Dietary Strategies for Remission of Type 2 Diabetes

Hypertension Clinical Trial

— CARBCOUNT  

Official title:

Dietary Strategies for Remission of Type 2 Diabetes - a Randomized Controlled Trial (CARBCOUNT)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04943926
• Other study ID #: CARBCOUNT Multicenter RCT
• Status: Recruiting
• Phase: N/A
• Start date: January 4, 2022
• Est. completion date: December 31, 2040

Study information

• Verified date: July 2022
• Source: University of Bergen
• Contact: Simon N Dankel, PhD
• Phone: +4794308637
• Email: Simon.Dankel[@]uib.no
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

In this project, the investigators will perform a multicenter randomised controlled trial to determine whether advice to consume a moderate, whole food-based low-carbohydrate high-fat (LCHF) ad libitum diet (CarbCount program) can produce and maintain equal remission rates of type 2 diabetes (T2D) as a nutritionally complete very-low-calorie formula diet followed by a energy-restrictive (i.e., calorie counting) diet (DiRECT principles). Within the principles of each approach, the dietary goals and change will be adjusted according to individual needs/capabilities conducive to long-term adherence. Furthermore, the investigators aim to determine whether the rate of diet-induced remission is reflected in/can be predicted by baseline or diet-induced changes in glucose variability (e.g., time-in-range measured by continuous glucose monitoring) and other factors such as anthropometric changes and genetic susceptibility. Each center will also conduct locally-lead standalone mechanistic research, including analyses of intra-abdominal/hepatic fat accumulation, adipose tissue biopsies and/or measurements of energy metabolism. Additionally, changes in medication use, nutritional status, cardiovascular disease risk, as well as adverse events, will be monitored.

Description:

At least 588 patients with T2D will be recruited, approximately 120-150 men and women at each research center. The participants will be randomised to 1) a nutritional complete formula diet for 3 months followed by an energy restricted diet for 12 months or 2) a very low-carbohydrate high-fat (VLCHF) diet for 3 months, followed by a low-carbohydrate high-fat diet (LCHF) for 12 months. Each of the diets will cover all basic requirements for essential nutrients including amino acids, fatty acids, vitamins and minerals. Participants will be encouraged to consume at least 200 g of vegetables per day. Furthermore, we will emphasize high-quality, minimally processed foods. In arm 2 they will receive advice to eat specific fat sources such as extra virgin olive oil, butter and high-fat cheeses.

The DiRECT trial showed remission in 46% of participants after 12 months. Assuming that both the DiRECT program and LCHF dietary strategies yield a 45% chance of T2D remission after 15 months, it is calculated (using nQuery v8) that each group needs 235 participants to complete the trial. This sample size yields 90% statistical power to conclude, with respect to the primary outcome, whether the CarbCount Program is no more than 15% more or less effective than the DiRECT principles (equivalence study, one-sided p-value at 0.025). To allow for expected loss to follow-up (estimated at 20%), each of the arms needs at least 294 participants for a total of 588.

Participants will have access to electronic platforms that include an online database of recipes (breakfast, easy-to-cook lunches, snacks, dinners, and food for special occasions). The platforms will facilitate planning of week menus, and include an e-learning course covering topics such as how to cook and prepare foods, meal planning, dining out, sleep and individual aspects that challenge habit change. If the participants are failing in their efforts to establish or maintain lifestyle change, they will be encouraged to seek possible solutions in the e-learning courses or to contact one of the study's health educators and/or dietitians. Specific rescue plans involving direct contact with study staff will be implemented if a participant regains more than 2 kg or experiences T2D relapse.

After individual assessment by a doctor, the participants will be taken off diabetes medication upon starting the diet, and be asked to self-monitor blood sugar changes during the first 2 weeks on the diet, followed by a consultation that includes evaluation of these changes. The need of reintroduction of medication will be done in consultation with the study doctor at least every 3 months.

Between visits, the participants will complete dietary assessments and an e-learning course, and at least once a month have follow-ups with dietitians/health educators and/or online group workshops.

