Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| Name | Class |
|---|---|
| University of South Florida | OTHER |
| Indiana University | OTHER |
Not provided
Not provided
Not provided
Not provided
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:
Participants will receive a combination of free meals, groceries, micronutrient supplements, and intensive diet and diabetes education for 9 months.
Comparison will be made between a ketogenic vs standard diet.
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, and 9 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 may be invited to 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. They may also be invited to participate in a follow-up visit to evaluate long-term effects after 24 months.
Not provided
Not provided
Not provided
Not provided
| Label | Type | Description | Intervention Names |
|---|---|---|---|
| ketogenic diet | Experimental | The diet will be high in protein and healthy fats and comprise meat, fish, fibrous vegetables, nuts, dairy, and berries. Macronutrient composition will be ~ 5% carbohydrate, 20% protein, 70% fat. Participants will receive a daily multi-vitamin, magnesium supplement, and supplemental salt (bouillon cubes) to ascertain micronutrient sufficiency and help with transition to the diet. |
|
| standard diet | Active Comparator | The diet will be consistent with prevailing dietary guidelines and recommendations and contain meat, fish, grains, vegetables, fruit and dairy. At least 50% of grain-based products will be whole grains. Meats will be primarily lean, and dairy products will be fat-free or low-fat. Macronutrient composition will be ~50% carbohydrate (<10% added sugars), 20% protein, 30% fat. Participants will receive a daily multi-vitamin supplement to ascertain micronutrient sufficiency. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Ketogenic diet, food delivery and education | Other | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| Decline in Beta-cell Function | Change in C-peptide 2-h area under the curve after a mixed-meal tolerance test (ΔCP). | Change over 1, 5, and 9 months, corrected for baseline |
| Measure | Description | Time Frame |
|---|---|---|
| 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 optional at 24 months |
| Duration of Clinical Diabetes Remission |
| Measure | Description | Time Frame |
|---|---|---|
| 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 optional at 24 months |
| Time above tight Range (TIR) >140 mg/dl |
Inclusion Criteria:
Exclusion Criteria:
Not provided
Not provided
Not provided
Not provided
| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Belinda Lennerz, MD PhD | Contact | 857-218-3896 | belinda.lennerz@childrens.harvard.edu |
| Name | Affiliation | Role |
|---|---|---|
| Belinda Lennerz | Boston Children's Hospital | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Boston Children's Hospital | Recruiting | Boston | Massachusetts | 02115 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 33393511 | Background | 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. | |
| 29735574 | Background | 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. |
Not provided
Not provided
Upon publication, de-identified raw data for each original article will be uploaded to the appropriate an NIH maintained repository.
Study protocol and statistical analysis plan will be shared prior to enrollment of the first participant.
De-identified data will be shared upon manuscript publication.
Data will be downloadable.
Not provided
Not provided
| ID | Term |
|---|---|
| D003922 | Diabetes Mellitus, Type 1 |
| D003920 | Diabetes Mellitus |
| ID | Term |
|---|---|
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D004700 | Endocrine System Diseases |
Not provided
Not provided
| ID | Term |
|---|---|
| D055423 | Diet, Ketogenic |
| D004522 | Educational Status |
| ID | Term |
|---|---|
| D050528 | Diet, Carbohydrate-Restricted |
| D004035 | Diet Therapy |
| D044623 | Nutrition Therapy |
| D013812 | Therapeutics |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| Standard diet, food delivery and education | Other | 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. |
|
Calculated based on percent children with insulin dose corrected HbA1c (IDAA1c) <9. |
| 1, 5, 9, and optional at 24 months |
| 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 optional at 24 months |
| 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 optional at 24 months |
| 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 optional at 24 months |
| 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 optional at 24 months |
| Average Blood Glucose | From CGM - will be computed throughout study participation in 2-week increments. | Over 9 months and optional at 24 months |
| 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 optional at 24 months |
| 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 optional at 24 months |
| 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 optional at 24 months |
| 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 optional at 24 months |
| BMI | Weight divided by height squared. | 1, 5, 9, and optional at 24 months |
| Lipid panel | Fasting blood - total, LDL and HDL cholesterol, and triglycerides. | 1, 5, 9, and optional at 24 months |
| HDL to Triglyceride Ratio | Fasting blood | 1, 5, 9, and optional at 24 months |
| Lipoprotein Subfractions | Fasting blood | 1, 5, 9, and optional at 24 months |
| Inflammasome, targeted | Interleukins 1β, 17, 23, 6, 10; high sensitivity c-reactive protein; tumor necrosis factor α, interferon gamma | 1, 5, 9, and optional at 24 months |
| 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 optional at 24 months |
| 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 optional at 24 months |
| Problem Areas in Diabetes (PAID-Ped) - child | Validated questionnaire, scored according to published standards. Scores range 0-100, higher scores indicate greater burden. | 1, 5, 9, and optional at 24 months |
| Problem Areas in Diabetes (PAID-PR) - parent | Validated questionnaire, scored according to published standards. Scores range 0-100, higher scores indicate greater burden. | 1, 5, 9, and optional at 24 months |
| 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, 5, 9, and optional at 24 months |
| 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, 5, 9, and optional at 24 months |
| 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, 5, 9, and optional at 24 months |
| 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, 5, 9, and optional at 24 months |
| Child Eating Disorder Examination Questionnaire (ChEDE-Q8) | Validated questionnaire, scored according to published standards. Scores range 0-42, higher scores are worse. | 1, 5, 9, and optional at 24 months |
| Perceptions on Diet Management of Diabetes | Questionnaire to assess participants' and caregivers' perceptions of the influence of the diet on their diabetes management. | 1, 5, 9, and optional at 24 months |
| Qualitative patient perspectives, interview - parent | Interviews will be held with children and caregivers separately after implementation and completion of the intervention. | optional at 9 months |
| Qualitative patient perspectives, interview - child | Interviews will be held with children and caregivers separately after implementation and completion of the intervention. | optional at 9 months |
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 optional at 24 months |
| BOHB (beta-hydroxybutyrate), fasting blood concentration | Obtained at daily increasing to weekly intervals as effect modifier of beta-cell function. | Over 9 months and optional at 24 months |
| 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 optional at 24 months |
| Growth velocity | Safety Measure - Growth velocity will be calculated from serial height measurements obtained during study visits. | 1, 5, 9, and optional at 24 months |
| 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, and optional at 24 months |
| 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 and optional at 24 months |
| 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 and optional at 24 months |
| 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 and optional at 24 months |
| 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 and optional at 24 months |
| Study termination for disordered eating | Safety Measure - ChEDE-Q8 diagnostic score with clinical confirmation. Total number of events. | Over 9 months |
| 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 |
| 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 |
| D001327 | Autoimmune Diseases |
| D007154 | Immune System Diseases |
| D004032 |
| Diet |
| D009747 | Nutritional Physiological Phenomena |
| D000066888 | Diet, Food, and Nutrition |
| D010829 | Physiological Phenomena |
| D012959 | Socioeconomic Factors |
| D011154 | Population Characteristics |