyses ranged from 0.90 (95% CI: 0.67–1.22) for both the “all comparator” and “all comparator except exenatide” cohorts to 1.46 (95% CI: 0.96–2.22) relative to exenatide. Latency analyses excluding the first year of follow-up yielded slightly attenuated point estimates. The TOD analyses of cumulative use of liraglutide suggested no increased risk of BC. Conclusion: Neither the ITT (overall or latency analysis) nor cumulative TOD analyses suggested an elevated risk of BC among liraglutide initiators. Short length of follow-up and the potential for confounding by unmeasured factors limit the full assessment of long-term risk. Keywords: glucagon-like peptide-1 receptor agonist, type 2 diabetes, administrative claims, intention-to-treat, time-on-drug

Background: An estimand defines the target of estimation for a clinical trial through specification of the treatment, target population, variable, population-level summary and of the strategies for intercurrent events. A carefully defined estimand aligns the clinical trial design and analysis with the scientific question of interest and adequately accounts for so-called intercurrent events. The ICH E9(R1) addendum suggests five estimand strategies. We evaluated to what extent current practice in drug development and regulatory assessment fits in the estimand framework.Methods: We systematically evaluated what estimands, especially what strategies for intercurrent events are advised in European Medicines Agency disease guidelines, used in sponsors' trials and additionally requested by the European Medicines Agency in assessment dossiers. We selected four therapeutic areas: nervous system, oncology, cardiovascular diseases and respiratory diseases. For each, we evaluated all disease guidelines with approved drugs, the dossiers of the most recently approved drugs matching the guidelines and corresponding regulatory questions.Results: Strategies for intercurrent events were present in 18 (53%) of 34 guidelines, in all 34 sponsor documentations and in 15 (44%) of 34 sets of regulatory questions. Treatment policy was advised in 13 (38%) guidelines and was applied in 9 corresponding sponsor documentations. Of these 9, it was the sole strategy in 4 cases and accompanied by another strategy in 5 cases. Hypothetical strategy was not advised in guidelines. However, it was the leading strategy applied in 25 (74%) sponsor documentations. Composite strategy was advised in 3 (9%) guidelines and applied accompanied by another strategy in 2 corresponding sponsor documentations. While on treatment strategy was not advised in guidelines, but was applied in 2 sponsor documentations. Principal stratum strategy was advised in 2 guidelines but not applied in corresponding sponsor documentations. Of the regulatory questions, treatment policy was present in 2 cases (6%), hypothetical in 6 cases (18%), composite in 6 cases (18%) and while on treatment in 1 case (3%).Conclusions: Estimand attributes are present in guidelines, sponsor documentations and regulatory questions, but not described as estimands. Treatment policy was most often advised in guidelines, but hypothetical was the leading strategy applied in sponsor documentations. Thus, results indicate not a full concordance between the regulatory target of estimation and what is actually estimated. The lack of concordance was mostly due to limitations in collection of intercurrent events data to enable a treatment policy strategy. There is, therefore, a need to better define estimands at the design stage and throughout the applications dossiers and assessment reports. [ABSTRACT FROM AUTHOR]

Background: Cluster randomized trials (CRTs) are a design used to test interventions where individual randomization is not appropriate. The mixed model for repeated measures (MMRM) is a popular choice for individually randomized trials with longitudinal continuous outcomes. This model's appeal is due to avoidance of model misspecification and its unbiasedness for data missing completely at random or at random.Methods: We extended the MMRM to cluster randomized trials by adding a random intercept for the cluster and undertook a simulation experiment to investigate statistical properties when data are missing at random. We simulated cluster randomized trial data where the outcome was continuous and measured at baseline and three post-intervention time points. We varied the number of clusters, the cluster size, the intra-cluster correlation, missingness and the data-generation models. We demonstrate the MMRM-CRT with an example of a cluster randomized trial on cardiovascular disease prevention among diabetics.Results: When simulating a treatment effect at the final time point we found that estimates were unbiased when data were complete and when data were missing at random. Variance components were also largely unbiased. When simulating under the null, we found that type I error was largely nominal, although for a few specific cases it was as high as 0.081.Conclusions: Although there have been assertions that this model is inappropriate when there are more than two repeated measures on subjects, we found evidence to the contrary. We conclude that the MMRM for CRTs is a good analytic choice for cluster randomized trials with a continuous outcome measured longitudinally.Trial Registration: ClinicalTrials.gov, ID: NCT02804698. [ABSTRACT FROM AUTHOR]

