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Comparison of Visual Methods to Reanalyze Provocative Test Data from Randomized Controlled Clinical Trials in New- or
Brenda Orozco1, Kurt J Griffin1
1University of South Dakota Sanford School of Medicine.
Introduction:
Over the last 13 years, the Immune Tolerance Network (ITN), has conducted trials of agents to abrogate the autoimmunity underlying type 1 diabetes. Primary endpoints center on the change of C-peptide production during mixed meal tolerance tests (MMTT), measured as the area under the curve (AUC) or AUC mean over 2-3 years. Studies permit rapid-acting insulin until a few hours before the MMTT, and thus do not exclude overnight hyperglycemia prior to testing. We hypothesize that overnight or fasting hyperglycemia will deplete pre-formed insulin and impact measurements of first-phase insulin secretion and C-peptide AUC.
Methods:
Publicly available, deidentified, subject-level data were obtained from ITN TrialShare. We developed several graphical analyses to reexamine results from each MMTT including combined glucose and C-peptide response curves, the centroids of polygons of MMTT timepoints, and ratios comparing extents of excursions of glucose and c-peptide production.
Results:
We have applied these graphical analyses to 1161 MMTT from 245 subjects in 8 studies. Graphical analyses of MMTT results for individuals over the course of the follow-up period reflect the expected loss of c-peptide and higher blood glucose during MMTT; centroids move accordingly, upwards and leftwards.
Conclusions:
We were able to analyze MMTT data from ITN studies with several graphical analyses. We are poised to apply these approaches to test our central hypothesis by comparing how deviations from modeled rates of predicted changes for an individual over time correlate with blood glucose levels in the hours before a MMTT. This may lead to refinement of future trial protocols to ensure tighter regulation of glycemic excursions ahead of provocative testing.
Insights
Hyperglycemia before a mixed meal tolerance test (MMTT) may affect type 1 diabetes trial results. New graphical analyses of MMTT data could refine protocols for better glycemic control during testing.
Area of Science:
- Immunology
- Endocrinology
- Clinical Trials
Background:
- The Immune Tolerance Network (ITN) has studied type 1 diabetes (T1D) autoimmunity for 13 years.
- Primary endpoints in T1D trials often involve C-peptide production measured by mixed meal tolerance tests (MMTT) over 2-3 years.
- Current protocols allow rapid-acting insulin before MMTTs, potentially leading to overnight hyperglycemia that may impact results.
Purpose of the Study:
- To investigate the impact of overnight or fasting hyperglycemia on MMTT outcomes in type 1 diabetes.
- To hypothesize that pre-test hyperglycemia depletes insulin and affects first-phase insulin secretion and C-peptide area under the curve (AUC).
Main Methods:
- Utilized publicly available, deidentified subject-level data from ITN TrialShare.
- Developed novel graphical analyses to re-examine MMTT results, including glucose and C-peptide response curves.
- Employed analysis of centroids and ratios of glucose/C-peptide excursions.
Main Results:
- Applied graphical analyses to 1161 MMTTs from 245 subjects across 8 ITN studies.
- Observed expected declines in C-peptide and increases in blood glucose over time in MMTT results.
- Graphical analysis showed centroids moving upwards and leftwards, reflecting these changes.
Conclusions:
- Successfully analyzed MMTT data using novel graphical approaches.
- Prepared to test the hypothesis by correlating pre-MMTT glycemic levels with predicted changes.
- Potential to refine future clinical trial protocols for tighter glycemic regulation before provocative testing.
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