Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12620001041943
Ethics application status
Approved
Date submitted
14/09/2020
Date registered
13/10/2020
Date last updated
21/01/2022
Date data sharing statement initially provided
13/10/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
Education and activity programs to improve health in people with painful knee osteoarthritis. A randomised controlled trial with cost-effectiveness analysis
Scientific title
Education and activity programs to improve health in people with painful knee osteoarthritis. A randomised controlled trial with cost-effectiveness analysis
Secondary ID [1] 302298 0
National Health and Medical Research Council (NHMRC) of Australia project grant ID 1161634
Universal Trial Number (UTN)
U1111-1249-1672
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Knee osteoarthritis 319046 0
Condition category
Condition code
Musculoskeletal 317002 317002 0 0
Osteoarthritis

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Description of interventions/exposure:
The two groups will have consistent graded walking and strengthening components, but a contrasting education component.

Intervention A:
Participants will attend four, 60-90 minute, in-person sessions with a physiotherapist at weekly intervals (over 4 weeks), during which they will receive Education A, a graded walking program and strengthening exercises. All in-person sessions will take place at the private physiotherapy clinic where the trial physiotherapist is employed. The in-person sessions will be followed by 4 weeks of at home activities (workbook and walking/strengthening progression) with weekly telephone calls or telehealth sessions by the Physiotherapist (20 mins each). A follow-up telephone call/telehealth sessions at 3 months (20 mins) and follow-up in-person sessions with the Physiotherapist (45-60mins) at 5 and 9 months will occur. All treatment components, including choice of telephone/telehealth for home sessions, will be individualised to the participant. To protect trial blinding, the nature of the treatment is being withheld from the registry but has been provided privately to ANZCTR staff and will be made publically available at the conclusion of the trial. The trial intervention will be provided by physiotherapists with a minimum of 5 years clinical experience.

Intervention adherence: This will be assessed via review of attendance records for in-person physiotherapy appointments, via review of participant workbook, walking, and strengthening diaries, and through adherence rating scales completed by participants.

Intervention fidelity: A random sample of treatment sessions (minimum of one for each therapist) will be audio recorded to allow audit of intervention fidelity for each group. Each physiotherapist (and physiotherapist clinic) will only provide one of the study interventions. Therapists’ case notes for each session, recorded via standardised templates, will also be used to evaluate intervention fidelity (e.g., ensure other treatments not given).
Intervention code [1] 318582 0
Treatment: Other
Intervention code [2] 318583 0
Lifestyle
Intervention code [3] 318584 0
Behaviour
Comparator / control treatment
Intervention B:
Participants will attend four, 45-60 minute, in-person sessions with a qualified physiotherapist at weekly intervals (over 4 weeks), during which they will receive Education B, a graded walking program and strengthening exercises. All in-person sessions will take place at the private physiotherapy clinic where the trial physiotherapists is employed. The in-person sessions will be followed by 4 weeks of at home activities (workbook and walking progression) with weekly telephone calls/telehealth sessions by the Physiotherapist (20 mins each). A follow-up telephone call/telehealth session (3 months) and follow-up in-person sessions with the Physiotherapist (30-45mins) at 5 and 9 months will occur. The walking and strengthening program will be personalised to the participant. To protect trial blinding, the nature of the treatment is being withheld from the registry but has been provided privately to ANZCTR staff and will be made publically available at the conclusion of the trial. The trial intervention will be provided by physiotherapists with a minimum of 5 years clinical experience.

The same protocols for assessing intervention adherence and fidelity as Intervention A group will be followed.
Control group
Active

