Bioavailability of dissolved and crushed single tablets of bictegravir, emtricitabine, tenofovir alafenamide in healthy adults: the SOLUBIC randomized crossover study.

BACKGROUND: Crushing or dissolving bictegravir/tenofovir alafenamide/emtricitabine (BIC/TAF/FTC) tablets is not recommended because there are no data supporting this practice. METHODS: A crossover, randomized trial in healthy adults (NCT04244448) investigated the bioavailability of two off-label uses of BIC/TAF/FTC (50/200/25 mg), dissolved in water or crushed in apple compote, compared with the solid tablet. Pharmacokinetic (PK) parameters were estimated from sequential intensive plasma antiretroviral concentrations over a 72 h period post dose. Bioequivalence was met if the 90% CIs of the geometric least-squares means ratios comparing BIC/TAF/FTC exposures (AUC and Cmax) from the experimental phases were within 80%-125% of the reference. RESULTS: Eighteen subjects participated in each of the three phases. Dissolved tablet Cmax geometric mean ratio (90% CI) for BIC/TAF/FTC was 105% (93-119)/97% (87-108)/96% (74-124), respectively. Dissolved tablet AUC geometric mean ratio (90% CI) for BIC/TAF/FTC was 111% (100-122)/100% (94 to 105)/99% (81 to 120), respectively. Crushed tablet Cmax geometric mean ratio (90%) CI for BIC/TAF/FTC was 110% (97 to 124)/70% (63-78)/66% (51-85), respectively. Crushed tablet AUC geometric mean ratio (90%) CI for BIC/TAF/FTC was 107% (96-118)/86% (82-91)/84% (69-103), respectively. CONCLUSIONS: Crushing BIC/TAF/FTC tablets may lead to suboptimal emtricitabine and tenofovir alafenamide drug exposures. Dissolving BIC/TAF/FTC in water may be acceptable if the tablet cannot be swallowed whole.

Gripwise Versus Jamar: The Challenge of a New Dynamometer Assessing Handgrip Strength.

BACKGROUND: Sarcopenia diagnosis is partly based on handgrip strength (HGS) assessment. The gold-standard dynamometer for this measurement is the Jamar. The electronic Gripwise is a smaller and lighter one, and its measurements are correlated with the Jamar's in laboratory tests. Our study aimed to confirm this correlation in aged patients. METHODS: This monocenter cross-sectional study was performed in patients of 65 years and older admitted at the University Hospital. Participants were assessed either in a seated or bedridden position, randomly allocated to begin the measurements with the Jamar or the Gripwise. RESULTS: Among 649 aged inpatients assessed for eligibility, 348 were included (mean age: 79 ±â€…9; 52% females). The intraclass correlation coefficient was 0.93 (95% confidence interval [CI] 0.92-0.94, p < .001) for the maximum value measured with both devices and 0.94 (95% CI 0.93-0.95, p < .001) for the mean values. However, there was a significant difference in detecting low values (<16 kg in women, <27 kg in men), found in 48% of patients with Jamar, and 71% with Gripwise (p < .001). Thus, we determined alternate cutoffs for diagnosing HGS low values with the Gripwise (<12 kg in women, <22 kg in men), further validated in a supplementary validation population (n = 70). The diagnostic performances of these alternative cutoffs were high (93% sensitivity and 87% specificity in women; 94% sensitivity and 96% specificity in men). CONCLUSIONS: The correlation of the Gripwise with the Jamar was confirmed in aged inpatients. However, lower values recorded with the Gripwise require alternate cutoffs for a relevant low HGS diagnosis.

Ability of procalcitonin to distinguish between bacterial and nonbacterial infection in severe acute exacerbation of chronic obstructive pulmonary syndrome in the ICU.

BACKGROUND: To assess the ability of procalcitonin (PCT) to distinguish between bacterial and nonbacterial causes of patients with severe acute exacerbation of COPD (AECOPD) admitted to the ICU, we conducted a retrospective analysis of two prospective studies including 375 patients with severe AECOPD with suspected lower respiratory tract infections. PCT levels were sequentially assessed at the time of inclusion, 6 h after and at day 1, using a sensitive immunoassay. The patients were classified according to the presence of a documented bacterial infection (including bacterial and viral coinfection) (BAC + group), or the absence of a documented bacterial infection (i.e., a documented viral infection alone or absence of a documented pathogen) (BAC- group). The accuracy of PCT levels in predicting bacterial infection (BAC + group) vs no bacterial infection (BAC- group) at different time points was evaluated by receiver operating characteristic (ROC) analysis. RESULTS: Regarding the entire cohort (n = 375), at any time, the PCT levels significantly differed between groups (Kruskal-Wallis test, p < 0.001). A pairwise comparison showed that PCT levels were significantly higher in patients with bacterial infection (n = 94) than in patients without documented pathogens (n = 218) (p < 0.001). No significant difference was observed between patients with bacterial and viral infection (n = 63). For example, the median PCT-H0 levels were 0.64 ng/ml [0.22-0.87] in the bacterial group vs 0.24 ng/ml [0.15-0.37] in the viral group and 0.16 ng/mL [0.11-0.22] in the group without documented pathogens. With a c-index of 0.64 (95% CI; 0.58-0.71) at H0, 0.64 [95% CI 0.57-0.70] at H6 and 0.63 (95% CI; 0.56-0.69) at H24, PCT had a low accuracy for predicting bacterial infection (BAC + group). CONCLUSION: Despite higher PCT levels in severe AECOPD caused by bacterial infection, PCT had a poor accuracy to distinguish between bacterial and nonbacterial infection. Procalcitonin might not be sufficient as a standalone marker for initiating antibiotic treatment in this setting.

