Overrunning in clinical trials: some thoughts from a methodological review.

BACKGROUND: In sequential and adaptive trials, the delay that happens after the trial is stopped, by a predetermined stopping criterion, takes the name of overrunning. Overrunning consists of extra data, collected by investigators while awaiting results of the interim analysis (IA). The inclusion of such extra data in the analyses is scientifically appropriate and follows regulatory advice. Nevertheless, its effect from a broader perspective is unclear. METHODS: This article aims at clarifying the overall impact of including such overrunning data, providing first a revision, and then a comparison of the several approaches proposed in the literature for treating such data. A simulation study is performed based on two real-life examples. RESULTS: The paper shows that overrunning inclusion could seriously change the decision of an early conclusion of the study. It also shows that some of the methods proposed in the literature to include overrunning data are more conservative than others. CONCLUSION: The choice of a more or a less conservative method could be considered more appropriate depending on the endpoint type or the design type.

Association of Pharmacological Treatments With Long-term Pain Control in Patients With Knee Osteoarthritis: A Systematic Review and Meta-analysis.

Importance: Even though osteoarthritis is a chronic and progressive disease, pharmacological agents are mainly studied over short-term periods, resulting in unclear recommendations for long-term disease management. Objective: To search, review, and analyze long-term (≥12 months) outcomes (symptoms, joint structure) from randomized clinical trials (RCTs) of medications for knee osteoarthritis. Data Sources and Study Selection: The databases of MEDLINE, Scopus, EMBASE, Web of Science, and the Cochrane Central Register of Controlled Trials were searched until June 30, 2018 (MEDLINE alerts through August 31, 2018) for RCTs of patients with knee osteoarthritis that had treatment and follow-up lasting 1 year or longer. Data Extraction and Synthesis: Data at baseline and at the longest available treatment and follow-up of 12 months' duration or longer (or the change from baseline) were extracted. A Bayesian random-effects network meta-analysis was performed. Main Outcomes and Measures: The primary outcome was the mean change from baseline in knee pain. Secondary outcomes were physical function and joint structure (the latter was measured radiologically as joint space narrowing). Standardized mean differences (SMDs) and mean differences with 95% credibility intervals (95% CrIs) were calculated. Findings were interpreted as associations when the 95% CrIs excluded the null value. Results: Forty-seven RCTs (22 037 patients; mean age range, mostly 55-70 years; and a higher mean proportion of women than men, around 70%) included the following medication categories: analgesics; antioxidants; bone-acting agents such as bisphosphonates and strontium ranelate; nonsteroidal anti-inflammatory drugs; intra-articular injection medications such as hyaluronic acid and corticosteroids; symptomatic slow-acting drugs in osteoarthritis such as glucosamine and chondroitin sulfate; and putative disease-modifying agents such as cindunistat and sprifermin. Thirty-one interventions were studied for pain, 13 for physical function, and 16 for joint structure. Trial duration ranged from 1 to 4 years. Associations with decreases in pain were found for the nonsteroidal anti-inflammatory drug celecoxib (SMD, -0.18 [95% CrI, -0.35 to -0.01]) and the symptomatic slow-acting drug in osteoarthritis glucosamine sulfate (SMD, -0.29 [95% CrI, -0.49 to -0.09]), but there was large uncertainty for all estimates vs placebo. The association with pain improvement remained significant only for glucosamine sulfate when data were analyzed using the mean difference on a scale from 0 to 100 and when trials at high risk of bias were excluded. Associations with improvement in joint space narrowing were found for glucosamine sulfate (SMD, -0.42 [95% CrI, -0.65 to -0.19]), chondroitin sulfate (SMD, -0.20 [95% CrI, -0.31 to -0.07]), and strontium ranelate (SMD, -0.20 [95% CrI, -0.36 to -0.05]). Conclusions and Relevance: In this systematic review and network meta-analysis of studies of patients with knee osteoarthritis and at least 12 months of follow-up, there was uncertainty around the estimates of effect size for change in pain for all comparisons with placebo. Larger RCTs are needed to resolve the uncertainty around efficacy of medications for knee osteoarthritis.

Silibinin hemisuccinate binding to proteins in plasma and blood cell/plasma partitioning in mouse, rat, dog and man in vitro.

BACKGROUND: The determination of plasma protein binding and blood cell/plasma partitioning is important when prescribing silibinin hemisuccinate to patients concomitantly receiving other drugs and to estimate the safety margins of exposure at the no observed adverse events levels determined from toxicity studies conducted in rats and dogs. METHODS: Protein binding of [3'-14C]silibinin hemisuccinate (1, 10, 100, 1000 and 4000 µM) was evaluated in human, dog, rat and mouse plasma by ultrafiltration. Blood cell/plasma partitioning in all these species was also determined. RESULTS: Silibinin hemisuccinate is highly bound to plasma proteins with percentage binding ranging from 94.3% to 97.8%. Its association with blood cells was negligible (<7%) in all species. The degree of protein binding was concentration independent up to the pharmacologically effective concentration of 100 µM. The blood cell/plasma partitioning indicates that distribution into blood cells is not an important feature for the disposition of silibinin hemisuccinate. CONCLUSIONS: No corrections for fraction unbound are needed when comparing human and preclinical pharmacokinetic and pharmacodynamic data at pharmacological doses, and it is appropriate to analyze plasma as opposed to whole blood for the determination of silibinin hemisuccinate concentrations.

ISYDE-2008. Study presentation. The Italian survey on cardiac rehabilitation: a snapshot of current cardiac rehabilitation programmes and providers in Italy.

