Reviews on Recent Clinical Trials - Volume 16, Issue 3, 2021

Background: The COVID-19 (2019-nCoV) pandemic is a major threat to public health worldwide; it has been identified as originating in Wuhan, Hubei province, China. It has spread across the globe, causing an outbreak of acute infectious pneumonia. Such a global outbreak is associated with adverse effects on mental health. Fear, stress and anxiety seem more definitely an outcome of mass quarantine. Methods: Keeping this pandemic situation in mind, existing literature on the COVID-19 crisis relevant to mental health was redeemed via a literature search from the PubMed database. Collected published articles were summarized according to their overall themes. Results: Preliminary evidence suggests that symptoms of self-reported stress, anxiety and depression have a common psychological impact due to the pandemic, and may be associated with disrupted sleep. Regional, state and National-international borders have almost been shut down, economies crashed, and billions of people quarantined or isolated at their own homes and quarantine centers. In this situational frame of covid-19, patients, frontline health-care professionals anf geriatric population with existing psychiatric conditions may be encountering further suffering. Conclusion: COVID-19 will continue to affect mental health, which plays an important role in battling the epidemic. With the scare of the COVID-19 pandemic on the rise, it is time that psychiatrists should try to integrate the health-care services keeping mental health at prime.

Background: Phase 1 studies comprise the first exposure of a promising new chemical entity in healthy volunteers or, when appropriate, in patients. To assure a solid foundation for subsequent drug development, this first step must carefully assess the safety and tolerance of a new compound and often provide some indication of potential effect, so that a safe dose or dose range can be confidently selected for the initial Phase 2 efficacy study in the target patient population. Methods: This review was based on a literature search using both Google Scholar and PubMed, dated back to 1970, using search terms including “healthy volunteers”, “Phase 1”, and “normal volunteers”, and also based on the authors’ own experience conducting Phase 1 clinical trials. This paper reviews the history of Phase 1 studies of small molecules and their rapid evolution, focusing on the critical single and multiple dose studies, their designs, methodology, use of pharmacokinetic and pharmacodynamic modeling, application of potentially helpful biomarkers, study stopping criteria, and novel study designs. Results: We advocate for determining the safe dose range of a new compound by conducting careful dose escalation in a well-staffed inpatient setting, defining the maximally tolerated dose (MTD) by reaching the minimally intolerated dose (MID). The dose immediately below the MID is then defined as the MTD. This is best accomplished by using appropriately screened patients for the target indication, as patients in many CNS indications often tolerate doses differently than healthy non-patients. Biomarkers for safety and pharmacodynamic measures can also assist in further defining a safe and potentially effective dose range for subsequent clinical trial phases. Conclusion: Phase 1 studies can yield critical insights into the pharmacology of a new compound in man and offer perhaps the only development period in which the dose range can be safely and thoroughly explored. Phase 1 studies often contain multiple endpoint objectives, the reconciliation of which can present a dilemma for drug developers and study investigators alike, but which can crucially determine whether a compound can survive to the next step in the drug development process.

Objective: Immediately after the outbreak of nCoV, many clinical trials are registered for COVID-19. The numbers of registrations are now raising inordinately. It is challenging to understand which research areas are explored in this massive pool of clinical studies. If such information can be compiled, then it is easy to explore new research studies for possible contributions in COVID-19 research. Methods: In the present work, a text-mining technique of artificial intelligence is utilized to map the research domains explored through the clinical trials of COVID-19. With the help of the open-- source and graphical user interface-based tool, 3007 clinical trials are analyzed here. The dataset is acquired from the international clinical trial registry platform of WHO. With the help of hierarchical cluster analysis, the clinical trials were grouped according to their common research studies. These clusters are analyzed manually using their word clouds for understanding the scientific area of a particular cluster. The scientific fields of clinical studies are comprehensively reviewed and discussed based on this analysis. Results: More than three-thousand clinical trials are grouped in 212 clusters by hierarchical cluster analysis. Manual intervention of these clusters using their individual word-cloud helped to identify various scientific areas which are explored in COVID19 related clinical studies. Conclusion: The text-mining is an easy and fastest way to explore many registered clinical trials. In our study, thirteen major clusters or research areas were identified in which the majority of clinical trials were registered. Many other uncategorized clinical studies were also identified as “miscellaneous studies”. The clinical trials within the individual cluster were studied, and their research purposes are compiled comprehensively in the present work.

Background: The outbreak of coronavirus disease (COVID-19) has posed a major threat to people's lives across the globe. It has drastically changed the way we perceive this world. A paradigm shift was observed globally as the world’s emphasis shifted to testing, diagnosis, treatment, and developing a coronavirus cure. Clinical trials were also not untouched by this. The coronavirus pandemic has abhorrently affected the day-to-day clinical trial activities at sites. Methods: The status of various ongoing clinical trials was assessed through a literature search, which also includes clinical trial portals. Our evaluations were based on these observations. Results: Multiple challenges were present in clinical trials as recruitment, retention, the safety of trial subjects, protocol compliance, and this made the world to re-think to incorporate newer strategies and to cope with this untoward situation. Conclusion: Digitalization of clinical trials as virtual management of adverse events, remote monitoring visits, and web-based consulting with trial subjects are potential directions that can be applied to better manage clinical trials worldwide.

Background: Infectious agents may be involved in the pathogenesis of vascular disease and related complications. The aim of this review is to analyze the most relevant information on the common infections related to vascular disease, discussing the main pathophysiological mechanisms. Methods: In the current review, the most important evidence on the issue of infections and vascular disease is searched on Medline, Scopus, and ScienceDirect database. Results: Among infectious agents, herpesviruses, parvovirus B19, hepatitis viruses, human immunodeficiency virus, severe acute respiratory syndrome coronavirus 2, treponema pallidum, mycobacterium tuberculosis, pseudomonas aeruginosa, staphylococcus aureus, and candida albicans seem to particularly related to vascular disease. Conclusion: Infectious agents may affect vessel’s homeostasis and functionality, both on the arterial and venous side, by means of several pathophysiological mechanisms such as dysregulation in vasomotor function, thromboembolic complications, initiation and progression of atherosclerosis, alteration of perivascular adipose tissue, recruiting inflammatory cells and molecules.

Introduction: Common purulent peritonitis is one of the most formidable complications in abdominal surgery. Evidence of this is the continuing high mortality rate, which according to various authors, ranges from 11% to 83%. According to modern concepts, the leading role in the development and progression of widespread purulent peritonitis is assigned to enteric insufficiency syndrome (EIS), which occurs in 90-100% of cases. Aim: The aim of the study was to improve the treatment outcomes of patients with peritonitis complicated by the development of enteric insufficiency syndrome and also by developing and introducing into clinical practice a complex of therapeutic measures, including the combined use of enterosorption in combination with antioxidant and antihypoxant therapy. Materials and Methods: The evaluation of the effectiveness of the proposed complex therapeutic measures was carried out on the basis of a prospective examination of 83 patients (26 men and 57 women) aged 24 to 76 years with diffuse peritonitis with III-IV degree of operational risk for ASA. The comparison group included 37 healthy people aged from 20 to 54 years. All examined patients were divided into two clinical groups. The first clinical group consisted of 67 patients with EI of the first degree and second clinical group comprising 16 patients with II degree EI. Before the operation, a suspension of enterosorbent was preliminarily prepared. Suspension of DS was injected through the inserted probe using a Janet syringe, creating an exposure for 10-15 minutes; and then restored the free outflow of the contents of the probe. After completion of the surgical intervention, in the conditions of the intensive care unit, enterosorption continued to perform every 8 hours (3 times a day). The study was carried out before the operation and in the terms of the 1-3rd and 10-14th days in the postoperative period. Anti-endotoxin antibodies of classes A, M and G (respectively anti-LPS-IgA, anti-LPS-IgM, anti-LPS-IgG) were determined by ELISA. Results: When used in the postoperative period for the treatment of enteric insufficiency with detoxification and antihypoxic therapy according to the developed method, a favorable effect is noted, which is confirmed by an assessment of the state of antiendotoxin immunity associated with the development of bacterial translocation and enterogenic toxemia. Conclusion: The use of the proposed intestinal therapy in combination with antioxidant and antihypoxic therapy helps to prevent the progression of endogenous intoxication, through inactivation and effective clearance of toxic metabolites, reducing the effects of hypoxia, which leads to a significant decrease in membrane-destabilizing effects from the intestinal cell structures and leads to a significant decrease in the expressed specific antigen of the immune system and better clinical outcomes.

Background: Similar anticonvulsants, such as gabapentin and pregabalin are recommended in neuropathic pain management, however little is known about their clinical differences in cases of low back pain. This paper aims to highlight some of the possible clinical differences between gabapentin and pregabalin in low back pain. Methods: Patients with moderate to severe low back pain were recruited. Eligible patients were randomised to receive either pregabalin (300 mg/day)or gabapentin (800 mg/day) for six weeks. The primary outcome measure was pain intensity according to the Visual Analogue Score (VAS) at baseline and at six weeks. The secondary outcome measures were: anxiety, insomnia, fatigue and the self-rated (GCI), measured at baseline, second, fourth, and the sixth week. Results: A total of 64 patients, pregabalin group (n=28), gabapentin group (n=36) completed the study. While pregabalin group showed a significantly lower pain score (p=0.039). The gabapentin group showed significant improvement in anxiety (p=0.001), insomnia (p=0.001), general fatigue (p=0.009), physical fatigue (p=0.001), reduce activity (p=0.001), and mental fatigue (p=0.014) higher than that of pregabalin. No difference in (GCI) was seen at six weeks. Conclusion: This is the first trial aimed at comparing gabapentin with pregabalin in NLBP. Although the results are preliminary, in our pilot study pregabalin was found to be superior in pain reduction, gabapentin demonstrated better effect on anxiety, insomnia and fatigue symptoms. The results are preliminary and studies with a larger sample size are still required.

Background: Severe postoperative pain is principally managed by opioids. While effective, opioids do not provide adequate relief in many patients and cause many side effects, including antinociceptive tolerance and opioid-induced hyperalgesia. To evaluate if a combination of intravenous Magnesium, Lidocaine, Ketorolac (MLK cocktail) is a useful rescue therapy through synergistic pharmacological mechanisms for acute pain relief. We present the intravenous combination of magnesium, lidocaine, and ketorolac (MLK cocktail) as a possible rescue for opioid insensitive severe post-operative pain. Materials and Methods: The principal settings were the post-operative care unit (PACU) and the surgical ward. We retrospectively analyzed the electronic medical record and anesthesia documents of 14 patients experiencing severe postoperative pain, >7/10 visual-analogue pain score (VAS), despite receiving at least 8 mg of intravenous morphine milligram equivalents (MME) after arrival in the LAC+USC Medical Center PACU between September 2012 and January 2013. The data reviewed included patients’ demographics, disease etiology, surgical procedure, opioids received perioperatively, and visual-analogue pain scores before and after each analgesic received, and after the MLK cocktail. The a priori primary outcome and a posteriori secondary outcome of this study are mean visual-analogue pain score and morphine milligram equivalent dose administered per hour, respectively. The main tool evaluated has been VAS score. Results: In patients who failed to respond to opioid analgesics, administration of the MLK cocktail improved the VAS pain scores immediately from 9.4 ± 1.0 to 3.6 ± 3.5. The MLK cocktail also decreased the MME doses/hour in the immediate 12 hours postoperative period from 12.4 ± 5.6 to 1.1 ± 0.9. Conclusion: In patients experiencing opioid-resistant severe postoperative pain, the magnesium, lidocaine, and ketorolac combination may be an effective nonopioid rescue therapy. Additionally, magnesium, lidocaine, and ketorolac may be utilized in cases complicated by either antinociceptive tolerance or opioid-induced hyperalgesia and can restore opioid responsiveness.

Background: At the time of writing this paper, no data was available for the clinical and epidemiological characteristics of African patients with COVID-19. Herein, we profiled retrospectively the epidemiological characteristics (clinical, laboratory, radiological, treatment, and clinical outcomes) of 64 confirmed cases of COVID-19 in the Regional Hospital Center (RHC) of Errachidia in Morocco. The aim of this study was to analyze the epidemiological characteristics and laboratory Findings of Covid-19 patients in Errachidia Province, Morocco. Methods: This is a retrospective single-center study that included all COVID-19 confirmed patients (died or discharged) hospitalized in the Regional Center of Errachidia, Morocco, between March 20, 2020 and May 23, 2020. Patients were confirmed by real-time RT-PCR and epidemiological, demographic, clinical, laboratory, treatment, and outcomes of patients were extracted manually from patient’s medical records. Results: In a total of 64 patients with COVID-19, 60.9% of patients were men, with a mean age of 41.5 years (SD 18.62). At the admission, 38 patients were asymptomatic (59.4%), and 58 (90.6%) were clinically classified as being in a benign state. Chronic illnesses were the most comorbidities observed, including diabetes with 8 cases (12.5%), hypertension 3 cases (4.7%), and hyperlipidemia 1 patient (1.6%). The main symptoms were cough 15 (23.4%), fever 10 (15.6), diarrhea 8 (12.5%), headache 5 (7.8%), and sore throat 5 (7.8%). Only 7 patients (10.9%) had lung lesions, and lymphopenia was present in only 7 patients (11.1%). The median duration of viral shedding was 14.5 days (9-22). Concerning deceased cases, they were elderly subjects aged 69.75 years, and they have presented dyspnea, breathing problems, and respiratory distress as specific symptoms. In addition, an increase of the medians of serum AST, CRP, and glucose levels was noticed in this group. During hospitalization, they presented acute respiratory distress syndrome (ARDS), and they were transferred to intensive care before they died. Conclusion: This study revealed that covid-19 infection often appeared in a benign form in the studied population (90.6% in this study). This finding may incriminate the implication of some protective parameters such as genetic, nutritional or other factors in the Moroccan population.

Background: Leaks are the major complication associated with laparoscopic sleeve gastrectomy. Objective: The study aimed to assess the efficacy and safety of specifically designed large covered metal stents for the management of post-laparoscopic sleeve gastrectomy leaks. Methods: Prospectively collected databases from three Italian Endoscopy Units were reviewed. The primary outcome of the study was to evaluate the clinical success of stents placement, defined as complete resolution of clinical and laboratory signs of sepsis with radiological evidence of leak closure. Secondary outcomes were stent-related adverse events and mortality. Results: Twenty-one patients (67% females, mean age 45 years) were included in the study and a total of 26 stents were placed. Technical success of stent placement was achieved in all cases (100%). Clinical success was observed in 85.5% of patients. Stent-related adverse events occurred in 9 patients (43%), with stent migration as the most frequent complication (33%). Adverse events were more frequently observed in patients who had undergone bariatric surgery prior to laparoscopic sleeve gastrectomy compared to patients without previous surgery (83% et al. 27%, p=0.018). Conclusion: The placement of specifically designed covered metal stents appears to be an effective and safe therapeutic approach for post-laparoscopic sleeve gastrectomy leaks. Stent migration can be a frequent complication.

Introduction: The first case of infection by SARS-CoV-2 (i.e., COVID-19) has been officially recorded by the Italian National Health Service on February 21^st, 2020. Lombardy was the first Italian region to be affected by the pandemic. Subsequently, the entire Northern part of Italy recorded a high number of cases, while the South was hit following the migratory waves. On March 8^th, the Italian Government has issued a decree that imposed a total lockdown, defining it as a state of isolation and restricting access in Lombardy and the other 14 provinces of Northern Italy. Methods: We analyzed the virus trend in the period between February 24^th and September 8^th, 2020, focusing on Calabria, with regards to the following items: new positives, change of total positives, and total cases. Furthermore, we included other information, such as the incubation period, symptom resolution period, quarantine period. Results: On March 27^th, the epidemic curve spiked with 101 new positive cases validating the hypothesis that this abnormal event was related to the displacement of non-residents people, living in the Northern part of Italy, to the home regions in the South. The epidemic curve showed a decreasing trend in the period after lockdown, proving the effectiveness of this measure. From the end of the lockdown May 04^th to September 8^th, the registered trend was -94.51%. A negative growth rate indicates that the number of new positive cases is lower than the number of healed patients. Conclusion: This study describes the effectiveness of the Italian Government policy, particularly the role of lockdown, for the containment of SARS-CoV-2 contagion in Calabria, a region with a low SARS-CoV-2 infection rate within the registered period.

Background and Objective: We aimed to examine the differences in life-space mobility and quality of life (QoL) of patients with cardiovascular disease (CVD) between the pre- and postnationwide state of emergency initiated by the Coronavirus disease 2019 (COVID-19) pandemic in Japan and to show the factors associated with the decrease in life-space mobility and QoL in these patients. Methods: We undertook a longitudinal study of 20 out of 51 consecutive CVD patients with coronary artery disease (CAD) who met the study criteria. We used the Life-Space Assessment (LSA) tool to evaluate Life-space mobility and assessed QoL with the five-level EuroQoL five-dimensional questionnaire (EQ-5D-5L) in Japanese. Results: The LSA scores and EQ-5D-5L QoL score decreased significantly from the pre- to postnationwide state of emergency in Japan (p < 0.01). ΔLSA was significantly positively associated with body mass index and significantly negatively associated with knee extensor muscle strength and pre-LSA score (p < 0.05). There were no significant relationships between ΔLSA and ΔEQ- 5D-5L QoL scores and between ΔEQ-5D-5L QoL scores and patient characteristics. Conclusion: The policies promoted to address the state of emergency in Japan might affect life-space mobility and QoL of CAD patients. Moreover, CAD patients in Japan who were not obese and maintained their physical function and activity tended to refrain from activity during the period between the pre- and post-nationwide state of emergency. Clarification of the effects of the COVID-19 pandemic on the relationship between living space motility and QoL in CAD patients will require further study.

