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Trial registered on ANZCTR


Registration number
ACTRN12614001302640
Ethics application status
Approved
Date submitted
24/11/2014
Date registered
15/12/2014
Date last updated
18/06/2021
Date data sharing statement initially provided
29/10/2020
Date results information initially provided
18/06/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
A trial to determine:
a) the effectiveness of fibre supplement, alpha-cyclodextrin, on cholesterol control in overweight and obese participants with pre diabetes
b) the effectiveness of ginseng derivative, Compound K, on blood sugar control in overweight and obese participants with pre diabetes
Scientific title
A double blinded, randomised controlled trial to determine
a) the efficacy of alpha-cyclodextrin on cholesterol control, and
b) the efficacy of Compound K on glycaemic control
in overweight and obese participants with pre-diabetes.
Secondary ID [1] 285728 0
Nil.
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Overweight 293611 0
Obesity 293612 0
Pre diabetes 293613 0
Dyslipidaemia 293658 0
Condition category
Condition code
Diet and Nutrition 293897 293897 0 0
Obesity
Metabolic and Endocrine 293898 293898 0 0
Diabetes

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Weight loss intervention (Baseline-Month 6):

Participants will be randomised to one of four groups (NB: 1 active ingredient tablet contains 1000 mg alpha-cyclodextrin and 1 active ingredient capsule contains 160 mg hydrolysed ginseng extract (high in Compound K):

Alpha-cyclodextrin (alpha-CD) group:
Participants in the alpha-CD group will be asked to take 2 placebo capsules prior to each meal, and 2 x 1 gram alpha-CD tablets directly (within 20 minutes) after each meal 3 times per day. Participants will take a total of 12 pills per day (6 tablets and 6 capsules) for 168 +/-7 days (24 weeks) (6 months).

Hydrolysed ginseng extract (HGE) group:
Participants in the HGE group will be asked to take 2 x 160 mg HGE capsules prior to each meal, and 2 placebo tablets directly (within 20 minutes) after each meal 3 times per day. Participants will take a total of 12 pills per day (6 tablets and 6 capsules) for 168 +/-7 days (24 weeks) (6 months).

Combined therapy group:
Participants in the combined therapy group will take 2 x 160 mg HGE capsules prior to each meal and 2 x 1 gram alpha-CD tablets directly (within 20 minutes) after each meal 3 times per day. Participants will take a total of 12 pills per day (6 tablets and 6 capsules) for 168 +/-7 days (24 weeks) (6 months).

Behavioural Management Programme:
Participants in the standard behavioural management programme alone will be required to take 2 placebo capsules prior to each meal, and 2 placebo tablets directly (within 20 minutes) after each meal 3 times per day. Participants will take a total of 12 pills per day (6 tablets and 6 capsules) for 168 +/-7 days (24 weeks) (6 months).

All participants will be enrolled in a lifestyle programme during the initial 6 month intervention period. The intervention will be delivered by an Accredited Practising Dietitian in a one on one, face to face consult, of approximately 30 minutes duration. All participants will attend a 30 minute dietary consult each month for six months. The weight loss diet (total fat intake of < 30% and saturated fat < 10% of total energy) will be hypo-caloric with a 500 kilocalorie deficit per day (based on the Harris Benedict Equation for estimating energy requirements).

During the intervention period, medication compliance will be monitored by drug tablet return.

Follow up weight maintenance period (Month 6-Month 12):

At the end of Month 6, participants will no longer be required to take the investigational supplements. Participants will be randomised to one of three weight maintenance groups. The weight maintenance phase will last for 6 months:

The usual care group (group 1): Encourage participants to continue with the individualised prescribed diet and lifestyle goals implemented during the intervention period (Baseline to month 6) to aid with weight maintenance. Participants will be asked to set a personal range for weight maintenance. If they go over that range they will be advised to use the strategies they learned in the weight loss phase to reduce their weight to keep in that target range.

