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data safety monitoring board [keywords]
- Sildenafil does not improve cardiomyopathy in Duchenne/Becker muscular dystrophy. [JOURNAL ARTICLE]
- Ann Neurol 2014 Jul 4.
Objective: Duchenne and Becker muscular dystrophy (DBMD) are allelic disorders caused by mutations in dystrophin. Adults with DBMD develop life-threatening cardiomyopathy. Inhibition of phosphodiesterase 5 (PDE5) improves cardiac function in mouse models of DBMD. To determine if the PDE5-inhibitor sildenafil benefits human dystrophinopathy, we conducted a randomized, double-blind, placebo-controlled trial (ClinicalTrials.gov, number NCT01168908). Methods: Adults with DBMD and cardiomyopathy (ejection fraction ≤50%) were randomized to receive sildenafil (20mg three times daily) or placebo for 6 months. All subjects received an additional 6 months of open-label sildenafil. The primary endpoint was change in left ventricular end-systolic volume (LVESV) on cardiac MRI. Secondary cardiac endpoints, skeletal muscle function, and quality of life were also assessed. Results: An interim analysis (performed after 15 subjects completed the blinded phase) revealed that 29% (4/14) of subjects had a ≥10% increase in LVESV after 6 months of sildenafil compared to 13% (1/8) of subjects receiving placebo. Subjects with LVESV >120ml at baseline were more likely to worsen at 12 months regardless of treatment assignment (p=0.035). Due to the higher number of subjects worsening on sildenafil, the Data and Safety Monitoring Board recommended early termination of the study. There were no statistically significant differences in outcome measures between treatment arms. Interpretation: Due to the small sample size, comparisons between groups must be interpreted with caution. However, this trial suggests that sildenafil is unlikely to improve cardiac function in adults with DBMD. ANN NEUROL 2014. © 2014 American Neurological Association.
- Blood pressure and LDL-cholesterol targets for prevention of recurrent strokes and cognitive decline in the hypertensive patient: design of the European Society of Hypertension-Chinese Hypertension League Stroke in Hypertension Optimal Treatment randomized trial. [JOURNAL ARTICLE]
- J Hypertens 2014 Jun 27.
The SBP values to be achieved by antihypertensive therapy in order to maximize reduction of cardiovascular outcomes are unknown; neither is it clear whether in patients with a previous cardiovascular event, the optimal values are lower than in the low-to-moderate risk hypertensive patients, or a more cautious blood pressure (BP) reduction should be obtained. Because of the uncertainty whether 'the lower the better' or the 'J-curve' hypothesis is correct, the European Society of Hypertension and the Chinese Hypertension League have promoted a randomized trial comparing antihypertensive treatment strategies aiming at three different SBP targets in hypertensive patients with a recent stroke or transient ischaemic attack. As the optimal level of low-density lipoprotein cholesterol (LDL-C) level is also unknown in these patients, LDL-C-lowering has been included in the design.The European Society of Hypertension-Chinese Hypertension League Stroke in Hypertension Optimal Treatment trial is a prospective multinational, randomized trial with a 3 × 2 factorial design comparing: three different SBP targets (1, <145-135; 2, <135-125; 3, <125 mmHg); two different LDL-C targets (target A, 2.8-1.8; target B, <1.8 mmol/l). The trial is to be conducted on 7500 patients aged at least 65 years (2500 in Europe, 5000 in China) with hypertension and a stroke or transient ischaemic attack 1-6 months before randomization. Antihypertensive and statin treatments will be initiated or modified using suitable registered agents chosen by the investigators, in order to maintain patients within the randomized SBP and LDL-C windows. All patients will be followed up every 3 months for BP and every 6 months for LDL-C. Ambulatory BP will be measured yearly.Primary outcome is time to stroke (fatal and non-fatal). Important secondary outcomes are: time to first major cardiovascular event; cognitive decline (Montreal Cognitive Assessment) and dementia. All major outcomes will be adjudicated by committees blind to randomized allocation. A Data and Safety Monitoring Board has open access to data and can recommend trial interruption for safety.It has been calculated that 925 patients would reach the primary outcome after a mean 4-year follow-up, and this should provide at least 80% power to detect a 25% stroke difference between SBP targets and a 20% difference between LDL-C targets.
