Use of condition-specific patient-reported outcome measures in clinical trials among patients with wrist osteoarthritis : a systematic review

Background. This paper aimed to identify condition-specific patient-reported outcome measures used in clinical trials among people with wrist osteoarthritis and summarise empirical peer-reviewed evidence supporting their reliability, validity, and responsiveness to change. Methods. A systematic review of randomised controlled trials among people with wrist osteoarthritis was undertaken. Studies reporting reliability, validity, or responsiveness were identified using a systematic reverse citation trail audit procedure. Psychometric properties of the instruments were examined against predefined criteria and summarised. Results. Thirteen clinical trials met inclusion criteria. The most common patient-reported outcome was the disabilities of the arm, shoulder, and hand questionnaire (DASH). The DASH, the Michigan Hand Outcomes Questionnaire (MHQ), the Patient Evaluation Measure (PEM), and the Patient-Reported Wrist Evaluation (PRWE) had evidence supporting their reliability, validity, and responsiveness. A post-hoc review of excluded studies revealed the AUSCAN Osteoarthritis Hand Index as another suitable instrument that had favourable reliability, validity, and responsiveness. Conclusions. The DASH, MHQ, and AUSCAN Osteoarthritis Hand Index instruments were supported by the most favourable empirical evidence for validity, reliability, and responsiveness. The PEM and PRWE also had favourable empirical evidence reported for these elements. Further psychometric testing of these instruments among people with wrist osteoarthritis is warranted.

Single-agent versus combination chemotherapy in patients with advanced non-small cell lung cancer and a performance status of 2 : prognostic factors and treatment selection based on two large randomized clinical trials

Purpose: Data from two randomized phase III trials were analyzed to evaluate prognostic factors and treatment selection in the first-line management of advanced non-small cell lung cancer patients with performance status (PS) 2. Patients and Methods: Patients randomized to combination chemotherapy (carboplatin and paclitaxel) in one trial and single-agent therapy (gemcitabine or vinorelbine) in the second were included in these analyses. Both studies had identical eligibility criteria and were conducted simultaneously. Comparison of efficacy and safety was performed between the two cohorts. A regression analysis identified prognostic factors and subgroups of patients that may benefit from combination or single-agent therapy. Results: Two hundred one patients were treated with combination and 190 with single-agent therapy. Objective responses were 37 and 15%, respectively. Median time to progression was 4.6 months in the combination arm and 3.5 months in the single-agent arm (p < 0.001). Median survival imes were 8.0 and 6.6 months, and 1-year survival rates were 31 and 26%, respectively. Albumin <3.5 g, extrathoracic metastases, lactate dehydrogenase ≥200 IU, and 2 comorbid conditions predicted outcome. Patients with 0-2 risk factors had similar outcomes independent of treatment, whereas patients with 3-4 factors had a nonsignificant improvement in median survival with combination chemotherapy. Conclusion: Our results show that PS2 non-small cell lung cancer patients are a heterogeneous group who have significantly different outcomes. Patients treated with first-line combination chemotherapy had a higher response and longer time to progression, whereas overall survival did not appear significantly different. A prognostic model may be helpful in selecting PS 2 patients for either treatment strategy. © 2009 by the International Association for the Study of Lung Cancer.

Safety and efficacy of the combination of trastuzumab with docetaxel for HER2-positive women with advanced breast cancer : a review of the existing clinical trials and results of the expanded access programme in the UK

Trastuzumab is a humanised monoclonal antibody against the extracellular domain of HER2 (human epidermal growth factor receptor-2) that is overexpressed in about 25% of human breast cancers. It has shown clinical benefit in HER2-positive breast cancer cases when used alone or in combination with chemotherapy. Trastuzumab increases the response rate to chemotherapy and prolongs survival when used in combination with taxanes. In this article, we review the clinical trials where trastuzumab has been administered together with docetaxel, and we present the results of the trastuzumab expanded access programme (EAP) in the UK. Combination of trastuzumab with docetaxel results in similar response rates and time-to-progression with the trastuzumab/paclitaxel combinations. The toxicity of the combination and the risk of heart failure are low. The clinical data for the docetaxel/trastuzumab combination indicate a favourable profile from both the efficacy and the safety point of view and confirm the feasibility and safety of trastuzumab administration both as monotherapy and in combination with docetaxel. © 2004 Blackwell Publishing Ltd.

Exenatide extended-release; clinical trials, patient preference, and economic considerations

Type 2 diabetes remains an escalating world-wide problem, despite a range of treatments. The revelation that insulin secretion is under the control of a gut hormone, glucagon-like peptide 1 (GLP-1) led to a new paradigm in the management of type 2 diabetes, medicines that directly stimulate, or that prolong the actions of the endogenous GLP-1, at its receptors. Exenatide is an agonist at the GLP-1 receptors, and was initially developed as a subcutaneous twice daily medication, ExBID. The clinical trials with ExBID established a role for exenatide in the treatment of type 2 diabetes. Subsequently, once weekly exenatide (ExQW) was shown to have advantages over ExBID, and there is now more emphasis on the development of ExQW. ExQW alone reduces glycosylated haemoglobin (HbA1c) and body weight, and is well tolerated. ExQW has been compared to sitagliptin, pioglitazone and metformin, and shown to have a greater ability to reduce HbA1c than these other medicines. The only preparation of insulin, which ExQW has been compared to, is insulin glargine, and the ExQW has some favourable properties in this comparison, notably causing weight loss, compared to the gain with insulin glargine. ExQW has been compared to another GLP-1 receptor agonist, liraglutide, and ExQW is non-inferior to liraglutide in reducing HbA1c. The small amount of evidence available, shows that subjects with type 2 diabetes, prefer ExQW to ExBID, and that adherence was high to these in the clinical trial setting. Healthcare and economic modelling suggests that ExQW will reduce diabetic complications and be cost-effective, compared to other medications, with long term use. Little is known about whether subjects with type 2 diabetes prefer ExQW to other medicines, and whether adherence is good to ExQW in practice, and these important topics require further study.

Registration of clinical trials: Challenges for global regulation

In 2004 the International Committee of Medical Journal Editors (ICMJE) issued a statement indicating that from 1 July 2005 registration in a publicly accessible trials registry would be a condition of publication in an ICMJE member journal. The World Health Organisation is coordinating the International Clinical Trials Registry Platform (ICTRP) as a means of providing a standardised framework for registration. This article considers the practical challenges and opportunities that arise from these developments and considers the relevance of trial registration for women and minorities and for developing countries.

BRAF inhibitors : from the laboratory to clinical trials

BRAF is one of the most commonly mutated proto-oncogenes and plays a significant role in the development of numerous cancers of high clinical impact. Due to the commonality of BRAF mutations, a number of BRAF inhibitors have been developed as tools in the management of patients with cancers dependent on the action of mutant BRAF to drive cellular proliferation. In this review, we examine the current state of clinical trials and laboratory research concerning BRAF inhibitors in development and available for clinical use. We contrast the effectiveness of type-I and type-II BRAF inhibitors, the former typically showing much more restricted inhibitory selectivity and greater patient response rates.

Clinical trials in pediatrics

“Children are not little adults.” Almost all aspects of children's health including clinical trials and drug development are poor cousins of adult health. Over the years, pediatricians worldwide caution against blind extrapolation of adult data to children as it may result in considerable harm [1,2]. Also, it is increasingly recognized that the roots of many chronic diseases in adulthood stem from childhood and tackling health issues in children lead to improved health in adults [3,4]. Furthermore, investment in early childhood has long-term benefits in adults not only in health but also in other aspects of life such as education and crime reduction [4,5]. Arguably, health at birth is the single most important predictor of health in adulthood as the inequality of an infant at birth has intergenerational effects [5]. The Carolina Abecedarian Project showed that early childhood programs that are of high quality result in substantial societal benefits (e.g., reduction of crime, increased earnings, better education) [4,5]. A recent publication from this project found that this benefit also translated into improved adult health outcomes [4]. In a randomized trial, Campbell and colleagues described that disadvantaged children who were randomized to the intervention group (early education, health screenings and nutrition program) had significantly lower rates of metabolic syndrome, obesity and hypertension, when aged in their mid-30s, compared with the control group [4]...

Standardising and assessing digital images for use in clinical trials : a practical, reproducible method that blinds the assessor to treatment allocation

With the increasing availability of high quality digital cameras that are easily operated by the non-professional photographer, the utility of using digital images to assess endpoints in clinical research of skin lesions has growing acceptance. However, rigorous protocols and description of experiences for digital image collection and assessment are not readily available, particularly for research conducted in remote settings. We describe the development and evaluation of a protocol for digital image collection by the non-professional photographer in a remote setting research trial, together with a novel methodology for assessment of clinical outcomes by an expert panel blinded to treatment allocation.

Comparator clinical trials of surrogate endpoints with albiglutide are in HARMONY

Introduction: Agonists of glucagon-like peptide-1 (GLP-1) receptors are used in the treatment of type 2 diabetes. Albiglutide is a new long acting GLP-1 receptor agonist being developed for once-weekly use. Areas covered: This evaluation is of 2 clinical trials in the HARMONY clinical trials series. HARMONY 3 compares albiglutide to sitagliptin and glimepiride in subjects with type 2 diabetes poorly controlled with metformin, and HARMONY 6 compares albiglutide to insulin lispro in subjects poorly controlled with slow/medium release preparations of insulin. Expert opinion: Both studies showed that albiglutide lowered HbA1c, and had advantages over its comparator drugs. However, questions remain about the safety of albiglutide. Albiglutide is not being used in subjects with a history of thyroid cancer, as it is not known whether this is a rare adverse effect with albiglutide. Also, the safety of albiglutide in subjects with type 2 diabetes and high cardiovascular risk is unknown.