The Italian Society of Cardiac Rehabilitation and Prevention (GICR) has developed the ISYDE-2008 survey with the purpose to take a detailed snapshot in terms of number, distribution, facilities, staffing levels, organization, and programme details of CR units in Italy and to compare actual provision with the recommendation of National GL for CR and secondary prevention. The study will be carried out with a web-based questionnaire running on the GICR website in 2 weeks from Jan. 28 to Feb. 10, 2008. The first part of the questionnaire is designed to collect information on the institutional organization of the CR unit, on its location and functional relationships within the hospital, on the number of beds for inpatient CR units and hours of activity for outpatient and home-based services, on the composition of the core and multidisciplinary teams, and finally on the components of CR programmes. In the second part of the survey, CR directors will be requested to report for each patient discharged during the 2 weeks of the study, indications for admission to CR, time of enrolment, comorbidity, complications, risk profile, diagnostic procedures, exercise and educational programme, discharge modalities, treatment at discharge and follow-up schedule. More than 2300 pts are expected to enter in the survey, whose results depicting the status of CR in Italy will be available within April 2008.

[ISYDE-Psi first step of the implementation of guidelines for psychology activities in cardiac rehabilitation and prevention. Italian SurveY on CarDiac REhabilitation-Psychology]. / ISYDE-Psi prima fase dell'implementazione delle linee guida per le attività di psicologia in cardiologia riabilitativa e preventiva. Italian SurveY on CarDiac REhabilitation-Psychology.

The Italian SurveY on CarDiac REhabilitation-Psychology (ISYDE-Psi) was developed, in line with the indications of the Italian National Guidelines Program, as part of a project to implement and apply the guidelines for psychology interventions in cardiac rehabilitation and prevention published in 2003. The Task Force on Psychological Interventions in Cardiac Rehabilitation conducted this pilot survey of the existing situation of Psychology in order to prepare the ground for implementation of the guidelines through interactive training. As part of the evaluation of training requirements a questionnaire was elaborated to gather information on the models of organization of and activities carried out by psychologists working in the surveyed cardiac rehabilitation facilities. Data collection for ISYDE-Psi terminated at the end of March 2005, with replies from 68/107 (63.6%) structures. In the light of this response, the Task Force has developed a training project for psychologists working in cardiac rehabilitation, sponsored by the Italian Council of Psychologists, that will be implemented in different regions of the country with the aim of disseminating the guidelines and promoting their correct application despite the existing regional disparities in organization.

[Nursing role in cardiac prevention]. / Il ruolo nursing nella prevenzione cardiovascolare.

The lack of a multidisciplinary approach is certainly among the causes of the ineffectiveness of intervention in the field of cardiovascular secondary prevention. By multidisciplinary approach is meant involving cardiologists, nurses, rehabilitation therapists, dieticians as well as psychologists in the framing of interventions tailor made to patients needs. In particular, people working in the nursing area can play a very important role which can be summed up into three different levels: a technical level, aiming at the cooperation with cardiologists to carry out diagnostic examinations and give a portrait of patients in terms of risks; a second level consists in giving information, and helping to face the disease, as well as stepping in during its evolution, almost a health counsellor for the patients; finally the nurse can act as a psychological support both to the patient and his/her family during acute illnesses and reassure him/her that he/she is being treated properly and that successively will resume a good quality of life. Hospital represent an ideal place for secondary prevention, at least in the first phases of the intervention. The results collected during hospitalization would be rapidly lost if they were not followed and sustained in the medium-long term by structured follow-up programmes. The development of ambulatories might represent a link between hospitals and the territory, i.e. the specialist and one's personal physician. The staff of ambulatories should comprise a cardiologist and a trained professional nurse, this being specialized, specifically, in cardiology and cardiovascular prevention. Staff of the type described could work independently, co-ordinating ambulatories on the territory within the framework of standardized recognized protocols and relating information concerning patients, general practitioners and other surgeries. In this way, an essential link of the continuity in medical care would be guaranteed.

[The ISYDE project. A survey on Cardiac Rehabilitation in Italy]. / Il progetto ISYDE (Italian Survey on Cardiac Rehabilitation). Lo stato della Cardiologia Riabilitativa in Italia.

In 2001-2002 the Italian Working Group on Cardiac Rehabilitation (CR) developed the ISYDE project, a survey on CR in Italy. In 2001, the CR units were 144 (57% in the North of the country), 58% in general hospitals, 23% in private hospitals, 8% in rehabilitative hospital, and only 2% in university clinics. Patients admitted to CR were 60,819 (vs 37.049 in 1996, +64%); 86% of CR units treated > 100 pts/year (vs 66% in 1996; +32%). Patients were admitted to CR units after cardiosurgery in 55% of cases, after myocardial infarction in 22%, and for chronic heart failure in 9.6%, without significant differences respect to 1996. A special survey investigated the work-up performed in patients with recent myocardial infarction. The admission ranges from 11th to 20th day, the mean duration of the CR programs ranges from 21 to 34 days. Most of italian CR units have a definite program for risk stratification and secondary prevention. In particular, the programs of exercise training, educational interventions concerning diet, lifestyle, and smoking cessation, and psychological intervention are well designed, developed, and evaluated before discharge in most cases. In conclusion, although in recent years the number of CR units are increasing, and the quality of care may be well-established by serial evaluations scheduled before discharge and during the long-term follow-up, a further development is mandatory to face the needs of cardiac patients in the post-acute and chronic phase of a cardiac disease.