The study will enroll eligible participants to the study continuously, until the total number of participants needed for the study is reached. Each participant will follow their own timeline, and attend visits at the study center at baseline, 3, 9 and 15 months.

During 2 weeks before each visit, participants will wear a continuous glucose monitor (CGM) and record food intake for at least 3 consecutive days during this period.

Measurements during visits will include anthropometric variables/body composition and energy expenditure, blood, saliva, urine and stool samples will be collected, and participants will be asked to fill out questionnaires on physical activity, sleep pattern, meal frequency, quality of life, problem areas in diabetes, eating efficacy and eating behaviors. They will also have a consultation with a registered dietitian and meet with the study medical doctor when needed.

A blinded statistician will perform the statistical analyses for the primary outcome of the study.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 600
• Est. completion date: December 31, 2040
• Est. primary completion date: December 31, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 24 Years to 70 Years

Eligibility

Inclusion Criteria:

• HbA1c =48 mmol/mol (with or without medical treatment)

• Less than 10 years since the diagnosis of T2D

• BMI =27 kg/m2 (=25 kg/m2 for Asians)

Exclusion Criteria:

• Treatment with insulin >25 IU

• HbA1c concentration of 12% or more (=108 mmol/mol)

• Insulin to C-peptide ratio <0.8 (indicative of insulin deficiency)

• Myocardial infarction within the previous 6 months, and severe or unstable heart failure or other severe diseases including cancer, psychiatric/eating disorders, severe depression and substance abuse

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 2
• Dyslipidemia Associated With Type II Diabetes Mellitus
• Dyslipidemias
• Glucose Intolerance
• Hypertension
• Insulin Resistance
• Overweight
• Overweight and Obesity

Intervention

Other:
• Energy restricted diet
Nutritional complete formula diet followed by an energy restricted diet
• Low carbohydrate high fat diet
Very low-carbohydrate high-fat ketogenic diet (VLCHF) diet followed by a low-carbohydrate high-fat diet (LCHF)

Locations

Country	Name	City	State
Norway	Department of Clinical Science	Bergen	Vestland

Sponsors (5)

Lead Sponsor	Collaborator
University of Bergen	Karolinska Institutet, Technische Universität München, University of Copenhagen, University of Glasgow

Country where clinical trial is conducted

Norway, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Rates of T2D remission dependent on polygenic risk scores for T2D	Polygenic risk scores are calculated based on the latest GWAS data for T2D, and rates of remission compared between patients with the top 20% high- and top 20% low scores, for all participants combined and the respective diets separately	3, 9 and 15 months
Other	Changes in ectopic fat accumulation from baseline	Body fat measured by MRI (abdominal adipose tissue distribution, hepatic-, intramuscular-, pericardial- and pancreatic fat)	3, 9 and 15 months
Other	Changes in liver fibrosis and steatosis from baseline	Liver fibrosis and steatosis measured by ultrasound-based transient elastography	3, 9 and 15 months
Other	Changes in markers of liver function from baseline	Alanine transaminase (ALT), C-reactive protein (CRP) and other markers of liver function measured in fasting blood samples	3, 9 and 15 months
Other	Changes in inflammatory markers from baseline	Circulating concentrations of selected markers of inflammation measured in fasting blood samples by ELISA	3, 9 and 15 months
Other	Changes in blood pressure and pulse from baseline	Blood pressure and pulse measured after 10 minutes in resting position	3, 9 and 15 months
Other	Change in CVD risk (NORRISK) from baseline	NORRISK calculated by the most current NORRISK calculator (https://hjerterisiko.helsedirektoratet.no/)	3, 9 and 15 months
Other	Changes in total-, low-density lipoprotein (LDL), high-density lipoprotein (HDL) and very-low-density (VLDL) cholesterol concentrations from baseline	Blood lipids measured in fasting blood samples	3, 9 and 15 months
Other	Changes in triacylglycerols (TGs) and TG/HDL-C ratio from baseline	Blood lipids measured in fasting blood samples	3, 9 and 15 months
Other	Changes in lipoprotein subfractions from baseline	Lipoprotein particle numbers and sizes (small/medium/large LDL, IDL, HDL, VLDL) measured in fasting blood samples	3, 9 and 15 months
Other	Changes in apolipoproteins from baseline	Apolipoproteins (including apoB, apoAs, ApoCs) measured in fasting blood samples	3, 9 and 15 months
Other	Changes in micronutrient status from baseline	Micronutrients measured in the circulation in fasting blood samples	3, 9 and 15 months
Other	Changes in gut and oral microbiota from baseline	Gut and oral microbiota measured by 16S sequencing in feces and saliva, respectively	3, 9 and 15 months
Other	Changes in appetite/satiety and ketones from baseline	Ghrelin and ketones measured in fasting blood samples, and correlations in the change of ghrelin and ketones (beta-hydroxybutyrate and acetoacetate) from baseline.	3, 9 and 15 months
Primary	Diabetes remission	Number of patients with diabetes remission, defined as no use of glucose-lowering drugs and HbA1c <48 mmol/mol (<6.5%) at 15 months	15 months
Secondary	Diabetes remission without anti-diabetes medications	Number of patients with HbA1c <48 and <42 mmol/mol at 3, 9 and 15 months, both on and off anti-diabetes medication (metformin etc.)	3, 9 and 15 months
Secondary	Changes in HbA1c and fasting glucose concentrations from baseline	HbA1c and fasting glucose concentrations (treatment targets in current clinical practice) measured in fasting blood samples	3, 9 and 15 months
Secondary	Changes in fasting insulin and insulin C-peptide concentrations from baseline	Insulin and insulin C-peptide measured in fasting blood samples	3, 9 and 15 months
Secondary	Changes in estimated insulin resistance and beta cell function from baseline	The HOMA2-calculator (https://www.dtu.ox.ac.uk/homacalculator/download.php) is used to estimate insulin resistance and beta cell function based on fasting glucose and C-peptide concentrations	3, 9 and 15 months
Secondary	Changes from baseline in the frequency of diabetes- and antihypertensive medication usage	The number of diabetes- and antihypertensive medications used/reintroduced by each study visit counted and compared between groups	3, 9 and 15 months
Secondary	Changes in eating behaviour from baseline and throughout the study	Eating behaviour measured by the The Weight Efficacy Lifestyle Questionnaire - Short form (WEL-SF). The questionnaire contains 8 items on a 10-point response scale (ranging from not at all confident/very confident). Responses to each item are given a score between 0-10, summed together and transformed to percentages. Changes in these scores will be compared between the study groups for the respective time-points throughout the intervention.	3, 9 and 15 months
Secondary	Changes in eating self-efficacy (Three-Factor Eating Questionnaire, TFEQ)	Eating self-efficacy assessed by the Three-Factor Eating Questionnaire (TFEQ), which measures 3 aspects of eating behaviour: cognitive restraint, uncontrolled eating, and emotional eating. The questionnaire consists of 18 items on a 4-point response scale ( ranging from definitely true/mostly true/mostly false/definitely false). Responses to each item are given a score between 1 and 4 and and total scores are summed by the 3 measured aspects mentioned above. The raw scale scores are transformed to a 0-100 scale. Changes in these scores will be compared between the study groups for the respective time-points throughout the intervention.	3, 9 and 15 months
Secondary	Changes in quality of life	Quality of life measured by the EQ-5D-5L questionnaire, which includes 5 dimensions: mobility, self-care, usual activities, pain /discomfort and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems and extreme problems. The levels are scored with a 1-digit number and the digits for the five dimensions are combined into a 5-digit number that describes the patient's health state. We will compare change at all timepoints between groups using both the 1-digit and the 5-digit number.; The questionnaire includes the patient's self-rated health on a Visual analog scale (VAS) ranging from 0-100. The endpoints are labelled "The best health you can imagine" and "The worst health you can imagine". The scale will be transposed into percentages and the percent change will be compared between the study groups.	3, 9 and 15 months