Introduction: The percentage of the heterosexual population that has experienced and regularly has anal intercourse ranges from 20% to 35% in the USA. This practice increases to 95% in certain populations, including lesbian, gay, bisexual, and transgender people. Due to the lack of data in the literature about the effect of proctologic surgery on anal intercourse, this study aimed to assess the impact of this surgery on sexual behavior in both genders. Materials and Methods: From March 2016 to February 2018, an anonymous questionnaire was submitted to all patients aged >18 who had undergone proctologic surgery in one of two surgical units at tertiary referral centers and was assessed independently of gender. The exclusion criteria were incomplete healing and <3 months follow-up. Results: In total, 929 patients answered the questionnaire in full. The overall prevalence of preoperative anal intercourse was 22.5%. The rate of anal intercourse among men was 16.7%, while among women, it was 28.9%. The overall postoperative rate of anal intercourse was 11.8%. The rate of postoperative anal intercourse among those who regularly engaged in anal intercourse preoperatively was 52.6%, with a 47.4% rate of non-completion (p <0.0001). The experiences reported during intercourse after surgery were mainly pain, stiffness, and partner discomfort. Conclusion: Considering the statistically significant postoperative AI abandonment rate following all types of proctologic surgery, the surgeon has a duty to both treat the disease and to inform the patient about the possible consequences regarding its influence on anal intercourse.

Background: Although FD may affect up to 10% of the general population, the therapy for FD is not standard. Recently, ginger-based food supplements have been proposed in order to restore FD symptoms. Our aim was to assess the efficacy of a new nutraceutical formulation containing extract of gingerol and thymus as a possible natural treatment in managing the symptoms of functional dyspepsia (FD). Methods: We retrospectively analyzed the efficacy and safety profiles of a nutraceutical formulation containing Zingiber officinalis root extract and a standardized Thymus extract. It was administered as 1 ml/day twice a day for 90 days. Patients were assessed at baseline and after 1, 2 and 3 months of treatment, following a month of pharmacological washout by completing a questionnaire reporting the trend of the following symptoms: epigastric pain, epigastric heaviness, early satiety, belching, and regurgitation. Every symptom was assessed by a Visual Analogic Scale (VAS), ranging from 0= absence to 10= maximal severity. Results: We enrolled 272 patients (99 males and 173 females; median IQR age 49.5, 36-64 yrs). Obesity (BMI>30) was present in 28 (12.5%) patients; smokers were 83 (30.5%); and comorbidities were present in 107 (39.3%) patients. Improvement of symptom scores during treatment and one month after its suspension was extremely significant (p<0.000). Conclusion: This large study found that nutraceutical formulation could be one of the tools for an empirical approach to treat patients with FD, especially when a non-conventional drug treatment is preferable for the patient and considered suitable by the physician.

Background and Objective: The purpose of this investigation was to examine the prevalence, related factors, and cut-off value of body mass index for sarcopenia in community-dwelling elderly covered by long-term care insurance. Methods: Design was a cross-sectional study, in which113 consecutive community-dwelling elderly with long-term care insurance who underwent rehabilitation at a daycare center in Japan from January 2016 to January 2018, those who were aged ≥65 years old and could walk were included. Those in whom skeletal muscle mass index could not be measured were excluded. The determination of sarcopenia was made according to the criteria of the Asian Working Group for Sarcopenia. We analyzed the data with the unpaired t-test, χ² test, logistic regression analysis, and receiver operating characteristic curves. Results: The 99 elderly meeting the criteria were included and divided into the sarcopenia group (n=36) and no sarcopenia group (n=63). The prevalence was 36.4%. The sarcopenia group was significantly older and had lower body mass index, skeletal muscle mass index, and grip strength than the group without sarcopenia (p <0.05). Age and body mass index were extracted as significant sarcopenia- related factors (p <0.05). The cut-off value of body mass index for sarcopenia was 22.6 kg/m². Conclusion: The prevalence of sarcopenia in the elderly in the long-term care insurance region was 36.4%, and age and body mass index were extracted as sarcopenia-related factors. The cut-off value of body mass index for sarcopenia was 22.6 kg/m².