Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12623001344684
Ethics application status
Approved
Date submitted
13/11/2023
Date registered
20/12/2023
Date last updated
16/05/2024
Date data sharing statement initially provided
20/12/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
Feasibility of anti-inflammatories and Physiotherapy for people with Knee Osteoarthritis: The AP-KO randomised controlled trial.
Scientific title
Feasibility of anti-inflammatories and Physiotherapy for people with Knee Osteoarthritis: The AP-KO randomised controlled trial.
Secondary ID [1] 310939 0
None
Universal Trial Number (UTN)
Trial acronym
AP-KO
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Knee osteoarthritis 332006 0
Condition category
Condition code
Musculoskeletal 328743 328743 0 0
Osteoarthritis

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Two arm trial
Both arms receive a 12-week pragmatic evidenced-based physiotherapy intervention incorporating aerobic exercise, resistance exercise, neuromuscular co-ordination exercise, passive joint mobilisation techniques, mobilisations with movement, education on knee osteoarthritis and advice to stay active and control body weight. Physiotherapy treatment will be tailored to the individual participant, based on their impairments, with the dose designed to physiologically change tissues, and regularly progressed. Treatment is delivered by a New Zealand (NZ) registered physiotherapist on an individual basis for 4-6 sessions in the first 4 weeks, and as weekly group exercise sessions in the following 8 weeks. There will be approximately 6 people in each group, and participants will exercise at moderate intensity, self-rated using the Borg rating of perceived exertion (RPE) scale. Treatment sessions will be between 30-60 minutes duration, and will take place in person at the School of Physiotherapy, Dunedin, NZ. Adherence to the trial protocol will be checked by regular audit of treatment notes. Participants will also have a home exercise and physical activity programme, which they will be asked to complete for the whole 12 weeks on days when they do not attend treatment. The aim is to complete between 150-180 minutes of physical activity per week. Adherence will be recorded in an exercise log. Prescribed exercises will include muscle strengthening for lower limb muscles, for example isometric quadriceps setting, squats and straight leg raise. There will also be range of motion and stretching exercises; for example active knee flexion and extension, and hamstring stretch or gastrocnemius stretch. Aerobic physical activity will be promoted such as walking, swimming or cycling. Exercises will be tailored to the individual with starting dose prescribed to promote engagement and limit flare-ups, and regularly progressed to promote physiological changes in tissues.
One arm of the trial will receive the active intervention. The active intervention is 1000mg of naproxen, a non-COX2 specific non-steroidal anti-inflammatory drug (NSAID); and 20 mg of omeprazole, a proton pump inhibitor (PPI). This is delivered orally on a daily basis for 4-weeks, and on an as need basis for the following 8 weeks. Use of medication will be monitored using a medication diary, and by return of unused medications and packaging. The physiotherapist providing the physiotherapy intervention will ask regularly about medication use during the first 4 weeks, and the home exercise programme over the whole 12 weeks, to promote adherence to the trial protocol.
Intervention code [1] 327370 0
Treatment: Drugs
Comparator / control treatment
The second arm of the trial will receive placebo medication identical in appearance and packaging to the active intervention, and at the same dose: daily for 4 weeks, then on an as need basis for 8 weeks. The placebo NSAID comprises inert Hypromellose and the placebo PPI comprises inert Calcium lactate.
The control group also receive the physiotherapy intervention described above. Participants and physiotherapists are blind to group allocation so the intervention will look identical in the active or control arms.
Control group
Placebo

