Individuals at Risk of Developing DiabetesNCT03689608
Daily vs Intermittent Restriction of Energy: Controlled Trial to Reduce Diabetes Risk (DIRECT)
A study testing Intermittent Fasting (IF) and Daily Restriction (DR) in people with Individuals at Risk of Developing Diabetes, run by University of Adelaide at 1 site in Australia.
Trial 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… Read more about this study
- Who is it for?
- Ages 35 to 75 yearsHealthy volunteers can take part
- Conditions the study is for
- Individuals at Risk of Developing Diabetes
- What is being tested?
- Intermittent Fasting (IF) and Daily Restriction (DR)
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 209 participants
- Where
- 1 siteAustralia
- Study dates
- 26 Sep 2018to 30 Nov 2021
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 35 to 75 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- 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)
Who cannot join
- 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
Show all 10Show fewer
- 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
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Daily vs Intermittent Restriction of Energy: Randomised Controlled Trial to Reduce Diabetes Risk (DIRECT)
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.
Read more
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.
- Being tested
- Intermittent Fasting (IF), Daily Restriction (DR), standard care (SC)
- Keywords
- intermittent fasting, calorie restriction, overweight and obesity
- Medical subject headings
- Intermittent Fasting, Overweight, Obesity
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Intermittent Fasting (IF)Other
Participants will fast 3 days per week. In fasting days, meal replacements at 30% of daily energy requirements will be provided for the first 6 months. Participants will have fortnightly nutrition assessment.
Daily Restriction (DR)Other
Participants are instructed to restrict energy intake by 30% of daily energy requirements. Meal replacements will be provided for the first 6 months. Participants will have fortnightly nutrition assessment.
standard care (SC)Other
Participants will receive current practice guidelines in a static information format, will not take part in any counselling or receive meal replacements.
| Study group | Role | What they receive |
|---|---|---|
| Intermittent Fasting (IF) | Experimental | 3 days fasting per week Receives: Other: Intermittent Fasting (IF) |
| Daily Restriction (DR) | Experimental | daily energy restriction Receives: Other: Daily Restriction (DR) |
| standard care (SC) | Other | usual care Receives: Other: standard care (SC) |
What is being measured
The primary outcome is the main question the study is designed to answer.
Postprandial glucose AUC
Change in postprandial glucose AUC
Measured: 6 months
Secondary outcomes (16)
HbA1c
Change in HbA1c
Measured: 2 months, 6 months, 18 months
Postprandial glucose
Change in postprandial glucose
Measured: 18 months
Body weight
Change in body weight in kilograms
Measured: 2 months, 6 months, 18 months
Body composition
Change in body fat mass (kg) and fat free mass (kg)
Measured: 6 months, 18 months
Waist and hip circumference
Change in waist and hip circumference
Measured: 2 months, 6 months, 18 months
Blood lipids
Changes in blood lipid profile (total cholesterol, HDL-, LDL-cholesterol and triglycerides)
Measured: 2 months, 6 months, 18 months
Dietary intake
Change in food intake measured by self-reported food diaries
Measured: 2 months, 6 months, 18 months
Blood pressure
Change in systolic blood pressure and diastolic blood pressure (mmHg)
Measured: 2 months, 6 months, 18 months
Changes in physical Activity assessed by accelerometer
Change in average step counts measured with waist-worn actigraphy monitors
Measured: 2 months, 6 months, 18 months
Fasting glucose
Change in fasting glucose
Measured: 2 months, 6 months, 18 months
Fasting insulin
Change in fasting insulin
Measured: 2 months, 6 months, 18 months
Fasting non-esterified fatty acids (NEFA)
Change in fasting NEFA levels
Measured: 2 months, 6 months, 18 months
Fasting triglyceride
Change in fasting triglyceride levels
Measured: 2 months, 6 months, 18 months
Postprandial insulin
Change in postprandial insulin
Measured: 6 months, 18 months
Postprandial non-esterified fatty acids (NEFA)
Change in postprandial NEFA levels
Measured: 6 months, 18 months
Postprandial triglyceride
Change in postprandial triglyceride levels
Measured: 6 months, 18 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted28 Sep 2018
- Study start26 Sep 2018
- Primary completion30 Nov 2020
- Study completion30 Nov 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for Individuals at Risk of Developing DiabetesStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 209 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Adelaide
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, A/Prof Leonie Heilbronn, University of Adelaide
- Investigators
- Leonie Heilbronn, PhD, Principal investigator, The University of Adelaide
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03689608
- Sponsor's protocol ID
- R20180319
- Status last verified
- Dec 2021
- First submitted
- 26 Sep 2018
- Last updated
- 11 Jan 2022
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
Publications
Teong XT, Liu K, Vincent AD, Liu B, Wittert GA, Hutchison AT, Heilbronn LK. Exploring the impact of intermittent fasting plus time-restricted eating versus calorie restriction on eating behavior, mood, sleep, quality of life in adults with obesity. Clin Nutr. 2026 Jul;62:106686. doi: 10.1016/j.clnu.2026.106686. Epub 2026 May 15.
PubMed 42208206Bensalem J, Teong XT, Hattersley KJ, Hein LK, Fourrier C, Dang LVP, Singh S, Liu K, Wittert GA, Hutchison AT, Heilbronn LK, Sargeant TJ. Intermittent time-restricted eating may increase autophagic flux in humans: an exploratory analysis. J Physiol. 2025 May;603(10):3019-3032. doi: 10.1113/JP287938. Epub 2025 May 9.
