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Trial registered on ANZCTR


Registration number
ACTRN12619000835145
Ethics application status
Approved
Date submitted
31/05/2019
Date registered
11/06/2019
Date last updated
3/11/2020
Date data sharing statement initially provided
11/06/2019
Date results information initially provided
3/11/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
Internet-based study of a supplement combination in hand osteoarthritis
Scientific title
The efficacy and safety of a supplement combination for hand osteoarthritis pain: an internet-based randomised placebo-controlled trial
Secondary ID [1] 297822 0
None
Universal Trial Number (UTN)
U1111-1230-7715
Trial acronym
RADIANT study
Linked study record
N/A

Health condition
Health condition(s) or problem(s) studied:
Hand Osteoarthritis 312187 0
Condition category
Condition code
Musculoskeletal 310736 310736 0 0
Osteoarthritis
Inflammatory and Immune System 311629 311629 0 0
Connective tissue diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
A supplement combination regimen composed of two investigational products:
(i) Combined supplement: Boswellia serrata extract (Boswellin® Super) 250 mg/d, Pine bark extract (Fenoprolic ™ 70 Organic) 100 mg/d, Methyl Sulfonyl Methane 1500mg/d
- the dose administered: 2 caps in the morning, 1 cap in the evening. Each capsule will contain 83.333 mg of BSE, 33.333 mg of PBE and 500 mg of MSM.
- the duration of administration: 12 weeks;
- the mode of administration: oral capsules.
(ii) Curcumin (Flexofytol®) 168 mg/d
- the dose administered: 2 caps in the morning, 2 caps in the evening. Each capsule will contain 42 mg of curcumin.
- the duration of administration: 12 weeks.
- the mode of administration: oral capsules.
Participants will be randomised to either the active or placebo group. Treatment adherence will be measured weekly by the self-reported nonadherence questionnaire and by the patient-reported capsule count at the end of the study.
(ii) Curcumin (Flexofytol®) 168 mg/d
Intervention code [1] 314063 0
Treatment: Other
Comparator / control treatment
The placebo version of the two investigational products:
(i) Placebo combined supplement: microcrystalline cellulose USP
- the dose administered: 2 caps in the morning, 1 cap in the evening.
- the duration of administration: 12 weeks;
- the mode of administration: oral capsules.
(ii) Placebo curcumin: sunflower seed oil
- the dose administered: 2 caps in the morning, 2 caps in the evening.
- the duration of administration: 12 weeks.
- the mode of administration: oral capsules.
Control group
Placebo

Outcomes
Primary outcome [1] 320243 0
Change in hand pain intensity from baseline to week 12 on a pain Visual Analogue Scale (VAS, 0-100) with the question “How much pain in your [left/right] hand did you experience on average over the last week on a scale from 0 (no pain) to 100 (worst pain possible)? Please consider the pain felt while using your hand during daily activities.”
Timepoint [1] 320243 0
12 weeks post intervention commencement
Secondary outcome [1] 370966 0
Adverse events - assessed by inspection of study specific weekly surveys
The possible adverse events include diarrhoea, bloating, abdominal pain, nausea, gastro-oesophageal reflux, dizziness, hypotension, headache, fatigue, insomnia, increased risk of bleeding and bruising, itching or worsening of allergy symptoms and possible decrease in blood sugar level.
Timepoint [1] 370966 0
week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 post intervention commencement
Secondary outcome [2] 370967 0
Change from baseline in hand pain intensity using 0-100 VAS
Timepoint [2] 370967 0
week 2 and 6 post intervention commencement
Secondary outcome [3] 370968 0
Change from baseline in hand function using the Functional Index for Hand Osteoarthritis (FIHOA)
Timepoint [3] 370968 0
week 2, 6 and 12 post intervention commencement
Secondary outcome [4] 370969 0
Change from baseline in the PGA of disease activity using the question “Considering all the ways your hand osteoarthritis affects you, how have you been during the last 48 hours?” along with a 0-100 VAS where 0 is very well, and 100 is very poor
Timepoint [4] 370969 0
Week 2, 6 and 12 post intervention commencement
Secondary outcome [5] 370970 0
Change from baseline in health-related quality of life assessed by AqoL-4D
Timepoint [5] 370970 0
Week 2, 6 and 12 post intervention commencement
Secondary outcome [6] 371021 0
Consumption of rescue medication to be measured by inspection of study-specific weekly surveys
Timepoint [6] 371021 0
week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 post intervention commencement
Secondary outcome [7] 371022 0
Treatment adherence to be measured weekly by the self-reported nonadherence questionnaire (Voils Medication Adherence Self-reported Questionnaire) and by the patient-reported capsule count at the end of the study
Timepoint [7] 371022 0
week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 post intervention commencement
Secondary outcome [8] 371023 0
Patient satisfaction with allocated treatment assessed by the Medication Satisfaction Questionnaire
Timepoint [8] 371023 0
week 12 post intervention commencement
Secondary outcome [9] 371024 0
Global rating of change for pain assessed by the question “Which option best represents the change in pain in your hand since you began the study?”, scored using a 5-point Likert scale ranging from much better to much worse.
Timepoint [9] 371024 0
week 12 post intervention commencement
Secondary outcome [10] 371025 0
Global rating of change for function assessed by the question “Which option best represents the change in function in your hand since you began the study?”, scored using a 5-point Likert scale ranging from much better to much worse.
Timepoint [10] 371025 0
week 12 post intervention commencement
Secondary outcome [11] 375410 0
Change in impairments in work and activities from baseline to week 12 after intervention commencement assessed by the Work Productivity and Activity Impairment Questionnaire General Health (WPAI-GH)
Timepoint [11] 375410 0
12 weeks post-intervention commencement

Eligibility
Key inclusion criteria
1. Ability and willingness to participate in the study.
2. Internet access and an active email account.
3. Functional English to be able to understand the study procedures, complete the questionnaires and consent to participating.
4. 40 years old or above, male or female
5. Australian permanent resident
6. Presence of pain in the index hand for at least half of the days in the previous month.
7. Hand pain intensity during a painful activity equal to or higher than 40 and equal to or lower than 90 out of 100 on the Visual Analogue Scale over the last week and under no influence of pain medication.
8. Hand functional impairment as assessed by FIHOA with scores equal to or higher than 6 out of 30.
9. Clinical diagnosis of HOA according to the American College of Rheumatology (ACR) classification criteria.
10. Radiographic evidence of osteoarthritis [Kellgren-Lawrence grade (KLG) equal to or higher than 2] in at least one of the joints that the patient reported as having pain.
11. Digital or hard copy of hand x-ray taken in the past 36 months or willingness to undergo a hand x-ray and ability to travel to a Castlereagh Imaging centre located throughout the greater Sydney region.
12. Willingness to avoid starting a new treatment for HOA during the study.
13. Willingness to stop or maintain a routine of exercise/splint usage during the study for patients that have been doing exercises or using a splint regularly.
14. Willingness to stop or maintain the same supplement regimen (not containing any of the study ingredients) on the same dosage and frequency and commit not to stop taking them for the duration of the study.
Minimum age
40 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Participants that are unable to be reached after completing their screening survey.
2. Women who are pregnant or breastfeeding, or women of childbearing potential but not willing to use contraceptive methods for the duration of the study.
3. History of crystal-related arthritis [e.g. gout, calcium pyrophosphate deposition disease (CPPD)], autoimmune arthritis (e.g. rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, ankylosing spondylitis), hemochromatosis or fibromyalgia.
4. Any painful syndrome of the upper limb contributing to the pain in the index hand which may interfere with the evaluation (e.g., hand fracture, carpal tunnel syndrome, DeQuervain tendinopathy, trigger finger or thumb, thumb laxity or injury, joint infection, cubital tunnel syndrome, diabetic neuropathy, pain referred from the neck, pain following hand or wrist trauma or surgery).
5. Significant injury in the index hand that led to substantial loss of function or surgery in the past 6 months such as fracture, joint dislocation, trauma, laceration or nerve damage.
6. Any clinically significant acute or ongoing chronic medical conditions (e.g., uncontrolled diabetes) that could compromise patient safety, limit the patient’s ability to complete the study, and/or compromise the objectives of the study.
7. People currently taking medications known to have potential pharmacological interaction with one or more supplements being tested.
8. People who are allergic to any ingredients of the study supplements.
9. Participants taking centrally acting analgesics (e.g., opioid analgesics, duloxetine and pregabalin) regularly.
10. People currently using NSAIDs (oral or topical) on a regular or occasional basis or people using centrally acting analgesics on an occasional basis but are unable to undergo a 1-week wash-out and/or are not willing to stop using NSAIDs and/or opioid analgesics for the duration of the study.
11. People who have been taking supplements containing any ingredients of the products (i.e., curcumin, Boswellia serrata extract, pine bark extract or MSM) and/or are not willing to undergo a 2-month wash-out and to stop using it for the duration of the study.
12. Surgery in the index hand in the last 12 months or plans to have surgery for the index hand in the next 6 months
13. Intra-articular injection in the index hand of hyaluronic acid in the past 6 months, corticosteroid in the past 3 months or autologous blood product in the past 12 months
14. Participation in another clinical trial and/or treatment received with any investigational agent within 30 days before enrolment.

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)
The allocation and respective study kit ID will be concealed from all investigators in sequentially numbered opaque, sealed and stapled envelopes. Aluminium foil inside the envelope will be used to render the envelope impermeable to intense light.
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 erosive or non-erosive HOA. The sequence generation will be prepared by a statistician not involved in the study.
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
The RADIANT study is an internet-based, 12-week, two-arm with 1:1 allocation ratio, parallel, double-blinded, superiority and placebo randomised controlled trial.
Phase
Phase 2 / Phase 3
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
Sample Size Estimation:
The change in pain VAS at week 12 was used to estimate the sample size using Stata 14. The calculation was based on detecting a minimal clinically important difference (MCID) of 15 on a 0-100 VAS. The reduction in pain on VAS within the given population is approximately 11.3 points (SD 24). It is hypothesised that a further reduction of at least 15 points would be clinically relevant. To detect a 15-point difference in the change in pain VAS between groups at 80% power and an alpha level of 0.05 and allowing for 20% dropout a total of 106 participants would need to be randomised (53 per group).

Statistical Analysis Plan:
Demographic characteristics and baseline scores will be presented to assess the comparability of treatment groups at baseline. Variables of interest will include age, gender, and body mass index. Participants’ characteristics will be described using mean and SD for continuous variables or medians (quartiles) if the distribution is skewed. Counts with percentages will be presented for categorical variables. For continuous outcomes, the mean scores (SD) will be presented at baseline, week 2, 6 and 12. The between-group differences in mean change from baseline with a 95% confidence interval will be presented for all primary and secondary outcomes and compared using independent t-tests or the Wilcoxon rank-sum tests as appropriate. Categorical outcomes will be examined by the chi-squared test or Fisher’s exact test if expected cell counts are small. The analysis adjusted for baseline score and other relevant demographic and clinical characteristics will also be performed using analysis of covariance models at week 2, 6 and 12 for all outcomes with the change from baseline as the dependent variable. No interim analyses will be carried out.
To assist with the interpretation of the results, we will calculate the minimal clinically important improvement (MCII) for pain and function using the Global Rating of Change (GRC) scale. The average score for pain and function of the people who answered the GRC as “slightly better” will be the cut-off value for MCII. We will also calculate the MICD between groups by using the GRC scale. The difference between the mean scores for pain and function of the people who answered the GRC as “no change” and “slightly better” will be the cut-off value for the MICD.

Recruitment
Recruitment status
Completed
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)
ACT,NSW,NT,QLD,SA,TAS,WA,VIC

Funding & Sponsors
Funding source category [1] 302346 0
Government body
Name [1] 302346 0
NHMRC Program Grant
Address [1] 302346 0
16 Marcus Clarke St, National Health and Medical Research Council. GPO Box 1421. Canberra ACT 2601
Country [1] 302346 0
Australia
Primary sponsor type
University
Name
The University of Sydney
Address
The University of Sydney
Research Portfolio, Level 3, Administration Building (F23), City Rd, Camperdown, NSW 2006.
Country
Australia
Secondary sponsor category [1] 302866 0
None
Name [1] 302866 0
Address [1] 302866 0
Country [1] 302866 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 303020 0
The University of Sydney Human Research Ethics Committee
Ethics committee address [1] 303020 0
Level 3, Administration Building (F23). University of Sydney NSW 2006
Ethics committee country [1] 303020 0
Australia
Date submitted for ethics approval [1] 303020 0
13/09/2017
Approval date [1] 303020 0
24/05/2019
Ethics approval number [1] 303020 0
2018/766

Summary
Brief summary
Currently, dietary supplements are widely used by patients with osteoarthritis. Some commonly used supplements such as glucosamine and chondroitin have been proven to be ineffective in reducing the symptoms of osteoarthritis. However, some lesser-known supplements such as: Boswellia serrata extract, Pine bark extract, Curcumin, and Methylsulfonylmethane have demonstrated promising results in clinical trials, but further research is needed. We have developed a new product combining the four supplements above to test its efficacy on people with hand osteoarthritis. We hypothesise that 12 weeks of active supplement combination is superior to its placebo in improving pain intensity in people with symptomatic hand osteoarthritis.
Trial website
www.tinyurl.com/RADIANTstudy
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 92190 0
Prof David Hunter
Address 92190 0
Rheumatology Department, Clinical Admin 7C, Royal North Shore Hospital, Reserve Road, St Leonards, NSW 2065, Australia.
Country 92190 0
Australia
Phone 92190 0
+61 2 94631887
Fax 92190 0
Email 92190 0
david.hunter@sydney.edu.au
Contact person for public queries
Name 92191 0
Dr Sarah Robbins
Address 92191 0
Rheumatology Department, Level 10 Kolling building, Royal North Shore Hospital, Reserve Road, St Leonards, NSW 2065, Australia
Country 92191 0
Australia
Phone 92191 0
+61 2 94631855
Fax 92191 0
Email 92191 0
sarah.robbins@sydney.edu.au
Contact person for scientific queries
Name 92192 0
Dr Sarah Robbins
Address 92192 0
Rheumatology Department, Level 10 Kolling building, Royal North Shore Hospital, Reserve Road, St Leonards, NSW 2065, Australia
Country 92192 0
Australia
Phone 92192 0
+61 2 94631855
Fax 92192 0
Email 92192 0
sarah.robbins@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 of the individual participant data collected during the trial, after de-identification
When will data be available (start and end dates)?
A de-identifiable dataset containing individual participant data will be published in an open access Data Repository 3 years after study close-out for sharing purposes, no end date.
Available to whom?
Open access
Available for what types of analyses?
Any purpose
How or where can data be obtained?
Open access data repository
What supporting documents are/will be available?
Study protocol
Statistical analysis plan
Informed consent form
Ethical approval
How or where can supporting documents be obtained?
Type [1] 5190 0
Ethical approval
Citation [1] 5190 0
Link [1] 5190 0
Email [1] 5190 0
Other [1] 5190 0
Type [2] 5191 0
Study protocol
Citation [2] 5191 0
Link [2] 5191 0
Email [2] 5191 0
sarah.robbins@sydney.edu.au
Other [2] 5191 0
Attachment [2] 5191 0
Type [3] 5192 0
Statistical analysis plan
Citation [3] 5192 0
Link [3] 5192 0
Email [3] 5192 0
sarah.robbins@sydney.edu.au
Other [3] 5192 0
Attachment [3] 5192 0
Type [4] 5193 0
Informed consent form
Citation [4] 5193 0
Link [4] 5193 0
Email [4] 5193 0
sarah.robbins@sydney.edu.au
Other [4] 5193 0
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