Statistical interpretation of data collected in a randomised controlled trial (RCT) is conducted on the intention‐to‐treat (ITT) and/or the per‐protocol (PP) study populations. ITT analysis is a comparison of treatment groups including all patients as originally allocated after randomisation regardless if treatment was initiated or completed. PP analysis is a comparison of treatment groups including only those patients who completed the treatment as originally allocated, although it is often criticised because of its potential to instil bias. A previous report from an RCT conducted to evaluate the efficacy of dehydrated human amnion/chorion membrane allograft (EpiFix) as an adjunct to standard comprehensive wound therapy consisting of moist dressings and multi‐layer compression in the healing of venous leg ulcers (VLUs) only reported PP study results (n = 109, 52 EpiFix and 57 standard care patients), although there were 128 patients randomised: 64 to the EpiFix group and 64 to the standard care group. Primary study outcome was the incidence of healing at 12 weeks. The purpose of the present study is to report ITT results on all 128 randomised subjects and assess if both ITT and PP data analyses arrive at the same conclusion of the efficacy of EpiFix as a treatment for VLU. Rates of healing for the ITT and PP populations were, respectively, 50% and 60% for those receiving EpiFix and 31% and 35% for those in the standard care cohort. Within both ITT and PP analyses, these differences were statistically significant; P = 0.0473, ITT and P = 0.0128, PP. The Kaplan‐Meier plot of time to heal within 12 weeks for the ITT and PP populations demonstrated a superior wound‐healing trajectory for EpiFix compared with VLUs treated with standard care alone. These data provide clinicians and health policymakers an additional level of assurance regarding the effectiveness of EpiFix. [ABSTRACT FROM AUTHOR]

Abstract Background Intention-to-treat (ITT) analysis is commonly recommended for use, due to its benefits on external validity, in randomized, controlled trials (RCTs). No published reports describe how ITT analysis, as well as alternative approaches, are used in anti-infective RCTs. The purpose of this study is to describe the extent to which ITT analysis and alternative data approaches are used, the practices used to handle missing subject data, and whether non-inferiority trials present both ITT and per protocol (PP) analyses. Results of this analysis will help guide end users of infectious diseases primary drug literature. Methods A cross-sectional study of RCTs of anti-infectives published from January 1, 2013 through December 31, 2014 was conducted. A PubMed search identified relevant articles published in five specialty infectious diseases journals and four general medical journals. Each article was reviewed by two independent investigators with discrepancies resolved by consensus. Descriptive statistics were used to quantify results. Results One hundred four articles met study criteria. The most common medication classes represented in the RCTs were hepatitis C antivirals (26 %), antibacterials (25 %), and antiretrovirals (21 %). Thirty studies (29 %) were non-inferiority trials. Most studies (77 %) described use of ITT or modified ITT (mITT) in their methods. Of the ITT and mITT studies, most (73 %) did not describe practices used to handle missing data. Most (97 %) non-inferiority trials described use of ITT, mITT, or both; however, only 15 (50 %) also described use of PP. Conclusions RCTs of anti-infectives commonly employ ITT and mITT. Most do not describe how missing data were addressed. Non-inferiority trials of anti-infectives do not consistently employ both ITT and PP populations.

