Carbohydrate Beta Cell Function and Glucose Control in Children With Diabetes

Diabetes Mellitus, Type 1 Clinical Trial

Official title:

Effect of Dietary Carbohydrate on Diabetes Control and Beta Cell Function in Children With Newly Diagnosed Diabetes

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05899166
• Other study ID #: IRB-P00044330
• Status: Recruiting
• Phase: N/A
• Start date: April 1, 2024
• Est. completion date: April 30, 2030

Study information

• Verified date: May 2024
• Source: Boston Children's Hospital
• Contact: Belinda Lennerz, MD PhD
• Phone: 857-218-3896
• Email: belinda.lennerz[@]childrens.harvard.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The goal of this clinical trial is to test the effects of a ketogenic diet on the progression and control of type 1 diabetes in children with newly diagnosed diabetes. The main questions to answer are: - Does a ketogenic diet prolong the honeymoon period of type 1 diabetes? - Does a ketogenic diet improve diabetes control? - Is a ketogenic diet safe, acceptable and sustainable in children with newly diagnosed diabetes? - What are the microbiome, inflammatory and metabolic changes linking diet to β-cell function? Participants will receive a combination of free meals, groceries, micronutrient supplements, and intensive diet and diabetes education for 9 months. - Diabetes care devices will be connected for cloud-based data collection. - Bi-weekly data downloads and remote check-ins will assess dietary intake, satisfaction with diet and study procedures, and possible safety concerns. - During five study visits held at at baseline, 1, 5, 9 and 24 months, an intravenous catheter (IV) will be placed for collection of 5 blood samples before and up to 2 hours after a liquid test meal (protein shake) to assess insulin response. A stool sample will also be collected to assess microbiome changes. - Children and their caregivers will participate in a semi-structured interview, and online questionnaires to assess their experience with the diet and diabetes care, general well-being and quality of life. Comparison will be made between a ketogenic vs standard diet.

Description:

Type I diabetes is caused by an autoimmune destruction of insulin producing β-cells in the pancreas, resulting in absolute insulin deficiency. In the first months after diagnosis, a small number of β-cells typically remain and, by producing insulin, significantly improve diabetes control and reduce disease burden. Preliminary data suggest that this early disease stage entitled the "honeymoon period" might be extended by a ketogenic diet, which would provide a major therapeutic advantage and may reduce chronic disease burden. To test the hypothesis that a ketogenic vs. standard diet will extend the honeymoon period and improve diabetes control in children, the researchers are conducting a study employing education and food deliveries of a ketogenic or standard diet to children and their families. Fifty-two children aged 5 to 12 years with newly diagnosed diabetes will participate. Children will be assigned by chance (randomized) to receive either a ketogenic or a standard diet for 9 months. Chances to be assigned to either diet are 50:50 like a coin flip, and 26 children will participate in each diet arm. Participants will receive a combination of free meals, groceries, micronutrient supplements, and intensive diet and diabetes education throughout the 9 months. Continuous glucose monitoring (CGM) and diaries will be used for cloud-based data collection. Bi-weekly data downloads and remote check-ins will be performed to assess dietary intake, satisfaction with diet and study procedures, and possible safety concerns. Participants are instructed to measure blood ketone levels with their home ketone meter anytime blood glucose levels exceed a safety threshold and to call the study physician for persistent low glucose levels or ketones above diet specific safety thresholds. Study visits are held at at baseline, 1, 5, 9 and 24 months to collect height, weight, stool and blood samples for hormones, metabolites and inflammatory biomarkers. At each visit, an intravenous catheter (IV) will be placed to collect fasting blood samples, followed by a liquid test meal (protein shake) and collection of four additional blood samples from the IV over the course of two hours. Prior to each visit, participants will collect stool samples at home using provided kits. In addition, participants and their families will participate in a semi-structured interview, and online questionnaires to asses their food intake, experience with the diet, diabetes care burden and complications, and general well-being and quality of life.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 52
• Est. completion date: April 30, 2030
• Est. primary completion date: April 30, 2029
• Accepts healthy volunteers: No
• Gender: All
• Age group: 5 Years to 12 Years

Eligibility

Inclusion Criteria:

• Children aged 5 to 12 years.
• Within one month of diabetes diagnosis.
• Type 1 diabetes confirmed by immediate insulin requirement with autoimmunity markers (=2 positive antibodies [glutamate decarboxylase-65, islet-antigen-2, zinc transporter-8, insulin [prior to first insulin dose]).
• Family committed and able to participate in study education and implement dietary intervention.

Exclusion Criteria:

• Dietary needs or habits incompatible with the study meal plans, (e.g., vegan, major food intolerances/allergies, ketogenic).
• Eating disorders as assessed by Chede-Q8.
• Major medical illness or use of medications other than insulin that could interfere with metabolic or glycemic variables.
• Major psychiatric illness.

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 1

Intervention

Other:
• Ketogenic diet, food delivery and education
Meals and groceries will be delivered and participants will receive education on nutrition, meal preparation, and diabetes care strategies. Participants will consume study-prescribed foods exclusively.
• Standard diet, food delivery and education
Meals and groceries will be delivered and participants will receive education on nutrition, meal preparation, and diabetes care strategies. Participants will consume study-prescribed foods exclusively.

Locations

Country	Name	City	State
United States	Boston Children's Hospital	Boston	Massachusetts

Sponsors (3)

Lead Sponsor	Collaborator
Boston Children's Hospital	Indiana University, University of South Florida

Country where clinical trial is conducted

United States, 

References & Publications (2)

Lennerz BS, Barton A, Bernstein RK, Dikeman RD, Diulus C, Hallberg S, Rhodes ET, Ebbeling CB, Westman EC, Yancy WS Jr, Ludwig DS. Management of Type 1 Diabetes With a Very Low-Carbohydrate Diet. Pediatrics. 2018 Jun;141(6):e20173349. doi: 10.1542/peds.2017-3349. Epub 2018 May 7. — View Citation

Lennerz BS, Koutnik AP, Azova S, Wolfsdorf JI, Ludwig DS. Carbohydrate restriction for diabetes: rediscovering centuries-old wisdom. J Clin Invest. 2021 Jan 4;131(1):e142246. doi: 10.1172/JCI142246. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Time in tight Range (TIR) 70-140 mg/dl	From CGM - percent time spent in the specified glycemic target range will be computed throughout study participation in 2-week increments.	Over 9 months and at 21 months
Other	Time above tight Range (TIR) >140 mg/dl	From CGM - percent time spent in the specified glycemic target range will be computed throughout study participation in 2-week increments.	Over 9 months and at 24 months
Other	BOHB (beta-hydroxybutyrate), fasting blood concentration	Obtained at daily increasing to weekly intervals as effect modifier of beta-cell function.	Over 9 months and at 24 months
Other	Growth	Safety Measure - Height standard deviation score will be calculated from serial height measurements obtained during study visits using CDC age and sex specific references.	1, 5, 9, and 24 months
Other	Growth velocity	Safety Measure - Growth velocity will be calculated from serial height measurements obtained during study visits.	1, 5, 9, and 24 months
Other	Weigh-gain	Safety Measure - Weight SDS and gain will be calculated from serial weight measures obtained during study visits with calibrated scale.	1, 5, 9, 24 months
Other	Confirmed Ketoacidosis	Safety Measure - Defined by elevated BOHB, blood pH <7.3 and serum bicarbonate <15. Rates will be computed as total number of events divided by total patient years of follow-up.	Over 9 months
Other	Severe Hypoglycemia	Safety Measure - Defined as blood glucose < 55 mg/dl and requiring glucagon or resulting in seizure or coma. Rates will be computed as total number of events divided by total patient years of follow-up.	Over 9 months
Other	Diabetes Related Emergency Visits	Safety Measure - Rates will be computed as total number of events divided by total patient years of follow-up.	Over 9 months
Other	Diabetes Related Hospitalizations	Safety Measure - Rates will be computed as total number of events divided by total patient years of follow-up.	Over 9 months
Other	Study termination for disordered eating	Safety Measure - ChEDE-Q8 diagnostic score with clinical confirmation. Total number of events.	Over 9 months
Other	Study termination for growth deceleration	Safety Measure - Undesired weight loss or significant deceleration in longitudinal growth may warrant termination of study participation. Total number of events will be computed.	Over 9 months
Other	Study termination for dyslipidemia	Safety Measure - LDL >200 mg/dl will trigger review of additional risk factors and may prompt diet modification to lower intake of saturated fats. If persistent, study participation may be terminated. Total number of events will be computed.	Over 9 months
Primary	Decline in Beta-cell Function	Change in C-peptide 2-h area under the curve after a mixed-meal tolerance test (?CP).	Change over 1, 5, and 9 months, corrected for baseline
Secondary	Time in Range (TIR) 70-180 mg/dl	From continuous glucose monitoring (CGM) - percent time spent in the specified glycemic target range will be computed throughout study participation in 2-week increments.	Over 9 months and at 24 months
Secondary	Longitudinal Change in Beta-cell Function	C-peptide 2-h area under the curve after a mixed-meal tolerance test.	1, 5, and 24 months
Secondary	Duration of Clinical Diabetes Remission	Calculated based on percent children with insulin dose corrected HbA1c (IDAA1c) <9.	1, 5, 9, and 24 months
Secondary	Time in low Range (TIR) <70 mg/dl	From CGM - percent time spent in the specified glycemic target range will be computed throughout study participation in 2-week increments.	Over 9 months and at 24 months
Secondary	Time in very low Range (TIR) <55 mg/dl	From CGM - percent time spent in the specified glycemic target range will be computed throughout study participation in 2-week increments.	Over 9 months and at 24 months
Secondary	Time in high Range (TIR) >180 mg/dl	From CGM - percent time spent in the specified glycemic target range will be computed throughout study participation 2-week increments.	Over 9 months and at 24 months
Secondary	Time in very high Range (TIR) >250 mg/dl	From CGM - percent time spent in the specified glycemic target range will be computed throughout study participation in 2-week increments.	Over 9 months and at 24 months
Secondary	Average Blood Glucose	From CGM - will be computed throughout study participation in 2-week increments.	Over 9 months and at 24 months
Secondary	Coefficient of Glycemic Variation (CV)	From CGM - will be computed by dividing glucose standard deviation by glucose average throughout study participation in 2-week increments.	Over 9 months and at 24 months
Secondary	Mean Amplitude of Glycemic Excursions (MAGE)	From CGM - will be computed using published formula throughout study participation in 2-week increments.	Over 9 months and at 24 months
Secondary	Total Daily Insulin Dose	From insulin administration device uploads - will be computed in units per kg throughout study participation in 2-week increments.	Over 9 months and at 24 months
Secondary	HOMA-IR (Homeostatic Model Assessment for Insulin Resistance)	Calculated from fasting blood draw [fasting insulin (µU/ml) × fasting plasma glucose (mg/dl)]/405.	1, 5, 9, and 24 months
Secondary	BMI	Weight divided by height squared.	1, 5, 9, and 24 months
Secondary	Lipid panel	Fasting blood - total, LDL and HDL cholesterol, and triglycerides.	1, 5, 9, and 24 months
Secondary	HDL to Triglyceride Ratio	Fasting blood	1, 5, 9, and 24 months
Secondary	Lipoprotein Subfractions	Fasting blood	1, 5, 9, and 24 months
Secondary	Inflammasome, targeted	Interleukins 1ß, 17, 23, 6, 10; high sensitivity c-reactive protein; tumor necrosis factor a, interferon gamma	1, 5, 9, and 24 months
Secondary	Microbiome, targeted and untargeted	Extraction and sequencing will be performed by Qiagen PowerSoil DNA extraction using Qiagen's DNeasy 96 PowerSoil Pro QIAcube HT Kit (480), followed by whole genome sequencing (WGS) using a miniaturized version of the NEBNext Ultra FS II method.	1, 5, 9, and 24 months
Secondary	Metabolome, targeted and untargeted	Blood samples will be processed using liquid chromatography-mass spectrometry (LC-MS) and nuclear magnetic resonance (NMR). The LC-MS analyses will be carried out on a Sciex triple quadrupole mass spectrometer couple to an Exion ultra-performance LC system. The targeted analysis will utilize the Biocrates Q500 targeted metabolomics assay which quantifies more than 500 metabolites over 26 chemical classes (Biocrates Inc., Innsbruck, Austria). Data processing to yield metabolite concentrations in micromolar units will utilize the Biocrates MetIDQ software. The NMR data will be acquired on a Bruker Avance NEO 700 MHz NMR equipped with a TCI cryoprobe and a SampleXPress automatic sample changer. The data will be processed using the Chenomx NMR Processor and Profiler packages (Chenomx, Edmonton, CA) to yield quantitative data in millimolar units.	1, 5, 9, and 24 months
Secondary	Problem Areas in Diabetes (PAID-Ped) - child	Validated questionnaire, scored according to published standards. Scores range 0-100, higher scores indicate greater burden.	1, 3, 5, 7, 9, and 24 months
Secondary	Problem Areas in Diabetes (PAID-PR) - parent	Validated questionnaire, scored according to published standards. Scores range 0-100, higher scores indicate greater burden.	1, 3, 5, 7, 9, and 24 months
Secondary	Pediatric Quality of Life (PEDSQL) General Module - parent	Validated questionnaire, scored according to published standards. Scores range 0-100, higher scores indicate better quality of life.	1, 3, 5, 7, 9, and 24 months
Secondary	Pediatric Quality of Life (PEDSQL) General Module - child	Validated questionnaire, scored according to published standards. Scores range 0-100, higher scores indicate better quality of life.	1, 3, 5, 7, 9, and 24 months
Secondary	Pediatric Quality of Life (PEDSQL) Diabetes Module - parent	Validated questionnaire, scored according to published standards. Scores range 0-100, higher scores indicate less problems.	1, 3, 5, 7, 9, and 24 months
Secondary	Pediatric Quality of Life (PEDSQL) Diabetes Module - child	Validated questionnaire, scored according to published standards. Scores range 0-100, higher scores indicate less problems.	1, 3, 5, 7, 9, and 24 months
Secondary	Child Eating Disorder Examination Questionnaire (ChEDE-Q8)	Validated questionnaire, scored according to published standards. Scores range 0-42, higher scores are worse.	1, 3, 5, 7, 9, and 24 months
Secondary	Perceptions on Diet Management of Diabetes	Questionnaire to assess participants' and caregivers' perceptions of the influence of the diet on their diabetes management.	1, 3, 5, 7, 9, and 24 months
Secondary	Qualitative patient perspectives, interview - parent	Interviews will be held with children and caregivers separately after implementation and completion of the intervention.	9 months
Secondary	Qualitative patient perspectives, interview - child	Interviews will be held with children and caregivers separately after implementation and completion of the intervention.	9 months