Assessment of digital perfusion as a surrogate outcome in Raynaud's phenomenon clinical trials.

OBJECTIVES: Measurement of digital perfusion, sometimes coupled with a cold challenge, has been widely used as an objective outcome in trials evaluating drug therapies in Raynaud's Phenomenon (RP), in addition to patient-reported outcomes or to establish the proof-of-concept in preliminary studies. However, whether digital perfusion is a valid surrogate for clinical outcomes in RP trials has never been explored. The principal aim of this study was to evaluate the potential surrogacy of digital perfusion, by combining individual-level and trial-level data. METHODS: We used individual data from a series of n-of-1 trials, and trial data from a network meta-analysis. We estimated individual-level surrogacy through coefficients of determination between digital perfusion and clinical outcomes (R2ind). We further calculated the coefficients of determination between treatment effect on the clinical outcomes and on digital perfusion, at the individual level (R2TEInd) and at the trial level (R2trial), using non-weighted linear regression, with their 95% CI calculated through bootstrapping. RESULTS: Results from 33 patients and 24 trials were included in the final analysis. At the individual level, there was no correlation between digital perfusion and clinical outcomes at rest and in response to various cooling tests (the highest R2ind was 0.03 [-0.07; 0.09]), and R2TEinf was also very low 0.07 [0; 0.29]. At the trial level, the highest value of R2trial was 0.1 [0; 0.477]. CONCLUSIONS: Digital perfusion, at rest or in response to a cold challenge, and whatever the method used, does not fulfill the criteria of a valid surrogate for existing patient-reported outcomes in RP trials.

Continuous assessment of volunteers' satisfaction in clinical research through simplified questionnaires.

OBJECTIVES: In our clinical research center, a 27 multiple-choice and 3 verbatim questions satisfaction questionnaire has been used since 2008 in order to assess the satisfaction of the volunteers participating in our studies. In this work, we aimed at reducing the number of questions of this cumbersome questionnaire while exploring the same dimensions. MATERIALS AND METHODS: We used k-mean and hierarchical clustering to determine which questions provided the same information or, on the contrary, which questions were able to discriminate a satisfied volunteer from an unsatisfied volunteer. RESULTS: We were able to reduce our satisfaction questionnaire from 30 questions to 6 closed-ended and 2 open-ended questions, which will allow to save volunteers time while increasing their participation rate. CONCLUSION: This questionnaire could be used in other structures practicing clinical research, as part of their quality process.

Lower urinary tract dysfunction in chronic Chagas disease: clinical and urodynamic presentation.

PURPOSE: To describe and give an estimation of the prevalence of urinary disorders in chronic Chagas disease, since most clinical research has been centered on the description of the cardiac and digestive forms. METHODS: To explore this topic, a cross-sectional study was conducted in 137 Bolivian adults of both sexes suffering from symptomatic chronic Chagas disease. All patients presenting confirmed chagasic cardiomyopathy, megacolon or both underwent a urologic symptom questionnaire, uroflowmetry, urinary tract ultrasonography and a creatinine assay. When urinary abnormality was detected, a complete urodynamic study was proposed including cystometry, pressure-flow studies and urethral pressure profile. RESULTS: Out of all study patients, 35 (26%) had a Chagas cardiomyopathy, 81 (59%) a megacolon, and 21 (15%) a megacolon associated with cardiomyopathy. In all, 63% presented urinary disorders defined by IPSS > 7 and/or ICIQ SF > 1. Among them, 62% were incontinent, mainly by bladder overactivity, and 45% presented grade 2 or 3 renal insufficiency. Of 49 patients, the urodynamic study identified 34 patients with detrusor overactivity (69%), mostly in those with Chagas megacolon. Median bladder functional capacity, urethral closure pressure and bladder compliance had normal values. Moreover, 36% of these patients presented moderate hypocontractility, without significant post-void residual. CONCLUSIONS: This study evidenced lower urinary tract dysfunction in a majority of chronic chagasic patients; those presenting megacolon were more likely to suffer from urinary incontinence. These results strongly suggest including routine urological clinical investigation in chronic Chagas patients, as urinary incontinence due to overactive bladder is frequently observed in this population.

On-Demand Sildenafil as a Treatment for Raynaud Phenomenon: A Series of n-of-1 Trials.

Background: Treatment of Raynaud phenomenon (RP) with phosphodiesterase-5 inhibitors has shown moderate efficacy. Adverse effects decrease the risk-benefit profile of these drugs, and patients may not be willing to receive long-term treatment. On-demand single doses before or during exposure to cold may be a good alternative. Objective: To assess the efficacy and safety of on-demand sildenafil in RP. Design: Series of randomized, double-blind, n-of-1 trials. (ClinicalTrials.gov: NCT02050360). Setting: Outpatients at a French university hospital. Participants: Patients with primary or secondary RP. Intervention: Each trial consisted of a multiple crossover study in a single patient. Repeated blocks of 3 periods of on-demand treatment were evaluated: 1 week of placebo, 1 week of sildenafil at 40 mg per dose, and 1 week of sildenafil at 80 mg per dose, with a maximum of 2 doses daily. Measurements: Raynaud Condition Score (RCS) and frequency and daily duration of attacks. Skin blood flow in response to cooling also was assessed with laser speckle contrast imaging. Mixed-effects models were used and parameters were estimated in a Bayesian framework to determine individual and aggregated efficacy. Results: 38 patients completed 2 to 5 treatment blocks. On the basis of aggregated data, the probability that sildenafil at 40 mg or 80 mg was more effective than placebo was greater than 90% for all outcomes (except for RCS with sildenafil, 80 mg). However, the aggregated effect size was not clinically relevant. Yet, substantial heterogeneity in sildenafil's efficacy was observed among participants, with clinically relevant efficacy in some patients. Limitation: The response to sildenafil was substantially heterogeneous among patients. Conclusion: Despite a high probability that sildenafil is superior to placebo, substantial heterogeneity was observed in patient response and aggregated results did not show that on-demand sildenafil has clinically relevant efficacy. In this context, the use of n-of-1 trials may be an original and relevant approach in RP. Primary Funding Source: GIRCI (Groupement Interrégional de Recherche Clinique et d'Innovation) Auvergne Rhône-Alpes (academic funding) and Pfizer.

Transrectal ultrasound-guided prostate biopsies vs. magnetic resonance imaging ultrasound fusion targeted biopsies: Who are the best candidates?

INTRODUCTION: The aim of this study was to compare the results of ultrasound-guided prostate biopsies (US-PB) and magnetic resonance imaging-ultrasound fusion biopsies (MRI-PB) in two contemporary cohorts and to describe the parameters orienting the choice of technique. METHODS: Two contemporary cohorts of patients undergoing US-PB or MR-PB using the Urostation® (Koelis, Grenoble, France) between November 2010 and July 2015 were analyzed retrospectively. Patients with metastatic cancer or recurrence after treatment, saturation biopsies, and US-PB performed after a negative MRI were excluded. Comparison of populations, biopsy results, and clinical and biological parameters guiding the choice of technique were studied on multivariate analysis (logistic regression) taking into account the following confounding factors: age, prostate-specific antigen (PSA) rate, prostatic volume, number of previous biopsies, and abnormal digital rectal examination. RESULTS: One hundred fourteen patients were included in the US-PB group and 118 in the MR-PB group. Prostate cancer was diagnosed among 65 patients in the US-PB group (detection rate 57.0%) and 70 patients in the MR-PB group (detection rate 59.3%) (odds ratio [OR] 3.00; 95% confidence interval [CI] 1.52-6.17; p=0.002). Among the cancers diagnosed in the MR-PB group, 21 were diagnosed by the two targeted biopsy cores only (15.5%). Patients undergoing MR-PB were significantly younger (p=0.0005), with a higher number of previous biopsy sessions (p<10-7) and larger prostate volume (p=0.001). PSA rate alone (p=0.23) and digital rectal examination (p=0.48) did not significantly interfere with the choice of a technique. CONCLUSIONS: Younger patients with larger prostates and prior negative biopsy were more likely to be offered the MR-PB technique. On multivariate analysis, the detection rate was higher in the MR-PB group.