Background: The cohort multiple randomized controlled trial (cmRCT) can tackle some of the weaknesses of an RCT which has triggered the interest of researchers considerably over time. Several challenges persist regarding the methods of analyzing such valued data. The paucity of international recommendations concerning the statistical methods for analyzing trial data has led to a variety of strategies further complicating the result comparison. Our aim was to review the different cmRCT analysis methods since cmRCT was first proposed in 2010., Methodology: A search for full-length studies presenting statistical analysis of the data collected adopting a cmRCT design was conducted on PubMed, Cochrane Library, EMBASE, JSTOR, Scopus, MEDLINE, and ClinicalTrials.gov., Results: Out of 186 studies screened, we selected 22 for the full-text screening and 11 were found eligible for data extraction. All 11 studies were conducted in high-income countries, reflecting the design being underutilized in other settings. All of the studies were found to have used intention-to-treat (ITT) analysis with four of them utilizing instrumental variables (IV) analysis or a complier average causal effect (CACE). Randomization was noted often to be interchangeably used for random selection. Sample size calculation was not clearly specified in the majority of the studies., Conclusion: Clarity regarding the distinction between an RCT and a cmRCT is warranted. The fundamental difference in design, which leads to certain biases that need to be taken care of by adopting IV or CACE analysis, has to be understood before taking up a cmRCT., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Narzari et al.)

Background: In recent years, berberine has become widely used as an effective alternative to treat dyslipidaemias; much clinical evidence has emerged. It is important to systematically and critically evaluate the existing evidence.Purpose: This study aims to evaluate the efficacy and safety of berberine in patients with dyslipidaemias.Study Design: A systematic review and meta-analysis of randomized clinical trials.Methods: Five electronic databases were searched up to Apr 15, 2018 to identify randomized controlled trials (RCTs) of berberine in treatment of dyslipidaemias. The outcomes were lipid profile parameters and adverse events. Study selection, data collection, risk of bias assessment, data analyses and interpretations were conducted according to the Cochrane handbook.Results: Sixteen trials with total of 2147 participants were judged to be eligible and were included in the meta-analysis. The included trials were assessed to be of high clinical heterogeneity. The methodological quality of the majority of the trials was generally low in terms of random sequence generation, allocation concealment, blinding and incomplete outcome data. Thus, selection bias, performance bias, detection bias, attrition bias and confounding bias might exist. Meta-analysis showed that berberine significantly reduced levels of total cholesterol (TC) (MD = -0.47  mmol/l 95% CI [-0.64, -0.31], p < 0.00001), low-density lipoprotein cholesterol (LDL-C) (MD =-0.38  mmol/l 95% CI [-0.53, -0.22], p < 0.00001) and triglycerides (TG) (MD = -0.28  mmol/l 95% CI [-0.46, -0.10], p = 0.002). Berberine also increased the level of high-density lipoprotein cholesterol (HDL-C) when used alone (MD = 0.08  mmol/l 95% CI [0.03, 0.12], p = 0.001). No significant differences were found between groups in terms of incidence of adverse events (RR = 0.64 95% CI [0.31, 1.30], p = 0.22). No severe adverse effects were reported in either group.Conclusion: Berberine improves lipid profiles in dyslipidaemias with satisfactory safety. Nevertheless, these findings should be interpreted with caution because of the high clinical heterogeneity and high risk of bias in the included trials. Rigorous clinical trials should be carried out to provide more reliable evidence. [ABSTRACT FROM AUTHOR]

Objective: To illustrate the impact of key quasi-experimental design elements on cost savings measurement for population health management (PHM) programs.Data Sources: Population health management program records and Medicaid claims and enrollment data from December 2011 through March 2016.Study Design: The study uses a difference-in-difference design to compare changes in cost and utilization outcomes between program participants and propensity score-matched nonparticipants. Comparisons of measured savings are made based on (1) stable versus dynamic population enrollment and (2) all eligible versus enrolled-only participant definitions. Options for the operationalization of time are also discussed.Data Collection/extraction Methods: Individual-level Medicaid administrative and claims data and PHM program records are used to match study groups on baseline risk factors and assess changes in costs and utilization.Principal Findings: Savings estimates are statistically similar but smaller in magnitude when eliminating variability based on duration of population enrollment and when evaluating program impact on the entire target population. Measurement in calendar time, when possible, simplifies interpretability.Conclusion: Program evaluation design elements, including population stability and participant definitions, can influence the estimated magnitude of program savings for the payer and should be considered carefully. Time specifications can also affect interpretability and usefulness. [ABSTRACT FROM AUTHOR]

