Current Issue : October - December Volume : 2015 Issue Number : 4 Articles : 7 Articles
Background: The intention-to-treat principle states that all randomised participants should be analysed in their randomised\ngroup. The implications of this principle are widely discussed in relation to the analysis, but have received limited\nattention in the context of handling errors that occur during the randomisation process. The aims of this article are to\n(1) demonstrate the potential pitfalls of attempting to correct randomisation errors and (2) provide guidance on handling\ncommon randomisation errors when they are discovered that maintains the goals of the intention-to-treat principle.\nMethods: The potential pitfalls of attempting to correct randomisation errors are demonstrated and guidance on\nhandling common errors is provided, using examples from our own experiences.\nResults: We illustrate the problems that can occur when attempts are made to correct randomisation errors and\nargue that documenting, rather than correcting these errors, is most consistent with the intention-to-treat principle.\nWhen a participant is randomised using incorrect baseline information, we recommend accepting the randomisation but\nrecording the correct baseline data. If ineligible participants are inadvertently randomised, we advocate keeping them in\nthe trial and collecting all relevant data but seeking clinical input to determine their appropriate course of management,\nunless they can be excluded in an objective and unbiased manner. When multiple randomisations are performed in error\nfor the same participant, we suggest retaining the initial randomisation and either disregarding the second randomisation\nif only one set of data will be obtained for the participant, or retaining the second randomisation otherwise. When participants\nare issued the incorrect treatment at the time of randomisation, we propose documenting the treatment\nreceived and seeking clinical input regarding the ongoing treatment of the participant.\nConclusion: Randomisation errors are almost inevitable and should be reported in trial publications. The intention to-\ntreat principle is useful for guiding responses to randomisation errors when they are discovered....
Background: Premature discontinuation and other forms of noncompliance with treatment assignment can complicate\ncausal inference of treatment effects in randomized trials. The intent-to-treat analysis gives unbiased estimates for causal\neffects of treatment assignment on outcome, but may understate potential benefit or harm of actual treatment. The corresponding\nupper confidence limit can also be underestimated.\nPurpose: To compare estimates of the hazard ratio and upper bound of the two-sided 95% confidence interval from\ncausal inference methods that account for noncompliance with those from the intent-to-treat analysis.\nMethods: We used simulations with parameters chosen to reflect cardiovascular safety trials of diabetes drugs, with a\nfocus on upper bound estimates relative to 1.3, based on regulatory guidelines. A total of 1000 simulations were run\nunder each parameter combination for a hypothetical trial of 10,000 total subjects randomly assigned to active treatment\nor control at 1:1 ratio. Noncompliance was considered in the form of treatment discontinuation and cross-over at specified\nproportions, with an assumed true hazard ratio of 0.9, 1, and 1.3, respectively. Various levels of risk associated with\nbeing a non-complier (independent of treatment status) were evaluated. Hazard ratio and upper bound estimates from\ncausal survival analysis and intent-to-treat were obtained from each simulation and summarized under each parameter\nsetting.\nResults: Causal analysis estimated the true hazard ratio with little bias in almost all settings examined. Intent-to-treat\nwas unbiased only when the true hazard ratio = 1; otherwise it underestimated both benefit and harm. When upper\nbound estimates from intent-to-treat were 1.3, corresponding estimates from causal analysis were also 1.3 in almost\n100% of the simulations, regardless of the true hazard ratio. When upper bound estimates from intent-to-treat were\n\\1.3 and the true hazard ratio = 1, corresponding upper bound estimates from causal analysis were 1.3 in up to 66%\nof the simulations under some settings.\nLimitations: Simulations cannot cover all scenarios for noncompliance in real randomized trials.\nConclusion: Causal survival analysis was superior to intent-to-treat in estimating the true hazard ratio with respect to\nbias in the presence of noncompliance. However, its large variance should be considered for safety upper bound exclusion\nespecially when the true hazard ratio = 1. Our simulations provided a broad reference for practical considerations\nof biasââ?¬â??variance trade-off in dealing with noncompliance in cardiovascular safety trials of diabetes drugs. Further\nresearch is warranted for the development and application of causal inference methods in the evaluation of safety upper\nbounds....
Pills prepared from Withania coagulans (Paneerdodi Ghanavati) were administered to 94 patients with Type 2 Diabetes for Nine months. It was observed that Withania coagulans significantly reduced fasting blood sugar of diabetic patients. The fruits of Withania coagulans have been traditionally used for the treatment of Type 2 Diabetes and this was confirmed in our clinical set up also....
Purpose Ixazomib is an investigational proteasome\ninhibitor with demonstrated antitumor activity in xenograft\nmodels of multiple myeloma (MM), lymphoma, and\nsolid tumors. This open-label, phase 1 study investigated intravenous\n(IV) ixazomib, in adult patients with advanced nonhematologic\nmalignancies. Methods Patients received IV\nixazomib twice-weekly for up to twelve 21-day cycles. The\n0.125 mg/m2 starting dose was doubled (one patient/dose)\nuntil 1.0 mg/m2 based on dose-limiting toxicities (DLTs) in\ncycle 1. This was followed by 3+3 dose-escalation and expansion\nat the maximum tolerated dose (MTD). Primary objectives\nincluded safety and MTD assessment. Secondary objectives\nincluded assessment of pharmacokinetics, pharmacodynamics,\nand disease response. Results Ixazomib was escalated\nfrom 0.125 to 2.34 mg/m2 to determine the MTD (n=\n23); patients were then enrolled to MTD expansion (n=73)\nand pharmacodynamic (n=20) cohorts. Five patients experienced\nDLTs (1.0 and 1.76 mg/m2: grade 3 pruritic rash;\n2.34 mg/m2: grade 3 and 4 thrombocytopenia, and grade 3\nacute renal failure); thus, the MTD was 1.76 mg/m2. Drugrelated\ngrade ?3 adverse events (AEs) included thrombocytopenia\n(23 %), skin and subcutaneous (SC) tissue disorders\n(16 %), and fatigue (9 %). Among 92 evaluable patients,\none (head and neck cancer) had a partial response and\n30 had stable disease. Ixazomib terminal half-life was\n3.8ââ?¬â??7.2 days; plasma exposures increased dose proportionally\nand drug was distributed to tumors. Inhibition\nof whole-blood 20S proteasome activity and upregulation\nof ATF-3 in tumor biopsies demonstrated target\nengagement. Conclusions In patients with solid tumors,\nixazomib was associated with a manageable safety\nprofile, limited antitumor activity, and evidence of\ndownstream proteasome inhibition effects....
Background: Transrectal ultrasound-guided prostate biopsies are prone to detection errors. Multiparametric\nMRI (MP-MRI) may improve the diagnostic pathway.\nMethods: PROMIS is a prospective validating paired-cohort study that meets criteria for level 1\nevidence in diagnostic test evaluation. PROMIS will investigate whether multi-parametric (MP)-\nMRI can discriminate between men with and without clinically-significant prostate cancer who\nare at risk prior to first biopsy. Up to 714men will have MP-MRI (index), 10ââ?¬â??12 core TRUS-biopsy\n(standard) and 5 mm transperineal template mapping (TPM) biopsies (reference). The conduct\nand reporting of each test will be blinded to the others.\nResults: PROMIS will measure and compare sensitivity, specificity, and positive and negative\npredictive values of bothMP-MRI and TRUS-biopsy against TPMbiopsies. The MP-MRI resultswill\nbe used to determine the proportion ofmenwho could safely avoid biopsywithout compromising\ndetection of clinically-significant cancers. For the primary outcome, significant cancer on TPM is\ndefined as Gleason grade N/= 4 + 3 and/or maximum cancer core length of ?6 mm. PROMIS\nwill also assess inter-observer variability among radiologists among other secondary outcomes.\nCost-effectiveness of MP-MRI prior to biopsy will also be evaluated.\nConclusions: PROMIS will determine whether MP-MRI of the prostate prior to first biopsy\nimproves the detection accuracy of clinically-significant cancer....
Introduction: Cotrimoxazole (CTX) prophylaxis is recommended by theWorld Health Organisation for HIV infected\npersons. However, once HIV infected patients have commenced ART in resource limited settings, the benefits\nof continued CTX prophylaxis are not known. The few studies that investigated the safety of discontinuing CTX\nprophylaxis in these settings had limitations due to their design.\nMaterials and methods: COSTOP is a randomised double blind placebo controlled non-inferiority trial among HIV\ninfected Ugandan adults stabilised on anti-retroviral treatment (ART). Participants with CD4 count of 250 or\nmore cells/mm3 are randomised to two arms: the intervention arm in which CTX is discontinued and the control\narminwhich CTX prophylaxis is continued. The study aims to assesswhether the intervention regimen is not inferior,\nwith respect to the incidence of pre-defined CTX-preventable events, to the control regimen and superior\nwith respect to the incidence of haematological adverse events.\nDiscussion: Studies that have previously evaluated the safety of discontinuing CTX prophylaxis among HIV infected\nadults in resource limited settings have provided moderate to low quality evidence owing in part to methodological\nlimitations. COSTOP is designed and conducted with sufficient rigour to answer this question. The results\nof the trial will assist in guiding policy recommendations...
This retrospective study is intended to provide vital information on the risk factors for diabetes so that one can take prophylactic measures to prevent diabetes. Diabetes check up camps was conducted and 1001 participants were interviewed. Anthropometrical measurements like height, weight, waist, hips were taken and on that basis Body Mass Index (BMI) as well as Ratio of Waist-to-Hips (WHR) were calculated. It was found that average BMI of diabetics was 31 (indicating to be obese) while that of non-diabetics was 24. Both diabetic males and females had WHR > 0.94 (indicating to be having Apple-shaped fat distribution) and non-diabetic males and females have < 0.79 (indicating to be having Pear-shaped fat distribution). While comparing the occupational and spare time physical activities it was found that diabetics were having very less physical activities. On the other hand non-diabetics were involved with regular exercises including yoga and had tendency to perform regular physical work. Diabetics were found to have more mental stress, prevalence of constipation (70%) and 30-40% of them are taking tobacco in different forms. All the cardinal symptoms of diabetes like higher fasting blood sugar ( > 140 mg/dl), polyuria ( > 7 micturation/day and > 3-4 micturation /night), polydipsia as well as polyphagia are significantly more among diabetics as compared to non-diabetics. Even systolic and diastolic blood pressures were also found to be comparatively higher than the normal values among diabetics. The target of healthy life include BMI < 25, WHR < 0.7, regular exercise including Yoga, less mental stress, less constipation and avoiding smoking....
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