[Medication errors reporting in drug clinical trials: Role of the clinical research pharmacist?] / Déclaration des erreurs médicamenteuses dans les recherches portant sur le médicament : place du pharmacien des essais cliniques ?

The investigational drugs circuit has specific risks, and medication errors may occur in clinical trials, possibly associated with adverse reactions. These risks must therefore be managed. In fact, there are few reports of medication errors during clinical trials. In a context of regulatory interpretation difficulties on this subject, we conducted a national survey that highlighted the heterogeneity of the methods used by academic sponsors to collect, code and report medication errors and the need to develop a culture of reporting these errors in clinical trials. This is why the REVISE group (safety officers of French institutional sponsors) has issued recommendations to clarify the sponsor and investigator responsibilities and guide them in the management of medication errors. These new guidelines recommend that any serious or potentially serious medication error or other "special situation" (e.g. overdose, misuse, quality defect) should be notified immediately to the sponsor by the investigator. The clinical research pharmacist place is strategic to detect medication errors and other special situations. The integration of the pharmacist into the reporting system, in collaboration with the investigator, could be discussed with clinical research professionals and health authorities.

Procalcitonin algorithm to guide initial antibiotic therapy in acute exacerbations of COPD admitted to the ICU: a randomized multicenter study.

PURPOSE: To compare the efficacy of an antibiotic protocol guided by serum procalcitonin (PCT) with that of standard antibiotic therapy in severe acute exacerbations of COPD (AECOPDs) admitted to the intensive care unit (ICU). METHODS: We conducted a multicenter, randomized trial in France. Patients experiencing severe AECOPDs were assigned to groups whose antibiotic therapy was guided by (1) a 5-day PCT algorithm with predefined cutoff values for the initiation or stoppage of antibiotics (PCT group) or (2) standard guidelines (control group). The primary endpoint was 3-month mortality. The predefined noninferiority margin was 12%. RESULTS: A total of 302 patients were randomized into the PCT (n = 151) and control (n = 151) groups. Thirty patients (20%) in the PCT group and 21 patients (14%) in the control group died within 3 months of admission (adjusted difference, 6.6%; 90% CI - 0.3 to 13.5%). Among patients without antibiotic therapy at baseline (n = 119), the use of PCT significantly increased 3-month mortality [19/61 (31%) vs. 7/58 (12%), p = 0.015]. The in-ICU and in-hospital antibiotic exposure durations, were similar between the PCT and control group (5.2 ± 6.5 days in the PCT group vs. 5.4 ± 4.4 days in the control group, p = 0.85 and 7.9 ± 8 days in the PCT group vs. 7.7 ± 5.7 days in the control group, p = 0.75, respectively). CONCLUSION: The PCT group failed to demonstrate non-inferiority with respect to 3-month mortality and failed to reduce in-ICU and in-hospital antibiotic exposure in AECOPDs admitted to the ICU.

Baseline results of the Depiscan study: a French randomized pilot trial of lung cancer screening comparing low dose CT scan (LDCT) and chest X-ray (CXR).

BACKGROUND: Lung cancer has the highest mortality-rate per cancer, with an overall 5-year survival <15%. Several non-randomized studies pointed out the high sensitivity of low dose computed tomography (LDCT) to detect early stage lung cancer. In France, Depiscan, a pilot RCT of LDCT versus chest X-ray (CXR), started on October 2002 to determine the feasibility of enrollment by general practitioners (GPs), investigations and diagnostic procedures by university hospital radiologists and multidisciplinary teams, data management by centralized clinical research assistants, and anticipate the future management of a large national trial. METHODS: GPs and occupational physicians (OPs) selected and enrolled 1000 subjects in 1 year. Eligible subjects were asymptomatic males or females aged 50-75 years with a current or former cigarette smoking history of >/=15 cigarettes per day for at least 20 years (former smokers having quit <15 years prior to enrollment). Based to randomization, annual LDCT or CXR screenings were planned at baseline and annually for 2 years. RESULTS: Between October 2002 and December 2004, 765 subjects were enrolled by 89 out of the 232 participating GPs and OPs. Complete clinical and imaging baseline data were available for 621 individuals out of the 765 enrolled, due to 144 noncompliant subjects who withdrew their consent. At least one nodule was detected in 152 out of 336 subjects (45.2%) in the LDCT screening, versus 21 out of 285 subjects (7.4%) in the CXR screening arm. Eight lung cancers were detected in the LDCT arm and one in the CXR arm. DISCUSSION: This pilot trial allows estimating that non-calcified nodules are 10 [6.36-17.07] times more often detected from LDCT than from CXR. However enrollment by GPs was more difficult than expected with 41% active investigators and a high rate (19%) of noncompliant patients. This experience speaks to the need for a high level of GPs formation and a large, coordinated clinical research team in such a trial. TRIAL REGISTRATION NUMBER: 02526.