Background: In a non-inferiority (NI) trial, analysis based on the intention-to-treat (ITT) principle is anti-conservative, so current guidelines recommend analysing on a per-protocol (PP) population in addition. However, PP analysis relies on the often implausible assumption of no confounders. Randomisation-based efficacy estimators (RBEEs) allow for treatment non-adherence while maintaining a comparison of randomised groups. Fischer et al. have developed an approach for estimating RBEEs in randomised trials with two active treatments, a common feature of NI trials. The aim of this paper was to demonstrate the use of RBEEs in NI trials using this approach, and to appraise the feasibility of these estimators as the primary analysis in NI trials.Methods: Two NI trials were used. One comparing two different dosing regimens for the maintenance of remission in people with ulcerative colitis (CODA), and the other comparing an orally administered treatment to an intravenously administered treatment in preventing skeletal-related events in patients with bone metastases from breast cancer (ZICE). Variables that predicted adherence in each of the trial arms, and were also independent of outcome, were sought in each of the studies. Structural mean models (SMMs) were fitted that conditioned on these variables, and the point estimates and confidence intervals compared to that found in the corresponding ITT and PP analyses.Results: In the CODA study, no variables were found that differentially predicted treatment adherence while remaining independent of outcome. The SMM, using standard methodology, moved the point estimate closer to 0 (no difference between arms) compared to the ITT and PP analyses, but the confidence interval was still within the NI margin, indicating that the conclusions drawn would remain the same. In the ZICE study, cognitive functioning as measured by the corresponding domain of the QLQ-C30, and use of chemotherapy at baseline were both differentially associated with adherence while remaining independent of outcome. However, while the SMM again moved the point estimate closer to 0, the confidence interval was wide, overlapping with any NI margin that could be justified.Conclusion: Deriving RBEEs in NI trials with two active treatments can provide a randomisation-respecting estimate of treatment efficacy that accounts for treatment adherence, is straightforward to implement, but requires thorough planning during the design stage of the study to ensure that strong baseline predictors of treatment are captured. Extension of the approach to handle nonlinear outcome variables is also required.Trial Registration: The CODA study: ClinicalTrials.gov, identifier: NCT00708656 . Registered on 8 April 2008. The ZICE study trial: ClinicalTrials.gov, identifier: NCT00326820 . Registered on 16 May 2006. [ABSTRACT FROM AUTHOR]

Evidence-based dental practice requires the developmment and evaluation of protocols that en-sure translational effectiveness: that is, the efficient incorporation of the best available efficacy and effec-tiveness findings in specific clinical dentistry settings and environments. Evidence-based dentistry predi-cates the synthesis of research for obtaining the best available evidence in a validated, stringent, systematic and unbiased fashion. Research synthesis is now established as a science in its own right, precisely because it adheres to the scientific process that is driven by a research question and a hypothesis, follows through clearly defined methodology and design, yielding quantifiable data that are analyzed statistically, and from which stringent statistical inferences are drawn. The conclusions from the protocol of research synthesis define the best available evidence, which is used in the process of evidence-based revision of clinical practice guidelines. One important hurdle of the process of applying research synthesis in evidence-based dentistry lies in the fact that the statistical inferences produced by research must be translated into clinical relevance. Here, we present a model to circumvent this limitation by means of text analysis/mining protocols, which could lead the path toward a novel, valid and reliable ap-proach for the inferential analysis of clinical relevance.

Background & Objectives: In clinical trials some of participants do not take assignment treatment. Intention-to-treat (ITT) is one of the strategies to analyze of clinical trials with control. ITT estimation will be invalid and incorrect to show of treatment effects in case of existing non-compliance in participants. In this study we adjusted noncompliance effect to compare of active treatment and placebo.Methods: To demonstrate efficiency of proposed model, a dataset of crossover clinical trial with 42 patients with knee osteoarthritis was used. To estimate the non-compliance’s effect adjusting at comparison of treatment effects, we use mean of compliance proportion at periods in sequences. The parameters were estimated by maximum likelihood method. ( could you ask authors to have a look at what they wrote and compare with Farsi version) Results: The results show that baseline variables distributions like duration of disease, severity of disease, age and sex, were not significant (p>0.05). The standard error estimation of treatment effects ( ) based on adjusted model were less than standard model (0.09 and 0.12, respectively). In addition, likelihood ratio statistics based on adjusted model were less than standard model (1177.7 versus 1205.1). Conclusion: Based on estimation of standard errors and likelihood ratio statistics at adjusted and standard models, we observe that adjusted model is more efficient than standard model.