- Analysis of warning letters issued by the US Food and Drug Administration to clinical investigators, institutional review boards and sponsors: a retrospective study. [JOURNAL ARTICLE]
- J Med Ethics 2014 Jun 25.
The US Food and Drug Administration (FDA) issues warning letters to all research stakeholders if unacceptable deficiencies are found during site visits. Warning letters issued by the FDA between January 2011 and December 2012 to clinical investigators and institutional review boards (IRBs) were reviewed for various violation themes and compared to similar studies in the past. Warning letters issued to sponsors between January 2005 and December 2012 were analysed for the first time for a specific set of violations using descriptive statistics. Failure to protect subject safety and to report adverse events to IRBs was found to be significant compared to prior studies for clinical investigators, while failure to follow standard operating procedures and maintain documentation was noted as significant in warning letters to IRBs. Failure to maintain minutes of meeting and to follow written procedures for continuing review were new substantial violations in warning letters issued to IRBs. Forty-six warning letters were issued to sponsors, the most common violations being failure to follow a monitoring schedule (58.69%), failure to obtain investigator agreement (34.78%), failure to secure investigators' compliance (30.43%), and failure to maintain data records and ship documents to investigators (30.43%). Appropriate methods for handling clinical trial procedural violations should be developed and implemented worldwide.
- FluMum: a prospective cohort study of mother-infant pairs assessing the effectiveness of maternal influenza vaccination in prevention of influenza in early infancy. [Journal Article]
- BMJ Open 2014; 4(6):e005676.
Influenza vaccination in pregnancy is recommended for all women in Australia, particularly those who will be in their second or third trimester during the influenza season. However, there has been no systematic monitoring of influenza vaccine uptake among pregnant women in Australia. Evidence is emerging of benefit to the infant with respect to preventing influenza infection in the first 6 months of life. The FluMum study aims to systematically monitor influenza vaccine uptake during pregnancy in Australia and determine the effectiveness of maternal vaccination in preventing laboratory-confirmed influenza in their offspring up to 6 months of age.A prospective cohort study of 10 106 mother-infant pairs recruited between 38 weeks gestation and 55 days postdelivery in six Australian capital cities. Detailed maternal and infant information is collected at enrolment, including influenza illness and vaccination history with a follow-up data collection time point at infant age 6 months. The primary outcome is laboratory-confirmed influenza in the infant. Case ascertainment occurs through searches of Australian notifiable diseases data sets once the infant turns 6 months of age (with parental consent). The primary analysis involves calculating vaccine effectiveness against laboratory-confirmed influenza by comparing the incidence of influenza in infants of vaccinated mothers to the incidence in infants of unvaccinated mothers. Secondary analyses include annual and pooled estimates of the proportion of mothers vaccinated during pregnancy, the effectiveness of maternal vaccination in preventing hospitalisation for acute respiratory illness and modelling to assess the determinants of vaccination.The study was approved by all institutional Human Research Ethics Committees responsible for participating sites. Study findings will be published in peer review journals and presented at national and international conferences.The study is registered with the Australia and New Zealand Clinical Trials Registry (ANZCTR) number: 12612000175875.
- Ethical pitfalls in neonatal comparative effectiveness trials. [Journal Article]
- Neonatology 2014; 105(4):350-1.
Evidence-based medicine has been embraced wholeheartedly, and rightly so, as the best approach for reducing clinical uncertainty and ensuring that patients receive treatment and care that are efficacious (i.e. they work) and effective (i.e. they work in real life). High-quality evidence comes from high-quality clinical research. It would hence be reasonable to assume that these two would form a closely integrated partnership. Alas, this is not yet the case. So many uncertainties in medical care relate to treatments and practices already widely in use. In neonatal medicine, for example, some of us use protein-carbohydrate fortification of human milk and some of us do not, some of us stop enteral feeds during blood transfusions whereas some of us do not, some of us reach for dopamine when blood pressure falls while some of us use dobutamine. For our patients, these uncertainties represent a lottery, the throw of the dice that determines whether they receive the treatment advocated by Dr. A or Dr. B. They deserve better than this. Randomization is considered the gold standard approach to eliminating the clinician bias that very often dominates the choice of treatments. Randomization reduces the influence on outcomes of confounding by unknown factors, and ensures that every patient has a fair and equal chance of receiving the best possible treatment when this is, in fact, not known. In an ideal world, every medical uncertainty would be addressed in this way. The evaluation of treatments that are in accepted use has been termed 'comparative effectiveness research', i.e. the comparison of existing healthcare interventions to determine which works best, for whom and under which circumstances. Recently a long-standing uncertainty, the optimum saturation target for preterm babies receiving oxygen was put to the test of randomization. The accepted standard-of-care saturation range of 85-95% has been used for a considerable time and its use is intended to avoid both levels of oxygen that are too low or too high. Investigators in the UK, Australia, New Zealand and the USA designed randomized controlled trials to provide more precise guidance, by determining whether targeting the lower end of the accepted range (85-89%) resulted in reduced retinopathy of prematurity when compared with the upper end of the accepted range (91-95%). Between 2004 and 2009, the US SUPPORT trial (Surfactant, Positive Pressure and Oxygenation Randomized Trial) recruited approximately 1,300 infants and showed that babies at the higher end of the recommended oxygen saturation range had a greater incidence of retinopathy of prematurity, but that, unexpectedly, babies at the lower end had a higher risk of death . The data monitoring committees of the BOOST II (Oxygen Saturation and Outcomes in Preterm Infants) trials in the UK, Australia and New Zealand reviewed their interim data, confirmed the higher risk of death in babies randomized to the lower saturation range, and halted further recruitment . Without the trials, the lower saturation target would have continued to be applied to many babies, and many would have died as a result. Though many uncertainties remain, the trials facilitated advances in care. However, in March 2013, the lead investigators for the SUPPORT trial were informed by the US 'Office for Human Research Protections' that they were 'in violation of the regulatory requirements for informed consent, stemming from the failure to describe the reasonably foreseeable risks of blindness, neurological damage and death' . This extraordinary conclusion indicates that the US regulators considered the researchers to be at fault for failing to foresee an unexpected trial result, and for randomizing babies to receive oxygen within the accepted standard-of-care limits. The ruling further implies that the regulators consider that clinicians are acting ethically when they deliver an accepted but non-evidence-based treatment based upon their personal bias, but are acting unethically when they make the selection by randomization. Clearly, there is a gulf between the view of the medical profession and that of the regulators regarding the ethical and scientific validity of randomization as a means to select treatments in comparative effectiveness research aimed at reducing uncertainties in care. What are the ways forward? I suggest that, in order for medicine to advance, a paradigm shift is necessary, involving a deeper public (and regulator) understanding of randomization as the fairest approach to allocating treatments that are in wide and accepted use, but where the evidence base is actually uncertain, so that the chance of receiving the as yet unknown best treatment is unaffected by clinician bias, and where care is delivered along a clearly designed, closely monitored pathway. In practice, peer review, regulatory approval, patient involvement and the delivery of explanation and information would be the same as for research involving experimental treatments. The key difference would be that randomization would be the recommended default and patients would be offered the opportunity to opt out, rather than be invited to opt in. For neonatal medicine, this would reduce the risk of 'injurious misconception', where trial entry is inappropriately rejected by parents because of an exaggerated and disproportionate perception of risk  that is brought on or magnified by the burden of making decisions at this difficult and stressful time. Randomization to treatments that fall within accepted practice and are considered standard-of-care involves no research-related risks to participants, and as trial data can increasingly be extracted from electronic clinical records , the costs and burden of data collection placed upon clinical teams will be minimized and, ultimately, the resolution of uncertainties about treatment can be hastened. It should also be noted that this approach fulfils the four cardinal principles of research ethics, namely: autonomy, justice, beneficence and nonmaleficence as well as upholding the responsibility of all doctors to strive to reduce uncertainty in the care they provide to their patients . © 2014 S. Karger AG, Basel.
- Enhancing Trial Integrity by Protecting the Independence of Data Monitoring Committees in Clinical Trials. [JOURNAL ARTICLE]
- J Biopharm Stat 2014 Jun 13.
Abstract Background: Data Monitoring Committees (DMCs) have important roles in safeguarding patient interests and enhancing trial integrity and credibility. To effectively fulfill their responsibilities, DMCs should be independent of study sponsors, study investigators and caregivers managing study participants. Unfortunately, in real world settings where DMCs are in place, there are some practices that threaten to diminish the level of independence of these committees. Purpose: Our goal is to inform those who have responsibilities in implementing the DMC process, or who are relying upon or participating as members, about some evolving issues that can meaningfully impact the DMC's ability to remain sufficiently independent to be able to effectively address its mission. Methods: We identified specific issues that are likely to be very important, both now and in the near future, with regard to the actual level of independence of DMCs. We provide insights into how these issues have emerged and to their importance, and provide recommendations for approaches to effectively address them. Results: Among the recommendations: a DMC Charter should outline the roles and responsibilities of the DMC without appearing to be a legal contract; the meetings of the DMC should be led by its chair, ideally with a meeting format that ensures independence from the investigators and sponsor; the DMC and those having leadership roles in the monitoring process should have adequate training and experience; procedures should be in place to enable the DMC to have access to interim safety and efficacy data that are accurate, current and comprehensive; these data should be presented to the DMC unblinded by treatment group, while being kept confidential from all others; DMC recommendations should be developed through consensus development rather than by casting votes; creative approaches are needed for the engagement of DMC members to increase the transparency that they are neither employees of, nor consultants to, the sponsor of the trial; meaningful conflicts of interest should be identified and addressed; finally, members of DMCs should have adequate indemnification that provides effective protection. Conclusions: The independence of DMCs is of integral importance to their ability to effectively carry out their responsibilities. We need wider recognition of the influence of some practices that could diminish the independence of DMCs, and a commitment to identify and implement approaches to enhance their independence.
- The role of perioperative sodium bicarbonate infusion affecting renal function after cardiothoracic surgery. [Journal Article]
- Front Pharmacol 2014.:127.
Cardiac surgery associated acute kidney injury (CSA-AKI) is associated with poor outcomes including increased mortality, length of hospital stay (LOS) and cost. The incidence of acute kidney injury (AKI) is reported to be between 3 and 30% depending on the definition of AKI. We designed a multicenter randomized controlled trial to test our hypothesis that a perioperative infusion of sodium bicarbonate (SB) during cardiac surgery will attenuate the post-operative rise in creatinine indicating renal injury when compared to a perioperative infusion with normal saline. An interim analysis was performed after data was available on the first 120 participants. A similar number of patients in the two treatment groups developed AKI, defined as an increase in serum creatinine the first 48 h after surgery of 0.3 mg/dl or more. Specifically 14 patients (24%) who received sodium chloride (SC) and 17 patients (27%) who received SB were observed to develop AKI post-surgery, resulting in a relative risk of AKI of 1.1 (95% CI: 0.6-2.1, chi-square p-value = 0.68) for patients receiving SB compared to those who received SC. The data safety monitoring board for the trial recommended closing the study early as there was only a 12% probability that the null hypothesis would be rejected. We therefore concluded that a perioperative infusion of SB failed to attenuate the risk of CSA-AKI.
