Reviews on Recent Clinical Trials - Volume 16, Issue 4, 2021

Machine Learning, a fast-growing technology, is an application of Artificial Intelligence that has provided important contributes to drug discovery and clinical development. In the last few years, the number of clinical applications based on Machine Learning has been constantly growing and this is now affecting the National Competent Authorities during the assessment of most recently submitted Clinical Trials that are designed, managed or that are generating data deriving from the use of Machine Learning or Artificial Intelligence technologies. We review current information available on the regulatory approach to Clinical Trials and Machine Learning. We also provide inputs for further reasoning and potential indications, including six actionable proposals for regulators to proactively drive the upcoming evolution of Clinical Trials within a strong regulatory framework, focusing on patient’s safety, health protection and fostering immediate access to effective treatments.

Background: Radiotherapy represents one of the main therapeutic modalities for localized prostate cancer. In the last two decades, emerging data regarding the radiobiology of prostate cancer suggests a very low α/β value, which has led the scientific community to evaluate the potential advantage of hypofractionation. Objective: The aim of this manuscript is to present the rationale of prostate radiobiology and the medical evidence of moderate hypofractionation for prostate cancer. Methods: Existing literature was reviewed, including data from prospective clinical trials dealing with the efficacy and toxicity of hypofractionated radiotherapy. Fifteen prospective phase II studies, nine randomized phase III studies and ten meta-analyses were selected. For every study included, the equivalent dose was calculated for both biochemical control and late toxicity. Results: The efficacy of hypofractionated radiotherapy, compared to conventional radiotherapy, regarding biochemical control, was evaluated in five superiority and four non-inferiority randomized phase III studies. The majority of participants in these studies were patients with low- and intermediate- risk prostate cancer. Even though the superiority criterion of the hypofractionation was not met in all studies, the noninferiority criterion was met. Prospective phase II studies of hypofractionation reported a low rate of acute and late toxicity. In randomized phase III studies, acute and late toxicity grade 3 and higher for the bowel and bladder was comparable between hypofractionated and conventional radiotherapy. The included meta-analyses showed no difference in efficacy and toxicity. Conclusion: Moderate hypofractionation is feasible and safe, and may be considered as an alternative option in low- and intermediate-risk prostate cancer patients.

Background: Hepatic Ischemia Reperfusion Injury (IRI) is a serious threat that characterizes the liver but also other transplantable organs. The worst effect of long-term IRI on an impaired graft could lead to irreversible damage and organ failure. Several events characterize the cascade that ultimately leads to organ failure. Among all, multiple strategies have been attempted to identify early phenomena of IRI with divergent results, and biomarkers might represent a novel approach to early detect ischemic damage. Methods: A literature review of the current state-of-the-art on IRI was conducted in the present manuscript. Information was collected from worldwide clinical trials conducted in highly specialized institutions. Experiments conducted on IRI animal models and clinical studies were screened. The final outcomes were analyzed and reported in the present review. Results: Matrix Metalloproteinases (MMPs) represent an interesting example of the early detector of neutrophil invasion after acute and chronic hepatic IRI. Neutrophil Gelatinase-associated Lipocalin (NGAL) is another biomarker which seems more predictable of the IRI gravity phase. Mitochondrial flavin mononucleotide (FMN) was recently discovered and might become a reliable biomarker of hepatic IRI during Hypothermic Oxygenation Machine Perfusion (HOPE). Conclusion: The available strategies to avoid IRI, despite constantly improving, are still lacking a gold standard method. Further studies are still needed to explore new options in the IRI diagnosis and treatment, and to this purpose, regenerative medicine and tissue engineering surely can play a pivotal role in the transplantation field.

