Clinical trial NCT03689608: Daily vs Intermittent Restriction of Energy: Controlled Trial to Reduce Diabetes Risk (DIRECT)
Official title: Daily vs Intermittent Restriction of Energy: Randomised Controlled Trial to Reduce Diabetes Risk (DIRECT)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Individuals at Risk of Developing Diabetes
Keywords: intermittent fasting
calorie restriction
overweight and obesity
Lead sponsor: University of Adelaide
Sponsor class: OTHER
First posted: 2018-09-28
Enrollment: 209
Sex: ALL
Minimum age (years): 35
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

Brief summary: In this randomized controlled trial, the investigators will compare the long term effectiveness of intermittent fasting (IF) versus an energy matched moderate calorie restriction (CR) over 18 months, and relative to a non-active intervention standard control (SC) in individuals who are at increased risk of developing type 2 diabetes. All participants will be required to attend the blood tests following a 12-hour overnight fast for the "A" visit at Month 0, 2, 6 (active) and 18 (follow up).

Fast424hGlucose: A subset of 100 participants enrolled in either IF or CR group in the parent study will be fitted with a continuous glucose monitor (CGM) to measure 24-hour glycaemic profile at month 0 and month 6.

Fast4Switch: Additional bloods will be collected after a "B" visit at month 6 to compare the fed to fasted switch. The B samples will be collected after a 12-hour overnight fast (CR, SC) or 20-hour fast (IF) to assess the metabolic switch to fasting in metabolites and hormones.

Fast4Stress: Additional subcutaneous adipose tissue, urine and saliva samples will be collected in \~32 men in IF and CR groups at month 0 and 6 at A and B visits to examine changes in stress response and resistance markers.

Experience2Fast: In-depth, semi-structured interviews will be carried out at month-8 follow-up visit in a subset of completers from IF or CR groups to explore the experience of intervention diets and understand contributing factors towards change and maintenance of dietary behaviours.

Fast4Flux: Additional blood samples will be collected in \~100 individuals in SC, IF and CR groups at month 0, month 2 and month 6 at A visit to measure autophagic flux in peripheral blood mononuclear cells following treatment of whole blood.


Eligibility criteria: Inclusion Criteria:

* weight-stable (\< 5 % fluctuation in their body weight for past 6-months at study entry)
* score 12 or greater on the AUSDRISK calculator
* HbA1c \<48 mmol/mol (measured at screening)

Exclusion Criteria:

* Personal history/diagnosis (self-reported) of diabetes (type 1 or 2), major psychiatric disorders (schizophrenia, major depressive disorder, bipolar disorder, eating disorders), gastrointestinal disorders, haematological disorders (i.e. thalassemia, iron-deficiency anaemia) insomnia, or any other medical condition, deemed unstable by the study physician.
* Participants currently taking the following medications will be excluded from participating: any medication used to lower blood glucose or antidiabetic medications (metformin, sulfonylureas, Glucagon-like peptide-1 GLP-1 analogues \[i.e. exenatide\], thiazolidinediones or DPP-IV inhibitors \[i.e. 'gliptins'\]), medications affecting weight, appetite or gut motility (i.e. domperidone, cisapride, orlistat, phentermine, topiramate). Participants who are taking stable doses (i.e. \> 12 months) of androgenic medications (i.e. testosterone) or SSRI's will not be excluded.
* weight change in past 3 months (\> 5% screening weight)
* uncontrolled asthma, current fever, upper respiratory infections
* individuals who regularly perform high intensity exercise (\>2 week)
* current intake of \> 140g alcohol/week
* current smokers of cigarettes/cigars/marijuana/e-cigarettes/vaporisers
* current intake of any recreational drugs
* regular blood donor
* unable to comprehend study protocol due to English language or cognitive difficulties