- R-CHOP with or without bevacizumab in patients with previously untreated diffuse large B-cell lymphoma: final MAIN study outcomes. [JOURNAL ARTICLE]
- Haematologica 2014 Jun 3.
Vascular endothelial growth factor is involved in lymphoma growth, suggesting a potential role for anti vascular endothelial growth factor therapies in hematological malignancies. In this phase III study, patients with CD20-positive diffuse large B-cell lymphoma were randomized to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone plus either placebo (R-CHOP) or bevacizumab (RA-CHOP). Treatment was administered every 21 (8 cycles) or 14 days (6 cycles plus 2 rituximab cycles) per institutional practice. An early analysis of risk/benefit by the Data and Safety Monitoring Board showed that RA-CHOP increased cardiotoxicity without prolonging progression-free survival compared with R-CHOP, and the trial was stopped early. The study protocol was amended to allow for 12 additional months of follow-up to evaluate safety. With 787 patients enrolled, median follow up was 23.7 and 23.6 months for R-CHOP and RA-CHOP, respectively. Median progression-free survival for R-CHOP and RA CHOP was 42.9 and 40.2 months, respectively (hazard ratio=1.09; P=0.49). The proportion of deaths was identical for R-CHOP (21%, 83/387) and RA-CHOP (21%, 82/390). Relative to R-CHOP, RA-CHOP had a higher rate of left ventricular ejection fraction perturbation (18% versus 8%; odds ratio=2.51; 95% confidence interval: 1.60-3.93) and congestive heart failure (16% versus 7%; odds ratio=2.79; 95% confidence interval: 1.72-4.54). Bevacizumab added to R-CHOP increased cardiac events, without increasing efficacy, arguing against further evaluation of RA-CHOP in patients with diffuse large B-cell lymphoma. The MAIN study is registered at clinicaltrials.gov, NCT00486759.
- Tolvaptan in hospitalized cancer patients with hyponatremia: A double-blind, randomized, placebo-controlled clinical trial on efficacy and safety. [Journal Article]
- Cancer 2014 Mar 1; 120(5):744-51.
The rate of hyponatremia is higher in hospitalized cancer patients than in hospitalized patients without cancer and is associated with poor clinical outcomes. The availability of V2 receptor antagonists has been a major breakthrough in the management of hyponatremia, but its efficacy and safety in treating hyponatremia in patients with cancer is not known.Adult patients with cancer who were admitted to The University of Texas MD Anderson Cancer Center with nonhypovolemic hyponatremia (125-130 mmol/L) were randomized to receive either tolvaptan or placebo in a double-blind, placebo-controlled, adaptive, randomized trial. Both groups received the standard of care for hyponatremia, except that patients were allowed to drink to thirst.A preplanned Data Safety Monitoring Board analysis of 30 of 48 randomized patients who completed the study revealed that the primary endpoint of hyponatremia correction was met by 16 of 17 patients who received tolvaptan and by 1 of 13 patients who received placebo (94% vs 8%; P < .001), which met the study stopping rule for superiority. The secondary endpoints between the tolvaptan and placebo groups (mean ± standard deviation) for length of stay (21 ± 15 days vs 26 ± 15 days, respectively) and change in the Mini-Mental State Examination score (-0.35 ± 1.66 vs 0.31 ± 2.42, respectively) were not significantly different. No overcorrection of serum sodium (>12 mmol/L per day) was noted in the tolvaptan group, and the main adverse events noted were dry mouth, polydipsia, and polyuria, leading to 13% study withdrawal.Although tolvaptan was effective for correcting hyponatremia in patients with cancer, studies with a larger sample size will be required to confirm the current findings, including the outcomes of secondary endpoints. Cancer 2014;120:744-751. © 2013 American Cancer Society.
- [A research roadmap for complementary and alternative medicine - what we need to know by 2020]. [Journal Article]
- Forsch Komplementmed 2014; 21(2):e1-e16.