Pharmacokinetics of Intraperitoneal Daptomycin in Patients with Peritoneal Dialysis-Related Peritonitis.

♦ BACKGROUND: Antibiotics are preferentially delivered via the peritoneal route to treat peritoneal dialysis-related peritonitis (PDRP) to ensure that maximal concentrations are delivered to the site of infection. Our study focused on the pharmacokinetics of daptomycin (DAP) administered via the intraperitoneal (IP) route in patients with PDRP. ♦ METHODS: According to the DaptoDP protocol (Clinical Trial No. 2012-005699-33), IP DAP was administered daily, i.e., during the 6-h Nutrineal (Baxter Healthcare Corporation, Deerfield, IL, USA) dwell time period, for 14 days, in addition to administration of the antibiotics used for the usual care of patients with PDRP. The plasma and IP levels of DAP were measured on days 1 and 5. The tested dose was 200 mg/day. The principal endpoint was the dialysate concentration after 6 hours of dwell time > 16 mg/L (corresponding to 4 x minimum inhibitory concentration [MIC] for E. faecalis). ♦ RESULTS: Three participants were evaluated. On day 5, the IP concentrations after 6 hours of dwell time were between 6.3 and 23.4 mg/L, and the peak plasma concentrations were between 13.0 and 15.3 mg/L. ♦ CONCLUSION: The results suggest that 200 mg/day is very likely sufficient for the treatment of PDRP by Staphylococci or Streptococci whereas it could be insufficient to treat PRDP by Enterococci. The good peritoneal bioavailability of DAP was quantitatively established, suggesting that IP administration could also be used as an alternate route for patients with damaged venous access. No DAP accumulation that could lead to toxic concentrations after repeated administration is expected, even in anuric patients. The protocol will further continue to assess whether a higher dose achieves the pharmacokinetic objectives.

Comparison of alcoholic chlorhexidine and povidone-iodine cutaneous antiseptics for the prevention of central venous catheter-related infection: a cohort and quasi-experimental multicenter study.

PURPOSE: Compare the effectiveness of different cutaneous antiseptics in reducing risk of catheter-related infection in intensive care unit (ICU) patients. METHODS: We compared the risk of central venous catheter-related infection according to four-step (scrub, rinse, dry, and disinfect) alcoholic 5 % povidone-iodine (PVI-a, n = 1521), one-step (disinfect) alcoholic 2 % chlorhexidine (2 % CHX-a, n = 1116), four-step alcoholic <1 % chlorhexidine (<1 % CHX-a, n = 357), and four-step aqueous 10 % povidone-iodine (PVI, n = 368) antiseptics used for cutaneous disinfection and catheter care during the 3SITES multicenter randomized controlled trial. Within this cohort, we performed a quasi-experimental study (i.e., before-after) involving the four ICUs which switched from PVI-a to 2 % CHX-a. We used propensity score matching (PSM, n = 776) and inverse probability weighting treatment (IPWT, n = 1592). The end point was the incidence of catheter-related infection (CRI) defined as catheter-related bloodstream infection (CRBSI) or a positive catheter tip culture plus clinical sepsis on catheter removal. RESULTS: In the cohort analysis and compared with PVI-a, the incidence of CRI was lower with 2 % CHX-a [adjusted hazard ratio (aHR), 0.51; 95 % confidence interval (CI) (0.28-0.96), p = 0.037] and similar with <1 % CHX-a [aHR, 0.73; (0.36-1.48), p = 0.37] and PVI [aHR, 1.50; 95 % CI (0.85-2.64), p = 0.16] after controlling for potential confounders. In the quasi-experimental study and compared with PVI-a, the incidence of catheter-related infection was again lower with 2 % CHX-a after PSM [HR, 0.35; 95 % CI (0.15, 0.84), p = 0.02] and in the IPWT analysis [HR, 0.31; 95 % CI (0.14, 0.70), p = 0.005]. The incidence of CRBSI or adverse event was not significantly different between antiseptics in all analyses. CONCLUSIONS: In comparison with PVI-a, the use of 2 % CHX-a for cutaneous disinfection of the central venous catheter insertion site and maintenance catheter care was associated with a reduced risk of catheter infection, while the benefit of <1 % CHX-a was uncertain. CLINICAL TRIALS IDENTIFIER: NCT01479153.