Rationale, study design, and analysis plan of the Alveolar Recruitment for ARDS Trial (ART): Study protocol for a randomized controlled trial

Background: Acute respiratory distress syndrome (ARDS) is associated with high in-hospital mortality. Alveolar recruitment followed by ventilation at optimal titrated PEEP may reduce ventilator-induced lung injury and improve oxygenation in patients with ARDS, but the effects on mortality and other clinical outcomes remain unknown. This article reports the rationale, study design, and analysis plan of the Alveolar Recruitment for ARDS Trial (ART). Methods/Design: ART is a pragmatic, multicenter, randomized (concealed), controlled trial, which aims to determine if maximum stepwise alveolar recruitment associated with PEEP titration is able to increase 28-day survival in patients with ARDS compared to conventional treatment (ARDSNet strategy). We will enroll adult patients with ARDS of less than 72 h duration. The intervention group will receive an alveolar recruitment maneuver, with stepwise increases of PEEP achieving 45 cmH(2)O and peak pressure of 60 cmH2O, followed by ventilation with optimal PEEP titrated according to the static compliance of the respiratory system. In the control group, mechanical ventilation will follow a conventional protocol (ARDSNet). In both groups, we will use controlled volume mode with low tidal volumes (4 to 6 mL/kg of predicted body weight) and targeting plateau pressure <= 30 cmH2O. The primary outcome is 28-day survival, and the secondary outcomes are: length of ICU stay; length of hospital stay; pneumothorax requiring chest tube during first 7 days; barotrauma during first 7 days; mechanical ventilation-free days from days 1 to 28; ICU, in-hospital, and 6-month survival. ART is an event-guided trial planned to last until 520 events (deaths within 28 days) are observed. These events allow detection of a hazard ratio of 0.75, with 90% power and two-tailed type I error of 5%. All analysis will follow the intention-to-treat principle. Discussion: If the ART strategy with maximum recruitment and PEEP titration improves 28-day survival, this will represent a notable advance to the care of ARDS patients. Conversely, if the ART strategy is similar or inferior to the current evidence-based strategy (ARDSNet), this should also change current practice as many institutions routinely employ recruitment maneuvers and set PEEP levels according to some titration method.Hospital do Coracao (HCor) as part of the Program 'Hospitais de Excelencia a Servico do SUS (PROADI-SUS)'Brazilian Ministry of Healt

Effect of diacerein on metabolic control and inflammatory markers in patients with type 2 diabetes using antidiabetic agents : a randomized controlled trial

Introduction. Studies have shown that T2DM is an inflammatory disease. Thus, the present study was aimed at evaluating whether diacerein could improve the metabolic and inflammatory profile among patients with T2DM under long-term treatment with glucose-lowering agents. Methods. This is a double-blind, parallel, placebo-controlled trial with 72 participants randomly assigned to diacerein 50 mg or placebo for 12 weeks. The primary endpoint was the between-group difference in change in HbA1c. Secondary endpoints included the proportion of patients achieving metabolic control [HbA1c ≤ 7 0% (53 mmol/mol)] and change in inflammatory mediators. Results. Participants in the diacerein group had greater reductions in mean HbA1c level in comparison to placebo (−0.98; 95% CI: −2.02 to 0.05, P = 0 06), independently of confounding factors. The difference in HbA1c level was −1.3 (95% CI: −2.3 to −0.4) in favor of diacerein (P = 0 007) in those with <14 years of diabetes duration versus 0.05 (−0.7 to 0.8; P = 0 9) in those with longer duration. The diacerein group had a 50% increase in the number of participants at the lowest TNF-α level (≤1.46 pg/mL). Conclusions. In patients with long-established T2DM under long-term treatment with glucose-lowering agents, diacerein improves metabolic control as measured by HbA1c level and has a favorable impact on inflammatory profile. Clinical Trial Registry. This trial is registered with Brazilian Clinical Trials Registry (ReBEC) number RBR-29j956

Asymptomatic carriers of Plasmodium spp. as infection source for malaria vector mosquitoes in the Brazilian Amazon

We have described the existence of asymptomatic carriers of Plasmodium vivax and Plasmodium falciparum infections in native Amazon populations. Most of them had low parasitemias, detected only by polymerase chain reaction (PCR). Because they remain symptomless and untreated, we wanted to determine whether they could infect Anopheles darlingi Root, the main Brazilian vector, and act as disease reservoirs. Fifteen adult asymptomatic patients (PCR positive only) were selected, and experimental infections of mosquitoes were performed by direct feeding and by a membrane-feeding system. Seventeen adult symptomatic patients with high parasitemias were used as controls. We found an infection rate in An. darlingi of 1.2% for the asymptomatic carriers and 22% for the symptomatic carriers. Although the asymptomatic group infected mosquitoes at a much lower rate, these patients remain infective longer than treated, symptomatic patients. Also, the prevalence of asymptomatic infections is 4 to 5 times higher than symptomatic infections among natives. These results have implications for the malaria control program in Brazil, which focuses essentially on the treatment of symptomatic patients. © 2005 Entomological Society of America

A Reduced Risk of Infection with Plasmodium vivax and Clinical Protection against Malaria Are Associated with Antibodies against the N Terminus but Not the C Terminus of Merozoite Surface Protein 1

Progress towards the development of a malaria vaccine against Plasmodium vivax, the most widely distributed human malaria parasite, will require a better understanding of the immune responses that confer clinical protection to patients in regions where malaria is endemic. The occurrence of clinical protection in P. vivax malaria in Brazil was first reported among residents of the riverine community of Portuchuelo, in Rondônia, western Amazon. We thus analyzed immune sera from this same human population to determine if naturally acquired humoral immune responses against the merozoite surface protein 1 of P. vivax, PvMSP1, could be associated with reduced risk of infection and/or clinical protection. Our results demonstrated that this association could be established with anti-PvMSP1 antibodies predominantly of the immunoglobulin G3 subclass directed against the N terminus but not against the C terminus, in spite of the latter being more immunogenic and capable of natural boosting. This is the first report of a prospective study of P. vivax malaria demonstrating an association of reduced risk of infection and clinical protection with antibodies against an antigen of this parasite

Effect of diacerein on metabolic control and inflammatory markers in patients with type 2 diabetes using antidiabetic agents : a randomized controlled trial

Introduction. Studies have shown that T2DM is an inflammatory disease. Thus, the present study was aimed at evaluating whether diacerein could improve the metabolic and inflammatory profile among patients with T2DM under long-term treatment with glucose-lowering agents. Methods. This is a double-blind, parallel, placebo-controlled trial with 72 participants randomly assigned to diacerein 50 mg or placebo for 12 weeks. The primary endpoint was the between-group difference in change in HbA1c. Secondary endpoints included the proportion of patients achieving metabolic control [HbA1c ≤ 7 0% (53 mmol/mol)] and change in inflammatory mediators. Results. Participants in the diacerein group had greater reductions in mean HbA1c level in comparison to placebo (−0.98; 95% CI: −2.02 to 0.05, P = 0 06), independently of confounding factors. The difference in HbA1c level was −1.3 (95% CI: −2.3 to −0.4) in favor of diacerein (P = 0 007) in those with <14 years of diabetes duration versus 0.05 (−0.7 to 0.8; P = 0 9) in those with longer duration. The diacerein group had a 50% increase in the number of participants at the lowest TNF-α level (≤1.46 pg/mL). Conclusions. In patients with long-established T2DM under long-term treatment with glucose-lowering agents, diacerein improves metabolic control as measured by HbA1c level and has a favorable impact on inflammatory profile. Clinical Trial Registry. This trial is registered with Brazilian Clinical Trials Registry (ReBEC) number RBR-29j956

Efficacy and safety of available treatments for visceral leishmaniasis in Brazil: A multicenter, randomized, open label trial

<div><p>Background</p><p>There is insufficient evidence to support visceral leishmaniasis (VL) treatment recommendations in Brazil and an urgent need to improve current treatments. Drug combinations may be an option.</p><p>Methods</p><p>A multicenter, randomized, open label, controlled trial was conducted in five sites in Brazil to evaluate efficacy and safety of (i) amphotericin B deoxycholate (AmphoB) (1 mg/kg/day for 14 days), (ii) liposomal amphotericin B (LAMB) (3 mg/kg/day for 7 days) and (iii) a combination of LAMB (10 mg/kg single dose) plus meglumine antimoniate (MA) (20 mg Sb⁺⁵/kg/day for 10 days), compared to (iv) standard treatment with MA (20 mg Sb⁺⁵/kg/day for 20 days). Patients, aged 6 months to 50 years, with confirmed VL and without HIV infection were enrolled in the study. Primary efficacy endpoint was clinical cure at 6 months. A planned efficacy and safety interim analysis led to trial interruption.</p><p>Results</p><p>378 patients were randomized to the four treatment arms<b>:</b> MA (n = 112), AmphoB (n = 45), LAMB (n = 109), or LAMB plus MA (n = 112). A high toxicity of AmphoB prompted an unplanned interim safety analysis and this treatment arm was dropped. Per intention-to-treat protocol final analyses of the remaining 332 patients show cure rates at 6 months of 77.5% for MA, 87.2% for LAMB, and 83.9% for LAMB plus MA, without statistically significant differences between the experimental arms and comparator (LAMB: 9.7%; CI95% -0.28 to 19.68, p = 0.06; LAMB plus MA: 6.4%; CI95% -3.93 to 16.73; p = 0.222). LAMB monotherapy was safer than MA regarding frequency of treatment-related adverse events (AE) (p = 0.045), proportion of patients presenting at least one severe AE (p = 0.029), and the proportion of AEs resulting in definitive treatment discontinuation (p = 0.003).</p><p>Conclusions</p><p>Due to lower toxicity and acceptable efficacy, LAMB would be a more suitable first line treatment for VL than standard treatment. ClinicalTrials.gov identification number: NCT01310738.</p><p>Trial registration</p><p>ClinicalTrials.gov <a href="https://clinicaltrials.gov/ct2/show/NCT01310738" target="_blank">NCT01310738</a></p></div

Early withdrawal rate due to the occurrence of AE/SAE during treatment as per ITT.

<p>Early withdrawal rate due to the occurrence of AE/SAE during treatment as per ITT.</p

CONSORT patient flowchart.

<p>Flow diagram of the progress through the phases of the trial. AmphoB = amphotericin B deoxycholate; MA = meglumine antimoniate; LAMB = Liposomal amphotericin B.</p

Frequency of AE and SAE related to study medication, and temporary and definitive treatment suspension due to the occurrence of AE per intervention arm.

<p>Frequency of AE and SAE related to study medication, and temporary and definitive treatment suspension due to the occurrence of AE per intervention arm.</p

Survival time until fever clearance.

<p>Survival time until fever clearance per treatment arm by the Kaplan Meier method. MA = meglumine antimoniate; LAMB = Liposomal amphotericin B.</p