Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12616000353493
Ethics application status
Approved
Date submitted
10/03/2016
Date registered
18/03/2016
Date last updated
9/05/2023
Date data sharing statement initially provided
3/09/2019
Date results provided
9/05/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
Effect of combined conservative therapies on clinical outcomes in patients with thumb base osteoarthritis: a randomised, controlled trial (COMBO)
Scientific title
Effect of combined conservative therapies on clinical outcomes in patients with thumb base osteoarthritis: a randomised, controlled trial (COMBO)
Secondary ID [1] 288479 0
None
Universal Trial Number (UTN)
U1111-1178-9992
Trial acronym
COMBO
Linked study record

Health condition
Health condition(s) or problem(s) studied:
thumb base osteoarthritis 297521 0
Condition category
Condition code
Musculoskeletal 297724 297724 0 0
Osteoarthritis

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The intervention will be composed of four components:

EDUCATION ABOUT THE DISEASE AND JOINT PROTECTION TECHNIQUES
All participants will be provided with education about disease and joint protection techniques through an educational brochure delivered at baseline and through face-to-face meetings of approximately 30 minutes each with the study therapist at baseline and 2-week visit. The brochure and the visit will aim to provide information about the disease including: diagnosis, disease course, objectives of treatment, self-management and instruction in joint protection techniques. The brochure was developed by a team of health professionals involved in this study (occupational therapists, physiotherapists and rheumatologists) with experience in the management of thumb base OA. The therapist will have a script to follow in order to be consistent with all participants regarding the joint protection advices.

SPLINTS
We will use prefabricated neoprene splints incorporating the base of the thumb and wrist and recommend its use during the activities of daily living (minimum of 4 hours/day) for 6 weeks, removing during rest, sleep, exercises, bathing and heat activities.

EXERCISES
The aim of the exercise programme in our study will be to optimize the range of motion (ROM) and joint stability, to increase strength and to prevent progression of deformities and loss of ROM. The programme will be consisted of five exercises: thumb opposition; paper tearing; line tracing on ball; objects collection with chopsticks and ball squeezing. Participants will receive instructions on how to do the exercises correctly through a supervised one-on-one 30 minute sessions with the study therapist at baseline and at two weeks after intervention commencement. They will be further instructed to perform individual unsupervised at-home sessions, three times per week for 6 weeks. Each exercise should be repeated 10 times during the first week. For the strength exercises (paper tearing and ball squeezing), the progression will be made by increasing the difficulty (e.g. tearing a thicker paper and squeezing the ball harder). For the remaining exercises, the number of repetitions will be increased, aiming for 12 repetitions during the second week and 15 repetitions for the following 4 weeks, if tolerated. Each home exercise session should last approximately 10 minutes.

TOPICAL NSAIDS
The usual prescription of topical NSAIDs for patients with hand OA involves the application of the medication over the affected joint three times a day. For the purpose of this trial, we will use Diclofenac diethylammonium gel (11.6 mg/g), a topical NSAID commonly used in clinical practice that has been studied in large, good quality trials with superiority over placebo . Participants will be instructed to administer the medication three times per day immediately prior to placing the splint for 6 weeks on a daily basis. In order to standardise the amount used, the participants will receive a small spatula with a permanent pen mark showing exactly how much product they should use. The advised amount corresponds with approximately 20 mg to be applied in an area of 40 cm2 as recommended by the drug instructions. The use of the medication for 6 weeks in this study and not for a shorter period of time is justifiable due to the chronic nature of OA. The topical NSAID will be free of charge.
To monitor adherence to the treatments, participants from the intervention group will receive a diary and will be asked to record their use of splints and topical NSAIDs on a daily basis. In addition, the participants will be requested to report which exercises were performed and how frequently they were performed on a weekly basis. Participants will be asked to bring their diaries in for the re-assessment visits.
Intervention code [1] 293823 0
Treatment: Devices
Intervention code [2] 293824 0
Treatment: Other
Intervention code [3] 293825 0
Treatment: Drugs
Comparator / control treatment
The control group will be provided with education about disease and joint protection techniques through an educational brochure delivered at baseline and through face-to-face meetings of approximately 30 minutes each with the study therapist at baseline and 2-week visit. The brochure and the visit will aim to provide information about the disease including: diagnosis, disease course, objectives of treatment, self-management and instruction in joint protection techniques. The brochure was developed by a team of health professionals involved in this study (occupational therapists, physiotherapists and rheumatologists) with experience in the management of thumb base OA. The therapist will have a script to follow in order to be consistent with all participants regarding the joint protection advices.
Control group
Active

Outcomes
Primary outcome [1] 297252 0
Change in pain level at the base of the thumb assessed by the visual analogue scale (VAS) (range, 0-100mm)
Timepoint [1] 297252 0
Baseline, and at 6 weeks after intervention commencement
Primary outcome [2] 297253 0
Change in hand function assessed by the Functional index for hand osteoarthritis (FIHOA)
Timepoint [2] 297253 0
Baseline, and at 6 weeks after intervention commencement
Secondary outcome [1] 320474 0
change in pain level at the base of the thumb assessed by VAS
Timepoint [1] 320474 0
Baseline, 2 and 12 weeks after intervention commencement and 6 months after intervention completion.
Secondary outcome [2] 320475 0
Change in hand function assessed by FIHOA
Timepoint [2] 320475 0
Baseline, 2 and 12 weeks after intervention commencement and 6 months after intervention completion.
Secondary outcome [3] 320476 0
Change in grip strength assessed by dynamometer
Timepoint [3] 320476 0
Baseline, and at 2, 6 and 12 weeks after intervention commencement
Secondary outcome [4] 320496 0
Change in patient global assessment assessed by the question “Considering all the ways your hand OA affects you, how have you been during the last 48 hours?”
Timepoint [4] 320496 0
Baseline, and at 2, 6 and 12 weeks after intervention commencement
Secondary outcome [5] 320497 0
Change in duration of first CMC joint stiffness assessed by the question “What is the duration of stiffness in your finger joints in the morning?”
Timepoint [5] 320497 0
Baseline, and at 2, 6 and 12 weeks after intervention commencement
Secondary outcome [6] 320498 0
Change in health related quality of life assessed by the Assessment of Quality of Life – 4D (AQol-4D)
Timepoint [6] 320498 0
Baseline, and at 2, 6 and 12 weeks after intervention commencement
Secondary outcome [7] 320499 0
Use of rescue medications for pain at the base of the thumb assessed by inspection of participant’s diary
Timepoint [7] 320499 0
2, 6 and 12 weeks after intervention commencement
Secondary outcome [8] 321202 0
Treatment expectation assessed by the credibility/expectancy questionnaire
Timepoint [8] 321202 0
Baseline
Secondary outcome [9] 321203 0
Global rating of change for pain, function and overall change assessed by the question “Which option best represents the change in pain/ change in function/overall change in your thumb since you began the study?”
Timepoint [9] 321203 0
6 and 12 weeks after intervention commencement
Secondary outcome [10] 321204 0
Adverse events (i.e. pain due exercises, skin reactions due the use of splint or topical diclofenac) assessed by inspection of participant's diary
Timepoint [10] 321204 0
2, 6 and 12 weeks after intervention commencement
Secondary outcome [11] 321205 0
Change in presence of swelling and tenderness assessed by joint examination
Timepoint [11] 321205 0
Baseline and at 2, 6 and 12 weeks after intervention commencement
Secondary outcome [12] 321819 0
Change in pinch strength (in kg) assessed by dynamometers
Timepoint [12] 321819 0
Baseline and at 2, 6 and 12 weeks after intervention commencement
Secondary outcome [13] 323198 0
Change in willingness to undergo thumb surgery assessed by the question "Which comment best describes your willingness to proceed with surgery for your thumb OA?" (unsure; probably not willing; probably willing; definitely not willing; definitely willing)
Timepoint [13] 323198 0
Baseline and at 2, 6 and 12 weeks after intervention commencement
Secondary outcome [14] 328461 0
Change in impairments in work and activities assessed by the Work Productivity and Activity Impairment Questionnaire General Health (WPAI-GH)
Timepoint [14] 328461 0
Baseline and at 2, 6 and 12 weeks after intervention commencement
Secondary outcome [15] 328462 0
Range of motion of the first metacarpal joint assessed with a goniometer
Timepoint [15] 328462 0
Baseline
Secondary outcome [16] 328463 0
Presence of first metacarpal joint collapse pattern during pinch movement.
Timepoint [16] 328463 0
Baseline

Eligibility
Key inclusion criteria
- Age greater than or equal to 40 years
- Clinical diagnosis of OA in the first CMC joint in at least one hand
- Chronic pain at the base of the thumb at least half of the days in the past month and at least 48 hours prior to the screening visit
- Average VAS pain greater than or equal to 40 out of 100 (range, 0 – 100) over past 30 days
- FIHOA scores greater than or equal to 6 (range, 0 - 30)
- Radiographic evidence of OA in the first CMC joint read by a trained rheumatologist (KLG greater than or equal to 2)
Minimum age
40 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
- Known diagnosis of crystal-related arthritis (e.g. gout, CPPD), autoimmune arthritis (e.g. rheumatoid arthritis, psoriatic arthritis), hemochromatosis or fibromyalgia
- Hand surgery in the last 6 months or planning to undergo surgery in the next 6 months
- Use of concomitant medications potentially directed at OA, unless at a stable dosage for at least 1 month for analgesics and NSAIDs or 3 months for slow acting symptomatic or structure modifying drugs
- Intra-articular hyaluronic acid injection in the affected joint in the past 6 months
- Intra-articular steroid injection in the affected joint in the past month
- Significant injury to the affected joint in the past 6 months
- Any other hand pathology that is likely to be contributing to the pain at the base of the thumb (e.g. scaphoid fracture, carpal tunnel syndrome, DeQuervain tendinopathy, trigger thumb, first CMC joint laxity or injury, joint infection, cubital tunnel syndrome, diabetic neuropathy, pain referred from the neck, pain following hand or wrist trauma or surgery)
- Poor general health likely to interfere with compliance or assessments, judged by the investigator.
- Known hypersensitivity to diclofenac
- Current history of advanced renal failure
- Past or current history of gastrointestinal ulceration, bleeding and/or perforation
- Women who are pregnant or breastfeeding
- Current use of any study interventions

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 sequence will be concealed from the researchers enrolling and assessing participants in sequentially numbered opaque, sealed and stapled envelopes. Aluminium foil inside the envelope will be used to render the envelope impermeable to intense light. Envelopes will be kept in the locked drawer of the study coordinator and will be opened only after the enrolled participant completes all baseline assessments and it is time to allocate the intervention.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Individuals who consent to take part in the study and fulfill all inclusion and exclusion criteria will be assigned to either intervention or control group with a 1:1 allocation as per a computer generated randomisation schedule stratified by OA severity using KLG (2 and 3 vs. 4) using random blocks of different sizes.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?


The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
SAMPLE SIZE ESTIMATION & JUSTIFICATION
The two primary outcome measures (FIHOA and VAS) were used to estimate the sample size. For the FIHOA, the minimal clinically important difference (MCID) is not known, thus the calculation was based on detecting a mean difference of 3 points (defined arbitrarily) on the FIHOA (range 0-30). The standard deviation used was based on the baseline scores presented in the FIHOA’s validation study (SD 6.2). For pain intensity, the calculation was based on detecting a MCID of 20 mm on a 100mm VAS assuming a standard deviation of 20 mm as used in previous study . Considering that the two primary outcomes are correlated (r=0.49) an alpha of 0.027 was used as the level of significance for both outcomes which preserves an overall 5% level of significance. To achieve a sample power of at least 80% for both outcomes a sample size of 81 individuals per group will be required, for the VAS the power was above 99%. To accommodate expected dropouts of 20% before study completion, we aim to include 102 participants in each group.

STATISTICAL METHODS TO BE UNDERTAKEN
An external statistician will perform the statistical analysis. Data will be analysed according to the intention-to-treat principle. Demographic characteristics and baseline scores will be presented to assess comparability of treatment groups at baseline. 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 each time-point by treatment group. The between-group difference in mean change from baseline with 95% confidence interval will be presented for all primary and secondary outcomes and compared using independent t-test or the Wilcoxon rank-sum test as appropriate. Categorical outcomes will be examined by ?2 test or Fisher’s exact test, if expected cell counts are small. Analysis adjusted for baseline score and other relevant demographic and clinical characteristics will also be performed using analysis of covariance models fitted separately at 2, 6 and 12 weeks for all outcomes with the change from baseline as the dependent variable. Furthermore, standardized mean differences (95% CI) will be computed as the adjusted between-group difference in scores divided by the pooled SD of the baseline scores.
In addition, outcomes will be analysed on a categorical basis. The basis for categorization will be the participant’s score on the perceived ratings of change (participants reporting feeling much better and slightly better will be considered to have undergone meaningful change), and the OMERACT-OARSI criteria. Logistic regression models adjusted for age, gender, BMI and KLG will be used to compare response between treatment groups. The OMERACT-OARSI criteria for a meaningful change (improvement) are one of the following:
1) High improvement:
- greater than or equal to 50% improvement + absolute change of greater than or equal to 20 in self-reported pain intensity (VAS, 0–100mm), OR
- greater than or equal to 50% improvement + absolute change of greater than or equal to 6 in self-reported hand function (FIHOA, 0–30);
OR
2) Improvement in at least 2 of the 3 following:
- greater than or equal to 20% improvement + absolute change greater than or equal to 10 in self-reported pain intensity (VAS, 0–100mm)
- greater than or equal to 20% improvement + absolute change greater than or equal to 10 in Patient Global Assessment of disease activity (VAS, 0–100mm)
- greater than or equal to 20% improvement + absolute change greater than or equal to 3 in self-reported hand function (FIHOA, 0–30).

Post-hoc subgroup analyses will be performed examining whether there is heterogeneity in treatment effect according to presence of the following: concomitant symptomatic interphalangeal joint OA, presence of erosive hand OA (defined based on radiographic score), presence of CMC joint subluxation (assessed by the ratio of the radial subluxation of the base of the first metacarpal to the total articular width of the first metacarpal, on the Eaton stress view radiograph and by baseline OA severity according to KLG.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
12/05/2016
Actual
26/05/2016
Date of last participant enrolment
Anticipated
30/03/2018
Actual
20/07/2018
Date of last data collection
Anticipated
26/04/2019
Actual
21/05/2019
Sample size
Target
204
Accrual to date
Final
204
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 5233 0
Royal North Shore Hospital - St Leonards
Recruitment postcode(s) [1] 12704 0
2065 - Royal North Shore Hospital

Funding & Sponsors
Funding source category [1] 292825 0
Government body
Name [1] 292825 0
National Health and Medical Research Council
Country [1] 292825 0
Australia
Funding source category [2] 300637 0
Charities/Societies/Foundations
Name [2] 300637 0
The Lincoln Centre For Research into Bone and Joint Diseases and Hand Surgery
Country [2] 300637 0
Australia
Primary sponsor type
University
Name
The University of Sydney a body corporate established pursuant to the University of Sydney Act 1989 represented and acting through the Dept of Rheumatology, Northern Clinical School
Address
The University of Sydney, Northern Clinical School
Level 7 – Clinical Administration 7C – Rheumatology Dept
Royal North Shore Hospital
Reserve Rd, St Leonards NSW 2065
Country
Australia
Secondary sponsor category [1] 291757 0
None
Name [1] 291757 0
Address [1] 291757 0
Country [1] 291757 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 294332 0
NSLHD Research Office
Ethics committee address [1] 294332 0
Ethics committee country [1] 294332 0
Australia
Date submitted for ethics approval [1] 294332 0
Approval date [1] 294332 0
20/01/2016
Ethics approval number [1] 294332 0
HREC/15/HAWKE/479

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

Contacts
Principal investigator
Name 63318 0
Prof David Hunter
Address 63318 0
Royal North Shore Hospital
Rheumatology Department , 7C Clinical Administration
Reserve Road
St. Leonards NSW 2065
University of Sydney School of Medicine, Northern.
Rheumatology Dept
Country 63318 0
Australia
Phone 63318 0
+61 2 94631887
Fax 63318 0
+61 2 94631077
Email 63318 0
david.hunter@sydney.edu.au
Contact person for public queries
Name 63319 0
Sarah Rubia Robbins
Address 63319 0
Royal North Shore Hospital
Rheumatology Department , 7C Clinical Administration
Reserve Road
St. Leonards NSW 2065
Country 63319 0
Australia
Phone 63319 0
+61 2 94631855
Fax 63319 0
+61 2 94631077
Email 63319 0
sarah.robbins@sydney.edu.au
Contact person for scientific queries
Name 63320 0
Sarah Rubia Robbins
Address 63320 0
Royal North Shore Hospital
Rheumatology Department , 7C Clinical Administration
Reserve Road
St. Leonards NSW 2065
Country 63320 0
Australia
Phone 63320 0
+61 2 94631855
Fax 63320 0
+61 2 94631077
Email 63320 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?
We will share the data of 196 consented participants including demographics, clinical characteristics and outcome measures at baseline, weeks 2, 6 and 12.
When will data be available (start and end dates)?
After a secondary researcher proposal has been approved by the data custodians. Data are available for an indefinite time.
Available to whom?
Researchers interested in using IPD for future studies
Available for what types of analyses?
Any type of analyses
How or where can data be obtained?
As of 1st July 2023, access can be requested via the Health Data Australia catalogue (https://www.researchdata.edu.au/health). Search for the ACTRN number in the catalogue to find datasets associated with this trial.


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
19133Study protocol https://bmjopen.bmj.com/content/7/1/e014498 
19134Informed consent form    370065-(Uploaded-31-03-2023-10-46-43)-Study-related document.pdf


Results publications and other study-related documents

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

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseEfficacy of combined conservative therapies on clinical outcomes in patients with thumb base osteoarthritis: Protocol for a randomised, controlled trial (COMBO).2017https://dx.doi.org/10.1136/bmjopen-2016-014498
EmbaseRadial subluxation in relation to hand strength and radiographic severity in trapeziometacarpal osteoarthritis.2018https://dx.doi.org/10.1016/j.joca.2018.06.014
EmbaseMusculoskeletal ultrasound in symptomatic thumb-base osteoarthritis: Clinical, functional, radiological and muscle strength associations.2019https://dx.doi.org/10.1186/s12891-019-2610-4
EmbaseCarpometacarpal and metacarpophalangeal joint collapse is associated with increased pain but not functional impairment in persons with thumb carpometacarpal osteoarthritis.2021https://dx.doi.org/10.1016/j.jht.2020.07.003
EmbaseEfficacy of a Combination of Conservative Therapies vs an Education Comparator on Clinical Outcomes in Thumb Base Osteoarthritis: A Randomized Clinical Trial.2021https://dx.doi.org/10.1001/jamainternmed.2020.7101
EmbaseGreater efficacy of a combination of conservative therapies for thumb base OA in individuals with lower radial subluxation - a pre-planned subgroup analysis of the COMBO trial.2021https://dx.doi.org/10.1016/j.joca.2021.07.010
EmbaseAssociations between radiographic features, clinical features and ultrasound of thumb-base osteoarthritis: A secondary analysis of the COMBO study.2022https://dx.doi.org/10.1111/1756-185X.14248
EmbaseHigh baseline pain is associated with treatment adherence in persons diagnosed with thumb base osteoarthritis: An observational study.2022https://dx.doi.org/10.1016/j.jht.2021.04.024
EmbasePain, function, and radiographic disease in trapeziometacarpal osteoarthritis.2023https://dx.doi.org/10.1016/j.jht.2021.10.001
N.B. These documents automatically identified may not have been verified by the study sponsor.