Strategies for the use of Ginkgo biloba extract, EGb 761® , in the treatment and management of mild cognitive impairment in Asia: Expert consensus.

BACKGROUND: Mild cognitive impairment (MCI) is a neurocognitive state between normal cognitive aging and dementia, with evidence of neuropsychological changes but insufficient functional decline to warrant a diagnosis of dementia. Individuals with MCI are at increased risk for progression to dementia; and an appreciable proportion display neuropsychiatric symptoms (NPS), also a known risk factor for dementia. Cerebrovascular disease (CVD) is thought to be an underdiagnosed contributor to MCI/dementia. The Ginkgo biloba extract, EGb 761® , is increasingly being used for the symptomatic treatment of cognitive disorders with/without CVD, due to its known neuroprotective effects and cerebrovascular benefits. AIMS: To present consensus opinion from the ASian Clinical Expert group on Neurocognitive Disorders (ASCEND) regarding the role of EGb 761® in MCI. MATERIALS & METHODS: The ASCEND Group reconvened in September 2019 to present and critically assess the current evidence on the general management of MCI, including the efficacy and safety of EGb 761® as a treatment option. RESULTS: EGb 761® has demonstrated symptomatic improvement in at least four randomized trials, in terms of cognitive performance, memory, recall and recognition, attention and concentration, anxiety, and NPS. There is also evidence that EGb 761® may help delay progression from MCI to dementia in some individuals. DISCUSSION: EGb 761® is currently recommended in multiple guidelines for the symptomatic treatment of MCI. Due to its beneficial effects on cerebrovascular blood flow, it is reasonable to expect that EGb 761® may benefit MCI patients with underlying CVD. CONCLUSION: As an expert group, we suggest it is clinically appropriate to incorporate EGb 761® as part of the multidomain intervention for MCI.

Benefit-Risk Assessment of Crataegus Extract WS 1442: An Evidence-Based Review.

Preparations from Crataegus (hawthorn) have a long history in the treatment of heart failure. WS 1442 is a dry extract from hawthorn leaves with flowers (4-6.6:1), extraction solvent of ethanol 45% (w/w), adjusted to 17.3-20.1% of oligomeric procyanidins. Nonclinical studies show that WS 1442 has positive inotropic and antiarrhythmic properties and protects the myocardium from ischemic damage, reperfusion injury, and hypertension-related hypertrophy, improves endothelial functions such as NO synthesis, and delays endothelial senescence. Randomized, controlled trials in patients with heart failure have demonstrated that the herbal medicinal product increases functional capacity, alleviates disabling symptoms, and improves health-related quality of life, all of which have become important targets of heart failure therapy according to current disease management guidelines. Clinical trials (including a 2-year mortality study with polypharmacy and > 1300 patients exposed) and post-marketing surveillance studies have shown that WS 1442 has a very favorable safety profile both as monotherapy and as add-on therapy, where no drug interactions have been observed. No specific adverse reactions to WS 1442 are known to date. WS 1442 may thus help to close the therapeutic gap between systolic and diastolic heart failure for which evidence of efficacy for other cardioactive drugs is sparse. Scientific evidence shows that WS 1442 is safe and has a beneficial effect in patients with heart failure corresponding to New York Heart Association classes II or III. The benefit-risk assessment for WS 1442 is therefore positive.

Barriers to the conduct of randomised clinical trials within all disease areas.

BACKGROUND: Randomised clinical trials are key to advancing medical knowledge and to enhancing patient care, but major barriers to their conduct exist. The present paper presents some of these barriers. METHODS: We performed systematic literature searches and internal European Clinical Research Infrastructure Network (ECRIN) communications during face-to-face meetings and telephone conferences from 2013 to 2017 within the context of the ECRIN Integrating Activity (ECRIN-IA) project. RESULTS: The following barriers to randomised clinical trials were identified: inadequate knowledge of clinical research and trial methodology; lack of funding; excessive monitoring; restrictive privacy law and lack of transparency; complex regulatory requirements; and inadequate infrastructures. There is a need for more pragmatic randomised clinical trials conducted with low risks of systematic and random errors, and multinational cooperation is essential. CONCLUSIONS: The present paper presents major barriers to randomised clinical trials. It also underlines the value of using a pan-European-distributed infrastructure to help investigators overcome barriers for multi-country trials in any disease area.

