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Trial registered on ANZCTR


Registration number
ACTRN12620000946910
Ethics application status
Approved
Date submitted
1/07/2020
Date registered
22/09/2020
Date last updated
5/07/2021
Date data sharing statement initially provided
22/09/2020
Date results information initially provided
5/07/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
The Effects of a Dietary Intervention on Chronic Pain: A Pilot Clinical Trial
Scientific title
Effects of a well-formulated low-carbohydrate ketogenic diet (WFKD) on reported pain, blood biomarkers and quality of life in patients with chronic pain. A pilot randomised clinical trial.
Secondary ID [1] 301664 0
none
Universal Trial Number (UTN)
U1111-1254-4909
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
chronic pain 318094 0
Condition category
Condition code
Musculoskeletal 316121 316121 0 0
Other muscular and skeletal disorders
Neurological 316122 316122 0 0
Other neurological disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This study will implement a run-in period of 3 weeks where all participants will undertake a whole-food diet (WFD) that focuses on improving diet quality, based on the NOVA classifications of unprocessed or minimally processed foods/ingredients (removal of NOVA category 4 foods from diet).

Participants will be supplied with informational handouts, education and links to online sites that provide recipes by the researcher at the week 0 initial contact. The material and online links have been developed specifically for the project from information provided from https://world.openfoodfacts.org/nova (the NOVA app will not be used as it does not apply to Australian products and is not in English). They will not be supplied with food but will be free to choose foods they prefer as long as they are minimally processed. They will not be required to monitor calories and can eat to satiety. They will commence the use of a daily online diary to record pain levels as well as self-evaluate their compliance to the diet (both as VAS scales). They will have phone and email access to the researchers for questions.

Participants will be randomised from the start of week 4 into either a well-formulated ketogenic diet WFKD (the intervention) or to continue with the WFD. The participants in the intervention WFKD group will receive education, written materials and online resources at the Week 3 contact with the researcher which aim to restrict the dietary carbohydrate intake to between 30-50 grams per day. This is material specifically developed for the study, but also includes publicly accessible links such as www.dietdoctor.com. The group will also measure blood ketone levels via finger prick test daily for the first week to provide objective feedback as to whether they are in the target ketosis range (0.5 - 3.0 mmol/L) and will titrate their carbohydrate intake up or down based on this measure. They will continue to measure ketones at least 3 times per week throughout the intervention period (recorded in the daily diary). They will not be provided with food, but will be able to choose from a range of recipes that suit their preferences. To ensure nutrient adequacy, a nutrient checklist has been developed by the researcher in conjunction with a dietitian to provide a list of the top 10 low-carbohydrate foods (per serving size) for each vitamin and mineral. The participant will aim to include foods from each of the different categories each week. They will continue to record their daily pain, any adverse symptoms and adherence to the diet in the online diary. The WFD group will also measure blood ketones weekly, record their daily pain, any adverse symptoms and adherence to the diet in the online diary.

Both groups will have fortnightly telehealth reviews during the intervention period (weeks 4-12) with the researcher which will allow for further education or assistance if required. Both groups will also complete an online 24 hour food recall (ASA24) at pre-screening, week 3,6,8,10 (on random days), at completion (week 13) and at follow-up (week 24). This will quantify changes in macronutrient and micronutrient intake.
Intervention code [1] 317976 0
Treatment: Other
Comparator / control treatment
At week 4 randomisation will occur to either the ketogenic diet or to continue with the WFD.
Control group
Active

Outcomes
Primary outcome [1] 324318 0
Reported pain on a 100mm visual analogue scale (VAS) (pain intensity subset adapted from the Brief Pain Index BPI and the daily diary)
Timepoint [1] 324318 0
BPI Weeks 0, 13 and 24, Daily diary weeks 4-12
Secondary outcome [1] 384298 0
Ketosis level: The level of ketones achieved and duration of ketone levels within the nutritional ketosis range (0.5-3mmol/L) as ascertained by a finger-prick test using a Abbott Freestyle Optium Neo
Timepoint [1] 384298 0
Intervention group: daily during week 4, then 3 times per week for weeks 5-12
WFD group: once per week for week 4-12
Secondary outcome [2] 384299 0
Blood glucose level: Measured at the same time as ketones using a different testing strip
Timepoint [2] 384299 0
Intervention group: daily during week 4, then 3 times per week for weeks 5-12
WFD group: once per week for week 4-12
Secondary outcome [3] 384300 0
Blood biomarker changes: (measured via phlebotomy from a local pathology lab) that reflect a composite outcome for metabolic status (fasting glucose and insulin [HOMA-IR for insulin resistance], blood lipids and lipoproteins)
Timepoint [3] 384300 0
Weeks 3 and 13
Secondary outcome [4] 384301 0
weight change measured by the researcher on digital scales
Timepoint [4] 384301 0
Weeks 3 and 13
Secondary outcome [5] 384302 0
Change in Quality of Life (QOL) scores: A composite of general health, quality of life and functional engagement questions adapted from validated QOL questionnaires (Rand SF36, & Health Assessment Questionnaire Disability Index HAQ-DI) as a single questionnaire
Timepoint [5] 384302 0
Weeks 3, 13 and 26
Secondary outcome [6] 384303 0
Pain medication usage change: Medication increase/decrease will be recorded in the daily diary.
Timepoint [6] 384303 0
Daily weeks 4-12
Secondary outcome [7] 384304 0
Diet satisfaction: Dietary satisfaction Questionnaire (DSQ) assessing convenience, flexibility and enjoyment
Timepoint [7] 384304 0
Week 0 and 13
Secondary outcome [8] 384305 0
Macronutrient/Micronutrients change: Measurement of increased nutrient density or changes in macronutrient distribution. This is assessed using the AS24-Australia online which is a 24 hour recall. This tool is demonstrated at https://asa24.nci.nih.gov/demo/
Timepoint [8] 384305 0
pre-screening, week 3, 6, 8, 10, 13 and 24
Secondary outcome [9] 384329 0
waist circumference measured with a tape measure at the level of the belly button
Timepoint [9] 384329 0
weeks 3 and 13
Secondary outcome [10] 384330 0
blood pressure using a digital blood pressure monitor
Timepoint [10] 384330 0
weeks 3 and 13
Secondary outcome [11] 385002 0
Blood biomarker changes: (measured via phlebotomy from a local pathology lab) that reflect a composite outcome for inflammation status (hsCRP, ESR)
Timepoint [11] 385002 0
weeks 3 and 13

Eligibility
Key inclusion criteria
• Body mass index >18.5.
• 18 years or over.
• Chronic musculoskeletal pain experienced daily that has extended beyond 3 months.
• Willing to be involved in dietary change and attend fortnightly videoconference/phone meetings.
• Willing to monitor blood glucose and ketones via finger-prick (up to) daily.
• Willing to be involved in dietary change that can include animal protein and fat.
• Habitual diet is consistent with a standard western / moderate or high carbohydrate diet (defined for the study as 20% / 75g or more of total energy intake from carbohydrates per day based on 1-day recall AS24 as part of screening questionnaire). If the tested day does not meet this criterion, they will be asked to complete the diary again for another day. If both days do not meet the criteria, they will be excluded.
• Willing to fill in a daily diary (5 mins per day).
• VAS > 30/100mm at intake (based on average of current pain and previous week’s pain). If the tested day does not meet this criterion, they will be asked to complete the BPI again for another day. If both days do not meet the criteria, they will be excluded.
• Use of other treatment therapies (such as physiotherapy, TENS, chiropractic, exercise program etc) must have been ongoing for 1 month prior to recruitment and subject is willing to continue therapy at the same level throughout the intervention.
• Willing to maintain regularly prescribed pain medication or record changes in optional pain medication usage.
• Access to a computer, laptop, tablet or smartphone along with internet access.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• Previous diagnosis of an eating disorder (including anorexia nervosa, bulimia or binge eating disorder).
• Significant weight loss in last 3 months (<5% total body weight).
• Previous bariatric surgery.
• Unable to communicate in English.
• Diagnosed psychiatric disorders (excluding anxiety or depression).
• Cognitive impairment that limits ability to give informed consent or understand the study requirements.
• Physical impairment that limits ability to meet the study requirements.
• Pregnancy or lactation, or plan to become pregnant in the next 3 months.
• Uncontrolled major medical conditions (including type 2 diabetes).
• Type 1 diabetic or insulin dependent Type 2 diabetic
• Prior history of hypoglycemia or insulinoma
• Inherited disorders pertaining to oxidation of fatty acids
• Metabolic or other disorders requiring medication (such as hypertension) unless they have consent of their GP to participate and agreement from the health care provider that they will be regularly monitored (fortnightly) by them to titrate medication if required.
• Cancer diagnosis or cancer-related pain.
• Pain presentations that include headache or migraine.
• Pain presentations that pertain to the reproductive or gastrointestinal systems (such as irritable bowel syndrome or endometriosis). The presence of these pain syndromes as co-morbidities is not an exclusion, only if they are the presenting chronic pain described.


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)
All participants will undertake a whole-foods diet (WFD) for the first 3 weeks. During week three of the run-in, computer generated random allocation will occur (by a researcher not involved in subject contact) with participants randomly allocated to either continue the WFD or transition to a WFKD. At the time of the initial assessment (week 0), the primary research will be unaware of what group they might be allocated to. The final assessment is comprised of online questionnaires as well as in person measurement of anthropometric data. The clinican completing the final measures will not be involved in the research project.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple computer generated randomisation
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?


The people assessing the outcomes
Intervention assignment
Parallel
Other design features
The participant consent form and information statement will describe a dietary intervention for chronic pain (that generally describes the WFD focus on real food and removal of processed foods), but will not reveal specifics regarding the reduction in carbohydrates for the WFKD intervention group. During week three of the run-in, computer generated random allocation will occur (by a researcher not involved in subject contact) with participants randomly allocated to either continue the WFD or transition to a WFKD. All participants will be aware that they are undertaking a dietary intervention for chronic pain management and will be unaware that this diet might change after three weeks. Both groups will assume they are involved in the intervention.
Phase
Not Applicable
Type of endpoint(s)
Efficacy
Statistical methods / analysis
The minimal clinical important difference (MCID) for pain change on a 100mm VAS is approximately 10mm or 15% change, however there is debate regarding whether this differs between groups starting with a higher pain rating versus lower pain rating. MCID values ranging from 8mm to 40mm on a VAS or between 13% and 85% change have been reported in the literature. The sample size was estimated at 20-25 based in similar trials . Based on a 0-10 numerical rating scale, the mean difference of 1.4 (SD 1.05), to achieve 80% power with alpha <0.05, a sample size n=9 per group (total n=18) is required. We aim to recruit 26 participants with chronic pain >30/100mm VAS to allow for dropouts.

Statistical analysis will be performed in either R or the latest version of SPSS (IBM). Data will be assessed for normal distribution. Analysis of the data using Pearson’s correlation (r) will evaluate relationships between variables. T-tests will analyse the significance of differences between outcome scores from baseline. One-way analysis of variance (ANOVA) to assess differences over time will be used. Alpha will be set at 0.05. Further consultation with a statistician at the Sydney Informatics Hub will develop additional direction for statistics.
Descriptive data for participants dropping out prior to randomisation or during the intervention period will used to assess impact of attrition rates on the outcomes. Data will be analysed using intention-to-treat analysis.

Recruitment
Recruitment status
Active, not recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment postcode(s) [1] 30680 0
2541 - Nowra
Recruitment postcode(s) [2] 30681 0
2529 - Shellharbour
Recruitment postcode(s) [3] 30682 0
2540 - Vincentia

