Clinical trial NCT05769335: Calories or Time Restriction to Alter Biomarkers of Aging and Diabetes
Official title: The Effects of Caloric Restriction Plus Time Restriction on Glycemia, Circadian Rhythms and Cardiometabolic Health
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Obesity
Keywords: Dietary intervention
Inflammation
Circadian rhythms
Cardiometabolic health
Lead sponsor: University of Adelaide
Sponsor class: OTHER
Collaborators: name: University of Sydney
name: Salk Institute for Biological Studies
First posted: 2023-03-15
Enrollment: 114
Sex: ALL
Minimum age (years): 35
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: The OMIT study will be a parallel, single-blinded, 3-arm randomised controlled trial.
Primary purpose: BASIC_SCIENCE

Brief summary: Type 2 diabetes and cardiovascular disease are an increasing problem in Australia and around the world, and are partly linked to increased rates of obesity, together with sedentary lifestyles. This study will compare caloric restriction (CR) diets that restrict the amount of food that is eaten with CR diets that also restrict the time that the food is eaten, to either early or late in the day, on risk factors for type 2 diabetes and cardiovascular diseases over 2 months.

Detailed description: In a parallel groups design, a total of 114 individuals will be recruited. After a two-week lead in and collection of data from activity monitors and continuous glucose monitors, plus a 28 hour (h) metabolic ward in-patient stay, participants will be randomised into one of three groups (eCR, 8-hour early time restriction + calorie restriction (e.g. 8:00-16:00); dCR, 8-hour delayed time restriction + calorie restriction (e.g. 12:00-20:00); CR, caloric restriction (\>12 hour eating window (e.g. 8:00-20:00). All participants will receive individualised menus and foods that will be delivered to their homes by a supermarket delivery service at energy balance for 1 week (baseline) and at 70% of energy balance for a further 8 weeks. Repeat assessment occurs from 6-8 weeks with the final metabolic ward stay at 8-weeks to assess changes in primary and secondary outcomes.

There are three preplanned sub-studies from the parent trial:

A. OMIT-Immune sub-study All participants will have blood samples collected at six timepoints over 24 hours and stool samples will be collected at two timepoints in a subset. The aims of this sub-study are to 1) characterize the changes in 24 h rhythm (mesor, amplitude and acrophase) of immune cells by flow cytometry over 24 hours, 2) describe the changes in the diversity of bacterial in response to intervention and 3) compare the effects of 8 weeks of CR versus eCR and dCR on immune profiles and gut microbiome.

B. OMIT-BP sub-study All participants will have blood and urine samples collected at six timepoints over 24 hours. A subset of participants will wear 24 h ambulatory blood pressure monitors. The aims of this sub-study are to compare the effects of CR versus eCR and dCR on 1) the 24-hour profile of blood pressure assessed by ambulatory blood pressure monitoring, 2) Plasma markers of blood pressure regulation and 3) markers of renal function. We hypothesise that both eCR and dCR will alter and enhance these parameters and markers in comparison to CR. Changes in the circadian mesor, amplitude and acrophase in: systolic blood pressure, diastolic blood pressure, heart rate, pulse pressure, mean arterial pressure, nocturnal blood pressure dipping, morning blood pressure surge, plasma renin, aldosterone, creatinine, Urinary potassium, sodium, cortisol, creatinine.

C. OMIT- Six month follow up. All participants will be instructed to continue their respective diet intervention and return to the clinic after an additional 16 weeks for a fasting blood sample and assessment of body composition. The aims of this sub-study are to 1) compare the 6 months effects of CR versus eCR and dCR on body composition and fasting blood samples metabolic health from baseline; 2) explore the factors that drive the intention-behaviour gap (describing the failure to translate intentions into action) relation to diet adherence. We hypothesize that participants will maintain the intervention-induced improvements in behavioural and metabolic health outcomes. Additionally, changes in body weight, waist and hip circumference, lean mass, fat mass, blood pressure, glycated hemoglobin, fasting plasma glucose, insulin, total cholesterol, LDL, HDL, triglycerides are assessed.

Eligibility criteria: Inclusion Criteria:

* Overweight or obesity (BMI 25.1 - 44.9 kg/m2)
* Elevated waist circumference (race specific),
* Elevated fasting blood glucose (\>5.6 mmol/L).

