ANZCTR - Registration

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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 information initially provided

3/09/2019

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]

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

Condition category

Condition code

Musculoskeletal

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]

Treatment: Devices

Intervention code [2]

Treatment: Other

Intervention code [3]

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]

Change in pain level at the base of the thumb assessed by the visual analogue scale (VAS) (range, 0-100mm)

Timepoint [1]

Baseline, and at 6 weeks after intervention commencement

Primary outcome [2]

Change in hand function assessed by the Functional index for hand osteoarthritis (FIHOA)

Timepoint [2]

Baseline, and at 6 weeks after intervention commencement

Secondary outcome [1]

change in pain level at the base of the thumb assessed by VAS

Timepoint [1]

Baseline, 2 and 12 weeks after intervention commencement and 6 months after intervention completion.

Secondary outcome [2]

Change in hand function assessed by FIHOA

Timepoint [2]

Baseline, 2 and 12 weeks after intervention commencement and 6 months after intervention completion.

Secondary outcome [3]

Change in grip strength assessed by dynamometer

Timepoint [3]

Baseline, and at 2, 6 and 12 weeks after intervention commencement

Secondary outcome [4]

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]

Baseline, and at 2, 6 and 12 weeks after intervention commencement

Secondary outcome [5]

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]

Baseline, and at 2, 6 and 12 weeks after intervention commencement

Secondary outcome [6]

Change in health related quality of life assessed by the Assessment of Quality of Life – 4D (AQol-4D)

Timepoint [6]

Baseline, and at 2, 6 and 12 weeks after intervention commencement

Secondary outcome [7]

Use of rescue medications for pain at the base of the thumb assessed by inspection of participant’s diary

Timepoint [7]

2, 6 and 12 weeks after intervention commencement

Secondary outcome [8]

Treatment expectation assessed by the credibility/expectancy questionnaire

Timepoint [8]

Baseline

Secondary outcome [9]

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]

6 and 12 weeks after intervention commencement

Secondary outcome [10]

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]

2, 6 and 12 weeks after intervention commencement

Secondary outcome [11]

Change in presence of swelling and tenderness assessed by joint examination

Timepoint [11]

Baseline and at 2, 6 and 12 weeks after intervention commencement

Secondary outcome [12]

Change in pinch strength (in kg) assessed by dynamometers

Timepoint [12]

Baseline and at 2, 6 and 12 weeks after intervention commencement

Secondary outcome [13]

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]

Baseline and at 2, 6 and 12 weeks after intervention commencement

Secondary outcome [14]

Change in impairments in work and activities assessed by the Work Productivity and Activity Impairment Questionnaire General Health (WPAI-GH)

Timepoint [14]

Baseline and at 2, 6 and 12 weeks after intervention commencement

Secondary outcome [15]

Range of motion of the first metacarpal joint assessed with a goniometer

Timepoint [15]

Baseline

Secondary outcome [16]

Presence of first metacarpal joint collapse pattern during pinch movement.

Timepoint [16]

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]

Royal North Shore Hospital - St Leonards

Recruitment postcode(s) [1]

2065 - Royal North Shore Hospital

Funding & Sponsors

Funding source category [1]

Government body

Name [1]

National Health and Medical Research Council

Address [1]

GHD Building Level 1, 16 Marcus Clarke St, Canberra ACT 2601

Country [1]

Australia

Funding source category [2]

Charities/Societies/Foundations

Name [2]

The Lincoln Centre For Research into Bone and Joint Diseases and Hand Surgery

Address [2]

North Shore Private Hospital
St Leonards, NSW 2065

Country [2]

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]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

NSLHD Research Office

Ethics committee address [1]

Research Office
Kolling Building, Level 13
Royal North Shore Hospital
St Leonards NSW 2065

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

Approval date [1]

20/01/2016

Ethics approval number [1]

HREC/15/HAWKE/479

Summary

Brief summary

Osteoarthritis (OA) is a chronic disorder affecting the joints, most commonly involving the hands, knees and hips. In view of the strong association of OA with ageing, major concerns with the disease exist due to the continuous rise in the number of elderly. Pain is the most common symptom in addition to progressive difficulty or incapacity to perform daily activities. Among the different disease phenotypes, OA of the hands is a frequent condition, causing symptoms in up to 15% of the population worldwide. The subtype affecting the base of the thumb, in particular, is probably caused by mechanical factors overloading the joint in addition to genetic predisposition. Debilitating symptoms can occur in this subset of patients, including pain during daily activities such as writing and grasping, loss of hand function and joint stiffness.
Due to modest effects, current non-surgical treatment frequently do not meet patients’ demand while surgery is only indicated in cases refractory to conservative therapy due to potential complications. For this reason, the need for novel studies addressing new conservative treatment strategies is emphasized by several reviews. Combination of therapies is often used in clinical practice but little evidence exists about its efficacy. Furthermore, the combination of non-pharmacological and pharmacological rehabilitation interventions has never been studied in the context of patients with thumb base OA. Therefore, the objective of this study is to investigate the effect of a combination of therapies compared to a control group receiving usual care. The new strategy will be delivered over a 6-week period and will consist of education about the disease and joint protection, exercises for the hand, splint for the base of the thumb and use of a topical NSAID. The control group will receive education and instructions on joint protection techniques alone.

Trial website

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

Prof David Hunter

Address

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

Australia

Phone

+61 2 94631887

Fax

+61 2 94631077

[email protected]

Contact person for public queries

Name

Dr Sarah Rubia Robbins

Address

Royal North Shore Hospital
Rheumatology Department , 7C Clinical Administration
Reserve Road
St. Leonards NSW 2065

Country

Australia

Phone

+61 2 94631855

Fax

+61 2 94631077

[email protected]

Contact person for scientific queries

Name

Dr Sarah Rubia Robbins

Address

Royal North Shore Hospital
Rheumatology Department , 7C Clinical Administration
Reserve Road
St. Leonards NSW 2065

Country

Australia

Phone

+61 2 94631855

Fax

+61 2 94631077

[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?

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.	Type	Citation	Link	Email	Other Details	Attachment
19133	Study protocol		https://bmjopen.bmj.com/content/7/1/e014498
19134	Informed consent form					370065-(Uploaded-31-03-2023-10-46-43)-Study-related document.pdf

Results publications and other study-related documents

Documents added manually

Type	Is Peer Reviewed?	DOI	Citations or Other Details	Attachment
Study results article	Yes		Citation: Deveza LA, Robbins SR, Duong V, et al. E... [More Details]

Documents added automatically

Source	Title	Year of Publication	DOI
Embase	Efficacy of combined conservative therapies on clinical outcomes in patients with thumb base osteoarthritis: Protocol for a randomised, controlled trial (COMBO).	2017	https://dx.doi.org/10.1136/bmjopen-2016-014498
Embase	Radial subluxation in relation to hand strength and radiographic severity in trapeziometacarpal osteoarthritis.	2018	https://dx.doi.org/10.1016/j.joca.2018.06.014
Embase	Associations between radiographic features, clinical features and ultrasound of thumb-base osteoarthritis: A secondary analysis of the COMBO study.	2022	https://dx.doi.org/10.1111/1756-185X.14248
Embase	High baseline pain is associated with treatment adherence in persons diagnosed with thumb base osteoarthritis: An observational study.	2022	https://dx.doi.org/10.1016/j.jht.2021.04.024
Embase	Pain, function, and radiographic disease in trapeziometacarpal osteoarthritis.	2023	https://dx.doi.org/10.1016/j.jht.2021.10.001
Embase	Greater 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.	2021	https://dx.doi.org/10.1016/j.joca.2021.07.010
Embase	Musculoskeletal ultrasound in symptomatic thumb-base osteoarthritis: Clinical, functional, radiological and muscle strength associations.	2019	https://dx.doi.org/10.1186/s12891-019-2610-4
Embase	Efficacy of a Combination of Conservative Therapies vs an Education Comparator on Clinical Outcomes in Thumb Base Osteoarthritis: A Randomized Clinical Trial.	2021	https://dx.doi.org/10.1001/jamainternmed.2020.7101
Embase	Carpometacarpal and metacarpophalangeal joint collapse is associated with increased pain but not functional impairment in persons with thumb carpometacarpal osteoarthritis.	2021	https://dx.doi.org/10.1016/j.jht.2020.07.003

N.B. These documents automatically identified may not have been verified by the study sponsor.

Trial Review

Documents added manually

Documents added automatically