Improvement of the comprehension of written information given to healthy volunteers in biomedical research: a single-blind randomized controlled study.

Writing an informed consent form (ICF) for biomedical research is a difficult task. We conducted a multicenter single-blind randomized controlled trial to identify whether a working group or the systematic improvement in lexico-syntactic readability or an association of the two could increase the comprehension of the written information given to healthy volunteers enrolled in biomedical research. Participants were randomized to read one of four versions of the ICF: unchanged ICF (A), ICF with systematic lexico-syntactic readability improvement (B), ICF modified by a working group (C), and ICF modified by the working group followed by systematic lexico-syntactic improvement (D). The primary end-point was the objective comprehension score at day 0 for each study group. The scores of objective comprehension at day 0 were statistically different between the four study groups (anovaP = 0.020). The pairwise analysis showed an improvement in the working group vs. the unchanged group (P = 0.003), and a tendency to improvement in the group who read the ICF modified using lexico-syntactic readability and in the group who read the ICF modified using the two methods (P = 0.020 and 0.027 respectively). We conducted a two-way anova to identify some characteristics of the population which could explain this score. There was a significant interaction between the type of informed consent document (ICD) and the gender. Improving the ICD in phase I biomedical research leads to better comprehension, whether the method used is systematic lexico-syntactic improvement or a review by a working group. The improvement is specifically observed in men compared with women. Conversely, while both methods diverge in their effect on lexico-syntactic readability, their association is not mandatory. We suggest that in all phase I clinical trials, the ICF be improved by either method.

Methodological issues in the assessment of skin microvascular endothelial function in humans.

The study of microvascular function can be performed in humans using laser Doppler flowmetry of the skin. This technology lends itself to a wide range of applications for studying the endothelial function of skin blood vessels. We review the advantages and limitations of postocclusive hyperemia, local thermal hyperemia, acetylcholine iontophoresis, flowmotion and association with microdialysis as tools with which to investigate skin microvascular endothelial function in humans. Postocclusive hyperemia, thermal hyperemia and acetylcholine iontophoresis provide integrated indexes of microvascular function rather than specific endothelial markers. However, they are valuable tools and can be used as surrogate endpoints in clinical trials in which the assessment of microvascular function in humans is required.

Postocclusive reactive hyperemia inversely correlates with urinary 15-F2t-isoprostane levels in systemic sclerosis.

Microvascular dysfunction and increased oxidative stress are major hallmarks of the systemic sclerosis disease process. The primary objective of this study was to test whether there is a link between peak postocclusive hyperemia and urinary levels of the F2-isoprostane 15-F2t-IsoP (8-iso-PGF2alpha) in patients suffering from systemic sclerosis. We enrolled 43 patients suffering from systemic sclerosis, 33 patients with primary Raynaud's phenomenon (RP), and 25 healthy volunteers. Microvascular function was assessed using the postocclusive hyperemia monitored by laser Doppler flowmetry. Endothelium-independent response was monitored after 0.4 mg sublingual nitroglycerin. Oxidative stress status was assessed by urinary levels of the F2-isoprostane 15-F2t-IsoP using GC-MS. The peak postocclusive vascular conductance was altered in subjects with systemic sclerosis and primary RP compared to controls (respectively 28 (7-48), 30 (13-48), and 39.9 (13-63) mV/mm Hg, p = 0.01). F2-isoprostanes were increased in the systemic sclerosis group compared to primary Raynaud's phenomenon and healthy controls (respectively 230 (155-387), 182 (101-284), and 207 (109-291) pg/mg, p = 0.006). In patients suffering from systemic sclerosis, there was a significant inverse correlation between F2-isoprostanes and postocclusive hyperemia, expressed as raw data (R = -0.45, p = 0.007) or as an increase over baseline (R = -0.28, p = 0.04). Conversely, no correlation was found with the nitroglycerin response. In conclusion, we provide evidence that there is an inverse correlation between postocclusive hyperemia and urinary F2-isoprostane levels in patients suffering from systemic sclerosis. Whether oxygen free radicals initiate the vascular dysfunction or whether there is an initial trigger that initiates both processes will need to be further clarified in future studies.

French adaptation and preliminary validation of a questionnaire to evaluate understanding of informed consent documents in phase I biomedical research.

The content of informed consent documents (ICD) is a crucial element in the process of providing information to participants in biomedical research. Clear comprehension of the information, i.e. the ability to understand its meaning and its consequences, is of utmost importance. The objective of this study was to describe the different steps in the French adaptation and preliminary validation of the Qualité de Compréhension des Formulaires d'information et de consentement (QCFic) questionnaire (http://www.lyon.inserm.fr/cic-grenoble) based on the American Quality of Informed Consent (QuIC) questionnaire. Adaptation and preliminary validation of the QuIC for use in France was composed of five principal steps: translation, scientific validation, lexical validation, edition of gold-standard answers and a pilot study. Each stage was conducted by independent groups of experts, under the coordination of the study board. Thirteen questions were added and one was suppressed. Two steps were required for the scientific validation and for lexical validation, 21 modifications were proposed. Relative to gold-standard answers, the three experts gave the same answer for 24 questions and for nine other questions, two of the three gave identical answers, which were validated by the study board. Results of a pilot study showed a global QCFic score of 88.99 (84.13-90.92) and no specific commentary was made about the content of the questions, so no more modification needed to be made. A preliminary validated French questionnaire, the QCFic, is now available to evaluate the quality of an informed consent document in phase I clinical trials. It is quick and easy to use.

Local hyperemia to heating is impaired in secondary Raynaud's phenomenon.

Accurate and sensitive measurement techniques are a key issue in the quantification of the microvascular and endothelial dysfunction in systemic sclerosis (SSc). Thermal hyperemia comprises two separate mechanisms: an initial peak that is axon reflex mediated; and a sustained plateau phase that is nitric oxide dependent. The main objective of our study was to test whether thermal hyperemia in patients with SSc differed from that in patients with primary Raynaud's phenomenon (RP) and healthy controls. In a first study, we enrolled 20 patients suffering from SSc, 20 patients with primary RP and 20 healthy volunteers. All subjects were in a fasting state. Post-occlusive hyperemia, 0.4 mg sublingual nitroglycerin challenge and thermal hyperemia were performed using laser Doppler flowmetry on the distal pad of the third left finger. In a second study, thermal hyperemia was performed in 10 patients with rheumatoid arthritis and 10 patients with primary RP. The thermal hyperemia was dramatically altered in terms of amplitude and kinetics in patients with SSc. Whereas 19 healthy volunteers and 18 patients with primary RP exhibited the classic response, including an initial peak within the first 10 minutes followed by a nadir and a second peak, this occurred only in four of the SSc patients (p < 0.0001). The 10 minutes thermal peak was 43.4 (23.2 to 63), 42.6 (31 to 80.7) and 27 (14.7 to 51.4) mV/mm Hg in the healthy volunteers, primary RP and SSc groups, respectively (p = 0.01), while the 44 degrees C thermal peak was 43.1 (21.3 to 62.1), 42.6 (31.6 to 74.3) and 25.4 (15 to 52.4) mV/mm Hg, respectively (p = 0.01). Thermal hyperemia was more sensitive and specific than post-occlusive hyperhemia for differentiating SSc from primary RP. In patients with rheumatoid arthritis, thermal hyperemia was also altered in terms of amplitude. Thermal hyperemia is dramatically altered in patients with secondary RP in comparison with subjects with primary RP. Further studies are required to determine the mechanisms of this altered response, and whether it may provide additional information in a clinical setting.