Exclusion Criteria:

A personal history/diagnosis (self-reported) of:

* diabetes (type 1 or 2)
* major psychiatric disorders (schizophrenia, major depressive disorder, bipolar disorder, eating disorders)
* gastrointestinal disorders/disease (including malabsorption)
* haematological disorders (i.e. thalassemia, iron-deficiency anaemia)
* insomnia
* obstructive sleep apnea
* night eating syndrome
* diagnosis or treatment of cancer in the past 3 years (excluding non-melanoma skin cancer)
* significant liver or kidney diseases that require ongoing medical care
* previous or planned gastro-intestinal surgery (including bariatric surgery)
* Congestive heart failure (NYHA stage 2 or above)
* Previous myocardial infarction or significant cardiac event ≤ 6 months prior to screening
* Previous cerebrovascular event ≤ 12 months prior to screening
* Any autoimmune disease (i.e. rheumatoid arthritis)
* Coeliac disease
* Score less than 12 of the Australian Diabetes (AUSD) risk assessment tool
* Do not eat for a 12 hour window each day for 5 or more days per week
* Have extreme or restricted patterns of eating (i.e. following an intermittent fasting diet) or already engage in CR
* Other dietary restrictions including vegans, gluten or nut allergies
* Night shift-workers (\>3 shifts per month)
* pregnant, planning a pregnancy or currently breastfeeding
* those who have lost or gained \>5% of body weight in the last 6 months
* donated blood in past 3 months
* current smokers of cigarettes/marijuana/e-cigarettes/vaporisers
* anyone unable to comprehend the study protocol or provide informed consent (i.e. due to English language or cognitive difficulties)
* do not own, or are not comfortable using, a smart phone and applications

Currently taking the following medications:

* Anti-diabetic medications that lower blood glucose including, but not limited to: SGLT2 inhibitors, metformin, sulfonylureas, glucagon-like peptide-1 (GLP-1) analogues \[i.e. semaglutide\], thiazolidinediones
* affecting weight, appetite or gut motility, including, but not limited to semaglutide, domperidone, cisapride, orlistat, phentermine, topiramate.
* Diuretics (i.e. frusemide, thiazides) or combination blood pressure medications containing a diuretic
* Beta-blockers
* Glucocorticoids
* Anti-epileptic medications (i.e. pregabalin and gabapentin)
* Tricyclic antidepressants
* Some serotonin and norepinephrine reuptake inhibitors (i.e. vortioxetine, mirtazapine and venlafaxine)
* Regular use of benzodiazepines or other sleep aids, including melatonin
* Antipsychotic medications
* Opioid medications unless combined with paracetamol in a single formulation and used occasionally on as needs basis

Primary outcomes:
measure: Glucose area under curve (AUC) after 3 meals
timeFrame: 8 weeks
Secondary outcomes:
measure: Insulin area under the curve (AUC)
timeFrame: 8 weeks
measure: Fasting insulin
timeFrame: 8 weeks
measure: Fasting glucose
timeFrame: 8 weeks
measure: Change in glycated hemoglobin (HbA1c)
timeFrame: 8 weeks
Other outcomes:
measure: Postprandial glucose and insulin AUC of each meal
timeFrame: 8 weeks
measure: Non-esterified fatty acids (fasting, postprandial AUC)
timeFrame: 8 weeks
measure: Triglycerides (fasting, postprandial AUC)
timeFrame: 8 weeks
measure: Insulin secretion rate
timeFrame: 8 weeks
measure: Insulin sensitivity (calculated by Matsuda index where a higher score means greater insulin sensitivity)
timeFrame: 8 weeks
measure: 24 h glucometrics on ward (by continuous glucose monitor [CGM])
timeFrame: 8 weeks
measure: HOMA-IR
timeFrame: 8 weeks
measure: Fasting C-peptide
timeFrame: 8 weeks
measure: Total cholesterol
timeFrame: 8 weeks
measure: HDL cholesterol
timeFrame: 8 weeks
measure: LDL cholesterol
timeFrame: 8 weeks
measure: C-reactive protein (CRP)
timeFrame: 8 weeks
measure: Physical activity by activity monitor
timeFrame: 8 weeks
measure: Sleep metrics
timeFrame: 8 weeks
measure: Adherence
timeFrame: 8 weeks
measure: Energy and macronutrient intake
timeFrame: 8 weeks
measure: Blood pressure
timeFrame: 8 weeks
measure: Body weight
timeFrame: 8 weeks
measure: Appetite sensations
timeFrame: 8 weeks
measure: Gastrointestinal hormones
timeFrame: 8 weeks
Locations:
city: Adelaide
country: Australia
facility: South Australian Health and Medical Research Institute / The University of Adelaide
state: South Australia
Study officials:
affiliation: The University of Adelaide
name: Leonie Heilbronn, PhD.
role: PRINCIPAL_INVESTIGATOR
References: