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Trial registered on ANZCTR


Registration number
ACTRN12616000726459
Ethics application status
Approved
Date submitted
26/05/2016
Date registered
2/06/2016
Date last updated
19/05/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
A randomised trial of krill oil for osteoarthritis of the knee
Scientific title
A randomised placebo controlled trial to evaluate the effect of krill oil on pain and effusion size in patients with knee osteoarthritis
Secondary ID [1] 288952 0
Nil
Universal Trial Number (UTN)
U1111-1181-7087
Trial acronym
KARAOKE Trial
Linked study record

Health condition
Health condition(s) or problem(s) studied:
osteoarthritis 298319 0
Condition category
Condition code
Musculoskeletal 298442 298442 0 0
Osteoarthritis

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
130 patients with clinical knee osteoarthritis, significant knee pain and effusion on imaging will receive 2g (2 capsules of 1 g each) of krill oil per day for 24 weeks. Adherence to treatment will be monitored by counting the return capsules at 12 and 24 week visits.
Intervention code [1] 294434 0
Treatment: Other
Comparator / control treatment
130 patients with clinical knee osteoarthritis, significant knee pain and effusion on imaging will receive 2g (2 capsules of 1 g each) of placebo (microcrystalline cellulose) per day for 24 weeks. Adherence to treatment will be monitored by counting the return capsules at 12 and 24 week visits.
Control group
Placebo

Outcomes
Primary outcome [1] 297932 0
Change in knee pain (assessed by 100mm VAS) over 24 weeks in patients with clinical knee OA, significant knee pain and effusions.
Timepoint [1] 297932 0
Mixed model accounting for overall pain at baseline, 4, 12, 16, 20 and 24 weeks
Primary outcome [2] 298456 0
Change in effusion size from baseline to 24 weeks measured using MRI quantitative measurements in patients with symptomatic OA of the knee and knee effusion.
Timepoint [2] 298456 0
Baseline and 24 weeks
Secondary outcome [1] 322676 0
Change in knee pain from baseline to each of the following visits at 4, 8, 12, 16, 20 and 24 weeks (assessed by 100mm VAS) in patients with clinical knee OA and effusion.
Timepoint [1] 322676 0
Linear regression using change in knee pain from baseline to each time point (4, 8, 12, 16, 20 and 24 weeks)
Secondary outcome [2] 323514 0
Change in WOMAC knee pain (total, weight bearing and non-weight bearing) from baseline to 4, 8, 12, 16, 20, and 24 weeks in patients with clinical knee OA, significant knee pain and effusions.
Timepoint [2] 323514 0
baseline and 4, 8, 12, 16, 20 and 24 weeks
Secondary outcome [3] 323515 0
Change in effusion-synovitis score (assessed using modified WORMS semi-quantitative scoring system) from baseline to 24 weeks in patients with clinical knee OA, significant knee pain and effusions.
Timepoint [3] 323515 0
baseline and 24 weeks
Secondary outcome [4] 323516 0
Change in bone marrow lesion size (assessed using MRI semi-quantitative and quantitative methods) from baseline to 24 weeks in patients with clinical knee OA, significant knee pain and effusions.
Timepoint [4] 323516 0
baseline and 24 weeks
Secondary outcome [5] 323517 0
Change in hand pain (assessed by 100mm VAS) from baseline to 4, 8, 12, 16, 20, and 24 weeks in patients with clinical knee OA, significant knee pain and effusions.
Timepoint [5] 323517 0
baseline and 4, 8, 12, 16, 20 and 24 weeks
Secondary outcome [6] 323518 0
Change in WOMAC knee function (assessed by WOMAC scoring system) from baseline to 4, 8, 12, 16, 20 and 24 weeks in patients with clinical knee OA, significant knee pain and effusions.
Timepoint [6] 323518 0
baseline and 4, 8, 12, 16, 20 and 24 weeks
Secondary outcome [7] 323519 0
OMERACT-OARSI responders at 4, 8, 12, 16, 20 and 24 weeks in patients with clinical knee OA, significant knee pain and effusions.
Timepoint [7] 323519 0
4,8,12,16,20 and 24 weeks
Secondary outcome [8] 323520 0
Change in CRP (assessed as hsCRP from serum assay) from baseline in patients with clinical knee OA, significant knee pain and effusions.
Timepoint [8] 323520 0
Baseline, 12 and 24 weeks
Secondary outcome [9] 323521 0
Change in blood lipids from baseline in patients with clinical knee OA, significant knee pain and effusions
Timepoint [9] 323521 0
Baseline, 12 and 24 weeks
Secondary outcome [10] 323522 0
Change in leg muscle strength (assessed by dynamometer) from baseline to 12, and 24 weeks in patients with clinical knee OA, significant knee pain and effusions.
Timepoint [10] 323522 0
baseline and 12, and 24 weeks
Secondary outcome [11] 323523 0
Change in analgesic use (assessed using the questionnaire designed for this study) from baseline to 12, and 24 weeks in patients with clinical knee OA, significant knee pain and effusions.
Timepoint [11] 323523 0
Baseline, 12, and 24 weeks
Secondary outcome [12] 323524 0
Change in quality of life (assessed by AQoL-6D) from baseline to 12 and 24 weeks in patients with clinical knee OA, significant knee pain and effusions.
Timepoint [12] 323524 0
Baseline, 12 and 24 weeks
Secondary outcome [13] 323525 0
Safety (assessed by recording any new symptoms, changes in medications and hospital admissions) of treatment and placebo will be assessed over 24 weeks in patients with clinical knee OA, significant knee pain and effusions.