Daily self weighing (group 2): Participants will receive the usual care intervention and will also be asked to weigh themselves daily using their own bathroom scales and record it on a record card.

Daily self weighing plus accountability (group 3): Participants will receive the usual care intervention and will also be provided with a set of scales and asked to weigh themselves daily and record it on a record card. The scales send the weights to an online program that the investigators can access to examine participants' progress. If the participant does not weigh themselves for 7 days, or if their weight increases by 2 kg or more in 7 days, participants will be emailed to remind them to weight themselves regularly or to restart the use of the behaviours they learned during the 6-month weight loss consultations.

All participants will see an Accredited Practising Dietitian for a 30 minute one on one, face to face consultation every three months.
Intervention code [1] 290684 0
Treatment: Other
Intervention code [2] 290685 0
Lifestyle
Intervention code [3] 290735 0
Behaviour
Comparator / control treatment
During the initial six month intervention period, participants in the Behavioural Management Programme will act as the control. Participants in this group will receive standard behavioural management and will be required to take 2 placebo capsules prior to each meal, and 2 placebo tablets directly (within 20 minutes) after each meal 3 times per day. Participants will take a total of 12 pills per day (6 tablets and 6 capsules) for 168 +/-7 days (24 weeks) (6 months).

During the six month weight maintenance period (Month 6-Month 12), the usual care group (group 1) will act as the control. Participants will be encouraged to continue with the individualised prescribed diet and lifestyle goals implemented during the intervention period (Baseline to month 6) to aid with weight maintenance. Participants will be asked to set a personal range for weight maintenance. If they go over that range they will be advised to use the strategies they learned in the weight loss phase to reduce their weight to keep in that target range.

Control group
Placebo

Outcomes
Primary outcome [1] 293675 0
To determine the efficacy of alpha-cyclodextrin on cholesterol control in an overweight or obese group with pre-diabetes. A venous blood sample will be collected and total cholesterol will be determined by a commercial laboratory.
Timepoint [1] 293675 0
Month 6
Primary outcome [2] 293676 0
To investigate the efficacy of hydrolysed ginseng extract (rich in Compound K) on glycaemic control in an overweight or obese group with pre-diabetes. A venous blood sample will be collected and fasting plasma glucose will be determined by a commercial laboratory.
Timepoint [2] 293676 0
Month 6
Secondary outcome [1] 311566 0
To determine the efficacy of each product and the combination of products on absolute weight loss (kg) and percentage of weight loss, relative to baseline body weight, in an overweight or obese group with pre-diabetes. Weight will be assessed using a calibrated, digital, weighing scale.
Timepoint [1] 311566 0
Month 6 and 12
Secondary outcome [2] 311567 0
To investigate the difference in full lipid profile (including total cholesterol, HDL, LDL), apolipoprotein B, plasma glucose, and HbA1c between groups. This is a composite outcome.

A venous blood sample will be collected. A commercial laboratory will analyse the sample to determine the lipid profile, apolipoprotein B, plasma glucose and HbA1c.
Timepoint [2] 311567 0
Month 6 and 12
Secondary outcome [3] 311568 0
To compare the percentage of participants in each category of glucose tolerance (normal, impaired fasting glucose, and type 2 diabetes) between groups.

Glucose tolerance will be assessed using a fasting plasma glucose reading. Participants will be categorized according to reference ranges based on their fasting plasma glucose.
Timepoint [3] 311568 0
Month 6 and 12
Secondary outcome [4] 311569 0
To examine changes in body composition by waist circumference, fat mass, fat free mass, and blood pressure. This is a composite outcome.

Waist circumference will be measured with a flexible tape measure with the Participant wearing light clothing, at the mid-point between the highest point of the iliac crest and lowest part of the costal margin in the mid-axillary line in expiration. Measurements will be collected at each clinic visits and recorded in centimeters to the nearest 0.5 centimeter.

Fat mass and fat free mass will be determined by a whole body DEXA scan.

Blood pressure will be measured using a digital sphygmomanometer.
Timepoint [4] 311569 0
Month 6 and 12
Secondary outcome [5] 311570 0
To investigate the difference in other biochemical parameters (liver enzymes and inflammatory markers) between groups.

A venous blood sample will be collected. A commercial laboratory will analyse the sample to determine levels of liver enzymes and inflammatory markers.
Timepoint [5] 311570 0
Month 6 and 12
Secondary outcome [6] 311571 0
To measure the side effect profile of each product using AE reporting.

The side effect profile will be assessed qualitatively by examining adverse events reported by participants during clinic visits.
Timepoint [6] 311571 0
Month 6 and 12
Secondary outcome [7] 311572 0
To investigate the change in vitality between groups using the vitality scale of the SF 36 Health Survey.
Timepoint [7] 311572 0
Month 6 and 12
Secondary outcome [8] 311573 0
To determine the cost effectiveness of each intervention relative to the lifestyle programme alone by measuring the cost per QALY.
Timepoint [8] 311573 0
Month 6 and 12
Secondary outcome [9] 311574 0
To measure the change in gut hormones and adipokines between groups.

A venous blood sample will be collected. The whole blood sample will be centrifuged to isolate the plasma. The plasma sample will be analysed to determine circulating levels of gut hormones and adipokines.
Timepoint [9] 311574 0
Month 6 and 12
Secondary outcome [10] 311575 0
To investigate the long-term outcome of the gut microbiota profile between groups.

Gut microbiota profile will be determined by stool sample analysis.
Timepoint [10] 311575 0
Month 6 and 12
Secondary outcome [11] 311576 0
To compare the metabolic activity of gut microbiota between all groups (short chain fatty acids (SCFA) production in plasma and faeces).
Timepoint [11] 311576 0
Month 6 and 12
Secondary outcome [12] 311577 0
To investigate the dynamics of the microbiota community as a result of dietary supplementation and elimination of alpha-cyclodextrin and hydrolysed ginseng extract across all groups. Dynamics of gut microbiota will be determined by stool sample analysis.
Timepoint [12] 311577 0
Month 6 and 12
Secondary outcome [13] 311578 0
To evaluate the effectiveness of three follow up programmes in preventing weight regain after a weight loss phase.

Weight will be assessed using a calibrated, digital, weighing scale.
Timepoint [13] 311578 0
Month 12 (6 months after randomisation for weight maintenance period)

Eligibility
Key inclusion criteria
*Aged 18 years or over
*BMI greater than or equal to 25
*Pre-diabetes (based on ADA guidelines, determined by bloods at the screening visit or 6 months prior to Screening):
- a fasting plasma glucose greater than or equal to 5.6 mmol/L AND/OR
- 2 hour post-challenge (oral glucose tolerance test) plasma glucose greater than or equal to 7.8 mmol/L AND/OR
- HbA1c greater than or equal to 5.7%
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
*Type 2 diabetes criteria are based on ADA guidelines. Participants will be excluded from the study if they have:
- a fasting plasma glucose greater than or equal to 7.0 mmol/L AND/OR
- 2 hour post-challenge (oral glucose tolerance test) plasma glucose greater than or equal to 11.1 mmol/L AND/OR
- HbA1c greater than or equal to 6.5%
*Use of lipid lowering medication
*Use of anti-diabetic medications for pre-diabetes
*Type 1 diabetes
*Unstable angina or recent onset of cardiovascular disease (within 1 month of screening)
*Bariatric surgery
*A history of significant liver, kidney or gastrointestinal disease AND/OR
- ALT or AST > 2.5 times upper limit of normal
- serum creatinine > 1.5 times upper limit of normal or
- eGFR < 60ml/min/1.73m^2 or presence of microalbuminuria
*Chronic diarrhoea, bowel motility problems, or other conditions that could affect intestinal fat absorption
*Untreated thyroid disease
*Greater than 10% change in body weight over the past 3 months
*Alcohol or illicit drug abuse
*Pregnant or breastfeeding women, and women who might be planning pregnancy during the duration of the study
*Use of weight loss medications and other drugs that may affect body weight e.g. anti-psychotics, anti-depressants, or corticosteroids
*Taking the following medications which may show reduced absorption of the investigational products: antibiotics, anticoagulants, anticonvulsants, antiarrhythmics, immunosuppressants, or any other drug that is necessary to take with a meal. Short-term and prophylactic antibiotics may be taken during study participation for up to 14 days, but they should be taken at least 2 hours apart from the study drug
*Commencement of a new prescription medication within 3 months of screening or change in dose regimen of a prescription medication within 1 month of screening
*A history or presence of malignancy [completely resected basal or squamous cell carcinoma of the skin if treatment completed > 6 months prior to enrolment and participants in remission for > 5 years prior to screening remain eligible]
*Inability to read and write English
*A history of frequently changed smoking habits, in addition to smoking cessation within 6 months prior to screening. Those who wish to take on the advice of a 'Quit' smoking programme at the time of screening will be eligible to start the trial after 6 months
*Participants may also be excluded, if in the opinion of the study investigators, they have some other condition or disorder that may adversely affect the outcome of the study or the safety of the participant
*Participation in a clinical trial in the last month
*Unable to commit to the appointment schedule or perform the tasks required in the study.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Initial weight loss intervention: Central randomisation by computer via an Interactive Web Response System (IWRS).
The IWRS provides a print out of the randomisation number and confirms which medication containers (A, B, C or D) will be dispensed to the participant. All containers will look identical between the groups other than the additional information of A, B, C or D.