Outcomes
Primary outcome [1] 325110 0
Western Ontario McMaster Universities OA Index (WOMAC) Total score
Timepoint [1] 325110 0
Baseline, week 12, week 26, and week 52 (primary timepoint)
Primary outcome [2] 325111 0
Physical activity level: Wrist-based accelerometry (GT9X Actigraph, Pensacola, US) will assess average daily step count over 7 days.
Timepoint [2] 325111 0
Baseline, week 12, week 26, and week 52 (primary timepoint)
Secondary outcome [1] 386864 0
Average pain over the past week will be assessed using an 11-point Numeric Rating Scale (NRS), and where 0 = no pain and 10 = worst pain possible.
Timepoint [1] 386864 0
Baseline, week 12, week 26, week 52
Secondary outcome [2] 386865 0
Knee pain intensity during walking: Average pain during walking over the past week will be assessed using a 11-point Numeric Rating Scale, where 0 = no pain and 10 = worst pain possible.
Timepoint [2] 386865 0
Baseline, week 12, week 26, week 52
Secondary outcome [3] 386866 0
Physical activity level: Wrist-based accelerometry (GT9X Actigraph, Pensacola, US) will assess average daily minutes of light, moderate, and vigorous physical activity
Timepoint [3] 386866 0
Baseline, week 12, week 26, week 52
Secondary outcome [4] 386867 0
Western Ontario McMaster Universities OA Index (WOMAC) Pain Subscale
Timepoint [4] 386867 0
Baseline, week 12, week 26, week 52
Secondary outcome [5] 386868 0
Western Ontario McMaster Universities OA Index (WOMAC) Function Subscale
Timepoint [5] 386868 0
Baseline, week 12, week 26, week 52
Secondary outcome [6] 386869 0
Pain self-efficacy as assessed by the Pain Self-Efficacy Questionnaire
Timepoint [6] 386869 0
Baseline, week 12, week 26, week 52
Secondary outcome [7] 386870 0
Depression as assessed by the 4-itme PROMIS Depression subscale
Timepoint [7] 386870 0
Baseline, week 12, week 26, week 52
Secondary outcome [8] 386871 0
Anxiety as assessed by the 4-item PROMIS Anxiety subscale
Timepoint [8] 386871 0
Baseline, week 12, week 26, week 52
Secondary outcome [9] 386872 0
Stress as assessed by the 4-item Perceived Stress Scale
Timepoint [9] 386872 0
Baseline, week 12, week 26, week 52
Secondary outcome [10] 386873 0
Fear of movement as assessed by the Brief Fear of Movement Scale
Timepoint [10] 386873 0
Baseline, week 12, week 26, week 52
Secondary outcome [11] 386874 0
Pain catastrophising as assessed by the 4-item Pain Catastrophizing Scale (PCS)
Timepoint [11] 386874 0
Baseline, week 12, week 26, week 52
Secondary outcome [12] 386875 0
Health-related quality of life as assessed by the EQ-5D-5L (used for health economic analyses)
Timepoint [12] 386875 0
Baseline, week 12, week 26, week 52
Secondary outcome [13] 386876 0
Perception of the knee as assessed by the Fremantle Knee Awareness questionnaire
Timepoint [13] 386876 0
Baseline, week 12, week 26, week 52
Secondary outcome [14] 386877 0
Global rating of change (GROC) as assessed by a 7-point Likert scale (1 = Much worse; 3 = No change; 7 – much better)
Timepoint [14] 386877 0
Week 12, week 26, week 52
Secondary outcome [15] 386878 0
Mediating factor: Conceptualisation of OA as assessed by the Osteoarthritis Pain and Physical Activity Conceptualisation Scale (custom-designed; psychometrics currently being evaluated)
Timepoint [15] 386878 0
Baseline, week 12, week 26, week 52
Secondary outcome [16] 386879 0
Mediating factor: Self-regulated learning ability (items taken from the Motivated Strategies for Learning Questionnaire and Regulation of Learning Questionnaire)
Timepoint [16] 386879 0
Baseline, week 12, week 26, week 52
Secondary outcome [17] 386880 0
Exploratory factor: Implicit movement bias as assessed by a computer-based implicit association test. [Note: this test might only be administered in a sub-sample of participants].
Timepoint [17] 386880 0
Baseline, week 12
Secondary outcome [18] 386881 0
Exploratory factor: Implicit environmental bias as assessed by hill steepness estimations using a computer-based task and via head-mounted display. [Note: this test might only be administered in a sub-sample of participants].
Timepoint [18] 386881 0
Baseline, week 12
Secondary outcome [19] 386896 0
Exploratory factor: Walking distance estimation task as assessed by in-person estimation of distance to set locations and estimation of ability to walk to those locations.
Timepoint [19] 386896 0
Baseline, week 12
Secondary outcome [20] 386897 0
Implicit motor imagery as assessed by left/right judgment tasks (for hands and feet images) using an app on a smartphone or tablet.
Timepoint [20] 386897 0
Baseline, week 12
Secondary outcome [21] 386898 0
Two point discrimination threshold as assessed using digital callipers; measured at the medial aspect of the knee (trial knee and control knee).
Timepoint [21] 386898 0
Baseline, week 12
Secondary outcome [22] 386899 0
Sensitivity to physical activity as assessed by the change in pain intensity from the start to the end of a modified 6-minute walk test (pain intensity measured at each minute)
Timepoint [22] 386899 0
Baseline, week 12
Secondary outcome [23] 386900 0
Osteoarthritis knee drawing: to assess changes in understanding of pain and the process of knee osteoarthritis, participants will be asked to ‘draw your osteoarthritis and how it hurts’. This will be a hypothesis generating measure.
Timepoint [23] 386900 0
Baseline, week 12, week 36 (at 9-month in-person session)
Secondary outcome [24] 386901 0
Procedural outcome: COVID-19 impact on physical activity as assessed by 7-item Likert scale
Timepoint [24] 386901 0
Baseline, week 12, week 26, week 52
Secondary outcome [25] 386902 0
Procedural outcome: Treatment expectancy as assessed by a 5-point Likert scale (0 = no effect at all; 4 = complete recovery) to the question, what effect do you think the physiotherapy intervention will have on your knee problem?
Timepoint [25] 386902 0
After first treatment session
Secondary outcome [26] 386903 0
Procedural outcome: Perceived treatment credibility as assessed by modified 4-item Credibility/Expectancy Questionnaire (CEQ)
Timepoint [26] 386903 0
After first treatment session
Secondary outcome [27] 386904 0
Procedural outcome: Intention to exercise via the total score of 3 items (I am committed to engage in physical activity over the next two weeks; I am motivated to engage…; I am determined to engage…), each assessed on a 7-point Likert scale (1 = very strongly disagree; 7 = very strongly agree)
Timepoint [27] 386904 0
After first treatment session, week 12, week 26, week 52
Secondary outcome [28] 386905 0
Procedural outcome: Adherence to walking program as assessed by four customised questions.
Timepoint [28] 386905 0
week 12, week 26, week 52
Secondary outcome [29] 386906 0
Procedural outcome: Adherence to strengthening program as assessed by four customised questions.
Timepoint [29] 386906 0
week 12, week 26, week 52
Secondary outcome [30] 386907 0
Procedural outcome: Therapist beliefs about exercise via Therapist beliefs about exercise questionnaire)
Timepoint [30] 386907 0
Baseline (pre-trial training) and end of the trial.
Secondary outcome [31] 386908 0
Procedural outcome: Therapist beliefs about pain via the Pain Attitudes and Beliefs Scale for Physiotherapists
Timepoint [31] 386908 0
Baseline (pre-trial training) and end of the trial.
Secondary outcome [32] 386909 0
Procedural outcome: Therapist pain knowledge via the revised Neurophysiology of Pain Questionnaire
Timepoint [32] 386909 0
Baseline (pre-trial training) and end of the trial.
Secondary outcome [33] 386910 0
Procedural outcome: Therapist self-rated connection with participant via the Therapist Connectedness Scale
Timepoint [33] 386910 0
At week 4 (for each participant they treat)
Secondary outcome [34] 386911 0
Procedural outcome: Therapist perceived intervention credibility via the modified credibility and expectancy questionnaire Connection with participant via the therapist connectedness scale via the revised Neurophysiology of Pain Questionnaire
Timepoint [34] 386911 0
After pre-trial training (baseline), after the first 8 weeks of treatment with their pilot participant, mid-way through the trial (i.e. halfway through recruitment), at the end of the trial
Secondary outcome [35] 386912 0
Procedural outcome: Blinding (assessed for participants and treating physiotherapists) as assessed by guesses about group allocation and reasons for guesses
Timepoint [35] 386912 0
week 52 (participants), end of trial (physiotherapists)
Secondary outcome [36] 386918 0
Adverse events (in the study knee or elsewhere in the body) measured via customised adverse events questionnaire
Timepoint [36] 386918 0
week 12, week 26, week 52

