Current Issue : April - June Volume : 2016 Issue Number : 2 Articles : 6 Articles
Background: Recruitment to clinical trials is often problematic, with many trials failing to recruit to their target\nsample size. As a result, patient care may be based on suboptimal evidence from underpowered trials or\nnon-randomised studies.\nMethods: For many conditions patients will require treatment on several occasions, for example, to treat symptoms\nof an underlying chronic condition (such as migraines, where treatment is required each time a new episode\noccurs), or until they achieve treatment success (such as fertility, where patients undergo treatment on multiple\noccasions until they become pregnant). We describe a re-randomisation design for these scenarios, which allows\neach patient to be independently randomised on multiple occasions. We discuss the circumstances in which this\ndesign can be used.\nResults: The re-randomisation design will give asymptotically unbiased estimates of treatment effect and correct type I\nerror rates under the following conditions: (a) patients are only re-randomised after the follow-up period from their\nprevious randomisation is complete; (b) randomisations for the same patient are performed independently; and (c) the\ntreatment effect is constant across all randomisations. Provided the analysis accounts for correlation between\nobservations from the same patient, this design will typically have higher power than a parallel group trial with\nan equivalent number of observations.\nConclusions: If used appropriately, the re-randomisation design can increase the recruitment rate for clinical\ntrials while still providing an unbiased estimate of treatment effect and correct type I error rates. In many\nsituations, it can increase the power compared to a parallel group design with an equivalent number of\nobservations....
Background: While ethicists have for many years called for human subject trial participants and, in some cases,\nlocal community members to benefit from participation in pharmaceutical and other intervention-based therapies,\nlittle is known about how these discussions are impacting the practice of research ethics boards (REBs) that grant\nethical approval to many of these studies.\nMethods: Telephone interviews were conducted with 23 REB members from across Canada, a major funder country\nfor human subject research internationally. All interviews were digitally recorded and transcribed verbatim. After\ncoding, the data was analyzed to identify central themes and topics. Themes were identified, application of the themes\nwas confirmed, and these themes were then used to populate the findings of this manuscript.\nResults: Our analysis of the interviews identified two primary themes when considering what benefits are owed to\nresearch participants and their communities. 1) Most study participants felt that given that these studies are led by\npersons in the role of researcher rather than health care provider, they had a limited obligation to provide benefits to\nstudy participants. 2) These REB members were all working in Canada, a high income country where most residents\nenjoy high levels of access to health care. As a result of this context, the study participants tended to focus on ethical\nconcerns including obtaining informed consent and avoiding undue inducement to participate in research rather than\nensuring that study participants directly benefit from successful trials.\nConclusions: Research on REB members� attitudes toward what benefits are owed to study participants and\ncommunity members is needed in other countries in order to determine how context affects these attitudes....
OBJECTIVE\nTo assess whether using intensive blood pressure\ntargets leads to lower blood pressure in a community\npopulation of people with prevalent cerebrovascular\ndisease.\nDESIGN\nOpen label randomised controlled trial.\nSETTING\n99 general practices in England, with participants\nrecruited in 2009-11.\nPARTICIPANTS\nPeople with a history of stroke or transient ischaemic\nattack whose systolic blood pressure was 125 mm Hg\nor above.\nINTERVENTIONS\nIntensive systolic blood pressure target (<130 mm Hg\nor 10 mm Hg reduction from baseline if this was <140\nmm Hg) or standard target (<140 mm Hg). Apart from\nthe different target, patients in both arms were actively\nmanaged in the same way with regular reviews by the\nprimary care team.\nMAIN OUTCOME MEASURE\nChange in systolic blood pressure between baseline\nand 12 months.\nRESULTS\n529 patients (mean age 72) were enrolled, 266 to the\nintensive target arm and 263 to the standard target\narm, of whom 379 were included in the primary analysis\n(182 (68%) intensive arm; 197 (75%) standard arm). 84\npatients withdrew from the study during the follow-up\nperiod (52 intensive arm; 32 standard arm). Mean\nsystolic blood pressure dropped by 16.1 mm Hg to 127.4\nmm Hg in the intensive target arm and by 12.8 mm Hg to\n129.4 mm Hg in the standard arm (difference between\ngroups 2.9 (95% confidence interval 0.2 to 5.7) mm Hg;\nP=0.03).\nCONCLUSIONS\nAiming for target below 130 mm Hg rather than 140 mm\nHg for systolic blood pressure in people with\ncerebrovascular disease in primary care led to a small\nadditional reduction in blood pressure. Active\nmanagement of systolic blood pressure in this\npopulation using a <140 mm Hg target led to a\nclinically important reduction in blood pressure.\nTRIAL REGISTRATION\nCurrent Controlled Trials ISRCTN29062286....
Background\nHypertension is a major risk factor for a spectrum of cardiovascular diseases (CVD), including\nmyocardial infarction, sudden death, and stroke. In the US, over 65 million people have\nhigh blood pressure and a large proportion of these individuals are prescribed antihypertensive\nmedications. Although large long-term clinical trials conducted in the last several\ndecades have identified a number of effective antihypertensive treatments that reduce the\nrisk of future clinical complications, responses to therapy and protection from cardiovascular\nevents vary among individuals.\nMethods\nUsing a genome-wide association study among 21,267 participants with pharmaceutically\ntreated hypertension, we explored the hypothesis that genetic variants might influence or modify\nthe effectiveness of common antihypertensive therapies on the risk ofmajor cardiovascular\noutcomes. The classes of drug treatments included angiotensin-converting enzyme inhibitors,\nbeta-blockers, calcium channel blockers, and diuretics. In the setting of the Cohorts for Heart\nand Aging Research in Genomic Epidemiology (CHARGE) consortium, each study performed\narray-based genome-wide genotyping, imputed to HapMap Phase II reference panels, and\nused additive genetic models in proportional hazards or logistic regressionmodels to evaluate\ndrug-gene interactions for each of four therapeutic drug classes. We used meta-analysis to\ncombine study-specific interaction estimates for approximately 2 million single nucleotide polymorphisms\n(SNPs) in a discovery analysis among 15,375 European Ancestry participants\n(3,527 CVD cases) with targeted follow-up in a case-only study of 1,751 European Ancestry\nGenHAT participants as well as among 4,141 African-Americans (1,267 CVD cases).\nResults\nAlthough drug-SNP interactions were biologically plausible, exposures and outcomes were\nwell measured, and power was sufficient to detect modest interactions, we did not identify any statistically significant interactions from the four antihypertensive therapy meta-analyses\n(Pinteraction > 5.0Ã?â??10âË?â??8). Similarly, findings were null for meta-analyses restricted to 66\nSNPs with significant main effects on coronary artery disease or blood pressure from large\npublished genome-wide association studies (Pinteraction 0.01). Our results suggest that\nthere are no major pharmacogenetic influences of common SNPs on the relationship\nbetween blood pressure medications and the risk of incident CVD....
STUDY QUESTION\nWhat is the prevalence of different types of potentially\nhazardous prescribing in general practice in the\nUnited Kingdom, and what is the variation between\npractices?\nMETHODS\nA cross sectional study included all adult patients\npotentially at risk of a prescribing or monitoring error\ndefined by a combination of diagnoses and\nprescriptions in 526 general practices contributing to\nthe Clinical Practice Research Datalink (CPRD) up to 1\nApril 2013. Primary outcomes were the prevalence of\npotentially hazardous prescriptions of anticoagulants,\nanti-platelets, NSAIDs, Ã?² blockers, glitazones,\nmetformin, digoxin, antipsychotics, combined\nhormonal contraceptives, and oestrogens and\nmonitoring by blood test less frequently than\nrecommended for patients with repeated prescriptions\nof angiotensin converting enzyme inhibitors and loop\ndiuretics, amiodarone, methotrexate, lithium, or\nwarfarin.\nSTUDY ANSWER AND LIMITATIONS\n49 927 of 949 552 patients at risk triggered at least one\nprescribing indicator (5.26%, 95% confidence interval\n5.21% to 5.30%) and 21 501 of 182 721 (11.8%, 11.6% to\n11.9%) triggered at least one monitoring indicator. The\nprevalence of different types of potentially hazardous\nprescribing ranged from almost zero to 10.2%, and for\ninadequate monitoring ranged from 10.4% to 41.9%.\nOlder patients and those prescribed multiple repeat\nmedications had significantly higher risks of triggering\na prescribing indicator whereas younger patients with\nfewer repeat prescriptions had significantly higher risk\nof triggering a monitoring indicator. There was high\nvariation between practices for some indicators.\nThough prescribing safety indicators describe\nprescribing patterns that can increase the risk of harm\nto the patient and should generally be avoided, there\nwill always be exceptions where the indicator is\nclinically justified. Furthermore there is the possibility\nthat some information is not captured by CPRD for\nsome practicesââ?¬â?for example, INR results in patients\nreceiving warfarin.\nWHAT THIS STUDY ADDS\nThe high prevalence for certain indicators emphasises\nexisting prescribing risks and the need for their\nappropriate consideration within primary care,\nparticularly for older patients and those taking\nmultiple medications. The high variation between\npractices indicates potential for improvement through\ntargeted practice level intervention.\nFUNDING, COMPETING INTERESTS, DATA SHARING\nNational Institute for Health Research through the\nGreater Manchester Primary Care Patient Safety\nTranslational Research Centre (grant No\nGMPSTRC-2012-1). Data from CPRD cannot be shared\nbecause of licensing restrictions....
Background: Biphasic immediate-release (IR)/extended-release (ER) hydrocodone bitartrate (HB)/acetaminophen\n(APAP) 7.5/325-mg tablets are formulated with gastroretentive ER drug delivery technology that has been\nassociated with clinically meaningful food effects in other approved products. Two phase 1 studies evaluated\npotential effects of food on single-dose pharmacokinetics of IR/ER HB/APAP tablets.\nMethods: These were single-center, open-label, randomized, single-dose, 3-period crossover studies in healthy\nvolunteers (aged 18ââ?¬â??55 years). IR/ER HB/APAP was administered as a single 2-tablet dose (study 1) or 3-tablet dose\n(study 2) under fed (high- and low-fat) and fasted conditions. Area under the plasma concentration-time curve\nfrom 0 h to time t (AUC0ââ?¬â??t) and from time 0 extrapolated to infinity (AUC0ââ?¬â??inf) and maximum observed plasma\nconcentration (Cmax) of hydrocodone and APAP under fed versus fasted conditions were compared using analysis\nof variance. A 90 % confidence interval of the geometric least squares mean ratio fully contained within 80 to\n125 % indicated no treatment difference. Safety and tolerability were assessed.\nResults: Forty of 48 participants in study 1 and 21 of 30 in study 2 completed all treatments. In both studies, under\nfed (high- or low-fat meal) versus fasted conditions, 90 % CIs for AUC0ââ?¬â??t and AUC0ââ?¬â??inf for both hydrocodone and\nAPAP were entirely contained within the bioequivalent range (80ââ?¬â??125 %), indicating that high- and low-fat meals\ndid not affect the extent of exposure. In both studies, a high-fat meal did not affect the Cmax for hydrocodone.\nHydrocodone Cmax was not affected by a low-fat meal in study 1 but increased by approximately 19 % in study 2.\nA high-fat meal decreased APAP Cmax by approximately 20 % (study 1) and 13 % (study 2); a low-fat meal\ndecreased APAP Cmax by 22 % (study 1) and 21 % (study 2). Approximately 50 % of participants in both studies\nreported ââ?°Â¥1 treatment-emergent adverse event (TEAE), with no notable difference based on food intake. There\nwere no serious or severe AEs. The most common TEAEs were nausea, vomiting, and dizziness.\n(Continued on next page) (Continued from previous page)\nConclusions: Pharmacokinetic and safety findings were similar regardless of food intake. TEAEs were consistent\nwith those reported with low-dose combination opioids. IR/ER HB/APAP can be administered without regard\nto food....
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