Follow up weight maintenance intervention: Allocation not concealed.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Initial weight loss intervention: Randomisation will occur via an Interactive Web Response System (IWRS). Randomisation will be based on a simple block randomisation. Participants will be stratified by age, sex, and BMI to ensure equal distribution across all treatment groups. It will not be possible to override this allocation.

Follow up weight maintenance intervention: Randomisation will occur via an Interactive Web Response System (IWRS). Randomisation will be based on a simple block randomisation.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Factorial
Other design features
Phase
Phase 3
Type of endpoint/s
Efficacy
Statistical methods / analysis
Alpha-cyclodextrin: Assuming a mean reduction in fasting total cholesterol from baseline of 0.50 mmol/L in the intervention compared to control group, with a standard deviation (SD) of 0.90 mmol/L and an estimated drop-out rate of 15% (at 6 months), a total of 143 Participants would be required to achieve 80% power to detect a difference between the two groups (at a 2-sided significance level of 2.5%).
Compound K (hydrolysed ginseng): Assuming a mean reduction in fasting plasma glucose from baseline of 0.47 mmol/L in the intervention compared to control group, with a standard deviation (SD) of 1 mmol/L and an estimated drop-out rate of 15% (at 6 months), a total of 200 Participants would be required to achieve 80% power to detect a difference between the two groups (at a 2-sided significance level of 2.5%).
Based on these calculations, 400 Participants (100 in each group) will be recruited and randomised to one of four treatment groups. All randomised Participants will be included in the final analysis.

Data will be analysed for normality using the Shapiro-Wilk test. For analysis of differences between treatments, an analysis of covariance (ANCOVA), or the non-parametric equivalent will be used. For within group changes, repeated measures ANOVA will be used. As well as an analysis of completers (those that attend the final visit), an intention to treat (ITT) analysis will also be included. For the ITT analysis, dropouts will be treated using a variety of sensitivity analyses.

With respect to weight loss, demonstration of a clinically significant degree of weight loss of at least 5-10% of baseline weight, which is also at least 5% greater than that associated with placebo, is considered to be a valid efficacy criterion in clinical trials evaluating new anti-obesity drugs.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
16/02/2015
Actual
1/07/2015
Date of last participant enrolment
Anticipated
31/07/2017
Actual
22/03/2018
Date of last data collection
Anticipated
Actual
29/03/2019
Sample size
Target
400
Accrual to date
Final
401

Funding & Sponsors
Funding source category [1] 290306 0
University
Name [1] 290306 0
The University of Sydney
Country [1] 290306 0
Australia
Funding source category [2] 307090 0
Commercial sector/Industry
Name [2] 307090 0
SFI Research Pty Ltd
Country [2] 307090 0
Australia
Primary sponsor type
University
Name
The University of Sydney
Address
The Boden Institute
Charles Perkins Centre D17
The University of Sydney NSW 2006
Country
Australia
Secondary sponsor category [1] 289017 0
None
Name [1] 289017 0
Address [1] 289017 0
Country [1] 289017 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 292012 0
University of Sydney Human Ethics Review Committee
Ethics committee address [1] 292012 0
Human Ethics Office
Margaret Telfer Building (K07)
University of Sydney
NSW 2006
Ethics committee country [1] 292012 0
Australia
Date submitted for ethics approval [1] 292012 0
26/11/2014
Approval date [1] 292012 0
22/04/2015
Ethics approval number [1] 292012 0
HREC/14/RPAH440

Summary
Brief summary
The current trial is designed to determine:
a) The efficacy of alpha-cyclodextrin on cholesterol control, and
b) The efficacy of hydrolysed ginseng extract (rich in Compound K) on glycaemic control
in overweight and obese participants with pre diabetes.

The aim of the weight maintenance sub study is to evaluate the effectiveness of three follow up programmes on weight regain six months after completing a weight loss programme.
Trial website
http://sydney.edu.au/medicine/research/units/boden/clinical-trials.php
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 53034 0
Dr Nicholas Fuller
Address 53034 0
The Boden Collaboration
Charles Perkins Centre D17
The University of Sydney NSW 2006
Country 53034 0
Australia
Phone 53034 0
+ 61 2 86271932
Fax 53034 0
+ 61 2 86270141
Email 53034 0
[email protected]
Contact person for public queries
Name 53035 0
Nicholas Fuller
Address 53035 0
The Boden Collaboration
Charles Perkins Centre D17
The University of Sydney NSW 2006
Country 53035 0
Australia
Phone 53035 0
+ 61 2 86271932
Fax 53035 0
+ 61 2 86270141
Email 53035 0
[email protected]
Contact person for scientific queries
Name 53036 0
Nicholas Fuller
Address 53036 0
The Boden Collaboration
Charles Perkins Centre D17
The University of Sydney NSW 2006
Country 53036 0
Australia
Phone 53036 0
+ 61 2 86271932
Fax 53036 0
+ 61 2 86270141
Email 53036 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
De-identified participant dataset will be available upon request.
When will data be available (start and end dates)?
After publication of the primary outcomes, researchers can contact Dr Nick Fuller. There is currently no end date specified for requests for data.
Available to whom?
Any external researchers
Available for what types of analyses?
Analysis plans should be provided to Dr Nick Fuller upon request of data for approval.
How or where can data be obtained?
Request from Dr Nick Fuller ([email protected])


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
9563Study protocolBessell E, Fuller NR, Markovic TP, et al. Effects of alpha-cyclodextrin on cholesterol control and Compound K on glycaemic control in people with pre-diabetes: protocol for a Phase III randomized controlled trial. Clin Obes. 2019;9(4):e12324. https://onlinelibrary.wiley.com/doi/full/10.1111/cob.12324 



Results publications and other study-related documents

Documents added manually
TypeIs Peer Reviewed?DOICitations or Other DetailsAttachment
Study results articleYes Bessell E, Fuller NR, Markovic TP, et al. Effects ... [More Details] 367494-(Uploaded-04-12-2020-15-25-01)-Journal results publication.pdf

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseEffects of alpha-cyclodextrin on cholesterol control and Compound K on glycaemic control in people with pre-diabetes: Protocol for a Phase III randomized controlled trial.2019https://dx.doi.org/10.1111/cob.12324
N.B. These documents automatically identified may not have been verified by the study sponsor.