PubMed 40345145Teong XT, Liu K, Vincent AD, Bensalem J, Liu B, Hattersley KJ, Zhao L, Feinle-Bisset C, Sargeant TJ, Wittert GA, Hutchison AT, Heilbronn LK. Intermittent fasting plus early time-restricted eating versus calorie restriction and standard care in adults at risk of type 2 diabetes: a randomized controlled trial. Nat Med. 2023 Apr;29(4):963-972. doi: 10.1038/s41591-023-02287-7. Epub 2023 Apr 6.
PubMed 37024596Teong 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.
PubMed 32057716
Study at a glance
From the registry record, last updated by the sponsor on 11 Jan 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Daily vs Intermittent Restriction of Energy: Randomised Controlled Trial to Reduce Diabetes Risk (DIRECT)
- ClinicalTrials.gov ID
- NCT03689608
- Acronym / sponsor ID
- R20180319
- Keywords
- intermittent fasting, calorie restriction, overweight and obesity
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 209 participants (actual)
- Lead sponsor
- University of AdelaideUniversity, hospital or other
- Study start
- 26 Sep 2018 (actual)
- Primary completion
- 30 Nov 2020 (actual)
- Study completion
- 30 Nov 2021 (actual)
- First posted
- 28 Sep 2018 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Intermittent Fasting (IF) | Experimental | Other: Intermittent Fasting (IF)3 days fasting per week |
| Daily Restriction (DR) | Experimental | Other: Daily Restriction (DR)daily energy restriction |
| standard care (SC) | Other | Other: standard care (SC)usual care |
Who may qualify
- Ages
- 35 to 75 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (3 listed)
- 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)
Key exclusion criteria (10 listed)
- 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)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Intermittent Fasting (IF)Participants will fast 3 days per week. In fasting days, meal replacements at 30% of daily energy requirements will be provided for the first 6 months. Participants will have fortnightly nutrition assessment. | Other | Intermittent Fasting (IF) |
| Daily Restriction (DR)Participants are instructed to restrict energy intake by 30% of daily energy requirements. Meal replacements will be provided for the first 6 months. Participants will have fortnightly nutrition assessment. | Other | Daily Restriction (DR) |
| standard care (SC)Participants will receive current practice guidelines in a static information format, will not take part in any counselling or receive meal replacements. | Other | standard care (SC) |
Primary outcome
Postprandial glucose AUC
Time frame: 6 months
Change in postprandial glucose AUC
16 secondary outcomes
HbA1c
Time frame: 2 months, 6 months, 18 months
Postprandial glucose
Time frame: 18 months
Body weight
Time frame: 2 months, 6 months, 18 months
Body composition
Time frame: 6 months, 18 months
Waist and hip circumference
Time frame: 2 months, 6 months, 18 months
Blood lipids
Time frame: 2 months, 6 months, 18 months
Dietary intake
Time frame: 2 months, 6 months, 18 months
Blood pressure
Time frame: 2 months, 6 months, 18 months
Changes in physical Activity assessed by accelerometer
Time frame: 2 months, 6 months, 18 months
Fasting glucose
Time frame: 2 months, 6 months, 18 months
Fasting insulin
Time frame: 2 months, 6 months, 18 months
Fasting non-esterified fatty acids (NEFA)
Time frame: 2 months, 6 months, 18 months
Fasting triglyceride
Time frame: 2 months, 6 months, 18 months
Postprandial insulin
Time frame: 6 months, 18 months
Postprandial non-esterified fatty acids (NEFA)
Time frame: 6 months, 18 months
Postprandial triglyceride
Time frame: 6 months, 18 months
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 11 Jan 2022.
- Derived from this study: PubMed 42208206Teong XT, Liu K, Vincent AD, Liu B, Wittert GA, Hutchison AT, Heilbronn LK. Exploring the impact of intermittent fasting plus time-restricted eating versus calorie restriction on eating behavior, mood, sleep, quality of life in adults with obesity. Clin Nutr. 2026 Jul;62:106686. doi: 10.1016/j.clnu.2026.106686. Epub 2026 May 15.
- Derived from this study: PubMed 40345145Bensalem J, Teong XT, Hattersley KJ, Hein LK, Fourrier C, Dang LVP, Singh S, Liu K, Wittert GA, Hutchison AT, Heilbronn LK, Sargeant TJ. Intermittent time-restricted eating may increase autophagic flux in humans: an exploratory analysis. J Physiol. 2025 May;603(10):3019-3032. doi: 10.1113/JP287938. Epub 2025 May 9.
- Derived from this study: PubMed 37024596Teong XT, Liu K, Vincent AD, Bensalem J, Liu B, Hattersley KJ, Zhao L, Feinle-Bisset C, Sargeant TJ, Wittert GA, Hutchison AT, Heilbronn LK. Intermittent fasting plus early time-restricted eating versus calorie restriction and standard care in adults at risk of type 2 diabetes: a randomized controlled trial. Nat Med. 2023 Apr;29(4):963-972. doi: 10.1038/s41591-023-02287-7. Epub 2023 Apr 6.
- Derived from this study: PubMed 32057716Teong 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.
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Leonie Heilbronn, PhD principal investigator
The University of Adelaide
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Intermittent Fasting (IF) and Daily Restriction (DR) in people with Individuals at Risk of Developing Diabetes, run by University of Adelaide at 1 site in Australia.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 11 Jan 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Australia. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Postprandial glucose AUC (time frame: 6 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03689608, which also lists 4 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 11 Jan 2022.