Krill oil is a very safe medication, with few known side effects.
1. Krill oil may reduce insulin sensitivity by a small amount, although whether this would be large enough to make a difference to blood sugar control in people with diabetes is not clear. However, if the participant has diabetes, they will be advised to discuss this with the study doctor and their GP before starting the study. We will be collecting the fasting blood glucose levels at baseline and 12 weeks and any incident diagnosis will be recorded in the medications and safety questionnaire forms.

2. Krill oil is not suitable for people who already use anticoagulants (eg warfarin), high dose aspirin or non-steroidal anti–inflammatory drugs (NSAIDs). If they are already using these medications, they will be excluded. Incident medical conditions and the use of these medications will be recorded in the medications and safety questionnaire forms.

3. Krill oil is not suitable for people who have allergies to seafood, and they will be excluded. Any incident allergic reaction will be recorded as new symptoms using the medications and safety questionnaire forms.
Timepoint [13] 323525 0
4, 8, 12, 16, 20 and 24 weeks
Secondary outcome [14] 335088 0
Change in T2 map values (assessed using non-contrast compositional MRI) from baseline to 24 weeks in patients with clinical knee OA, significant knee pain and effusions.
Timepoint [14] 335088 0
baseline and 24 weeks

Eligibility
Key inclusion criteria
1. Aged over 40 years old.
2. Men and women with significant knee pain on most days (defined as a VAS >40mm).
3. Knee effusion–synovitis on MRI: In TASOAC study the proportion of participants who had effusion–synovitis on MRI was high (67%), suggesting that localised knee inflammation is common and that MRI is an appropriate screening tool.
4. Meet American College of Rheumatology (ACR) clinical criteria for knee OA confirmed by a rheumatologist.
Minimum age
40 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Inability to have an MRI (claustrophobia, metal in eyes or selected knee, pacemakers).
2. Severe knee OA (joint space narrowing (JSN) on X-ray of Grade 3 using the Osteoarthritis Research Society International (OARSI) atlas).
3. Use of anticoagulants, high dose aspirin or non-steroidal anti–inflammatory drugs (NSAIDs), as krill oil is contra–indicated in such people.
4. Unwillingness to stop taking krill oil and fish oil medications 30 days prior to the trial and during the trial.
5. Other forms of inflammatory arthritis (especially rheumatoid arthritis and gout).
6. Seafood allergy.
7. Significant knee injury within the last 6 months.
8. Arthroscopy or open surgery in the index knee in the last 12 months, or planned.
9. Injections of corticosteroids (last 3 months) or hyaluronic acid (last 6 months) in the index knee.
10. Pregnancy or breastfeeding.
11. Use of any investigational drug(s) and/or devices within 30 days prior to randomisation
12. Presence of any serious medical illness that may preclude 24 week follow up.
13. Inability to provide informed consent.

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)
central randomisation by computer
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software
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
Phase 4
Type of endpoint(s)
Efficacy
Statistical methods / analysis
Visual Analog Scale knee pain scores and WOMAC scores will be analyzed using a repeated-measures mixed model with terms for age, sex, body mass index (calculated as weight in kilograms divided by height in meters squared), treatment, week, and trial center. The correlation within the repeated measures will be addressed by using an individual participant identification as a random effect. The effect of treatment will be evaluated by the month × treatment interaction.

Linear regression will be used to compare changes in maximal effusion size and function in univariate and multivariable modelling (if groups are not well matched at baseline) between groups using intention to treat analysis for all outcomes. Per protocol analyses will be completed for study participants consuming >=80% of capsules. Significance will be p < 0.05 (two tailed). Missing data will be accounted for by using propensity weighting, as appropriate.

Based on in–house data, assuming 10mm difference between krill oil and placebo on the VAS pain scale (reduction in VAS pain scores in the placebo group by -15.5 +/- 25.5 mm over 12 weeks), 90% power, and 5% probability of type 1 error (alpha=0.05), we will need 234 participants. Adjusting for 10% loss to follow up, we need 260 participants (130 in each arm). Based on data from Tasmanian Older Adult Cohort (TASOAC) and Vitamin D Effects on Osteoarthritis (VIDEO) trial , this will give us 96% power to detect a difference in effusion size of 20% (mean 2.24cm2, SD of change 1.35).