Introduction A previous randomized controlled trial (RCT) of the Swedish National Tobacco Quitline detected no significant differences in smoking cessation outcomes between proactive and reactive services at 12-month follow-up. However, the response rate was only 59 % and non-responders were over-represented in the proactive service. We performed a drop-out analysis to assess the smoking status of initial responders and non-responders. Material and Methods At 29–48 months after the first call, a postal questionnaire with six questions was sent to 150 random clients from the RCT database, with equal numbers from the proactive and reactive services as well as responders and non-responders at 12-month follow-up. Clients who did not return the questionnaire were contacted by telephone. The outcome measures were point prevalence (PP) and 6-month continuous abstinence (CA), and their associations with response status at 12 months were assessed by logistic regression. Results The response rate was 74 % (111/150). Abstinence was significantly higher among initial responders than non-responders (PP 54 % vs. 32 %, p = .023 and CA 49 % vs. 21 %, p = .003). The odds ratios for initial responders vs. initial non-responders were, for PP = 2.5 (95 % CI 1.1–5.6, p = .024), and for CA = 3.7 (95 % CI 1.5–8.9, p = .004), after adjusting for proactive/reactive service. Conclusions Non-responders to a 12-month follow-up smoking cessation questionnaire in a quitline setting were more likely to be smokers 1.5–3 years later. We propose a conservative correction factor of 0.8 for self-reported abstinence in telephone-based cessation studies if the response rate is approximately 55–65 %.

Background: A considerable proportion of intended pulmonary metastasectomies is known to turn out as new incidental primary lung cancers in final pathology. We aimed to analyse the trends and results of pulmonary metastasectomies using the intention-to-treat approach with an emphasis on final histopathological findings., Methods: All intention-to-treat pulmonary metastasectomies performed in Oulu University Hospital between 2000 and 2020 were included in the study. Long term survival was analysed with the Kaplan-Meier method and log-rank tests. A binary logistic regression analysis was performed to calculate odds ratios for incidental primary lung cancer in final histology., Results: A total of 154 intended pulmonary metastasectomies were performed to 127 individual patients. There was an increasing trend in pulmonary metastasectomies during the study period. Despite the increasing trend in comorbidities of the operated patients, the length of hospital stays decreased, and the postoperative complication rates remained stable. In final pathology reports, 9.7% were new primary lung cancers and 13.0% were benign nodules. A long disease-free interval (≥24 months) and smoking history were associated with incidental primary lung cancer in final histology. The short-term 30- and 90-day mortalities after pulmonary metastasectomy were 0.7%. The 5-year survival after pulmonary metastasectomy from all histologies was 52.8%, and from colorectal cancer metastasectomies (n=34) it was 73.5%., Conclusions: The significant amount of new primary lung cancer lesions in pulmonary metastasectomy specimens highlight the diagnostic importance of pulmonary metastasectomy. A segmentectomy could be considered as a primary procedure in pulmonary metastasectomy in patients with a long disease-free interval and a heavy smoking history., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-22-1647/coif). The authors have no conflicts of interest to declare., (2023 Journal of Thoracic Disease. All rights reserved.)

