Reviews on Recent Clinical Trials - Volume 13, Issue 4, 2018

Rosmarinus officinalis L. (Lamiaceae), popularly known as rosemary, is used for food flavoring, and in folk medicine, as an antispasmodic, analgesic, anti-rheumatic, diuretic, and antiepileptic agent. Rosemary is an herb widely used in folk medicine, cosmetics, and phytotherapy and for flavoring of food products. Studies have focused on various biological activities of the secondary metabolites of this plant, such as rosmarinic acid, which have powerful antioxidant, hepato-protective, antimicrobial, anti-nociceptive, and anti-inflammatory properties.

Background: Sepsis and septic shock remain a major cause of morbidity and mortality globally. In recent years, the outcome of patients with sepsis and septic shock has gradually improved, in part due to early recognition and timely appropriate management. Bedside physical examination can be of limited value to identify the source of infection and to decide appropriate management. Moreover, the clinical status of these patients can change rapidly, as a part of disease progression or in response to treatment or intervention. Methods: Research articles, review papers and online contents related to point-of-care ultrasound for the management of patients with sepsis and septic shock were reviewed. Results: Point-of-care ultrasonography can be a valuable bedside tool to rapidly identify the potential source of infection and associated organ dysfunction. It can also help to guide management to predict fluid responsiveness by assessing the variation of inferior venacava with respiration, ventricular size and aortic flow variation. Response to various interventions like a fluid challenge or administration of inotropes can be assessed at the bedside. Point-of-care ultrasound can also enhance safety and increase the success of bedside procedures like central venous cannulation and drainage of pleural effusion. Conclusion: Bedside ultrasound can help to individualize management of patients with sepsis and septic shock and may potentially improve patient outcome.

Background: Globally, there have been tremendous efforts by regulatory authorities to make clinical trials safer by making stringent clinical trial regulations. Despite this, we witnessed several tragic events. TGN1412 and BIA 10-2474 phase I trials are infamous trails in which healthy volunteers either succumbed to severe adverse effects or faced irreversible impairments of the test drug. Such afflictions in clinical trials are not only turbulent to the image of pharmaceutical industry but it also conveys dispiriting message for clinical trial participants. Objective: To make clinical trials safer for participants, some regulatory changes are warranted. Methods: Some stipulated measures to improve safety of clinical trial participants include inclusion of patients instead of healthy volunteers in phase I clinical trials, all compounds which are used for first time in humans should be considered as high risk compounds, amendments in first in human clinical trial design to N of 1 randomized control trial in place of 6+2 design with the sequential dosing of subjects both within and between cohorts and the individual patient pharmacokinetic and pharmacodynamic data should be used to calculate sequential dosing. Besides these, there should be appropriate process for systematic risk assessment involving the use of statistical techniques to select pertinent risk factors with high predictive values of studies or sites that may be procumbent to non-compliance. Conclusion: Inclusion of above mentioned measures in clinical trials are bound to make them safer and may help in pacifying the insecurity that has emerged among humans to participate in clinical trials.

Background: Screening tests are typically evaluated for a single disease, but multiple tests for multiple diseases are performed in practice. The Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial assessed testing for four cancers simultaneously and can be viewed as a multiphasic cancer intervention. This paper presents overall and multiphasic findings of this trial. Methods: The PLCO trial was a randomized multi-center trial conducted at ten screening centers in the US. Participants were 76,682 men and 78,215 women ages 55 - 74 and free of the target cancers at trial entry. Screening tests were PSA and digital rectal examination for prostate cancer, chest x-ray for lung cancer, flexible sigmoidoscopy for colorectal cancer, CA125 and transvaginal ultrasound for ovarian cancer. Outcomes and harms of screening were assessed including compliance, test results, incidence, mortality, false positives and overdiagnosis. Results: Screening compliance was 82%, 72,820 (8%) of 906,064 exams were positive, the overall PPV was 4.2% and the cancer detection rate was 3.38/1000. A mortality reduction was observed only for colorectal cancer (RR 0.72, 95% CI 0.61 - 0.85) with no effect on all-cause mortality. Ninety-six percent of positive exams were falsely positive and there was a suggestion of overdiagnosis of prostate and possibly ovarian cancers. Multiphasic testing resulted in 7374 men and 2748 women experiencing multiple false positive results from multiple types of tests. Conclusion: Multiphasic cancer screening led to reduced mortality for one target cancer and imposed a burden on the health care system that included substantial false positives and likely overdiagnosis.

Aims and Background: The main purpose of our psycho-educational groups was to help women with breast cancer, learn how to cope with the physical, emotional, and lifestyle changes associated with cancer as well as with medical treatments that can be painful and traumatic. With this study, we wanted to detect the effects that group action had on the women who participated in it. Methods: We studied a total of 97 patients who participated in 13 psycho-education groups. The whole sample was female patients who had breast cancer with no recurrence or metastases. Results: All patients were evaluated with the Hospital Anxiety and Depression Scale (HADS) and the Body Image Scale (BIS). We found no significant effect on anxiety and body image for the brief psycho- educational group for women with breast cancer in this study. It is possible to highlight a statistical difference and hence an improvement between the results of the HADS depression test at T0 (first evaluation at the first meeting) and T1 (retest in the final meeting). Conclusion: The tests did not show a significant effect on anxiety and body image perception, but the patients reported that the psycho-educational group was an important intervention for their life. Outcome measurement is more complex in psychosocial research because many variables come into play and each phase of treatment is characterized by different types of problems for the patient: physical, relational and psychological aspects are involved.

Background: Systemic Lupus Erythematosus (SLE) is a chronic inflammatory disorder affecting multiple systems of the body. Clinical features show wide variations in patients with the different ethnic background. Renal involvement is a predictor of poor prognosis. Immunological workup is an integral part of SLE diagnostic criteria. Anti-ribosomal P Protein (anti-P) antibodies are highly specific for SLE. They may be present in Antinuclear Antibodies (ANA) negative SLE patients. Their role in Lupus Nephritis (LN) is under debate, some researchers found them associated with poor prognosis whereas others found favorable effect of these antibodies on renal disease. Objective: In this study, we investigated frequency of anti-P antibodies and the effect of these antibodies on renal functions in the LN patients. Methods: A total of 133 SLE patients were enrolled in this study. All patients had ANA in their sera. Anti-P antibodies along with other autoantibodies against extractable nuclear antigens (anti-Sm, anti- SS-A, anti-SS-B, anti-histones and anti-RNP) were detected by Immunoblot assay. Anti-dsDNA antibodies were detected by indirect Immunofluorescence Assay (IFA). Results: We found anti-P antibodies in 10.5% LN patients. Interestingly their presence in association with anti-dsDNA was associated with improved renal functions in comparison to those who had antidsDNA antibodies in isolation (serum creatinine: 1.3 ± 0.8 mg/dl vs. 3.0 ± 3.0; P= 0.091). Conclusion: Anti-dsDNA antibodies are directly involved in renal pathology in SLE patients. As these antibodies are nephrotoxic, concomitant occurrence of anti-P antibodies seems to offer a shielding effect on renal functions, which was evident by normal serum creatinine levels. Therefore, anti-P antibodies may be considered as a good prognostic marker in these patients.

Background: Intravenous treatment with ceftriaxone, a commonly used third-generation cephalosporin, is associated with a risk of the potentially fatal side-effect of neutropenia. Objective: The first systematic study to determine whether six to 12 days' intravenous ceftriaxone treatment is associated with a reduction in the neutrophil count and the extent to which biochemical and/or haematological parameters routinely measured at baseline predict such a fall. Method: Baseline and follow-up haematological and biochemical blood indices were measured in 86 patients (mean age 39.4 years; 55 female) receiving 2 g intravenous ceftriaxone daily. Results: At follow-up, the mean (standard error) neutrophil count had fallen from 3.93 109 (0.16 109) L-1 to 3.15 109 (0.15 109) L-1 (p < 0.000001). This reduction was predictable according to the following multifactor linear regression model: (baseline neutrophil count (109 L-1)) – (follow-up neutrophil count (× 109 L-1)) = 76 + 159.2(baseline haematocrit) – 14.5(baseline red blood cell count (1012 L-1)) – 0.724(baseline mean corpuscular volume (fL)) + 0.474(baseline neutrophil count (109 L-1)) + 0.0448(baseline total iron binding capacity (μM)) + 7.15(baseline calcium ion concentration (mM)) – 13.2(baseline corrected calcium ion concentration (mM)) + 0.0166(baseline alkaline phosphatase (IU L-1)). The residuals were normally distributed and model testing by random partition of the original data into two parts, with training of the model using the first part and model testing with the second part, gave highly satisfactory results. Conclusion: Intravenous ceftriaxone treatment is associated with a fall in neutrophils, which can be predicted by routine baseline blood indices.

Purpose: Prolonged Postoperative Ileus (PPOI) after abdominal surgery may affect unfavourably the patient recovery. The aim of this study was to estimate the incidence of PPOI in patients elective for colorectal resection and investigate perioperative variables associated with PPOI. Methods: A consecutive series of 428 patients undergoing colorectal resection (median age 72, range 24-92, years; men/women ratio 1.14) were analyzed. Data were extracted retrospectively throughout a five-year period from an electronic prospectively maintained database. PPOI was defined as the need for postoperative insertion of a nasogastric tube in a patient experiencing nausea and two episodes of vomiting and further showing absence of adequate bowel function (absence of flatus/stool) with lack of bowel sounds and abdominal distension. Results: Incidence of PPOI was 7% [95% confidence interval (95%CI), 4.8-9.9%]. Mean hospital stay was 8 days longer in patients with PPOI. Male gender, cancer, cardiac and respiratory co-morbidity, rectal resection, open/converted access, duration of operation, stoma formation and body mass index were associated with PPOI at univariate analysis (0.001< P< 0.048). PPOI was independently associated with male gender [adjusted odds ratio (OR), 4.2; 95%CI, 1.5-11.5], stoma formation (OR, 2.8; 95%CI, 1.2-6.8) and obesity (OR of obese vs. normal weight patients, 3.8, 95%CI, 1.2-12.0). Conclusion: After colorectal resection, PPOI leads to a prolonged hospital stay and slower patient's recovery. An international standardized definition of PPOI is strongly needed to make comparable results from researches and to reliably identify patients with increased risk, also to improve the therapeutic preventive policies in these patients.

Objectives: There have been increasing concerns regarding inappropriate usage of vena caval filters. Our study was done to analyze the current trends in vena caval filter placement. Methods: This study used the data from Nationwide Inpatient Sample database for the years 2002- 2012 to identify patients with vena caval filter placement. Trends in both therapeutic and prophylactic vena caval filter use over the eleven years' period were analyzed. Multiple simple logistic regression model was used to assess trends. Results: The overall incidence of vena caval filter placement increased from 2002 to 2012. The odds of vena caval filter placement in 2012 were 1.340 (95% CI: 1.236, 1.453) times the odds of vena caval filter placement in 2002. However, a downward trend was observed after the year 2010. The odds of vena caval filter placement in 2012 were 0.854 (95% CI: 0.801, 0.911) times the odds in 2010. Similar trends were seen in both therapeutic and prophylactic placements. The proportion of prophylactic vena caval filter placements with indications of morbid obesity (P<0.0001), head injury (P=0.0007), surgery of the eye, brain, spine or other major surgery (P<0.0001) hemorrhage/bleeding (P=0.0046) significantly increased in 2012 when compared to 2002. Conclusion: Vena caval filter placement rates have increased significantly from 2002 to 2012 for both prophylactic and therapeutic indications. However, there seems to be downward trend when comparing 2012 to 2010. Measures such as physician education and hospital audits can be done to further bring down inappropriate vena caval filter placements.

Background and Objectives: The association between preoperative Urine Neutrophil Gelatinase-associated Lipocalin (uNGAL) and interleukin-18 (uIL-18) with poor 1-year allograft function has been shown in deceased-donor kidney transplant recipients previously, and also these markers could predict 3-month allograft function. However, it is unknown whether there is an association between these postoperative biomarkers with important recipient outcomes beyond this time in livedonor transplants. Methods: NGAL and IL-18 four and 24 hours were measured in live-donor kidney transplant recipients after transplantation. The relationships between changes in these markers with clinical outcomes as well as kidney function were examined at 1 month and 2 years. Moreover, the association between delayed graft function with clinical outcome and Serum Creatinine (SrCr) was evaluated during this period. Results: The Mean age for kidney recipients was 23.9 years. Significant interaction was observed between uNGAL 24 hr (pvalue=0.01) and uIL-18 four and 24 hr after transplantation (pvalue=0.04, 0.03; respectively) with patients' outcome after 1 month and changes in uNGAL with outcomes after 2 years (pvalue= 0.04). Conclusion: Changes in urine NGAL postoperative are associated with worst outcomes, 2 years after kidney transplantation, suggesting its potential role in identifying patients that are at high risk for diminished allograft function, outcome and survival.

Background: Apathy, commonly defined as the loss of motivation, is a symptom frequently encountered in Alzheimer's Disease (AD). The treatment of apathy remains challenging in the absence of any truly effective medications. Transcranial Magnetic Stimulation (rTMS) or Transcranial Direct Current Stimulation (tDCS) can improve cognitive disorders, but do not appear to improve apathy. Isolated cognitive training also appears to have no effect on apathy. We propose to test the efficacy of a new procedure for the treatment of apathy in AD patients consisting of a combination of tDCS and cognitive training, based on the latest guidelines for the design of therapeutic trials in this field. Methods/Design: This article primarily describes the design of a monocentre, randomized, doubleblind trial to be conducted in France to evaluate the effect of the combination of tDCS and cognitive training on apathy compared to a group treated exclusively by cognitive training (sham tDCS). Twenty- four patients under the age of 90 years with mild-to-moderate Alzheimer's disease (Mini Mental State Examination score between 15 and 26/30) (MMSE)) presenting clinically significant apathy evaluated by the Apathy Inventory (AI) and the NeuroPsychiatric Inventory (NPI) apathy subscore will be enrolled. Severe depression will be excluded by using the NPI depression subscore. Treatment will comprise 10 sessions (D0-D11) including tDCS (bilateral prefrontal, temporal and parietal targets) and Cognitive Training (Cog) (6 simple tasks involving working memory, language and visuospatial function). After randomization (ratio 2:1), 16 patients will receive the complete treatment comprising tDCS and Cog (group 1) and 8 patients will be treated exclusively by Cog (sham tDCS) (group 2). The primary endpoint will be a significant improvement of the AI score by comparing baseline measures (D-15) to those recorded one month after stopping treatment (D44). Secondary endpoints will be an improvement of this score immediately after treatment (D14), 2 weeks (D29) and 2 months (D74) after stopping treatment and improvement of the MMSE score, NPI apathy subscore, ADAS Cog (Alzheimer Disease Assessment cognitive Scale subsection), ADCS-ADL (Alzheimer Disease Cooperative Study-Activities of Daily Living), FAB (Frontal Assessment Battery) and the latency of P300 evoked potentials at the same timepoints. Conclusion: The purpose of our study is to check the assumption of tDCS and cognitive training efficacy in the treatment of apathy encountered in AD patients and we will discuss its effect over time.