Primary outcomes:
measure: Postprandial glucose AUC
timeFrame: 6 months
Secondary outcomes:
measure: HbA1c
timeFrame: 2 months, 6 months, 18 months
measure: Postprandial glucose
timeFrame: 18 months
measure: Body weight
timeFrame: 2 months, 6 months, 18 months
measure: Body composition
timeFrame: 6 months, 18 months
measure: Waist and hip circumference
timeFrame: 2 months, 6 months, 18 months
measure: Blood lipids
timeFrame: 2 months, 6 months, 18 months
measure: Dietary intake
timeFrame: 2 months, 6 months, 18 months
measure: Blood pressure
timeFrame: 2 months, 6 months, 18 months
measure: Changes in physical Activity assessed by accelerometer
timeFrame: 2 months, 6 months, 18 months
measure: Fasting glucose
timeFrame: 2 months, 6 months, 18 months
measure: Fasting insulin
timeFrame: 2 months, 6 months, 18 months
measure: Fasting non-esterified fatty acids (NEFA)
timeFrame: 2 months, 6 months, 18 months
measure: Fasting triglyceride
timeFrame: 2 months, 6 months, 18 months
measure: Postprandial insulin
timeFrame: 6 months, 18 months
measure: Postprandial non-esterified fatty acids (NEFA)
timeFrame: 6 months, 18 months
measure: Postprandial triglyceride
timeFrame: 6 months, 18 months
Other outcomes:
measure: Change in perceived hunger and fullness assessed by visual analogue scales (VAS)
timeFrame: 6 months, 18 months
measure: Change in perceived sleep quality
timeFrame: 2 months, 6 months, 18 months
measure: Change in perceived eating behaviour
timeFrame: 2 months, 6 months, 18 months
measure: Change in perceived quality of life
timeFrame: 2 months, 6 months, 18 months
measure: Change in perceived well-being
timeFrame: 2 months, 6 months, 18 months
measure: Change in food addition score
timeFrame: 6 months, 18 months
measure: Change in psychological distress
timeFrame: 6 months, 18 months
measure: Change in self-reported depression, anxiety and stress level
timeFrame: 2 months, 6 months, 18 months
measure: Change in self-reported mood
timeFrame: 2 months, 6 months, 18 months
measure: Change in glucagon-like peptide 1 (GLP-1)
timeFrame: 6 months
measure: Change in peptide YY
timeFrame: 6 months
measure: Change in ghrelin
timeFrame: 6 months
measure: Change in gastric inhibitory polypeptide (GIP)
timeFrame: 6 months
measure: Change in estradiol
timeFrame: 6 months
measure: Change in testosterone
timeFrame: 6 months
measure: Change in glucose (DIRECT- Fast4Switch)
timeFrame: 6 months
measure: Change in non-esterified fatty acids (DIRECT- Fast4Switch)
timeFrame: 6 months
measure: Change in insulin (DIRECT- Fast4Switch)
timeFrame: 6 months
measure: Change in triglycerides (DIRECT- Fast4Switch)
timeFrame: 6 months
measure: 24 hours glycaemia (DIRECT-Fast424hGlucose)
timeFrame: 6 months
measure: Salivary cortisol (DIRECT-Fast4Stress)
timeFrame: 6 months
measure: Gene expression (DIRECT- Fast4Stress)
timeFrame: 6 months
measure: Change in urinary adrenaline (DIRECT- Fast4Stress)
timeFrame: 6 months
measure: Change in urinary noradrenaline (DIRECT- Fast4Stress)
timeFrame: 6 months
measure: Qualitative analysis (DIRECT-Experience2Fast)
timeFrame: 8 months
measure: Change in autophagic flux (DIRECT-Fast4flux)
timeFrame: 2 months, 6 months
Locations:
city: Adelaide
country: Australia
facility: University of Adelaide
state: South Australia
Study officials:
affiliation: The University of Adelaide
name: Leonie Heilbronn, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Teong XT, Liu K, Hutchison AT, Liu B, Feinle-Bisset C, Wittert GA, Lange K, Vincent AD, Heilbronn LK. Rationale and protocol for a randomized controlled trial comparing daily calorie restriction versus intermittent fasting to improve glycaemia in individuals at increased risk of developing type 2 diabetes. Obes Res Clin Pract. 2020 Mar-Apr;14(2):176-183. doi: 10.1016/j.orcp.2020.01.005. Epub 2020 Feb 11.