World Congress on Clinical Trials in Diabetes 2018

Martin J. Kurian, Peter J. Rentzepis, Ann M. Carracher, and Kelly L. Close are of Close Concerns ( http://www.closeconcerns.com ), a healthcare information company focused exclusively on diabetes and obesity care. Close Concerns publishes Closer Look, a periodical that brings together news and insights in these areas. Each month, the Journal of Diabetes includes this News feature, in which Kurian, Rentzepis, Carracher, and Close review the latest developments relevant to researchers and clinicians.     

Site Selection in Community-Based Clinical Trials for Substance Use Disorders: Strategies for Effective Site Selection

Background: The importance of conducting substance use disorder treatment research in real-world settings is now well recognized. While this approach to clinical trials research offers a variety of benefits, challenges also arise. Selecting high-quality sites to participate is critical to recruitment, retention, and overall trial performance when conducting multi-site, community-based clinical trials of treatments for substance use disorders. Objectives: Over the past 10 years, the National Institute on Drug Abuse-sponsored National Drug Abuse Treatment Clinical Trials Network (CTN) has strived to conduct high-quality, well-managed clinical trials. This includes developing methods for site selection to be used by investigators conducting CTN trials. Methods: We review site selection strategies from two community-based multi-site clinical trials conducted under the auspices of the National Drug Abuse Treatment Clinical Trials Network. Results: Issues relevant to site selection include the clinical trial design, availability of appropriate clinical population, and organizational attributes of potential clinical research sites. Site selection strategies include reviewing regional epidemiologic data, collecting standard site selection surveys, evaluating clinic data on existing patient populations, and site selection interviews and visits. Conclusion: This article describes considerations for selecting research sites and identifies specific strategies to employ when selecting community-based sites for participation in clinical trials.     

Transforming Dementia Care Through Pragmatic Clinical Trials Embedded in Learning Healthcare Systems

The current evidence base for testing nonpharmacological interventions for people living with dementia (PLWD) and their caregivers is limited, especially within care settings such as ambulatory care, assisted living communities, nursing homes, hospitals, and hospices. There has been even less attention to translation of effective interventions for PLWD into delivery of care. Thus, there is an urgent need for researchers to partner with these care settings, especially those that follow a learning healthcare systems (LHSs) model, and vice versa to conduct embedded pragmatic clinical trials (ePCTs). These trials are conducted within sites that offer routine care and are designed to answer important, relevant clinical questions and leverage existing electronic health and administrative data. ePCTs set in LHSs create a unique opportunity for researchers, healthcare providers, and PLWD and their families to work and learn together as potentially effective interventions are studied and stress tested in real-world situations. Healthcare settings that embrace research or quality improvement as part of a culture of continuous learning are ideal settings for ePCTs. In this article, we summarize what we have learned from the National Institutes of Health's Health Care Systems Research Collaboratory–funded ePCTs, discuss challenges of ePCTs within settings that serve PLWD, and describe the work of the Health Care Systems Core within the National Institute on Aging's IMbedded Alzheimer's Disease and Related Dementias Clinical Trials Collaboratory that will occur over the next 5 years. J Am Geriatr Soc 68:S43–S48, 2020 .     

Viral Hepatitis and Diabetes: Clinical Implications of Diabetes Prevention Through Hepatitis Vaccination

Viral hepatitis has been posited to play a role in the development of type 2 diabetes. Thus, prevention of viral hepatitis through vaccination has the potential to reduce the burden of type 2 diabetes. We have shown that successful hepatitis B vaccination reduces the risk of diabetes by 33 %. Although diabetes can be prevented by behavior modification and pharmaceutical agents, these require significant personal commitment and cost. In contrast, diabetes prevention through hepatitis B vaccination would require little personal commitment and relatively low cost. In this review, we discuss hepatitis viruses A, B, and C and their interaction with diabetes; explore the potential underlying mechanisms and potential for hepatitis vaccination to reduce diabetes; and estimate the medical expense savings that would result from such an intervention. Given the projected increase of diabetes prevalence in the developing regions, where hepatitis B is endemic, exploration of such an intervention is very timely.     

Clinical Trials of COVID-19 Therapies Should Account for Diabetes and Hyperglycemia

Complications of Coronavirus Disease 2019 (COVID-19) occur with increased frequency in people admitted to the hospital with diabetes or hyperglycemia. The increased risk for COVID-19 infections in the presence of these metabolic conditions is in part due to overlapping pathophysiologic features of COVID-19, diabetes, and glucose control. Various antiviral treatments are being tested in COVID-19 patients. We believe that in these trials, it will be useful to evaluate treatment effect differences in patients stratified according to whether they have diabetes or hyperglycemia. In this way, it will be possible to better facilitate development of antiviral treatments that are most specifically beneficial for the large subset of COVID-19 patients who have diabetes or hyperglycemia.     

Modeling Site Effects in the Design and Analysis of Multi-site Trials

Background: Careful consideration of site effects is important in the analysis of multi-site clinical trials for drug abuse treatment. The statistical choices for modeling these effects have implications for both trial planning and interpretation of findings. Objectives: Three broad approaches for modeling site effects are presented: omitting site from the analysis; modeling site as a fixed effect; and modeling site as a random effect. Both the direct effect of site and the interaction of site and treatment are considered. Methods: The statistical model, and consequences, for each approach are presented along with examples from existing clinical trials. Power analysis calculations provide sample size requirements for adequate statistical power for studies utilizing 6, 8, 10, 12, 14, and 16 treatment sites. Results: Results of the power analyses showed that the total sample required falls rapidly as the number of sites increases in the random effect approach. In the fixed effect approach in which the interaction of site and treatment is considered, the required number of participants per site decreases as the number of sites increases. Conclusions: Ignoring site effects is not a viable option in multi-site clinical trials. There are advantages and disadvantages to the fixed effect and random effect approaches to modeling site effects. Scientific Significance: The distinction between efficacy trials and effectiveness trials is rarely sharp. The choice between random effect and fixed effect statistical modeling can provide different benefits depending on the goals of the study.     

Current Status and Future Prospects for Electronic Point-of-Care Clinical Decision Support in Diabetes Care

Early efforts to use point-of-care clinical decision support (CDS) were limited to the use of prompts and reminders, which improved test ordering but not intermediate outcomes of care, such as glucose, blood pressure, or lipid levels. More sophisticated diabetes CDS tools are now available that use electronic medical record data to provide patient-specific advice on medication use on the basis of previous treatment, distance from goal, and other clinical data. These tools have shown modest but significant improvement in glucose and blood pressure control. Promising next-generation developments will include prioritizing clinical actions that have maximum benefit to a given patient at the point of care and developing effective methods to communicate CDS information to patients to better incorporate patient preferences in care decisions.     

An Integrated Mobile Platform for Automated Data Collection and Real-Time Patient Monitoring in Diabetes Clinical Trials

We present a new mobile platform to be used in clinical trials aimed at both collecting data and assessing new technologies and treatments for diabetes care. The main components of the platform are a mobile app, that automatically collects data from continuous glucose monitoring sensors and activity trackers, and also allows users to manually log daily events; a cloud database for safe data storage; a web interface, which allows clinicians to monitor patients’ status in real-time. The platform is modular and highly customizable for a multitude of purposes in clinical research. Preliminary tests performed for daily-life data gathering by both clinicians and users are extremely encouraging.     

Clinical Trials of Carvedilol in Heart Failure

Carvedilol is a non-selective ₁ and -adrenergic antagonist with antioxidant properties. This novel, competitive antagonist has been studied in 8 placebo-controlled clinical trials involving over 1800 heart failure patients with systolic dysfunction in varying degrees of severity. Overall, carvedilol is well-tolerated in heart failure patients, with a predictable reduction in heart rate and favorable hemodynamic actions. The overall incidence of side effects including hypotension, dizziness, bradycardia and worsening heart failure are no worse than placebo, and can be minimized with careful titration. Improvement in left ventricular ejection fraction has been observed with carvedilol in all studies. A significant reduction in the risks of dying or being hospitalized has also been demonstrated. Some studies have demonstrated improvements in clinical parameters such as symptom status and exercise tolerance, but these benefits have been more difficult to demonstrate conclusively. These clinical trials have established an important role of carvedilol in the management of heart failure. The results from the recent survival trials of beta-adrenergic antagonists have confirmed the mortality benefit of this class of drug in the management of patients with heart failure.     