Background: Intention-to-treat (ITT) analysis is commonly recommended for use, due to its benefits on external validity, in randomized, controlled trials (RCTs). No published reports describe how ITT analysis, as well as alternative approaches, are used in anti-infective RCTs. The purpose of this study is to describe the extent to which ITT analysis and alternative data approaches are used, the practices used to handle missing subject data, and whether non-inferiority trials present both ITT and per protocol (PP) analyses. Results of this analysis will help guide end users of infectious diseases primary drug literature.Methods: A cross-sectional study of RCTs of anti-infectives published from January 1, 2013 through December 31, 2014 was conducted. A PubMed search identified relevant articles published in five specialty infectious diseases journals and four general medical journals. Each article was reviewed by two independent investigators with discrepancies resolved by consensus. Descriptive statistics were used to quantify results.Results: One hundred four articles met study criteria. The most common medication classes represented in the RCTs were hepatitis C antivirals (26 %), antibacterials (25 %), and antiretrovirals (21 %). Thirty studies (29 %) were non-inferiority trials. Most studies (77 %) described use of ITT or modified ITT (mITT) in their methods. Of the ITT and mITT studies, most (73 %) did not describe practices used to handle missing data. Most (97 %) non-inferiority trials described use of ITT, mITT, or both; however, only 15 (50 %) also described use of PP.Conclusions: RCTs of anti-infectives commonly employ ITT and mITT. Most do not describe how missing data were addressed. Non-inferiority trials of anti-infectives do not consistently employ both ITT and PP populations. [ABSTRACT FROM AUTHOR]

Background: A previous randomized controlled trial (RCT) of the Swedish National Tobacco Quitline detected no significant differences in smoking cessation outcomes between proactive and reactive services at 12-month follow-up. However, the response rate was only 59 % and non-responders were over-represented in the proactive service. We performed a drop-out analysis to assess the smoking status of initial responders and non-responders. Methods: At 29-48 months after the first call, a postal questionnaire with six questions was sent to 150 random clients from the RCT database, with equal numbers from the proactive and reactive services as well as responders and non-responders at 12-month follow-up. Clients who did not return the questionnaire were contacted by telephone. The outcome measures were point prevalence (PP) and 6-month continuous abstinence (CA), and their associations with response status at 12 months were assessed by logistic regression. Results: The response rate was 74 % (111/150). Abstinence was significantly higher among initial responders than non-responders (PP 54 % vs. 32 %, p = .023 and CA 49 % vs. 21 %, p = .003). The odds ratios for initial responders vs. initial non-responders were, for PP = 2.5 (95 % CI 1.1-5.6, p = .024), and for CA = 3.7 (95 % CI 1.5-8.9, p = .004), after adjusting for proactive/reactive service. Conclusions: Non-responders to a 12-month follow-up smoking cessation questionnaire in a quitline setting were more likely to be smokers 1.5-3 years later. We propose a conservative correction factor of 0.8 for self-reported abstinence in telephone-based cessation studies if the response rate is approximately 55-65 %. [ABSTRACT FROM AUTHOR]

Background: Randomised controlled trials are widely acknowledged as the gold standard in medical research although their validity can be undermined by non-compliance with the randomly allocated treatment and missing data. Due to the nature of the intervention, surgical trials face particular threat to compliance and data collection. For example, ineligibility for the intervention may only become apparent once the operation has commenced. It is unclear how such cases are reported and handled. Objective: The objective was to assess non-compliance and missing data in reports of trials of surgical interventions. Methods: Searches for reports of trials involving at least one surgical procedure and published in 2010 were carried out in the Medical Literature Analysis and Retrieval System Online (MEDLINE®). Data on missing data, non-compliance and methods of handling missing data were extracted from full texts. Descriptive data analyses were carried out on the data. Results: Forty-five (55 %) studies reported non-compliance with treatment allocation and 52 (63 %) reported primary outcome missing data. The median levels of non-compliance and missing data were 2 % [IQR (0, 5), range (0-29)] and 6 % [IQR (0, 15), range (0-57)], respectively. Fifty-two (63 %) studies analysed as randomised, 17 (21 %) analysed per protocol and 3 (4 %) analysed as treated. Complete case analysis was the most common method used to deal with missing data, 35/52 (67 %). Conclusions: The reporting of non-compliance to allocation and the handling of missing data were typically suboptimal. There is still room for improvement on the use of the CONSORT statement particularly in accounting for study participants. Transparency in reporting would facilitate evidence synthesis. [ABSTRACT FROM AUTHOR]