Background: Coronavirus disease (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has become a global issue today. There exists an ongoing health crisis all over the world, and efficacious drugs against COVID-19 are not available yet. Therefore, on an urgent basis, scientists are looking for safe and efficacious drugs against SARSCoV- 2. Methods: The reported individual patient data and clinical outcomes, including the rate of recovery and mortality, patients’ characteristics, and complications, are reviewed. Randomized controlled trials, single-center cohort studies, and different case studies are provided, and the PICO model is used to illustrate the outcomes. Results: There exist several FDA (U.S Food and Drug Administration) approved anti coronavirus drugs that sometimes are unsuccessful in curing COVID-19 critical conditions. It has been observed that a humanized monoclonal antibody, Tocilizumab (licensed for the treatment of rheumatoid arthritis), targeting the interleukin-6 (IL-6) receptor, has an integral role in the treatment of COVID-19. Conclusion: The cause behind the mortality of COVID-19 patients was found to be the Cytokine Release Syndrome (CRS). Therefore, besides other antiviral drugs, the utilization of tocilizumab should also be considered as it can effectively block IL-6 and reduce the inflammatory signal.

Background: Laryngopharyngeal Reflux (LPR) may be part of Gastroesophageal Reflux Disease (GERD). However, sometimes suspected LPR seems refractory to Proton Pump Inhibitors (PPI), questioning therefore the GERD diagnosis. Our aim was to evaluate the real-life prevalence of GERD in patients with a recent laryngoscopic diagnosis of LPR, and unresponsive to PPI. We also assessed whether other causes than GERD could explain the laryngoscopic findings in those patients. Methods: We retrospectively analyzed patients with the diagnosis of LPR, and unresponsive to PPI. Those patients must have been investigated by: upper gastrointestinal endoscopy with biopsies; multichannel intraluminal impedance and pH monitoring (MII-pH); X-ray of the chest and/or of the paranasal sinuses; hormonal thyroid assessment; prick tests to assess food and/or inhalants and pollen allergy. Results: We enrolled 28 patients (18, 64.3%, males and 10, 35.7%, females; median, IQR age 39.4, 21-75 yrs). Endoscopic hiatal hernia was found in 9/28 (32.1%) patients; the MII-pH analysis showed abnormality in 2/28 (7.14%) patients (both having also GERD symptoms); Chest X-ray found chest diseases in 2/28 (7.14%) patients and X-rays of the paranasal sinuses found sinusitis in 1/28 (3.6%); 2/28 (7.14%) patients had hyperthyroidism; food and/or inhalants and pollen allergy was found in 9 (32.1%) patients. In 12/28 (42.9%) patients, any of the investigated diseases was found. Conclusions: This study found that the real prevalence of GERD in patients with a recent laryngoscopic diagnosis of LPR, and unresponsive to PPI, is low. Moreover, more than 40% of them did not show any of the investigated diseases in real life.

Introduction: HCV infection elimination is set to be carried out by 2030. To achieve this goal, the WHO has set minor achievable short-term “mini-goals.” One of these is treating “difficult to reach and treat populations,” such as prisoners. One of the biggest obstacles to achieving this mini goal is the poor knowledge of the real HCV prevalence in such a population and the barriers to its detection, treatment, and follow-up. Even if HCV testing in Italian prisons is feasible and recommended, it is not however always carried out. To worsen the picture, the peculiar status of conviction is correlated to difficulty in caring out the antiviral therapy due to loss in follow-up and to the refusals by inmates. Aims: A point-of-care test-and-treat program was set up in a penitentiary in Southern Italy to reduce the number of patients Lost To Follow-Up (LTFU) between detection and treatment. A secondary aim was to evaluate the prevalence of HCV-infected patients in a cohort of newly arrived inmates. Methods: This prospective-observational study was carried out from January 2020 to February 2020. We performed an HCV-RNA blood capillary quick test on all newly arrived inmates. As a routine, the new inmates underwent clinical and laboratory assessments. To those who were detected HCV-RNA positive, the shortest possible antiviral treatment was offered, according to genotype and clinical features. Results: We observed 122 new inmates in the period between January and February of 2020. Overall, 62 (50.8%) subjects took HCV-RNA quick testing through blood sampling. Four (6.4%) subjects were found to be HCV-RNA positive; 1 refused antiviral therapy, while 3 accepted, obtaining 100% SVR. None of the HCV-active inmates were lost to follow up between detection and treatment proposal. Conclusion: The use of a high-speed test-and-treat protocol for HCV infection was demonstrated to be effective in avoiding LTFU in HCV-positive new inmates in the period between detection and treatment. We observed an apparent prevalence of HCV incident cases in newly arrived inmates of 6.4%. Antiviral therapy was quickly provided and found to be effective and successful.

Background: Interim analysis is an integral component of clinical research and drug development in particular and helps reduce ‘time to market’ for an intervention or stop further development of unsafe and ineffective interventions. In this audit, we evaluated the extent of use of interim analyses in published RCTs in three leading journals and their impact on regulatory approval. Methodology: RCTs published in JAMA, NEJM and Lancet in the year 2012 to 2018 were extracted. Each RCT was scrutinized using the filter term ‘Interim’. Both descriptive and inferential statistics were used to analyze the data. The factors (therapeutic areas, nature of interventions, source of funding and phases of trials) associated with Interim analysis and its impact on drug approval were analyzed. Results: The majority of RCTs with interim analysis belonged to oncology (27%) and cardiology (17.2%) and were related to drugs (70%). Majority of the RCTs were in phase 3 (56.3%) and funded exclusively by Pharmaceutical industry (36.2%). A total of 2% and 14% studies led to accelerated approval and normal regulatory approval. The choice of alpha spending function was not mentioned in 44.8% studies and 21% studies used O-Brien Fleming method. A total of 18.5% studies were stopped early. The oncology trials, drug as intervention and Phase 3 trials were associated with the conduct of interim analysis which was associated with significantly higher numbers of accelerated and routine regulatory approvals. Conclusion: Majority of the RCTs with interim analysis were from oncology and most did not report a stopping rule. Interventions that were drugs (rather than devices or surgical procedures). and phase 3 trials (relative to other phases of RCTs). were associated with significantly higher number of interim analyses which was also associated with significantly higher number of regulatory approvals.

Background: Alcohol dependence is a significant public health problem, contributing to the global health burden. Due to its immense socio-economic burden, various psychosocial, psychological, and pharmacological approaches have attempted to alter the behaviour of the patient misusing or abusing alcohol, but their efficacy is modest at best. Therefore, there is a search for newer treatment approaches, including non-invasive brain stimulation in the management of alcohol dependence. We plan to study the efficacy of Prefrontal Cortex Transcranial direct current stimulation Treatment in Alcohol dependence syndrome (PreCoTTA). Methods: Two hundred twenty-five male patients with alcohol dependence syndrome will be randomized into the three study arms (2 active, left dorsolateral prefrontal cortex and left orbitofrontal cortex, and 1 sham) to receive a total of 14 tDCS sessions (10 continuous and 4 booster sessions). Data will be collected from these sessions at five different time points on clinical, neuropsychological and biochemical parameters. In addition, 225 healthy age and education matched controls will be administered the neuropsychological test battery at baseline for comparison with the patient group. Discussion: The proposed study aims to explore the use of non-invasive brain stimulation; tDCS as a treatment alternative. We also aim to overcome the methodological gaps of limited sample sizes, fewer tDCS intervention sessions, lack of long-term follow-ups to measure the sustainability of gains, and lack of comprehensive measures to track changes in functioning and abstinence after tDCS intervention. The main outcomes include clinical (reduction in cue-induced craving, time to first drink, and QFI); neuropsychological (risk-taking, impulsivity, and other neuropsychological domains), and biochemical markers (BDNF, leptin and adiponectin). The findings of the study will have translational value as they may help to improve the clinician’s ability to effectively manage craving in patients with alcohol dependence syndrome. Furthermore, we will have a better understanding of the neuropsychological and biochemical effects of non-invasive brain stimulation techniques which are of interest in the comprehensive treatment of addiction disorders. Trial registration: The study has been registered with the Clinical Trials Registry-India (CTRI/ 2020/09/027582) on September 03rd 2020.