Use of comprehensive recruitment strategies in the glycemia reduction approaches in diabetes: A comparative effectiveness study (GRADE) multi-center clinical trial

Background/Aims: We present and describe recruitment strategies implemented from 2013 to 2017 across 45 clinical sites in the United States, participating in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study, an unmasked, randomized controlled trial evaluating four glucose-lowering medications added to metformin in individuals with type 2 diabetes mellitus (duration of diabetes <10 years). We examined the yield of participants recruited through Electronic Health Records systems compared to traditional recruitment methods to leverage access to type 2 diabetes patients in primary care. Methods: Site selection criteria included availability of the study population, geographic representation, the ability to recruit and retain a diverse pool of participants including traditionally underrepresented groups, and prior site research experience in diabetes clinical trials. Recruitment initiatives were employed to support and monitor recruitment, such as creation of a Recruitment and Retention Committee, development of criteria for Electronic Health Record systems queries, conduct of remote site visits, development of a public screening website, and other central and local initiatives. Notably, the study supported a dedicated recruitment coordinator at each site to manage local recruitment and facilitate screening of potential participants identified by Electronic Health Record systems. Results: The study achieved the enrollment goal of 5000 participants, meeting its target with Black/African American (20%), Hispanic/Latino (18%), and age ≧60 years (42%) subgroups but not with women (36%). Recruitment required 1 year more than the 3 years originally planned. Sites included academic hospitals, integrated health systems, and Veterans Affairs Medical Centers. Participants were enrolled through Electronic Health Record queries (68%), physician referral (13%), traditional mail outreach (7%), TV, radio, flyers, and Internet (7%), and other strategies (5%). Early implementation of targeted Electronic Health Record queries yielded a greater number of eligible participants compared to other recruitment methods. Efforts over time increasingly emphasized engagement with primary care networks. Conclusion: Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness successfully recruited a diverse study population with relatively new onset of type 2 diabetes mellitus, relying to a large extent on the use of Electronic Health Record to screen potential participants. A comprehensive approach to recruitment with frequent monitoring was critical to meet the recruitment goal

Mapping Site-Specific Changes that Affect Stability of the NTerminal Domain of Calmodulin

Biophysical tools have been invaluable in formulating therapeutic proteins. These tools characterize protein stability rapidly in a variety of solution conditions, but in general, the techniques lack the ability to discern site-specific information to probe how solution environment acts to stabilize or destabilize the protein. NMR spectroscopy can provide site-specific information about subtle structural changes of a protein under different conditions, enabling one to assess the mechanism of protein stabilization. In this study, NMR was employed to detect structural perturbations at individual residues as a result of altering pH and ionic strength. The N-terminal domain of calmodulin (N-CaM) was used as a model system, and the 1H-15N heteronuclear single quantum coherence (HSQC) experiment was used to investigate effects of pH and ionic strength on individual residues. NMR analysis revealed that different solution conditions affect individual residues differently, even when the amino acid sequence and structure are highly similar. This study shows that addition of NMR to the formulation toolbox has the ability to extend understanding of the relationship between site-specific changes and overall protein stability

Study of emotional distress in a comparative effectiveness trial of diabetes treatments: Rationale and design.

Emotional distress, including depression and diabetes-specific distress (e.g., feeling overwhelmed by living with diabetes, feelings of failure related to diabetes self-care), is a significant and prevalent problem for patients with type 2 diabetes. Both depression and diabetes distress have been associated with metabolic/glycemic control, diabetes complications, mortality, and quality of life. Recent findings further suggest that risk for emotional distress is influenced by diabetes treatment. The GRADE Study (Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study) is generating prospective data that will provide a unique opportunity to examine the relationships between emotional distress, diabetes treatment, and outcomes in an experimental design. The GRADE study is a randomized clinical trial that will compare the metabolic effects of four common anti-hyperglycemic drugs when combined with metformin. This sub-study recruited a subset (n = 1739) of GRADE participants and will examine patient-level variation in baseline emotional distress as a predictor of glycemic control and other health outcomes, independent of treatment effects. The study will also provide an experimental examination of treatment regimen effects on emotional distress over time as part of the overall evaluation of comparative effectiveness. Evaluation of emotional distress using validated measures will allow us to disentangle the roles of depressive symptoms and diabetes distress, factors that share significant overlap but require distinct approaches to screening and treatment. Study findings may directly influence practice decisions regarding screening and treatment for emotional distress as part of diabetes care

Fall in C-peptide during first 2 years from diagnosis: evidence of at least two distinct phases from composite Type 1 Diabetes TrialNet data.

Interpretation of clinical trials to alter the decline in β-cell function after diagnosis of type 1 diabetes depends on a robust understanding of the natural history of disease. Combining data from the Type 1 Diabetes TrialNet studies, we describe the natural history of β-cell function from shortly after diagnosis through 2 years post study randomization, assess the degree of variability between patients, and investigate factors that may be related to C-peptide preservation or loss. We found that 93% of individuals have detectable C-peptide 2 years from diagnosis. In 11% of subjects, there was no significant fall from baseline by 2 years. There was a biphasic decline in C-peptide; the C-peptide slope was -0.0245 pmol/mL/month (95% CI -0.0271 to -0.0215) through the first 12 months and -0.0079 (-0.0113 to -0.0050) from 12 to 24 months (P < 0.001). This pattern of fall in C-peptide over time has implications for understanding trial results in which effects of therapy are most pronounced early and raises the possibility that there are time-dependent differences in pathophysiology. The robust data on the C-peptide obtained under clinical trial conditions should be used in planning and interpretation of clinical trials

Nutritional Intervention to Prevent (NIP) Type 1 Diabetes A Pilot Trial

The objective of this study was to describe a pilot trial of using an omega-3 fatty acid (docosahexaenoic acid [DHA]) to prevent islet cell autoimmunity in infants with an increased risk for developing type 1 diabetes (T1D). Infants from pregnant mothers who either have T1D (or the father or a previous child has T1D) and who entered the study in the third trimester or infants younger than age 5 months having a first-degree family member with T1D were eligible for the study. Infants from either group also had to have an increased genetic (HLA) risk for T1D (or multiple first-degree relatives with T1D) to be eligible. The study is a multicenter, 2-arm, randomized, double-masked clinical trial that will last 4 years (1 year of recruitment and 3 years of treatment). Treatment with DHA (or control) began in the last trimester of pregnancy or in the first 5 months after birth. Inflammatory mediators, including cytokines, chemokines, eicosanoids, and C-reactive protein, are being measured along with fatty acids in maternal and infant blood. Ninety-eight infants were enrolled (41 during pregnancy and 57 in the 5 months after birth). HLA results of the 97 eligible infants (1 infant had a protective 0602 allele and was thus ineligible) showed that 90 have DR3 and/or DR4. Seven infants were enrolled without DR3/4 but who instead had multiple first-degree relatives with T1D. Compliance has been excellent, and no families have discontinued participation. Intervention trials in this high-risk group are feasible but require significant effort to identify potential participants