Evolución de la sintomatología autista de los 2 a los 4 años: un estudio de seguimiento / Evolution of autistic symptoms from two to four years: a follow-up study / Evolució de la simptomatologiaautistadels dos als quatre anys: un estudi de seguiment

La detección e intervención temprana en el trastorno del espectro autista (TEA) es de gran relevancia para su pronóstico y su evolución. El principal objetivo de este estudio es analizar y detectar qué síntomas destacan como más significativos y cuáles son los que se mantienen en el tiempo. Se ha realizado un estudio longitudinal de tres años con una muestra clínica de 15 niños, de 24 a 47 meses de edad. Los síntomas han sido evaluados mediante los instrumentos ATA y ADI-R. Los resultados indican que las dimensiones detectadas en la escala ATA manipulación del ambiente, lenguaje y comunicación, hiper e hipoactividad, son las que presentan mayor estabilidad temporal. Las dimensiones restantes presentan menor estabilidad

Early detection and intervention in autism spectrum disorder (ASD) is of great importance for prognosis and evolution. The article aims to highlight the importance of detection and early intervention. Specifically in children with autism spectrum disorders (ASD), difficulty in detection involves a delay in the onset of therapeutic intervention, and therefore affects their prognosis and devolution. The aim of the study to analyze and detect the symptoms that stand out as especially significant and determine which are maintained over time. We performed a three-year longitudinal study with a clinical sample of 15 children, aged from 24 to 47 months. ATA-scales and ADI-R were used to evaluate symptoms. The results indicate that of the dimensions measured on the ATA scale, the manipulation of the environment, difficulties in language and communication and hyper and hypoactivity are those that display the greatest degree of stability over time. The other symptoms show lesser stability

La detecció i interven­ció primerenca en el trastorn de l’espectre autista (TEA) és de gran rellevància pel seu pronòstic i evolució. El principal objectiu d’aquest estudi és analitzar i detectar quins símptomes destaquen com a més significatius i quins són els que es mantenen en el temps. S’ha realitzat un estudi longitudinal de tres anys amb una mostra clínica de 15 nens, de 24 a 47 mesos d’edat. Els símptomes han estat avaluats mitjançant els instruments ATA i ADI-R. Els resultats indiquen que les dimensions detectades a l’escala ATA manipulació de l’ambient, llenguatge i comunicació, hiper i hipoactivitat són les que presenten més estabilitat temporal. La resta de dimensions presenten menys estabilitat

Occipital Nerve Stimulation for Migraine: Update from Recent Multicenter Trials.

Occipital nerve stimulation (ONS) continues to be investigated for the treatment of refractory chronic migraine. Results from case series and from prospective, sham-controlled clinical trials remain inconclusive regarding the efficacy of ONS for migraine treatment. Safety and implantation techniques require improvements since rates of lead migration, infection, and persistent stimulator-related pain continue to be high. Existing data justify further ONS trials with carefully chosen primary outcome(s), adequate statistical power, and improved surgical techniques.

Exploration of scanning effects in multi-site structural MRI studies.

BACKGROUND: Pooling of multi-site MRI data is often necessary when a large cohort is desired. However, different scanning platforms can introduce systematic differences which confound true effects of interest. One may reduce multi-site bias by calibrating pivotal scanning parameters, or include them as covariates to improve the data integrity. NEW METHOD: In the present study we use a source-based morphometry (SBM) model to explore scanning effects in multi-site sMRI studies and develop a data-driven correction. Specifically, independent components are extracted from the data and investigated for associations with scanning parameters to assess the influence. The identified scanning-related components can be eliminated from the original data for correction. RESULTS: A small set of SBM components captured most of the variance associated with the scanning differences. In a dataset of 1460 healthy subjects, pronounced and independent scanning effects were observed in brainstem and thalamus, associated with magnetic field strength-inversion time and RF-receiving coil. A second study with 110 schizophrenia patients and 124 healthy controls demonstrated that scanning effects can be effectively corrected with the SBM approach. COMPARISON WITH EXISTING METHOD(S): Both SBM and GLM correction appeared to effectively eliminate the scanning effects. Meanwhile, the SBM-corrected data yielded a more significant patient versus control group difference and less questionable findings. CONCLUSIONS: It is important to calibrate scanning settings and completely examine individual parameters for the control of confounding effects in multi-site sMRI studies. Both GLM and SBM correction can reduce scanning effects, though SBM's data-driven nature provides additional flexibility and is better able to handle collinear effects.

Intraclass correlation coefficients for cluster randomized trials in care pathways and usual care: hospital treatment for heart failure.

BACKGROUND: Cluster randomized trials are increasingly being used in healthcare evaluation to show the effectiveness of a specific intervention. Care pathways (CPs) are becoming a popular tool to improve the quality of health-care services provided to heart failure patients. In order to perform a well-designed cluster randomized trial to demonstrate the effectiveness of Usual care (UC) and CP in heart failure treatment, the intraclass correlation coefficient (ICC) should be available before conducting a trial to estimate the required sample size. This study reports ICCs for both demographical and outcome variables from cluster randomized trials of heart failure patients in UC and care pathways. METHODS: To calculate the degree of within-cluster dependence, the ICC and associated 95% confidence interval were calculated by a method based on analysis of variance. All analyses were performed in R software version 2.15.1. RESULTS: ICCs for baseline characteristics ranged from 0.025 to 0.058. The median value and interquartile range was 0.043 [0.026-0.052] for ICCs of baseline characteristics. Among baseline characteristics, the highest ICCs were found for admission by referral or admission from home (ICC = 0.058) and the disease severity at admission (ICC = 0.046). Corresponding ICCs for appropriateness of the stay, length of stay and hospitalization cost were 0.069, 0.063, and 0.001 in CP group and 0.203, 0.020, 0.046 for usual care, respectively. CONCLUSION: Reported values of ICCs from present care pathway trial and UC results for some common outcomes will be helpful for estimating sample size in future clustered randomized heart failure trials, in particular for the evaluation of care pathways.

Rationale and design of a randomized controlled trial of the effect of retinol and vitamin D supplementation on treatment in active pulmonary tuberculosis patients with diabetes.

BACKGROUND: The association between pulmonary tuberculosis (PTB) and diabetes mellitus (DM) has been previously attracted much attention. Diabetes alters immunity to tuberculosis, leading to more frequent treatment failure in TB patients with DM. Moreover, TB and DM often coincide with micronutrients deficiencies, such as retinol and vitamin D, which are especially important to immunity of the body and may influence pancreas ß-cell function. However, the effects of retinol and vitamin D supplementation in active TB patients with diabetes on treatment outcomes, immune and nutrition state are still uncertain. We are conducting a randomized controlled trial of vitamin A and/or D in active PTB patients with DM in a network of 4 TB treatment clinics to determine whether the supplementation could improve the outcome in the patients. METHODS/DESIGN: This is a 2×2 factorial trial. We plan to enroll 400 active PTB patients with DM, and randomize them to VA (2000 IU daily retinol); VD (400 IU daily cholecalciferol); VAD (2000 IU daily retinol plus 400 IU cholecalciferol) or control (placebo) group. Our primary outcome measure is the efficacy of anti-tuberculosis treatment and ameliorating of glucose metabolism, and the secondary outcome measure being immune and nutrition status of the subjects. Of the first 37 subjects enrolled: 8 have been randomized to VA, 10 to VD, 9 to VAD and 10 to control. To date, the sample is 97.3% Han Chinese and 91.9% female. The average fasting plasma glucose level is 12.19 mmol/L. DISCUSSION: This paper describes the design and rationale of a randomized clinical trial comparing VA and/or VD supplementation to active pulmonary TB patients with DM. Our trial will allow rigorous evaluation of the efficacy of the supplementation to active TB and DM therapy for improving clinical outcomes and immunological condition. This detailed description of trial methodology can serve as a template for the development of future treatment scheme for active TB patient with DM. TRIAL REGISTRATION: ChiCTR-TRC-12002546.

Longitudinal Pediatric Palliative Care: Quality of Life & Spiritual Struggle (FACE): design and methods.