Eligibility
Key inclusion criteria
i) Aged greater than or equal to 50 years
ii) Average knee pain intensity of at least 4/10 (overall and/or while walking) over past week using a 0-10 numerical rating scale, where 0 = no pain at all and 10 = worst pain possible
iii) Moderate disability due to the knee over the past week (greater than or equal to 3 on the Global Disability Rating Scale)
iv) Painful knee OA at least 6 months duration that meets the NICE diagnostic criteria for symptomatic knee OA
Minimum age
50 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
i) Conditions that prevent safe participation in physical activity as listed in the American College of Sports Medicine guidelines (e.g., cardiac or lung disease)
ii) Pain in other body areas that currently limits walking ability (e.g., back pain, foot pain, hip pain)
iii) Neurological disorders affecting lower limb movement (e.g., multiple sclerosis, stroke)
iv) Inflammatory arthritis (including rheumatoid arthritis)
v) Fibromyalgia
vi) Previous knee replacement (on painful knee) or planned knee replacement/surgery (next 6 months) or recent knee replacement on the non- or less-painful knee (<6 months)
vii) Previously operated knee is the most painful knee
viii) Intra-articular therapy use in the 12 weeks preceding enrolment
ix) Any condition impacting decision-making/memory (e.g., Alzheimer’s, dementia)
x) Severe depression (>17 on the 4-item PROMIS depression subscale)
xi) Current moderate/vigorous physical activity levels above guideline recommendations (>150 minutes/week; assessed using the Active Australia Physical Activity Questionnaire)
xii) Current purposeful walking for exercise of 30 mins or more per day on 5 or more days per week.
xiii) Unable to commit to study requirements (unable to attend study appointments or complete study outcomes)

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 will be concealed using central automated allocation, with security in place to ensure data cannot be accessed/influenced. It will be stored within an electronic system (REDCap) that will be password-protected (as well as via a hardcopy of the raw randomisation schedule in case the electronic system fails, which will be stored in a secure location). The person who determines if a participant is eligible for inclusion in the trial will be unaware, when this decision is made, to which group the participant will be allocated.

Eligible patients who have provided informed consent will be allocated to the treatment groups by the trial coordinator who will then coordinate treatment appointment scheduling with the appropriate physiotherapist. Only the unblinded trial coordinators (Adelaide, Melbourne) will have access to raw copies of the randomisation schedules.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Participants will be randomly allocated (1:1), using permutated blocks of varying size (4 and 6), and stratified by sex (due to its influence physical activity) and site (South Australia or Victoria). An independent statistician will create the randomisation schedule (using computer generated random numbers).
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s

The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Participants will be advised that they will be randomised to receive one of two active physiotherapy treatments that aim to improve overall health (i.e., limited disclosure). We will not disclose the details of group interventions prior to randomisation. After randomisation, participants will be provided only with details of the intervention they will be undertaking. Given that both groups receive active treatment and that we will not disclose the primary outcomes of the trial, we anticipate that this will be sufficient for blinding the participants to group assignment.

The outcome assessor will be a researcher whose role is independent to treatment allocation and delivery, thus will remain blinded to group. Participants will be explicitly instructed not to discuss their treating therapist with the outcome assessor. In-person follow-up assessments will occur at baseline and week 8, and will be performed by the same, blinded assessor at each site. The remaining outcome assessments will be completed by participants independently (i.e. self-reported) via electronic or postal surveys.

Treating therapists will be unavoidably aware of group assignment, but each therapist will be assigned to deliver only one intervention only, and both groups are providing an active intervention. Therapists will not be involved in any outcome assessment.

An independent, blinded statistician will perform data analyses.
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
A total of 198 participants will be recruited (n=99/group). Sample size calculation details have been withheld from the registry to protect trial blinding, but detailed calculations have been provided privately to ANZCTR staff and will be made publically available at the conclusion of the trial.

Primary analysis plan:
The data will be analysed by intention-to-treat and by a statistician blinded to group allocation. We will use linear mixed models with random intercepts for individuals (account for correlation for repeated measures) and will analyse the effect of treatment separately for each outcome. The model will include terms for important prognostic factors, measured prior to randomisation (e.g., sex, age, BMI). We will also include terms for treating therapist and site. Depending on the trial circumstances due to COVID-19, a time-varying covariate for COVID impact may be included (via data derived estimation of COVID impact on the ability to undertake physical activity), as well as a term for treatment mode (e.g., as intended versus telehealth replacing in-person sessions). If necessary, multiple imputation will be used for missing data. We will construct linear contrasts to compare the adjusted mean change in outcome from baseline to each time point between the groups (and 95% confidence interval) to obtain estimates of the effect.

Exploratory mediation analyses:
Using contemporary methodology, we will perform causal mediation analysis to understand the mechanisms by which the intervention of interest works. Details have been withheld from the registry to protect trial blinding, but the proposed analyses have been provided privately to ANZCTR staff and will be made publically available at the conclusion of the trial.

A detailed statistical analysis plan will be published online prior to analysis and unblinding.