Background Missing outcome data is a threat to the validity of treatment effect estimates in randomized controlled trials. We aimed to evaluate the extent, handling, and sensitivity analysis of missing data and intention-to-treat (ITT) analysis of randomized controlled trials (RCTs) in top tier medical journals, and compare our findings with previous reviews related to missing data and ITT in RCTs. Methods Review of RCTs published between July and December 2013 in the BMJ, JAMA, Lancet, and New England Journal of Medicine, excluding cluster randomized trials and trials whose primary outcome was survival. Results Of the 77 identified eligible articles, 73 (95%) reported some missing outcome data. The median percentage of participants with a missing outcome was 9% (range 0 - 70%). The most commonly used method to handle missing data in the primary analysis was complete case analysis (33, 45%), while 20 (27%) performed simple imputation, 15 (19%) used model based methods, and 6 (8%) used multiple imputation. 27 (35%) trials with missing data reported a sensitivity analysis. However, most did not alter the assumptions of missing data from the primary analysis. Reports of ITT or modified ITT were found in 52 (85%) trials, with 21 (40%) of them including all randomized participants. A comparison to a review of trials reported in 2001 showed that missing data rates and approaches are similar, but the use of the term ITT has increased, as has the report of sensitivity analysis. Conclusions Missing outcome data continues to be a common problem in RCTs. Definitions of the ITT approach remain inconsistent across trials. A large gap is apparent between statistical methods research related to missing data and use of these methods in application settings, including RCTs in top medical journals. [ABSTRACT FROM AUTHOR]

Abstract Noninferiority trials are intended to show that the effect of a new treatment is not worse than that of an active control by more than a specified margin. These trials have a number of inherent weaknesses that superiority trials do not: no internal demonstration of assay sensitivity, no single conservative analysis approach, lack of protection from bias by blinding, and difficulty in specifying the noninferiority margin. Noninferiority trials may sometimes be necessary when a placebo group can not be ethically included, but it should be recognized that the results of such trials are not as credible as those from a superiority trial.

Background The growing prevalence of health care ethics consultation (HCEC) services in the U.S. has been accompanied by an increase in calls for accountability and quality assurance, and for the debates surrounding why and how HCEC is evaluated. The objective of this study was to evaluate the effectiveness of HCEC as indicated by several novel outcome measurements in East Asian medical encounters. Methods Patients with medical uncertainty or conflict regarding value-laden issues, and requests made by the attending physicians or nurses for HCEC from December 1, 2009 to April 30, 2012 were randomly assigned to the usual care group (UC group) and the intervention group (HCEC group). The patients in the HCEC group received HCEC conducted by an individual ethics consultant. Data analysis was based on the intention-to-treat principle. Mann-Whitney test and Chi-squared test were used depending on the scale of measurement. Results Thirty-three patients (53.23%) were randomly assigned to the HCEC group and 29 patients were randomly assigned to the UC group. Among the 33 patients in the HCEC group, two (6.06%) of them ultimately did not receive a HCEC service. Among the 29 patients in the UC group, four (13.79%) of them received a HCEC service. The survival rate at hospital discharge did not differ between the two groups. Patients in the HCEC group showed significant reductions in the entire ICU stay and entire hospital stay. HCEC significantly facilitated achieving the goal of medical care (p < .01). Furthermore, patients in the HCEC group had a shorter ICU stay and shorter hospital stay after the occurrence of medical uncertainty or conflict regarding value-laden issues than those in the UC group. Conclusions Our findings demonstrated that HCEC were associated with reduced consumption of medical resources as indicated by shorter entire ICU stay, entire hospital stay, and shorter ICU and hospital stay after the occurrence of the medical uncertainty or conflict regarding value-laden issues. This study also showed that HCEC facilitated achieving a consensus regarding the goal of medical care, which conforms to the goal of HCEC. [ABSTRACT FROM AUTHOR]

Abstract: Using a difference-in-differences framework, we estimate the impact of Ramadan on educational outcomes of Muslim students living in a non-Muslim country. For identification we exploit that the number of Ramadan weeks during the course that we study, varies from year to year, ranging from zero to four. Our main finding is that Ramadan observance has a negative impact on performance; one additional Ramadan week lowers the final grade of Muslim students by almost 10% of a standard deviation. [Copyright &y& Elsevier]