As life expectancy increases for adolescents ever diagnosed with AIDS due to treatment advances, the optimum timing of advance care planning is unclear. Left unprepared for end-of-life (EOL) decisions, families may encounter miscommunication and disagreements, resulting in families being charged with neglect, court battles and even legislative intervention. Advanced care planning (ACP) is a valuable tool rarely used with adolescents. The Longitudinal Pediatric Palliative Care: Quality of Life & Spiritual Struggle study is a two-arm, randomized controlled trial assessing the effectiveness of a disease specific FAmily CEntered (FACE) advanced care planning intervention model among adolescents diagnosed with AIDS, aimed at relieving psychological, spiritual, and physical suffering, while maximizing quality of life through facilitated conversations about ACP. Participants will include 130 eligible dyads (adolescent and family decision-maker) from four urban cities in the United States, randomized to either the FACE intervention or a Healthy Living Control. Three 60-minute sessions will be conducted at weekly intervals. The dyads will be assessed at baseline as well as 3-, 6-, 12-, and 18-month post-intervention. The primary outcome measures will be in congruence with EOL treatment preferences, decisional conflict, and quality of communication. The mediating and moderating effects of threat appraisal, HAART adherence, and spiritual struggle on the relationships among FACE and quality of life and hospitalization/dialysis use will also be assessed. This study will be the first longitudinal study of an AIDS-specific model of ACP with adolescents. If successful, this intervention could quickly translate into clinical practice.

Towards the Grade of Recommendations, Assessment, Development and Evaluation system: methods and results of budesonide/formoterol maintenance and reliever therapy research.

PURPOSE OF REVIEW: Guidelines for clinical practice are expected to gather evidence-based recommendations to support optimal medical behaviours. The aim of the current review is to explore how currently available research regarding the strategy of using budesonide/formoterol (BUD/FORM) as maintenance and reliever therapy (Symbicort SMART) covers the items considered by the Grade of Recommendations, Assessment, Development and Evaluation (GRADE) system, through a comparative analysis of methodological approaches, clinical outcomes, patient-reported outcomes and costs, in order to highlight uncovered areas. RECENT FINDINGS: Thirteen trials providing data on 21 095 analysed patients were available. No serious limits in methodological study features were found. Evaluation of the clinical outcome was consistent with the efficacy of BUD/FORM maintenance and reliever therapy. As the time to first exacerbation was the primary outcome in most of the studies, conclusive indications cannot be drawn regarding other clinical outcomes or patient-reported outcomes, which were investigated as secondary outcomes. A comprehensive systematic review exploring all critical and important outcomes is desirable, but further research concerning the safety issues of Long Acting ß2 Agonists (LABA) and patients' reported outcomes about the SMART in respect to alternative strategies is likely to affect a clear recommendation in the near future. SUMMARY: The efficacy of BUD/FORM maintenance and reliever therapy in extending the time to first exacerbation appears consistent between studies. Further studies exploring all patients' important outcomes are needed. Clinical and economic assessments are worthy of being investigated to verify the directness of the evidence in respect to real life patients and different geographical realities.

Treatment of chronic migraine headache with onabotulinumtoxinA.

Chronic migraine headache remains an exceedingly difficult entity to manage. Treatment of chronic migraine headache with onabotulinumtoxinA has recently been shown to be effective in reducing the severity and frequency of chronic migraine headache, in the PREEMPT trials, a landmark achievement. However, the studies use a primarily fixed dose and site approach to treatment, allowing some individualized injections. However, the authors do not address the issue of myofascial trigger points as potential triggers of migraine that could be inactivated using onabotulinumtoxinA, despite several studies that support the role of myofascial trigger points in initiating some migraine headaches.

Redesigning a large-scale clinical trial in response to negative external trial results: the CAMUS study of phytotherapy for benign prostatic hyperplasia.