Outcomes
Primary outcome [1] 336551 0
Feasibility
Timepoint [1] 336551 0
Baseline, 5 weeks and 13 weeks after commencement of intervention, and 26 weeks post-baseline
Secondary outcome [1] 428778 0
Pain
Timepoint [1] 428778 0
Baseline, 5 weeks and 13 weeks after commencement of intervention, and 26 weeks post-baseline
Secondary outcome [2] 428779 0
Everyday function
Timepoint [2] 428779 0
Baseline, 5 weeks and 13 weeks after commencement of intervention, and 26 weeks post-baseline
Secondary outcome [3] 428780 0
Symptoms of knee osteoarthritis such as stiffness, joint range of motion, swelling, noises, catching or giving way of the knee
Timepoint [3] 428780 0
Baseline, 5 weeks and 13 weeks after commencement of intervention, and 26 weeks post-baseline
Secondary outcome [4] 428781 0
Quality of life
Timepoint [4] 428781 0
Baseline, 5 weeks and 13 weeks after commencement of intervention, and 26 weeks post-baseline
Secondary outcome [5] 428782 0
Sport and recreational function
Timepoint [5] 428782 0
Baseline, 5 weeks and 13 weeks after commencement of intervention, and 26 weeks post-baseline
Secondary outcome [6] 428783 0
Physical performance
Timepoint [6] 428783 0
Baseline, 5 weeks and 13 weeks after commencement of intervention, and 26 weeks post-baseline
Secondary outcome [7] 428785 0
Costs and resource use
Timepoint [7] 428785 0
Baseline, 26 weeks post-baseline
Secondary outcome [8] 428786 0
Health related quality of life
Timepoint [8] 428786 0
Baseline, 5 weeks and 13 weeks after commencement of intervention, and 26 weeks post-baseline
Secondary outcome [9] 428787 0
Participant rated change in condition
Timepoint [9] 428787 0
5 weeks and 13 weeks after commencement of intervention, and 26 weeks post-baseline
Secondary outcome [10] 428790 0
Inflammation
Timepoint [10] 428790 0
Baseline, 5 weeks and 13 weeks after commencement of intervention, and 26 weeks post-baseline
Secondary outcome [11] 428791 0
Adherence to trial protocols
Timepoint [11] 428791 0
26 weeks post-baseline
Secondary outcome [12] 429782 0
Physical performance
Timepoint [12] 429782 0
Baseline, 5 weeks and 13 weeks after commencement of intervention, 26 weeks post-baseline
Secondary outcome [13] 429783 0
Physical performance
Timepoint [13] 429783 0
Baseline, 5 week and 13 week after commencement of intervention, 26 weeks post-baseline
Secondary outcome [14] 429784 0
Physical performance
Timepoint [14] 429784 0
Baseline, 5 weeks and 13 weeks after commencement of intervention, 26 weeks post-baseline

Eligibility
Key inclusion criteria
Adults aged 45 years or over, with activity-related joint pain and morning stiffness less than or equal to 30 minutes.
Participants should have pain on most days in the last month (>15 days), at a minimum of 4 out of 10 on a numeric rating scale in the past week.
Minimum age
45 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• Comorbidities precluding safe participation in moderate exercise or safe prescription of NSAIDs including: uncontrolled or severe hypertension, cardiac arrhythmia, uncontrolled cardiovascular disease, chronic respiratory disease, including asthma, unstable diabetes, chronic gluco-corticosteroid treatment, or short term gluco-corticosteroid treatment at any dose within last 6 weeks prior to study, heart failure (NYHA Class II or above), a history of peptic ulcer, osteoporosis (diagnosed by DEXA scan and requiring regular medication), chronic kidney disease (Stage 3B or above).
• Following screening, people with a higher risk of GI or CV events, or any risk of renal compromise will be excluded.
• People will be excluded if their estimated glomerular filtration rate (e-GFR) is below 75mls/min , or their Hb less than 115g/L.
• The study GP will utilise routine clinical decision-making to evaluate people with low or moderate risk of GI or CV events, taking into account other clinical and demographic information to determine eligibility for safe participation in the trial.
• Specialist/surgical consultation for OA or on waiting-list for knee surgery
• Inflammatory arthritis (e.g. Rheumatoid Arthritis or psoriatic arthritis), including gout affecting the knee or on urate lowering medication (Allopurinol)
• Recent intra-articular injection of knee with corticosteroid or physiotherapy treatment (in previous six months)
• Pain medication dependence, including regular prescribed NSAIDs
• Prescribed regular PPI
• Previous intolerance or allergy to NSAIDs
• Anti-coagulant medication.

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)
Baseline screening for eligibility and screening for safe participation in the trial will be conducted by the study General Practitioner prior to randomisation.
The Clinical Trial Administrator (CTA) will allocate eligible participants to a study group on a 1:1 basis, using a randomisation table generated by computer software. The CTA will then inform participants if they are in Group A or Group B. Group allocation will be concealed from participants and all other research staff, except the trial safety monitor.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation on a 1:1 basis, using a randomisation table generated by computer software.
Randomisation will be stratified for ethnicity to promote an equal distribution of Maori participants to each group.
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
Safety
Statistical methods / analysis
Although sample size calculation is not necessary for a feasibility study, we used an approach based on a medium effect size of 0.5, with 90% power and two-sided significance of 5%, giving 15 participants per arm, total 30 participants.

Analysis of feasibility: Descriptive statistics will characterize the sample and will be used to report the feasibility outcomes. The number of a priori feasibility criteria met, the number and severity of adverse events, and the preliminary findings of secondary outcome analysis will be considered when determining the feasibility for a future RCT.

Analyses of secondary clinical outcomes: Analyses will be conducted on an intention-to -treat basis (using all available data and multiple imputation to replace missing values). Tests will be two-sided and alpha level set at 0.05. Adequacy of participant randomisation will be assessed by comparing baseline characteristics of the two groups using descriptive statistics and simple statistical tests (e.g. Chi-squared for categorical variables).
Between group differences for all KOOS subscales and physical performance measures will be compared using a multiple regression model whilst controlling for any unbalanced baseline characteristics, with suitable adjustments (e.g. transformation) if found to be necessary, and employing regression diagnostic techniques to ensure adherence to underlying assumptions. Secondary outcomes in binary, categorical, and count scales will be analysed similarly using a type of regression suitable for each outcome type.

Economic analysis: Quality adjusted life years (QALYs) will be calculated via NZ general population utility weights applied to the EQ-5D-5L and gains in QALYs from baseline to 26 weeks will be compared in two groups . Total costs will be calculated using data acquired from the OCC-Q. ICURs will be calculated by dividing the difference in healthcare costs between groups by the difference in QALYs between groups indicating of value for money.

Analysis of serum biomarkers: At baseline, logistic regression will investigate correlation between biomarkers and clinical outcomes (KOOS subscales and physical performance measures), as there is a mix of continuous and ordinal data.
To examine the change in biomarkers over time we will use a mixed model to account for repeated measures. The mixed model will include fixed effects and random effects. Fixed effects will include the intervention group, timing of measurement (baseline, 5-week, 13-week, and 26-week) and intervention group x time interaction. Random effects will include outcome response (biomarkers), and baseline recordings.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
29/01/2024
Actual
30/04/2024
Date of last participant enrolment
Anticipated
31/08/2024
Actual
Date of last data collection
Anticipated
25/10/2024
Actual
Sample size
Target
30
Accrual to date
3
Final
Recruitment outside Australia
Country [1] 25965 0
New Zealand
State/province [1] 25965 0
Otago

Funding & Sponsors
Funding source category [1] 315200 0
Government body
Name [1] 315200 0
Health Research Council of New Zealand
Country [1] 315200 0
New Zealand
Funding source category [2] 315212 0
Charities/Societies/Foundations
Name [2] 315212 0
Jack Thompson Arthritis Trust, Otago Medical Research Foundation
Country [2] 315212 0
New Zealand
Primary sponsor type
Individual
Name
Dr Cathy Chapple
Address
School of Physiotherapy, University of Otago, PO Box 56, Dunedin 9054
Country
New Zealand
Secondary sponsor category [1] 317238 0
Individual
Name [1] 317238 0
Professor Simon Stebbings
Address [1] 317238 0
Dunedin School of Medicine, University of Otago, PO Box 913, Dunedin 9054
Country [1] 317238 0
New Zealand

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 314126 0
Southern Health and Disability Ethics Committee of New Zealand
Ethics committee address [1] 314126 0
Ministry Of Health, 133 Molesworth Street, PO Box 5013, Wellington 6011
Ethics committee country [1] 314126 0
New Zealand
Date submitted for ethics approval [1] 314126 0
26/10/2023
Approval date [1] 314126 0
24/11/2023
Ethics approval number [1] 314126 0
2023 EXP 18561

Summary
Brief summary
Providing effective treatment for osteoarthritis is challenging. Both non-steroidal anti-inflammatory medication (NSAIDs) and physiotherapy are effective treatments for people with knee OA, but it is unclear whether combining the two provides additional benefit. We aim to investigate clinical and cost effectiveness of this combined intervention in a future double blind randomised controlled trial (RCT). This feasibility trial is proposed to establish the acceptability and safety of the intervention and trial procedures, test participant recruitment and screening, and accurately estimate the cost of conducting the full RCT. Additionally, serum biomarkers of inflammation will be investigated to explore their association to the clinical signs and symptoms of knee OA, and their responsiveness to treatment.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 130502 0
Dr Cathy Chapple
Address 130502 0
School of Physiotherapy, University of Otago, PO Box 56, Dunedin 9054
Country 130502 0
New Zealand
Phone 130502 0
+64 479 5235
Fax 130502 0
Email 130502 0
[email protected]
Contact person for public queries
Name 130503 0
Dr Cathy Chapple
Address 130503 0
School of Physiotherapy, University of Otago, PO Box 56, Dunedin 9054
Country 130503 0
New Zealand
Phone 130503 0
+64 479 5235
Fax 130503 0
Email 130503 0
[email protected]
Contact person for scientific queries
Name 130504 0
Dr Cathy Chapple
Address 130504 0
School of Physiotherapy, University of Otago, PO Box 56, Dunedin 9054
Country 130504 0
New Zealand
Phone 130504 0
+64 479 5235
Fax 130504 0
Email 130504 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Feasibility study with small sample size so limited benefit
Some Maori and Pacifica participants may be unwilling for their data to be shared, making the pool of available data even smaller


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
No additional documents have been identified.