Health economic evaluation:
A cost-utility analysis will be undertaken from the perspective of the health system with health related quality of life as assessed by the EQ5D-5L as the main measure of outcome. We will also utilise the primary clinical outcome measures from the trial (WOMAC Total, physical activity levels) as secondary outcome measures for assessing cost effectiveness. Utility-based outcomes generated from application of the EQ5D-5L will be incorporated into the economic analysis to calculate the incremental costs per quality adjusted life year (QALY) gained for the intervention. The resource use items associated with the development and administration of the education intervention including staff time spent in a) the development and provision of face-to-face, evidence-based education sessions and b) development and provision of home activities and weekly development goals, workbook and telephone contacts will be measured and valued using appropriate unit costs. Health service utilisation data for the trial duration including the frequency and duration of hospital in-patient admissions will be accessed from administrative data-sets, and PBS and MBS data will be extracted from Medicare following participant consent. Unit costs will be derived from hospital finance departments, published data sets including PBS and MBS and Refined Diagnosis Related Groups cost weights. Incremental cost effectiveness ratios and their associated confidence intervals will be estimated and cost effectiveness acceptability curves for varying threshold values of cost effectiveness will also be presented. An assessment of the sensitivity of the results obtained to variation in measured resource use, effectiveness and/or unit costs will be undertaken using appropriate one-way and multi-way sensitivity analysis.

A detailed health economic analysis plan will be published online prior to analysis and unblinding.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
2/11/2020
Actual
3/03/2021
Date of last participant enrolment
Anticipated
1/12/2022
Actual
Date of last data collection
Anticipated
1/12/2023
Actual
Sample size
Target
198
Accrual to date
68
Final
Recruitment in Australia
Recruitment state(s)
SA,VIC

Funding & Sponsors
Funding source category [1] 306723 0
Government body
Name [1] 306723 0
National Health and Medical Research Council (NHMRC)
Country [1] 306723 0
Australia
Primary sponsor type
University
Name
The University of South Australia
Address
IIMPACT in Health, Allied Health & Human Performance, G.P.O. Box 2471, Adelaide, South Australia, 5001
Country
Australia
Secondary sponsor category [1] 307275 0
None
Name [1] 307275 0
Address [1] 307275 0
Country [1] 307275 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 306893 0
University of South Australia Human Research Ethics Committee
Ethics committee address [1] 306893 0
Ethics committee country [1] 306893 0
Australia
Date submitted for ethics approval [1] 306893 0
02/07/2019
Approval date [1] 306893 0
12/09/2019
Ethics approval number [1] 306893 0
20237
Ethics committee name [2] 306896 0
Central Adelaide Local Health Network Human Research Ethics Committee
Ethics committee address [2] 306896 0
Ethics committee country [2] 306896 0
Australia
Date submitted for ethics approval [2] 306896 0
16/12/2019
Approval date [2] 306896 0
06/01/2020
Ethics approval number [2] 306896 0
12579
Ethics committee name [3] 306897 0
University of Melbourne Human Research Ethics Committee
Ethics committee address [3] 306897 0
Ethics committee country [3] 306897 0
Australia
Date submitted for ethics approval [3] 306897 0
28/07/2020
Approval date [3] 306897 0
06/08/2020
Ethics approval number [3] 306897 0
2057540

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

Contacts
Principal investigator
Name 105374 0
A/Prof Tasha Stanton
Address 105374 0
The University of South Australia
IIMPACT in Health, Allied Health & Human Performance
G.P.O. Box 2471,
Adelaide, SA
5001
Country 105374 0
Australia
Phone 105374 0
+61 883022090
Fax 105374 0
Email 105374 0
tasha.stanton@unisa.edu.au
Contact person for public queries
Name 105375 0
Felicity Briathwaite
Address 105375 0
The University of South Australia
IIMPACT in Health, Allied Health & Human Performance
G.P.O. Box 2471,
Adelaide, SA
5001
Country 105375 0
Australia
Phone 105375 0
+61450638971
Fax 105375 0
Email 105375 0
felicity.braithwaite@unisa.edu.au
Contact person for scientific queries
Name 105376 0
Tasha Stanton
Address 105376 0
The University of South Australia
IIMPACT in Health, Allied Health & Human Performance
G.P.O. Box 2471,
Adelaide, SA
5001
Country 105376 0
Australia
Phone 105376 0
+61 883022090
Fax 105376 0
Email 105376 0
tasha.stanton@unisa.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)?
Immediately following publication, no end date
Available to whom?
Case-by-case basis at the discretion of Primary Sponsor
Available for what types of analyses?
For IPD meta-analyses, etc.
How or where can data be obtained?
Access subject to approvals by Primary Investigator (email contact: tasha.stanton@unisa.edu.au).


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
9145Informed consent form    380579-(Uploaded-14-09-2020-13-47-23)-Study-related document.docx



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