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Trial registered on ANZCTR


Registration number
ACTRN12618001656224
Ethics application status
Approved
Date submitted
18/09/2018
Date registered
8/10/2018
Date last updated
18/05/2022
Date data sharing statement initially provided
5/03/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
DICKENS - A randomised controlled trial of diacerein to treat knee osteoarthritis with effusion-synovitis
Scientific title
DICKENS - A randomised controlled trial of DIaCerein to treat KneE osteoarthritis with effusioN-Synovitis
Secondary ID [1] 296122 0
Nil
Universal Trial Number (UTN)
Trial acronym
DICKENS
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Knee osteoarthritis 309703 0
Condition category
Condition code
Musculoskeletal 308511 308511 0 0
Osteoarthritis

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Diacerein (50 mg twice daily).

Participants will start the trial taking one capsule daily with food, containing 50 mg of diacerein, for the first 2 weeks. This will then be increased to two capsules daily with food, equating to 100 mg of diacerein, to be taken for the remainder of the 6 month trial.

Depending on the side-effect profile, it is possible for participants to remain on 50 mg/day at week 2 or for participants to reduce their dose from 100 mg/day back to 50 mg/day anytime during the trial. This decision will be made in consultation with the medical doctor at each site. The reason participants can remain on half the dose is that the effect of diacerein on pain improvement does not appear to be dose-responsive. For example the literature suggests that 50 mg/day has a similar efficacy compared to 100mg per day (-15.6 vs -18.3).

Participant adherence will be monitored by counting the unused capsules at the week 12 and 24 visits.
Intervention code [1] 312453 0
Treatment: Drugs
Comparator / control treatment
Identical placebo. Sucrose capsule.

Control group
Placebo

Outcomes
Primary outcome [1] 307483 0
Knee pain, as assessed by visual analogue scale (VAS)
Timepoint [1] 307483 0
24 weeks post-enrolment
Secondary outcome [1] 352032 0
Knee pain as assessed by visual analogue scale (VAS)
Timepoint [1] 352032 0
4, 8, 12, 16, 20 weeks post-enrolment
Secondary outcome [2] 352033 0
Knee effusion-synovitis as assessed by MRI
Timepoint [2] 352033 0
24 weeks post-enrolment
Secondary outcome [3] 352034 0
Knee pain as assessed by WOMAC (Western Ontario and McMasters Universities Osteoarthritis Index)
Timepoint [3] 352034 0
4, 8, 12, 16, 20 and 24 weeks post-enrolment
Secondary outcome [4] 352035 0
Knee function as assessed by WOMAC (Western Ontario and McMasters Universities Osteoarthritis Index)
Timepoint [4] 352035 0
4, 8, 12, 16, 20 and 24 weeks post-enrolment
Secondary outcome [5] 352036 0
Knee stiffness as assessed by WOMAC (Western Ontario and McMasters Universities Osteoarthritis Index)
Timepoint [5] 352036 0
4, 8, 12, 16, 20 and 24 weeks post-enrolment
Secondary outcome [6] 352037 0
OMERACT-OARSI responder criteria
Timepoint [6] 352037 0
4, 8, 12, 16, 20 and 24 weeks post-enrolment
Secondary outcome [7] 352038 0
Co-pathology present on MRI (bone marrow lesions, cartilage defects, meniscal extrusion)
Timepoint [7] 352038 0
24 weeks post-enrolment
Secondary outcome [8] 352039 0
Lower limb muscle strength as assessed by dynamometry at the lower limb (involving both legs simultaneously)
Timepoint [8] 352039 0
12 and 24 weeks post-enrolment
Secondary outcome [9] 352040 0
Whether the participant underwent any knee surgery (including arthroscopies or joint replacement surgery) during the trial, as assessed by self-report questionnaire and data linkage to the Australian Orthopaedic Association National Joint Replacement Registry (AOANJRR).
Timepoint [9] 352040 0
4, 8, 12, 16, 20 and 24 weeks post-enrolment
Secondary outcome [10] 352041 0
Whether the participant underwent any joint injections during the trial, as assessed by self-report questionnaire designed specifically for this study.
Timepoint [10] 352041 0
4, 8, 12, 16, 20 and 24 weeks post-enrolment
Secondary outcome [11] 352042 0
Medication usage (including prescription, over-the-counter, and natural/herbal remedies), as assessed by self-reported questionnaire designed specifically for this study.
Timepoint [11] 352042 0
4, 8, 12, 16, 20 and 24 weeks post-enrolment
Secondary outcome [12] 352043 0
The Assessment of Quality of Life (AQoL-8D)
Timepoint [12] 352043 0
12 and 24 weeks post-enrolment
Secondary outcome [13] 352044 0
EQ-5D-5L
Timepoint [13] 352044 0
12 and 24 weeks post-enrolment
Secondary outcome [14] 352045 0
Health service use (composite secondary outcome), as assessed by self-reported questionnaire and includes visits to GPs, specialist doctors, physiotherapists, and medical imaging for knee pain designed specifically for this study.
Timepoint [14] 352045 0
12 and 24 weeks post-enrolment
Secondary outcome [15] 352046 0
Days absent from work, as assessed by self-reported questionnaire designed specifically for this study.
Timepoint [15] 352046 0
12 and 24 weeks post-enrolment
Secondary outcome [16] 352048 0
Treatment guessing: Participants will be asked what treatment they think they received with the following options: diacerein (active treatment), placebo, or not sure.
Timepoint [16] 352048 0
12 and 24 weeks post-enrolment
Secondary outcome [17] 352525 0
Inflammatory markers are a secondary, exploratory outcome as assessed by serum samples.
Timepoint [17] 352525 0
12 and 24 weeks post-enrolment
Secondary outcome [18] 352526 0
Cartilage degradation markers are a secondary, exploratory outcome as assessed by serum samples.
Timepoint [18] 352526 0
12 and 24 weeks post-enrolment
Secondary outcome [19] 352527 0
Synovial degradation markers are a secondary, exploratory outcome as assessed by serum samples.
Timepoint [19] 352527 0
12 and 24 weeks post-enrolment

Eligibility
Key inclusion criteria
1. Males and females aged 40 to 64 years old.
2. Significant knee pain on most days (defined as a visual analogue scale (VAS) greater than or equal to 40mm).
3. Meet American College of Rheumatology (ACR) clinical criteria for knee osteoarthritis confirmed by a rheumatologist.
4. Any knee effusion-synovitis present on MRI.
5. Participants who are screened via Telehealth must have radiographic knee osteoarthritis defined as joint space narrowing or an osteophyte present (score >=1 on the OARSI atlas).
5. Are willing to participate in the study for 6 months.
Minimum age
40 Years
Maximum age
64 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Inability to provide informed consent.
2. Contraindication to MRI scanning (for example, implanted pacemaker, metal sutures, presence of shrapnel or iron filings in the eye, claustrophobia, knee too large for scanner).
3. Severe knee osteoarthritis (defined as joint space narrowing (JSN) on X-ray as Grade 3 using the OARSI atlas.
4. Other forms of arthritis (e.g., rheumatoid arthritis, gout or other inflammatory arthritis).
5. Significant knee injury in the study knee within the last 6 months.
6. Arthroscopy or open surgery in the study knee in the last 12 months.
7. Receiving intra-articular therapy (e.g. corticosteroids, hyaluronic acid) in the study knee in the last 6 months.
8. Planned arthroscopy or joint replacement surgery during the study period.
9. Contraindication to diacerein use including:
a. Patients with a known tendency towards diarrhoea.
b. Patients with inflammatory bowel disease (e.g. Crohn’s disease, ulcerative colitis).
c. Patients who have stomach problems whose cause is unknown.
d. Patients who are taking a diuretic medication or heart failure medication (digitalis glycoside).
e. Patients that have a current and/or history of liver disease (alanine transaminase (ALT) greater than or equal to 110 U/L) .
f. Patients with abnormal kidney function (creatinine clearance < 30 ml/min).
g. Patients with a known hypersensitivity to this sort of medication, i.e. anthraquinone derivatives (includes some laxatives (dantron, emodin, aloe emodin and some senna glycolsides), antimalarials, and antineoplastics used in the treatment of cancer (mitoxantrone, pixantrone, and the anthracyclines).
h. Patients who are having ongoing antibiotic and/or chemotherapy treatment.
i. Patients who are lactose intolerant, as the study medication contains lactose.
j. Women who are pregnant or breastfeeding.
10. Use of any investigational drug(s) and/or devices within 30 days or 5 half-lives (whichever is longer) prior to randomisation.

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)
Allocation concealed: Central randomisation by phone/fax/computer
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Permuted block randomisation, stratified by site and effusion–synovitis level.
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 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
The primary analyses will be intention-to-treat analyses of primary and secondary outcomes. Per protocol analyses will be performed as the secondary analyses, for study participants consuming =80% of study medication between baseline and week 24 (allowing for 1 capsule (50 mg) per day).

Changes in pain scores and total effusion volume will be analysed using a linear mixed-effects model with treatment, month and their interaction (treatment ?x month) as covariates. The correlation within trial centres and the repeated measures will be addressed using trial centre and participant identification as random intercepts. Month will be treated as random effect to allow different treatment effects among participants over time. Change in outcome measures within each group and difference of the changes between groups from baseline to follow-up will be calculated using linear combinations of the estimated coefficients adjusted for the baseline values of the corresponding outcome measure (e.g. change in pain scores will be adjusted for baseline pain scores). We will also run a model that additionally adjusts the primary outcome for sex, analgesic medication, and depression. Missing data caused by loss to follow-up and nonresponses will be addressed by adding baseline complete variables that can explain the missingness to the regression models.

Secondary analysis for missing data will be performed using multiple imputation by chained equations, with 20 imputations performed by treatment group using baseline complete variables and nonmissing values of the outcomes at baseline and each follow-up, assuming missing at random.

Based on our hypothesis that diacerein will be more effective in participants with moderate to severe effusion-synovitis, we will perform stratified analysis based on size of effusion-synovitis at baseline (mL), and ordinal effusion-synovitis score (Grade 1 or 2/3) at baseline. Other pre-specified stratification analyses will be performed to examine which subgroups may respond better to treatment based on these variables: radiographic knee OA severity, degree of neuropathic pain, depression, fibromyalgia-ness, and co-pathology present on MRI. S

Statistical significance will be set as a two-sided P value <0.05.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/11/2018
Actual
18/03/2019
Date of last participant enrolment
Anticipated
30/06/2022
Actual
Date of last data collection
Anticipated
31/12/2022
Actual
Sample size
Target
260
Accrual to date
241
Final
Recruitment in Australia
Recruitment state(s)
SA,TAS,WA,VIC

Funding & Sponsors
Funding source category [1] 300711 0
Government body
Name [1] 300711 0
National Health and Medical Research Council (NHMRC)
Country [1] 300711 0
Australia
Primary sponsor type
University
Name
University of Tasmania
Address
University of Tasmania, Churchill Avenue
Private Bag 1
Hobart TAS 7001
Country
Australia
Secondary sponsor category [1] 300246 0
None
Name [1] 300246 0
Nil
Address [1] 300246 0
Nil
Country [1] 300246 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 301494 0
Tasmania Health & Medical Human Research Ethics Committee [EC00337]
Ethics committee address [1] 301494 0
Ethics committee country [1] 301494 0
Australia
Date submitted for ethics approval [1] 301494 0
Approval date [1] 301494 0
17/09/2018
Ethics approval number [1] 301494 0

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

Contacts
Principal investigator
Name 87190 0
Dr Dawn Aitken
Address 87190 0
Menzies Institute for Medical Research, University of Tasmania
Private Bag 23
Hobart, TAS 7000
Country 87190 0
Australia
Phone 87190 0
+61 03 6226 7769
Fax 87190 0
Email 87190 0
dawn.aitken@utas.edu.au
Contact person for public queries
Name 87191 0
Dawn Aitken
Address 87191 0
Menzies Institute for Medical Research, University of Tasmania
Private Bag 23
Hobart, TAS 7000
Country 87191 0
Australia
Phone 87191 0
+61 03 6226 7769
Fax 87191 0
Email 87191 0
dawn.aitken@utas.edu.au
Contact person for scientific queries
Name 87192 0
Dawn Aitken
Address 87192 0
Menzies Institute for Medical Research, University of Tasmania
Private Bag 23
Hobart, TAS 7000
Country 87192 0
Australia
Phone 87192 0
+61 03 6226 7769
Fax 87192 0
Email 87192 0
dawn.aitken@utas.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
No - IPD will not be available.


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
SourceTitleYear of PublicationDOI
EmbaseStudy protocol for a randomised controlled trial of diacerein versus placebo to treat knee osteoarthritis with effusion-synovitis (DICKENS).2022https://dx.doi.org/10.1186/s13063-022-06715-w
N.B. These documents automatically identified may not have been verified by the study sponsor.