Placebos in Clinical Trials of Peptic Ulcer

Placebo use in controlled clinical trials is often challenged as being unethical, as though the investigator in a clinical trial and the clinician are in conflict, one interested primarily in scientific validity, the other in patient care. This paper will review the specific issues in trials for short term (4–8 wk) peptic ulcer disease, demonstrating that controlled trials utilizing placebo are worthwhile, are safe, offer distinct advantages over alternative trials, and impose no real ethical conflict. The ethics regarding the use of a placebo for a controlled trial have been reviewed previously in this column (1). Placebo controls are appropriate in therapeutic trials when 7) standard therapy is either unavailable, of un-proven efficacy, or possesses unacceptable side effects, 2) placebo itself is an effective therapy, or 5) the ongoing disease has little adverse effect on the patient. Furthermore, the use of placebo is considered advisable (2), "when the disease process is characterized by frequent spontaneous exacerbations and remissions." Certainly, peptic ulcer is such a disease. It has been argued that the decision to utilize placebo might he between only two individuals, the physician and his patient (3), hut realistically, many more must approve the trial, through multi-center participation, involvement by the pharmaceutical industry, and peer review (including human research committee approvals).     

Effects of Sitagliptin on Lipid Profiles in Patients With Type 2 Diabetes Mellitus: A Meta-analysis of Randomized Clinical Trials

Sitagliptin has been reported to improve lipid profiles, but findings from these studies are conflicting. We conducted this meta-analysis to evaluate the effects of sitagliptin on serum lipids in patients with type 2 diabetes mellitus.We made a comprehensive literature search in PubMed, EMBASE, Cochrane Library, China National Knowledge Infrastructure, Wanfang, and VIP database until June 2015. Eligible studies were randomized clinical trials (RCTs) that investigated the effect of sitagliptin on serum triglycerides (TGs), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), or high-density lipoprotein cholesterol (HDL-C).Eleven RCTs with 2338 patients were identified. Compared with controls, sitagliptin alone or in combination significantly improved serum TG (weighted mean difference [WMD] −0.24 mmol/L; 95% confidence interval [CI] −0.40 to −0.09; P = 0.002) and HDL-C (WMD 0.05 mmol/L; 95% CI 0.02–0.07; P < 0.001).However, no statistical significances were observed in LDL-C (WMD −0.07 mmol/L; 95% CI −0.22 to 0.08; P = 0.337) and TC (WMD −0.14; 95% CI −0.33 to 0.06; P = 0.177). Subgroup analyses revealed that sitagliptin alone achieved greater improvement in serum TG, TC, and HDL-C levels.These findings suggested that sitagliptin alone or in combination significantly improved serum TG and HDL-C levels in patients with type 2 diabetes mellitus.     

他汀类药物临床试验及应用最新进展

新近临床试验证实对高危患者降胆固醇治疗的益处 ,并提出低密度脂蛋白胆固醇 (LDL C)的最新控制目标是 <70mg/dl(1.81mmol/L) ,并进一步证实他汀类独立于降胆固醇之外的作用。     

Importance of Placebo Effect in Cough Clinical Trials

Cough is a unique symptom because, unlike sneeze and other symptoms, it can be under voluntary control and this complicates clinical trials on cough medicines. All over-the-counter cough medicines (OTC) are very effective treatments because of their placebo effect. The placebo effect is enhanced by expectancy related to advertising, brand, packaging, and formulation. This placebo effect creates a problem for the conduct of clinical trials on OTC cough medicines that attempt to demonstrate the efficacy of a pharmacological agent above that of any placebo effect. Up to 85% of the efficacy of some cough medicines can be attributed to a placebo effect. The placebo effect apparent in clinical trials consists of several components: natural recovery, regression of cough response toward mean, demulcent effect, effect of sweetness, voluntary control, and effects related to expectancy and meaning of the treatment. The placebo effect has been studied most in the pain model, and placebo analgesia is reported to depend on the activation of endogenous opioid systems in the brain; this model may be applicable to cough. A balanced placebo design may help to control for the placebo effect, but this trial design may not be acceptable due to deception of patients. The placebo effect in clinical trials may be controlled by use of a crossover design, where feasible, and the changes in the magnitude of the placebo effect in this study design are discussed.     

Patient-Reported Outcomes in Clinical Trials of Rare Diseases

The science of measuring patient-reported outcomes (PROs) has advanced substantially in recent decades, allowing evaluation of how patients feel and function in clinical research. Assessment of the patient experience in populations with rare diseases can be successfully achieved using PRO measures when careful planning and rigorous methods are employed. A number of challenges exist when designing and implementing PRO analyses in rare disease contexts, including heterogeneity of outcomes, availability of suitable measures, recruitment, and selection of appropriate data collection methods. Strategies to address these exist and have been employed in past clinical research, particularly in pediatric populations. PRO assessments in rare disease clinical trials have been particularly successful through partnerships between investigators, PRO methodologists, and patient organizations. The overall goal of PRO measurement is to understand the patient experience and it provides an essential part of evaluating the impact of disease and treatment.