Recruitment
Recruitment status
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,SA,TAS,WA,VIC
Recruitment hospital [1] 5844 0
Royal Hobart Hospital - Hobart
Recruitment hospital [2] 5845 0
The Alfred - Prahran
Recruitment hospital [3] 5846 0
The Queen Elizabeth Hospital - Woodville
Recruitment hospital [4] 5847 0
Royal North Shore Hospital - St Leonards
Recruitment hospital [5] 5848 0
Fiona Stanley Hospital - Murdoch

Funding & Sponsors
Funding source category [1] 293674 0
Government body
Name [1] 293674 0
National Health and Medical Research Council Australia
Address [1] 293674 0
Level 1
16 Marcus Clarke Street
Canberra ACT 2601
Country [1] 293674 0
Australia
Funding source category [2] 296520 0
Charities/Societies/Foundations
Name [2] 296520 0
Tasmanian Community Fund
Address [2] 296520 0
Tasmanian Community Fund
GPO Box 1350
HOBART TAS 7001
Country [2] 296520 0
Australia
Primary sponsor type
University
Name
University of Tasmania
Address
Menzies Institute for Medical Research
17 Liverpool street
Hobart
Tasmania 7000
Country
Australia
Secondary sponsor category [1] 292538 0
Individual
Name [1] 292538 0
Graeme Jones
Address [1] 292538 0
Menzies Institute for Medical Research
17 Liverpool Street
Hobart
Tasmania 7000
Country [1] 292538 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 295111 0
Tasmania Health & Medical Human Research Ethics Committee (EC00337)
Ethics committee address [1] 295111 0
Sarah Day
Menzies Institute for Medical Research
University of Tasmania
17 Liverpool Street
Hobart
Tasmania 7000
Ethics committee country [1] 295111 0
Australia
Date submitted for ethics approval [1] 295111 0
15/12/2015
Approval date [1] 295111 0
07/03/2016
Ethics approval number [1] 295111 0
H0015465

Summary
Brief summary
Background: Knee osteoarthritis (OA) is a significant and increasing cause of pain and disability in the Australian population. So far, interventions aimed at structural modification have been disappointing. OA affects the whole joint, and inflammation of the joint lining (synovitis and joint fluid) is now recognised as a key part of OA.

Animal studies suggest that krill oil is anti–inflammatory. Pilot data in humans shows that krill oil reduces knee pain and systemic inflammation after 30 days, suggesting that an approach targeted at specific mechanisms of disease may be effective for OA. However, this study was of short duration, did not collect any data on structural factors, and included patients with a variety of disorders. Longer, larger follow up studies are required.

Aim: To compare, using a randomised, placebo–controlled double–blind design over six months, the efficacy of krill oil vs identical placebo to treat knee osteoarthritis (OA) (both pain and structure) in 260 patients with clinical knee OA, significant knee pain and effusion on imaging.

Primary hypothesis:
1) Krill oil decreases pain (assessed by 100mm VAS) by 10mm more than identical placebo over 24 weeks in patients with clinical knee OA, significant knee pain and effusions.
2) Krill oil decreases effusion size by 20% over 24 weeks in patients with symptomatic OA of the knee and knee effusion.

Significance and Innovation: If krill oil can both improve symptoms and decrease effusion in OA it has the potential to slow progression to joint replacement. The proposed study represents an innovative approach to this and lends itself to easy implementation as krill oil is already available over–the–counter in Australian pharmacies.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 65026 0
Prof Graeme Jones
Address 65026 0
Menzies Institute for Medical Research
17 Liverpool Street
Hobart
Tasmania 7000
Country 65026 0
Australia
Phone 65026 0
+61 3 6226 7705
Fax 65026 0
Email 65026 0
Graeme.Jones@utas.edu.au
Contact person for public queries
Name 65027 0
Dr Laura Laslett
Address 65027 0
Menzies Institute for Medical Research
17 Liverpool Street
Hobart
Tasmania 7000
Country 65027 0
Australia
Phone 65027 0
+61 417 865 075
Fax 65027 0
Email 65027 0
Laura.Laslett@utas.edu.au
Contact person for scientific queries
Name 65028 0
Prof Graeme Jones
Address 65028 0
Menzies Institute for Medical Research
17 Liverpool Street
Hobart
Tasmania 7000
Country 65028 0
Australia
Phone 65028 0
+61 3 6226 7705
Fax 65028 0
Email 65028 0
Graeme.Jones@utas.edu.au

No information has been provided regarding IPD availability
Summary results
No Results