Caroline J Doré

SPIRIT 2013 Statement: defining standard protocol items for clinical trials.

The protocol of a clinical trial serves as the foundation for study planning, conduct, reporting, and appraisal. However, trial protocols and existing protocol guidelines vary greatly in content and quality. This article describes the systematic development and scope of SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) 2013, a guideline for the minimum content of a clinical trial protocol.The 33-item SPIRIT checklist applies to protocols for all clinical trials and focuses on content rather than format. The checklist recommends a full description of what is planned; it does not prescribe how to design or conduct a trial. By providing guidance for key content, the SPIRIT recommendations aim to facilitate the drafting of high-quality protocols. Adherence to SPIRIT would also enhance the transparency and completeness of trial protocols for the benefit of investigators, trial participants, patients, sponsors, funders, research ethics committees or institutional review boards, peer reviewers, journals, trial registries, policymakers, regulators, and other key stakeholders.

Shear-wave Elastography Improves the Specificity of Breast US: The BE1 Multinational Study of 939 Masses

PURPOSE To determine whether adding shear-wave (SW) elastographic features could improve accuracy of ultrasonographic (US) assessment of breast masses. MATERIALS AND METHODS From September 2008 to September 2010, 958 women consented to repeat standard breast US supplemented by quantitative SW elastographic examination in this prospective multicenter institutional review board-approved, HIPAA-compliant protocol. B-mode Breast Imaging Reporting and Data System (BI-RADS) features and assessments were recorded. SW elastographic evaluation (mean, maximum, and minimum elasticity of stiffest portion of mass and surrounding tissue; lesion-to-fat elasticity ratio; ratio of SW elastographic-to-B-mode lesion diameter or area; SW elastographic lesion shape and homogeneity) was performed. Qualitative color SW elastographic stiffness was assessed independently. Nine hundred thirty-nine masses were analyzable; 102 BI-RADS category 2 masses were assumed to be benign; reference standard was available for 837 category 3 or higher lesions. Considering BI-RADS category 4a or higher as test positive for malignancy, effect of SW elastographic features on area under the receiver operating characteristic curve (AUC), sensitivity, and specificity after reclassifying category 3 and 4a masses was determined. RESULTS Median participant age was 50 years; 289 of 939 (30.8%) masses were malignant (median mass size, 12 mm). B-mode BI-RADS AUC was 0.950; eight of 303 (2.6%) BI-RADS category 3 masses, 18 of 193 (9.3%) category 4a lesions, 41 of 97 (42%) category 4b lesions, 42 of 57 (74%) category 4c lesions, and 180 of 187 (96.3%) category 5 lesions were malignant. By using visual color stiffness to selectively upgrade category 3 and lack of stiffness to downgrade category 4a masses, specificity improved from 61.1% (397 of 650) to 78.5% (510 of 650) (P<.001); AUC increased to 0.962 (P=.005). Oval shape on SW elastographic images and quantitative maximum elasticity of 80 kPa (5.2 m/sec) or less improved specificity (69.4% [451 of 650] and 77.4% [503 of 650], P<.001 for both), without significant improvement in sensitivity or AUC. CONCLUSION Adding SW elastographic features to BI-RADS feature analysis improved specificity of breast US mass assessment without loss of sensitivity.

A 6-month randomized trial of thyroxine treatment in women with mild subclinical hypothyroidism

PURPOSE The role of thyroxine replacement in subclinical hypothyroidism remains unclear. We performed a 6-month randomized, double-blind, placebo-controlled trial to evaluate the effects of thyroxine treatment for mild subclinical hypothyroidism, defined as a serum thyroid-stimulating hormone level between 5 to 10 microU/mL with a normal serum free thyroxine level (0.8-16 ng/dL). SUBJECTS AND METHODS We randomly assigned 40 women with mild subclinical hypothyroidism who had presented to their family practitioners to either thyroxine treatment (n = 23; 50 to 100 microg daily) or placebo (n = 17). Health-related quality of life (Hospital Anxiety and Depression scale, 30-item General Health Questionnaire), fasting lipid profiles, body weight, and resting energy expenditure were measured at baseline and 6 months. RESULTS The most common presenting symptoms were fatigue (n = 33 [83%]) and weight gain (n = 32 [80%]). At presentation, 20 women (50%) had elevated anxiety scores and 22 (56%) had elevated scores on the General Health Questionnaire. Thirty-five women completed the study. There were no significant differences in the changes from baseline to 6 months between women in the thyroxine group and the placebo group for any of the metabolic, lipid, or anthropometric variables measured, expressed as the mean change in the thyroxine group minus the mean change in the placebo group: body mass index, -0.3 kg/m(2) (95% confidence interval [CI]: -0.9 to 0.4 kg/m(2)); resting energy expenditure, -0.2 kcal/kg/24 h (95% CI: -1.3 to 1.0 kcal/kg/24 h); and low-density lipoprotein cholesterol, -4 mg/dL (95% CI: -23 to 15 mg/dL). There was a significant worsening in anxiety scores in the thyroxine group (scores increased in 8 of 20 women and were unchanged in 2 of 20) compared with the placebo group (scores increased in 1 of 14 women and were unchanged in 6 of 14; P = 0.03). CONCLUSIONS; We observed no clinically relevant benefits from 6 months of thyroxine treatment in women with mild subclinical hypothyroidism.