Funding & Sponsors
Funding source category [1] 306098 0
University
Name [1] 306098 0
The University of Sydney
Address [1] 306098 0
Charles Perkins Centre (D17)
The University of Sydney
NSW 2006 AUSTRALIA
Country [1] 306098 0
Australia
Funding source category [2] 306313 0
Other
Name [2] 306313 0
NSW Rural Doctors Network
Address [2] 306313 0
Suite 1, 53 Cleary Street
Hamilton, NSW 2303
Country [2] 306313 0
Australia
Primary sponsor type
Individual
Name
Assoc Professor Kieron Rooney
Address
Charles Perkins Centre (D17)
The University of Sydney
NSW 2006 AUSTRALIA
Country
Australia
Secondary sponsor category [1] 306567 0
Individual
Name [1] 306567 0
Rowena Field
Address [1] 306567 0
Charles Perkins Centre (D17)
The University of Sydney
NSW 2006 AUSTRALIA
Country [1] 306567 0
Australia
Secondary sponsor category [2] 306573 0
Individual
Name [2] 306573 0
Dr Fereshteh Pourkazemi
Address [2] 306573 0
Charles Perkins Centre (D17)
The University of Sydney
NSW 2006 AUSTRALIA
Country [2] 306573 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 306317 0
Human Ethics Committee of The University of Sydney
Ethics committee address [1] 306317 0
Research Integrity and Ethics Administration
Research Portfolio
THE UNIVERSITY OF SYDNEY
Level 3, Administration Building (F23)
The University of Sydney, NSW 2006

Ethics committee country [1] 306317 0
Australia
Date submitted for ethics approval [1] 306317 0
06/07/2020
Approval date [1] 306317 0
17/09/2020
Ethics approval number [1] 306317 0
2020/557

Summary
Brief summary
The modern diet is nutrient poor and high in processed sugary food promoting inflammation and metabolic dysregulation. Nutrition can play a crucial role in the modulation of inflammatory processes and may be a useful pain management tool. The aim of this research is to determine if a well-formulated ketogenic diet (WFKD) will alter reported pain in patients with chronic pain. The primary hypothesis is that a WFKD will result in a reduction in reported pain for patients with chronic pain. This study will implement a run-in period of 3 weeks where all participants will undertake a whole-food diet (WFD) that focuses on improving diet quality based on the NOVA classifications of unprocessed or minimally processed foods/ingredients (removal of NOVA category 4 foods from diet). Participants will be randomised from the start of week 4 into either a WFKD (intervention) or to continue the WFD. The WFKD will adjust carbohydrate level for the individual participant to achieve average blood ketone levels of between 0.5 and 3.0 mmol/L. The intervention will run for 9 weeks (total trial intervention 12 weeks). Participants will meet with the study researcher fortnightly via telehealth for education and monitoring. Participants will be followed up 12 weeks after completing the intervention.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 103482 0
Ms Rowena Field
Address 103482 0
Charles Perkins Centre (D17)
The University of Sydney
NSW 2006 AUSTRALIA
Country 103482 0
Australia
Phone 103482 0
+61 437575407
Fax 103482 0
Email 103482 0
rfie5606@uni.sydney.edu.au
Contact person for public queries
Name 103483 0
A/Prof Kieron Rooney
Address 103483 0
Charles Perkins Centre (D17)
The University of Sydney
NSW 2006 AUSTRALIA
Country 103483 0
Australia
Phone 103483 0
+61 2 8627 1877
Fax 103483 0
Email 103483 0
kieron.rooney@sydney.edu.au
Contact person for scientific queries
Name 103484 0
A/Prof Kieron Rooney
Address 103484 0
Charles Perkins Centre (D17)
The University of Sydney
NSW 2006 AUSTRALIA
Country 103484 0
Australia
Phone 103484 0
+61 2 8627 1877
Fax 103484 0
Email 103484 0
kieron.rooney@sydney.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
all the collected de-identified participant raw data will be available
When will data be available (start and end dates)?
following publication, no end date
Available to whom?
sharing will be via mediated access where a record of the dataset is created in the University Research Data Store with public access restricted to the research data metadata. Any researcher wishing to access the raw data set will need approval from Assoc Prof Rooney and meet the appropriate ethics requirements (kieron.rooney@sydney.edu.au)
Available for what types of analyses?
any purpose
How or where can data be obtained?
sharing will be via mediated access where a record of the dataset is created in the University Research Data Store with public access restricted to the research data metadata. Any researcher wishing to access the raw data set will need approval from Assoc Prof Rooney and meet the appropriate ethics requirements (kieron.rooney@sydney.edu.au)
What supporting documents are/will be available?
No other documents available
Summary results
Have study results been published in a peer-reviewed journal?
No
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary