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Trial registered on ANZCTR


Registration number
ACTRN12623000380695
Ethics application status
Approved
Date submitted
5/04/2023
Date registered
14/04/2023
Date last updated
15/07/2024
Date data sharing statement initially provided
14/04/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
An online study of an oral supplement combination in knee osteoarthritis.
Scientific title
An online, double-blind, randomised, placebo-controlled study to assess the efficacy and safety of an oral supplement combination in people with symptomatic knee osteoarthritis
Secondary ID [1] 309351 0
2021/877
Universal Trial Number (UTN)
U1111-1290-8590
Trial acronym
ATLAS study
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Knee osteoarthritis (OA) 329556 0
Condition category
Condition code
Musculoskeletal 326487 326487 0 0
Osteoarthritis

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
- The intervention is a combined supplement composed of Boswellia serrata extract (BSE, Boswellin® Super) 250 mg/day, Pine bark extract (PBE, Fenoprolic ™ 70 Organic) 100 mg/day, Curcumin 500mg/day, Piperine 5mg/day and Methylsulfonylmethane (MSM) 1500 mg/day.
- The frequency and duration of the intervention is 4 capsules daily (2 capsules/morning and 2 capsules/night) for 12 weeks.
- The mode of administration is oral capsules.
- Treatment adherence will be measured weekly by the online, study-specific, self-reported questionnaire and by the patient-reported capsule count at the end of the study.
Intervention code [1] 325786 0
Treatment: Other
Comparator / control treatment
- The placebo is composed of Microcrystalline cellulose USP.
- The frequency and duration of the placebo is 4 capsules daily (2 capsules/morning and 2 capsules/night) for 12 weeks.
- The mode of administration is oral capsules.
Control group
Placebo

Outcomes
Primary outcome [1] 334330 0
Knee pain intensity measured by the visual analogue scale (VAS).
Timepoint [1] 334330 0
12 weeks post-treatment allocation in comparison to baseline.
Secondary outcome [1] 420260 0
Knee pain intensity measured by the visual analogue scale (VAS).
Timepoint [1] 420260 0
Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and 11 post-treatment allocation in comparison to baseline.
Secondary outcome [2] 420261 0
Knee pain intensity measured by the Knee Injury and Osteoarthritis Outcome Score (KOOS)' Pain subscale.
Timepoint [2] 420261 0
Weeks 2, 6 and 12 post-treatment allocation in comparison to baseline.
Secondary outcome [3] 420262 0
Knee function in daily living measured by the KOOS' Function in daily living subscale.
Timepoint [3] 420262 0
Weeks 2, 6 and 12 post-treatment allocation in comparison to baseline.
Secondary outcome [4] 420263 0
Sport- and recreation-related knee function measured by the KOOS' Function in sport and recreation subscale.
Timepoint [4] 420263 0
Weeks 2, 6 and 12 post-treatment allocation in comparison to baseline.
Secondary outcome [5] 420264 0
Knee-related quality of life measured by the KOOS' knee-related quality of life subscale.
Timepoint [5] 420264 0
Weeks 2, 6 and 12 post-treatment allocation in comparison to baseline.
Secondary outcome [6] 420265 0
Other knee symptoms, measured by the KOOS' other Symptoms subscale.
Timepoint [6] 420265 0
Weeks 2, 6 and 12 post-treatment allocation in comparison to baseline.
Secondary outcome [7] 420266 0
KOOS total score using all five subscales: pain, other symptoms, function in daily living, function in sport and recreation and knee-related quality of life.
Timepoint [7] 420266 0
Weeks 2, 6 and 12 post-treatment allocation in comparison to baseline.
Secondary outcome [8] 420276 0
Change in patient global assessment (PGA).
Timepoint [8] 420276 0
Weeks 2, 6 and 12 post-treatment allocation in comparison to baseline.
Secondary outcome [9] 420277 0
Health-related quality of life: Independent living, senses and pain using the Physical Super Dimensions of the Assessment of Quality of Life (AQoL-8D) instrument (composite).
Timepoint [9] 420277 0
Weeks 2, 6 and 12 post-treatment allocation in comparison to baseline.
Secondary outcome [10] 420278 0
Health-related quality of life: mental health, happiness, self-worth, coping and relationships using the Psycho-Social Super Dimensions of the AQoL-8D instrument (composite).
Timepoint [10] 420278 0
Weeks 2, 6 and 12 post-treatment allocation in comparison to baseline.
Secondary outcome [11] 420461 0
Health related quality of life: AQoL-8D total score using Assessment of Quality of Life (AQoL-8D) instrument.
Timepoint [11] 420461 0
Weeks 2, 6 and 12 post-treatment allocation in comparison to baseline.
Secondary outcome [12] 420462 0
Treatment satisfaction to be assessed by the PASS "yes/no" question: "Taking into account all the activities you have during your daily life, your level of pain, and also your functional impairment, do you consider that your current state is satisfactory?" For those who answer "no", their opinion of treatment failure will be assessed using a "yes/no" question "Would you consider your current state as being so unsatisfactory that you think the treatment has failed?" will determine treatment failure.
Timepoint [12] 420462 0
Weeks 6 and 12 post-treatment allocation.
Secondary outcome [13] 420463 0
Perceived improvement to be assessed by the Global Rating of Change (GRC) question: : "Which option best represents the change in PAIN in your RIGHT/LEFT knee since you began the study?" using a 5-point Likert scale ranging from 'much better' to 'much worse'.
Timepoint [13] 420463 0
Weeks 6 and 12 post-treatment allocation in comparison to baseline.
Secondary outcome [14] 420464 0
Participant safety to be assessed through an online weekly adverse events study-specific questionnaire. The products of this study are assumed to be safe to use, however, some of the expected adverse events related to this study include diarrhoea, bloating, abdominal pain, nausea and gastro-oesophageal reflux.
Timepoint [14] 420464 0
Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 post-treatment allocation.
Secondary outcome [15] 420465 0
Consumption of pain medication to be measured by inspection of weekly online study-specific surveys.
Timepoint [15] 420465 0
Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 post-treatment allocation.
Secondary outcome [16] 420466 0
Treatment adherence to be measured by self-reported intake of the study products and capsule count at the end of the study using online study-specific surveys.
Timepoint [16] 420466 0
Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 post-treatment allocation.
Secondary outcome [17] 437553 0
Knee or hip osteoarthritis flare occurrence in the past 4 weeks measured by the Flare-OA-16 questionnaire.
Timepoint [17] 437553 0
Secondary outcome [18] 437554 0
Knee or hip osteoarthritis flare occurrence in the past 4 weeks measured by the Flare-OA-16 questionnaire.
Timepoint [18] 437554 0
Weeks 6 and 12 post treatment allocation compared to baseline.

Eligibility
Key inclusion criteria
- Be able and willing to participate and complete the study.
- Have internet access and an active email account.
- Have a fixed address in Australia for the duration of the study.
- Have at least functional English (i.e., able to provide informed consent, understand study procedures, communicate with the research team, and complete questionnaires).
- Be 40 years of age or older.
- Have pain in the index knee for at least half of the days in the previous month before the online screening (If both knees are affected by OA, the index knee will be the most symptomatic. If both knees are equally affected, the study doctor will determine the index knee upon radiological assessment)
- Have a moderate average index knee pain intensity over the week before the online screening and baseline assessment (i.e., = 40 on a 0-100 VAS.
- Be unsatisfied with the current symptomatic state [i.e., negative Patient acceptable symptom state (PASS)] before the online screening and baseline surveys.
- Fulfil the clinical and radiographic criteria for knee OA according to the American College of Rheumatology using participant-reported symptoms/signs.
- Have a Kellgren-Lawrence Grade (KLG) = 2 in the tibiofemoral (TF) or patellofemoral (PF) compartment based on an X-ray of the index knee
- Be willing to maintain a routine (i.e., consistent dosage and frequency) of non-pharmacological and pharmacological therapies for the duration of the study.
- Be willing to abstain from protocol-specified prohibited medications for the duration of the study.
- Be willing to abstain from any supplements targeting osteoarthritis for the duration of the study.
Minimum age
40 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Do not complete the submission of the online screening survey, leaving the form incomplete after 28 days.
- Become non-responders after completing their online screening survey but before being enrolled in the study.
- Have known hypersensitivity to the active or placebo components of the study products (i.e., Boswellia serrata extract, Curcumin, Piperine, Pine bark extract, MSM, and Microcrystalline cellulose USP) or other ingredients of the capsule (Gelatin and Titanium dioxide).
- Are not willing to undergo a 48h washout before the weekly pain assessments.
- Are not willing to discontinue products containing the active ingredients - Boswellia serrata extract, Curcumin (use of food spice is allowed), Piperine, Pine bark extract or MSM.
- Regularly take centrally acting analgesics (e.g., opioid, duloxetine, pregabalin).
- Are currently taking medications known to have potential pharmacological interaction with one or more supplements being tested.
- Have a history of crystalline diseases [e.g., gout, calcium pyrophosphate deposition disease (CPPD)], autoimmune arthritis (e.g., rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, ankylosing spondylitis), hemochromatosis or fibromyalgia. (Participants diagnosed with gout are eligible for the study as long as the condition is being appropriately treated and they have not experienced flare-ups for at least 12 months and participants diagnosed with hemochromatosis but with normal iron levels for at least 12 months are eligible for the study).
- Are pregnant or breastfeeding, or a woman of childbearing potential but not willing to use contraceptive methods for the duration of the study.
- Have any condition that could confound the participant's assessment of index knee pain in the investigator's judgment. For example, same-side hip pain referred to the knee, diabetic or peripheral neuropathy or knee pain referred from the back.
- Have a history of knee infection diagnosis within one month of screening.
- Had an acute knee injury to index knee within 6 months of screening.
- Anticipate any invasive procedure (or surgery) on the index knee during the study duration.
- Had previous intra-articular (IA) therapies (IA hyaluronic acid injection in the study knee in the past six months; IA steroid injections in any joint in the past six months; IA autologous blood product or stem cell injection in the study knee in the past 12 months).
- Have any unstable concurrent clinically significant acute, chronic medical conditions or abnormal laboratory findings that, in the investigator's judgment, would jeopardise the participant's safety, interfere with the protocol's objectives, or affect the participant's compliance.
- Have cancer or other tumour-like lesions (except non-melanoma skin cancer) which has been active in the last three years.
- Are participating in another clinical trial or used an investigational drug or device within 30 days of screening.

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)
After completing all baseline measures, the study coordinator will notify the unblinded researcher who will then reveal the participant's group allocation using the REDCap randomisation module. The randomisation survey in REDCap will be made available only to the unblinded researcher via user rights. The subject enrolment log containing participant's group allocation will be available to the unblinded researchers only through file encryption. The study doctor, study coordinators and study statistician will remain blinded to the treatment allocation until the main results are analysed. Participants will not be told which group they were allocated to until the end of the study (12 weeks after baseline).
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Individuals who qualify and consent to take part in the study will be assigned to either active or placebo group with a 1:1 allocation rate as per computer-generated randomisation scheduled using random permuted block sizes and stratified by radiographic disease severity (KLG 2&3 vs KLG 4).
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
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
The statistical analysis will be performed by a qualified biostatistician who will be blinded to the group allocation. Subjects will be analysed according to the intention-to-treat (ITT) principle. Descriptive statistics of baseline characteristics will be provided for each group. Continuous variables will be summarised in terms of means and standard deviation (SD) where appropriate or median (range), and categorical variables will be presented as frequency (percentage).
Pain intensity will be summarised by timepoint as mean (SD). The primary analysis for the difference in change in pain VAS from baseline to 12 weeks between groups will be an ANalysis of COVAriance (ANCOVA), including adjustment for baseline score to account for possible floor and ceiling effects. A secondary adjusted analysis will also be performed, including additional adjustments for clinical characteristics such as gender, age, and body mass index (BMI). Finally, unadjusted differences between groups will also be calculated, and their significance will be assessed using independent samples t-tests.
Secondary outcomes will be summarised by means (SD) at each time point. The primary analysis will be ANCOVA to compare the change between treatment arms in outcome scores from baseline to the 2-week assessment, from baseline to 6 weeks, and from baseline to 12 weeks. It will include an adjustment for the respective baseline score. Unadjusted differences between groups will also be calculated, and their significance assessed using independent samples t-tests. Differences in dichotomous outcome measures such as adverse events and rescue medication consumption will be compared using chi-squared tests (or Fisher's Exact test if expected cell counts are small).
Placebell©™ covariates will be calculated for each participant to characterise the subjects' placebo response. The correlation between the Placebell©™ covariates and the primary endpoint will be assessed using Pearson's correlation. Adjusted comparisons between groups will also be performed while considering both the baseline values of the primary endpoints and the Placebell©™ Covariate.
Cognivia will use data from placebo-treated subjects to calibrate new Placebell©™ models. If the calibration is successful, the new model will be available for covariate production in future studies.
We will perform subgroup analysis for: i) knee OA phenotypes: tibiofemoral OA vs patellofemoral OA; ii) KLG grade: KLG 2 and 3 vs 4; and iii) Technology self-efficacy: not confident <80 vs confident =80.
Post hoc analysis will include the proportion of participants who achieved at least 20% and 50% improvement in pain VAS and PGA using chi-squared tests. We will use logistic regression models adjusted for age, gender, body mass index (BMI) to compare responses between treatment groups.
A per-protocol analysis will also be performed, including only participants who achieved a minimum of 80% treatment adherence. No interim analyses will be carried out.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
15/04/2024
Actual
4/07/2024
Date of last participant enrolment
Anticipated
15/12/2024
Actual
Date of last data collection
Anticipated
15/03/2025
Actual
Sample size
Target
82
Accrual to date
2
Final
Recruitment in Australia
Recruitment state(s)
ACT,NSW,NT,QLD,SA,TAS,WA,VIC

Funding & Sponsors
Funding source category [1] 313550 0
Government body
Name [1] 313550 0
National Health and Medical Research Council
Country [1] 313550 0
Australia
Primary sponsor type
University
Name
The University of Sydney
Address
Camperdown NSW 2006
Country
Australia
Secondary sponsor category [1] 315328 0
None
Name [1] 315328 0
Address [1] 315328 0
Country [1] 315328 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 312731 0
The University of Sydney Human Research Ethics Committee (HREC)
Ethics committee address [1] 312731 0
Ethics committee country [1] 312731 0
Australia
Date submitted for ethics approval [1] 312731 0
23/09/2021
Approval date [1] 312731 0
22/04/2022
Ethics approval number [1] 312731 0
2021/877

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 125706 0
Prof David Hunter
Address 125706 0
Rheumatology Department, Level 10 Kolling Building, Royal North Shore Hospital, Reserve Road, St Leonards, NSW 2065, Australia
Country 125706 0
Australia
Phone 125706 0
+61 02 9463 1887
Fax 125706 0
Email 125706 0
[email protected]
Contact person for public queries
Name 125707 0
Mimi Collins
Address 125707 0
Rheumatology Department, Level 10 Kolling Building, Royal North Shore Hospital, Reserve Road, St Leonards, NSW 2065, Australia
Country 125707 0
Australia
Phone 125707 0
+61 02 9463 1855
Fax 125707 0
Email 125707 0
[email protected]
Contact person for scientific queries
Name 125708 0
Jocelyn Bowden
Address 125708 0
Rheumatology Department, Level 10 Kolling Building, Royal North Shore Hospital, Reserve Road, St Leonards, NSW 2065, Australia
Country 125708 0
Australia
Phone 125708 0
+61 02 9463 1898
Fax 125708 0
Email 125708 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?
A de-identified dataset containing individual participant data (of those who consented to have their anonymised data used in future studies) will be published in an open-access Data Repository by the Coordinating Principal Investigator three years after study close-out.
When will data be available (start and end dates)?
Three years after study close-out with no end date.
Available to whom?
Anyone who wishes to access it, since it will be published in an open-access Data Repository.
Available for what types of analyses?
Any purpose.
How or where can data be obtained?
Data will be published in an open-access Data Repository (link to be provided once data has been published).


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.