TY - JOUR
T1 - A Pilot randomized trial to examine effects of a hybrid closed-loop insulin delivery system on neurodevelopmental and cognitive outcomes in adolescents with type 1 diabetes
AU - the Diabetes Research in Children Network (DirecNet) Consortium
AU - Reiss, Allan L.
AU - Jo, Booil
AU - Arbelaez, Ana Maria
AU - Tsalikian, Eva
AU - Buckingham, Bruce
AU - Weinzimer, Stuart A.
AU - Fox, Larry A.
AU - Cato, Allison
AU - White, Neil H.
AU - Tansey, Michael
AU - Aye, Tandy
AU - Tamborlane, William
AU - Englert, Kimberly
AU - Lum, John
AU - Mazaika, Paul
AU - Foland-Ross, Lara
AU - Marzelli, Matthew
AU - Mauras, Nelly
AU - Tong, Gabby
AU - Shen, Hanyang
AU - Li, Zetan
AU - Kingman, Ryan
AU - Levandoski, Lucy
AU - Coffey, Julie
AU - Bisbee, Rachel
AU - Stephen, Amy
AU - Weyman, Kate
AU - Bird, Keisha
AU - Ponthieux, Kimberly
AU - Marrero, Juan
N1 - Funding Information:
The authors are grateful to University of Florida Shands Jacksonville Medical Center (Jacksonville, FL), University of California at San Francisco (San Francisco, CA), and El Camino Hospital (Mountain View, CA) for MRI technologist support and use of their neuroimaging facilities; to the Juvenile Diabetes Research Foundation for support of the Jaeb Center for Health Research glucose analytics; to the members of the Data Safety Management Board, Mark Sperling, MD (Chair), Emeritus University of Pittsburgh (PA), Dorothy M. Becker, MBBCh, University of Pittsburgh, Carla Greenbaum, MD, Benaroya Research Institute, Seattle, WA, Antoinette Moran, MD, University of Minnesota, Minneapolis, MN and Jane Khoury, PhD, Cincinnati Children’s Hospital, Cincinnati, OH; to Medtronic for their generous supply of the 670 G HCL system used; to LifeScan, Inc. for their supply of glucose test strips; to Dr. Karen Winer, NICHD Program Officer for her unwavering support of this project; and to the children with type 1 diabetes and their parents who participated in this trial. Finally, the first author wishes to thank his late father, Dr. Robert Reiss, for inspiration to work in the field of diabetes. This research was supported by grants from the National Institutes of Health (NIH) Eunice Kennedy Shriver National Institute of Child Health and Human Development 5R01-HD-078463 (Mauras, Reiss, PIs), and by a grant from the Juvenile Diabetes Research Foundation (Jaeb Center for Health Research). None of the sponsors of this research contributed to study design, data collection, or manuscript writing.
Funding Information:
N.M. had institutional device supply agreements from Medtronic for CGM and LifeScan for test strips for the study, research support from Novo Nordisk. B.B. had consultant agreements with Medtronic Diabetes, Novo Nordisk, Dexcom, ConvaTec, Lilly, and Tolerion; has provided expert testimony for Dexcom; and has research grants with Insulet, Tandem, Medtronic, and Beta Bionics. E.T. had institutional research grants with AstraZeneca, Boehringer Ingelheim, Novo Nordisk, Grifols Therapeutics, Takeda, and Amgen. S.A.W. had consultant agreements with Zealand; institutional grant support from Abbott and Medtronic; and speaker honoraria from Abbott, Dexcom, and Insulet. L.A.F. had a device supply agreement with Dexcom. A.M.A. had a device supply agreement with Dexcom. M.T. had a data safety monitoring board agreement with Daiichi Sankyo. W.T. had consultant agreements with AstraZeneca, Boehringer Ingelheim, Eli Lilly, Novo Nordisk, and Sanofi and data safety monitoring board agreements with Eisai, MannKind, and Tolerion. K.E. had a consultant agreement with PicoLife Technology. J.L. received consulting fees, paid to his institution, from Animas Corporation, Bigfoot Biomedical, Tandem Diabetes Care, and Eli Lilly and Company. No other potential competing interests relevant to this article were reported.
Funding Information:
The authors are grateful to University of Florida Shands Jacksonville Medical Center (Jacksonville, FL), University of California at San Francisco (San Francisco, CA), and El Camino Hospital (Mountain View, CA) for MRI technologist support and use of their neuroimaging facilities; to the Juvenile Diabetes Research Foundation for support of the Jaeb Center for Health Research glucose analytics; to the members of the Data Safety Management Board, Mark Sperling, MD (Chair), Emeritus University of Pittsburgh (PA), Dorothy M. Becker, MBBCh, University of Pittsburgh, Carla Greenbaum, MD, Benaroya Research Institute, Seattle, WA, Antoinette Moran, MD, University of Minnesota, Minneapolis, MN and Jane Khoury, PhD, Cincinnati Children’s Hospital, Cincinnati, OH; to Medtronic for their generous supply of the 670 G HCL system used; to LifeScan, Inc. for their supply of glucose test strips; to Dr. Karen Winer, NICHD Program Officer for her unwavering support of this project; and to the children with type 1 diabetes and their parents who participated in this trial. Finally, the first author wishes to thank his late father, Dr. Robert Reiss, for inspiration to work in the field of diabetes. This research was supported by grants from the National Institutes of Health (NIH) Eunice Kennedy Shriver National Institute of Child Health and Human Development 5R01-HD-078463 (Mauras, Reiss, PIs), and by a grant from the Juvenile Diabetes Research Foundation (Jaeb Center for Health Research). None of the sponsors of this research contributed to study design, data collection, or manuscript writing.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - Type 1 diabetes (T1D) is associated with lower scores on tests of cognitive and neuropsychological function and alterations in brain structure and function in children. This proof-of-concept pilot study (ClinicalTrials.gov Identifier NCT03428932) examined whether MRI-derived indices of brain development and function and standardized IQ scores in adolescents with T1D could be improved with better diabetes control using a hybrid closed-loop insulin delivery system. Eligibility criteria for participation in the study included age between 14 and 17 years and a diagnosis of T1D before 8 years of age. Randomization to either a hybrid closed-loop or standard diabetes care group was performed after pre-qualification, consent, enrollment, and collection of medical background information. Of 46 participants assessed for eligibility, 44 met criteria and were randomized. Two randomized participants failed to complete baseline assessments and were excluded from final analyses. Participant data were collected across five academic medical centers in the United States. Research staff scoring the cognitive assessments as well as those processing imaging data were blinded to group status though participants and their families were not. Forty-two adolescents, 21 per group, underwent cognitive assessment and multi-modal brain imaging before and after the six month study duration. HbA1c and sensor glucose downloads were obtained quarterly. Primary outcomes included metrics of gray matter (total and regional volumes, cortical surface area and thickness), white matter volume, and fractional anisotropy. Estimated power to detect the predicted treatment effect was 0.83 with two-tailed, α = 0.05. Adolescents in the hybrid closed-loop group showed significantly greater improvement in several primary outcomes indicative of neurotypical development during adolescence compared to the standard care group including cortical surface area, regional gray volumes, and fractional anisotropy. The two groups were not significantly different on total gray and white matter volumes or cortical thickness. The hybrid closed loop group also showed higher Perceptual Reasoning Index IQ scores and functional brain activity more indicative of neurotypical development relative to the standard care group (both secondary outcomes). No adverse effects associated with study participation were observed. These results suggest that alterations to the developing brain in T1D might be preventable or reversible with rigorous glucose control. Long term research in this area is needed.
AB - Type 1 diabetes (T1D) is associated with lower scores on tests of cognitive and neuropsychological function and alterations in brain structure and function in children. This proof-of-concept pilot study (ClinicalTrials.gov Identifier NCT03428932) examined whether MRI-derived indices of brain development and function and standardized IQ scores in adolescents with T1D could be improved with better diabetes control using a hybrid closed-loop insulin delivery system. Eligibility criteria for participation in the study included age between 14 and 17 years and a diagnosis of T1D before 8 years of age. Randomization to either a hybrid closed-loop or standard diabetes care group was performed after pre-qualification, consent, enrollment, and collection of medical background information. Of 46 participants assessed for eligibility, 44 met criteria and were randomized. Two randomized participants failed to complete baseline assessments and were excluded from final analyses. Participant data were collected across five academic medical centers in the United States. Research staff scoring the cognitive assessments as well as those processing imaging data were blinded to group status though participants and their families were not. Forty-two adolescents, 21 per group, underwent cognitive assessment and multi-modal brain imaging before and after the six month study duration. HbA1c and sensor glucose downloads were obtained quarterly. Primary outcomes included metrics of gray matter (total and regional volumes, cortical surface area and thickness), white matter volume, and fractional anisotropy. Estimated power to detect the predicted treatment effect was 0.83 with two-tailed, α = 0.05. Adolescents in the hybrid closed-loop group showed significantly greater improvement in several primary outcomes indicative of neurotypical development during adolescence compared to the standard care group including cortical surface area, regional gray volumes, and fractional anisotropy. The two groups were not significantly different on total gray and white matter volumes or cortical thickness. The hybrid closed loop group also showed higher Perceptual Reasoning Index IQ scores and functional brain activity more indicative of neurotypical development relative to the standard care group (both secondary outcomes). No adverse effects associated with study participation were observed. These results suggest that alterations to the developing brain in T1D might be preventable or reversible with rigorous glucose control. Long term research in this area is needed.
UR - http://www.scopus.com/inward/record.url?scp=85136949369&partnerID=8YFLogxK
U2 - 10.1038/s41467-022-32289-x
DO - 10.1038/s41467-022-32289-x
M3 - Article
C2 - 36042217
AN - SCOPUS:85136949369
SN - 2041-1723
VL - 13
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 4940
ER -