BACKGROUND: Benign prostatic hyperplasia (BPH), a common condition among older men, confers its morbidity through potentially bothersome lower urinary tract symptoms. Treatments for BPH include drugs such as alpha-adrenergic receptor blockers and 5-alpha reductase inhibitors, minimally invasive therapies that use heat to damage or destroy prostate tissue, and surgery including transurethral resection of the prostate. Complementary and alternative medicines are gaining popularity in the US. Two phytotherapies commonly used for BPH are extracts of the fruit of Serenoa repens, the Saw palmetto dwarf palm that grows in the Southeastern US, and extracts of the bark of Pygeum africanum, the African plum tree. PURPOSE: The objective of the Complementary and Alternative Medicines for Urological Symptoms (CAMUS) clinical trial is to determine if phytotherapy is superior to placebo in the treatment of BPH. METHODS: CAMUS was originally designed as a 3300-participant, four-arm trial of S. repens, P. africanum, an alpha-adrenergic blocking drug, and placebo with time to clinical progression of BPH, a measure of long-term efficacy, as the primary endpoint. Before enrollment started, a randomized, double-blind, placebo-controlled, single institution clinical trial showed that S. repens at the usual dose did not demonstrate any benefit over placebo with respect to symptom relief at 1 year. Consequently, the focus of CAMUS shifted from evaluating long-term efficacy to determining if any short-term (6-18 months) symptom relief could be achieved with increasing doses of S. repens, the phytotherapy most commonly used in the US for BPH. RESULTS: Results are anticipated in 2011. CONCLUSIONS: Trial design occurs in an environment of continually evolving information. In this case, emerging results from another trial suggested that a study of long-term efficacy was premature, and that an effective dose and preparation of S. repens had to be established before proceeding to a long-term clinical trial.

Use of pegfilgrastim support on day 9 to maintain relative dose intensity of chemotherapy in breast cancer patients receiving a day 1 and 8 CMF regimen

AIM: In several commonly used regimens, chemotherapy doses are split across different days of the cycle. We aimed to determine the feasibility of growth factor support with once-per-cycle pegfilgrastim in this setting. METHODS: This phase II study in breast cancer patients assessed the utility of a single 6 mg subcutaneous dose of pegfilgrastim administered on day 9 of an intravenous (IV) "split" CMF (cyclophosphamide 600 mg/m(2), methotrexate 40 mg/m(2) and 5-fluorouracil 600 mg/m(2)) chemotherapy regimen administered on days 1 and 8 and repeated every 28 days for 6 cycles. RESULTS: Fifty-eight patients were enrolled, with 49 completing the study. For the primary endpoint, 48 patients (83%) received >or=85% of the relative dose intensity (RDI) of chemotherapy over all 6 cycles (95% confidence interval [CI], 71-91%). Across all chemotherapy cycles, 41 patients (71%) received all scheduled cycles on time and most patients (n=49, 84%) received >or=85% of the planned dose of all chemotherapy agents in all cycles. In total, 295/319 cycles (92%) were delivered on schedule and >or=85% of the planned dose of all chemotherapy agents were administered in 309/319 cycles (97%). Febrile neutropenia was reported in only 2 patients (3%). There were no grade 4 adverse events related to pegfilgrastim. DISCUSSION: Day 9 pegfilgrastim administration was well tolerated and provided effective protection against neutropenia in patients receiving IV CMF on days 1 and 8, allowing chemotherapy to be delivered on time and at the scheduled dose in most patients (AU)

No disponible

Epidemiologic study to assess patient involvement in choice of adjuvant chemotherapy for breast cancer (PROSA Study)

INTRODUCTION: The objective of the current study was to assess patient involvement in adjuvant chemotherapy choice, reasons for treatment choice and satisfaction with the chosen treatment, given that improvement in breast cancer survival has been accompanied by a greater demand for disease information from patients. MATERIAL AND METHODS: An epidemiologic, prospective, multicentre study was conducted with patients aged over 18 diagnosed with breast cancer stages I, II and III. The study, which was conducted prior to these patients initiating adjuvant chemotherapy, was based on a baseline visit and a follow-up visit. Data on sociodemographic and clinical variables were collected and a survey was administered to assess both the reasons for choosing particular treatments and ultimate satisfaction with the chosen treatment. Statistical procedures included a descriptive analysis, bivariate tests and logistic regression. RESULTS: A total of 613 patients were recruited with a mean (SD) age of 53.3 (10.8) years. Most patients had stage II breast cancer (53.9%) and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 (82.8%). Of these patients, 58.3% were treated with taxanes (48.2% docetaxel, doxorubicin and cyclophosphamide) and 41.7% without (43.5% 5-fluorouracil, epirubicin and cyclophosphamide). At the baseline visit and final visit, 73.8% and 72.6% of patients, respectively, were aware of their diagnosis and prognosis. A total of 77.1% patients (64.7% who had followed their physician's advice) were involved in treatment choice and this involvement was directly related to improved ECOG performance status and information. A total of 78.7% of patients were very satisfied or satisfied with their treatment and 5.4% of patients refused to continue treatment (with 39.3% giving toxicity as the reason). CONCLUSIONS: Although a high proportion of patients were involved in choosing their treatment, this involvement was not related to greater treatment satisfaction. Further research in routine clinical settings is needed in order to assess other factors related to choice of adjuvant chemotherapy, treatment satisfaction and long-term effectiveness (3-5 years) (AU)

Preventing AVF thrombosis: the rationale and design of the Omega-3 fatty acids (Fish Oils) and Aspirin in Vascular access OUtcomes in REnal Disease (FAVOURED) study.

BACKGROUND: Haemodialysis (HD) is critically dependent on the availability of adequate access to the systemic circulation, ideally via a native arteriovenous fistula (AVF). The Primary failure rate of an AVF ranges between 20-54%, due to thrombosis or failure of maturation. There remains limited evidence for the use of anti-platelet agents and uncertainty as to choice of agent(s) for the prevention of AVF thrombosis. We present the study protocol for a randomised, double-blind, placebo-controlled, clinical trial examining whether the use of the anti-platelet agents, aspirin and omega-3 fatty acids, either alone or in combination, will effectively reduce the risk of early thrombosis in de novo AVF. METHODS/DESIGN: The study population is adult patients with stage IV or V chronic kidney disease (CKD) currently on HD or where HD is planned to start within 6 months in whom a planned upper or lower arm AVF is to be the primary HD access. Using a factorial-design trial, patients will be randomised to aspirin or matching placebo, and also to omega-3 fatty acids or matching placebo, resulting in four treatment groups (aspirin placebo/omega-3 fatty acid placebo, aspirin/omega-3 fatty acid placebo, aspirin placebo/omega-3 fatty acid, aspirin/omega-3 fatty acid). Randomisation will be achieved using a dynamic balancing method over the two stratification factors of study site and upper versus lower arm AVF. The medication will be commenced pre-operatively and continued for 3 months post surgery. The primary outcome is patency of the AVF at three months after randomisation. Secondary outcome measures will include functional patency at six and twelve months, primary patency time, secondary (assisted) patency time, and adverse events, particularly bleeding. DISCUSSION: This multicentre Australian and New Zealand study has been designed to determine whether the outcome of surgery to create de novo AVF can be improved by the use of aspirin and/or omega-3 fatty acids. Recently a placebo-controlled trial has shown that clopidogrel is effective in safely preventing primary AVF thrombosis, but ineffective at increasing functional patency. Our study presents significant differences in the anti-platelet agents used, the study design, and surgical and patient demographics that should contribute further evidence regarding the efficacy of anti-platelet agents. TRIAL REGISTRATION: Australia & New Zealand Clinical Trials Register (ACTRN12607000569404).

Feasibility of a randomized controlled trial testing nifedipine vs. placebo for the treatment of preterm labor.

AIMS: Nifedipine is believed to be a superior tocolytic agent on the basis of efficacy and side-effect profile, but was never prospectively evaluated in a placebo-controlled randomized clinical trial (RCT). In our study, we sought to identify limitations in participation for a would-be RCT comparing nifedipine to placebo. METHODS: A prospective feasibility study was conducted at Ste-Justine Hospital, a tertiary care center, on women between 24 and 34 weeks' gestation, presenting to the labor and delivery room with obstetrical complaints. Patient information was collected and would-be participants were identified on the basis of pre-established clinical and ultrasound criteria as well as on willingness to participate, as determined by the study research nurse. RESULTS: During a 6-month period, 483 women presenting with signs and symptoms of preterm labor (PTL) were eligible for further evaluation. A total of 321 (66.5%) women were excluded for obstetrical and medical reasons whereas 125 (25.9%) did not meet strict inclusion criteria (cervical length <25 mm or positive fetal fibronectin). When using strict criteria, only 37 women (7.6%) were found to be eligible for study participation. Subject willingness to participate as assessed by the research nurse was 50%. CONCLUSIONS: If adhering to strict inclusion/exclusion criteria, the feasibility of an appropriately sampled RCT testing tocolytic therapy against a placebo would require a large concerted multicenter effort to meet sample size demands.