The accuracy of platelet counting in thrombocytopenic blood samples distributed by the UK National External Quality Assessment Scheme for General Haematology.

A knowledge of the limitations of automated platelet counting is essential for the effective care of thrombocytopenic patients and management of platelet stocks for transfusion. For this study, 29 external quality assessment specimen pools with platelet counts between 5 and 64 × 10(9)/L were distributed to more than 1,100 users of 23 different hematology analyzer models. The same specimen pools were analyzed by the international reference method (IRM) for platelet counting at 3 reference centers. The IRM values were on average lower than the all-methods median values returned by the automated analyzers. The majority (~67%) of the automated analyzer results overestimated the platelet count compared with the IRM, with significant differences in 16.5% of cases. Performance differed between analyzer models. The observed differences may depend in part on the nature of the survey material and analyzer technology, but the findings have implications for the interpretation of platelet counts at levels of clinical decision making.

Baseline vWF factor predicts the development of elevated pulmonary artery pressure in systemic sclerosis

Objectives. This study aims to examine the utility of von Willebrand factor (vWF) as a biomarker in lcSSc, in particular the ability of vWF to predict the future development of disease manifestations in this disease. Methods. vWFAg concentrations were measured in the serum of patients with lcSSc at baseline and at 3 years, during the QUINs trial [Prevention of Vascular Damage in Scleroderma with Angiotensin-Converting Enzyme (ACE) Inhibition]. %DLCO, %KCO, %FVC, pulmonary artery pressure (PAP) estimation by echocardiography, Raynaud’s attack frequency, Raynaud’s severity, digital ulcer frequency, urinary protein excretion, estimated glomerular filtration rate (eGFR), modified Rodnan skin score and Medsger disease activity score were also measured at baseline and 3 years. Results. Baseline serum vWF concentrations were related to concurrent Medsger disease activity score, %DLCO, %FVC, urinary protein excretion, eGFR and PAP >30 mmHg. In logistic regression models, baseline serum vWF concentrations were able to predict the future development of elevated PAP by echocardiography (PAP >40 mmHg, P = 0.001). Conclusions. Pulmonary artery hypertension is a life-threatening complication of lcSSc. vWF is a marker of endothelial cell activation. Raised serum concentrations of vWF in lcSSc increase the risk of developing subsequent elevation in PAP. Therefore screening patients with lcSSc for vWF may identify a group at risk of developing PAH. These patients could potentially be targeted with agents that stabilize the endothelium, e.g. statins.

Flow dependence and repeatability of interrupter resistance in lower airways and nose

The interrupter technique, the simplest method for measuring airflow resistance (R(int)) is particularly valuable under field conditions. We investigate whether during tidal breathing, variations in the flow at which interruption occurs contribute to variability of results. Using a portable device with mouthpiece, sets of 10 measurements of R(int) (R(int,mo)) were made in inspiration and expiration at 0.05 l s(-1) intervals from 0.1 up to 0.9 l s(-1) flow in 22 normal adults, 11 children (5-9 years) and 12 COPD patients. R(int) was also measured via nasal-mask in normal adults (R(int,na)). Intra-subject coefficient of variation was obtained at each flow and flow-dependence of R(int) was assessed. In normal subjects, R(int)-flow relationships were consistent, with a narrow range of absolute values. R(int,na), but not R(int,mo), rose with increasing flow, especially >0.4 l s(-1). Repeatability was poor at flows <0.3 l s(-1) but improved with increasing flow and was better in inspiration than expiration. In children, repeatability was better than in adults and R(int,mo) was not flow dependent at < or =0.4 l s(-1). By contrast, in COPD patients repeatability was less good and R(int,mo) increased with increasing flows. R(int,mo) and R(int,na) should be measured at fixed inspiratory flows. The best signal-to-noise ratios were obtained at 0.4 l s(-1) for R(int) in normal adults and COPD patients and at 0.3 l s(-1) in children.

Spirit 2013 statement: Defining standard protocol items for clinical trials

The protocol of a clinical trial serves as the foundation for study planning, conduct, reporting, and appraisal. However, trial protocols and existing protocol guidelines vary greatly in content and quality. This article describes the systematic development and scope of SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) 2013, a guideline for the minimum content of a clinical trial protocol. The 33-item SPIRIT checklist applies to protocols for all clinical trials and focuses on content rather than format. The checklist recommends a full description of what is planned; it does not prescribe how to design or conduct a trial. By providing guidance for key content, the SPIRIT recommendations aim to facilitate the drafting of high-quality protocols. Adherence to SPIRIT would also enhance the transparency and completeness of trial protocols for the benefit of investigators, trial participants, patients, sponsors, funders, research ethics committees or institutional review boards, peer reviewers, journals, trial registries, policymakers, regulators, and other key stakeholders.