Clinical trial NCT04943926: Dietary Strategies for Remission of Type 2 Diabetes
Official title: Dietary Strategies for Remission of Type 2 Diabetes - a Randomized Controlled Trial (CARBCOUNT)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Diabetes Mellitus, Type 2
Overweight and Obesity
Hypertension
Glucose Intolerance
Insulin Resistance
Dyslipidemia Associated With Type II Diabetes Mellitus
Keywords: Low-carbohydrate high-fat diet
Energy restricted diet
Lifestyle change
Ketogenic diet
Total meal replacement
Lead sponsor: University of Bergen
Sponsor class: OTHER
Collaborators: name: Karolinska Institutet
name: University of Glasgow
name: University of Copenhagen
name: Technical University of Munich
First posted: 2021-06-29
Enrollment: 600
Sex: ALL
Minimum age (years): 24
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomised controlled trail (RCT)
Primary purpose: TREATMENT

Brief 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.

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: Diabetes remission
timeFrame: 15 months
Secondary outcomes:
measure: Diabetes remission without anti-diabetes medications
timeFrame: 3, 9 and 15 months
measure: Changes in HbA1c and fasting glucose concentrations from baseline
timeFrame: 3, 9 and 15 months
measure: Changes in fasting insulin and insulin C-peptide concentrations from baseline
timeFrame: 3, 9 and 15 months
measure: Changes in estimated insulin resistance and beta cell function from baseline
timeFrame: 3, 9 and 15 months
measure: Changes from baseline in the frequency of diabetes- and antihypertensive medication usage
timeFrame: 3, 9 and 15 months
measure: Changes in eating behaviour from baseline and throughout the study
timeFrame: 3, 9 and 15 months
measure: Changes in eating self-efficacy (Three-Factor Eating Questionnaire, TFEQ)
timeFrame: 3, 9 and 15 months
measure: Changes in quality of life
timeFrame: 3, 9 and 15 months
Other outcomes:
measure: Rates of T2D remission dependent on polygenic risk scores for T2D
timeFrame: 3, 9 and 15 months
measure: Changes in ectopic fat accumulation from baseline
timeFrame: 3, 9 and 15 months
measure: Changes in liver fibrosis and steatosis from baseline
timeFrame: 3, 9 and 15 months
measure: Changes in markers of liver function from baseline
timeFrame: 3, 9 and 15 months
measure: Changes in inflammatory markers from baseline
timeFrame: 3, 9 and 15 months
measure: Changes in blood pressure and pulse from baseline
timeFrame: 3, 9 and 15 months
measure: Change in CVD risk (NORRISK) from baseline
timeFrame: 3, 9 and 15 months
measure: Changes in total-, low-density lipoprotein (LDL), high-density lipoprotein (HDL) and very-low-density (VLDL) cholesterol concentrations from baseline
timeFrame: 3, 9 and 15 months
measure: Changes in triacylglycerols (TGs) and TG/HDL-C ratio from baseline
timeFrame: 3, 9 and 15 months
measure: Changes in lipoprotein subfractions from baseline
timeFrame: 3, 9 and 15 months
measure: Changes in apolipoproteins from baseline
timeFrame: 3, 9 and 15 months
measure: Changes in micronutrient status from baseline
timeFrame: 3, 9 and 15 months
measure: Changes in gut and oral microbiota from baseline
timeFrame: 3, 9 and 15 months
measure: Changes in appetite/satiety and ketones from baseline
timeFrame: 3, 9 and 15 months
Locations:
city: Bergen
country: Norway
facility: Department of Clinical Science
state: Vestland
Study officials:
References: