Accepted Manuscript Maximum tolerated dose of walking for people with severe osteoarthritis of the knee: a phase I trial Jason A. Wallis, B.Phty, M.Phty (MSK), PhD Candidate, Mr, Kate E. Webster, PhD, Pazit Levinger, PhD, Parminder J. Singh, MBBS, MRCS, FRCS (Tr&Orth), MS, FRACS, Chris Fong, MBBS, FRACP, Nicholas F. Taylor, PhD PII:
S1063-4584(15)01121-8
DOI:
10.1016/j.joca.2015.04.001
Reference:
YJOCA 3450
To appear in:
Osteoarthritis and Cartilage
Received Date: 22 October 2014 Revised Date:
10 February 2015
Accepted Date: 2 April 2015
Please cite this article as: Wallis JA, Webster KE, Levinger P, Singh PJ, Fong C, Taylor NF, Maximum tolerated dose of walking for people with severe osteoarthritis of the knee: a phase I trial, Osteoarthritis and Cartilage (2015), doi: 10.1016/j.joca.2015.04.001. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Maximum tolerated dose of walking for people with severe osteoarthritis of the knee: a phase I trial Authors
Physiotherapy, Eastern Health. 2. Kate E Webster, PhD, School of Allied Health, La Trobe University.
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1. Jason A Wallis, B.Phty, M.Phty (MSK), PhD Candidate La Trobe University; Department of
3. Pazit Levinger, PhD, Institute of Sport, Exercise & Active Living (ISEAL), Victoria University.
Eastern Health; Lecturer Monash and Deakin University.
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4. Parminder J Singh, MBBS, MRCS, FRCS (Tr&Orth), MS, FRACS. Department of Orthopaedics,
University.
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5. Chris Fong, MBBS, FRACP. Department of Rheumatology, Eastern Health; Lecturer Monash
6. Nicholas F Taylor, PhD, School of Allied Health, La Trobe University. Allied Health Clinical Research Office, Eastern Health.
Correspondence (for review and publication): Mr Jason A Wallis
Department
Physiotherapy Department
Institution
Eastern Health, Box Hill, Victoria 3128
Country
Australia
Tel
(work) +61 3 9895 3463 (work) +61 3 9895 4852 [email protected]; [email protected]
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Email
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Name
Running Title: Maximum tolerated dose of walking for severe knee osteoarthritis Key words: osteoarthritis; knee; physical activity; maximum tolerated dose of walking Word Count: Abstract: 250; Manuscript: 3990 References: 39 Tables: 3 Figures: 5
Appendices: 0
Ethics Committee approval: La Trobe University and Eastern Health
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Abstract: Objective: To determine how much physical activity, in the form of walking, can be safely
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and feasibly tolerated for people with severe knee osteoarthritis.
Design: Phase I dose response trial with escalating walking doses of 10, 20, 35, 50, 70, and 95 minutes over one week, were prescribed non-randomly to people with severe knee
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osteoarthritis. The primary stopping rule was a substantial increase in knee pain. The primary outcomes were an estimation of the maximum tolerated dose of walking; and the proportion
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of people who did not complete the dose for feasibility reasons. The secondary outcomes were pain, stiffness and activity limitation (WOMAC).
Results: Twenty-four participants (13 women) aged 53 to 83 years, and average body mass index of 34 kg/m2 (SD 9) were recruited. Three participants were assigned to each dose
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between 10 and 70 minutes, and nine participants assigned to the 95-minute dose. The trial was stopped at 95 minutes due to the maximum number of adverse events occurring at this dose. Therefore, the maximum tolerated dose was 70 minutes. No participant stopped due to
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reasons related to feasibility. There was a moderate association between dose and increased activity (linear R2=0.31, cubic R2=0.69) and reduced stiffness (linear R2=0.20, cubic
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R2=0.52), with increased benefits at moderate to higher doses.
Conclusions: There is preliminary evidence that 70 minutes per week of moderate intensity supervised walking was safe and feasible for people with severe osteoarthritis of the knee; for higher doses there was a risk of exacerbating knee pain levels.
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The maximum tolerated dose of walking for people with severe osteoarthritis of the knee: a
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phase I trial
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INTRODUCTION
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Increasing physical activity is important for people with osteoarthritis of the knee as their risk of
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mortality from cardiovascular causes is substantially increased (1). Physical activity is defined as
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any bodily movement produced by the skeletal muscles that requires energy expenditure
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including recreational tasks as well as structured activities like exercise and is categorised into
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light, moderate and vigorous intensity (2). Physical activity guidelines for older adults
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recommend at least 150 minutes per week of at least moderate physical activity in a minimum of
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10 minute bouts (3). Maintaining these levels of physical activity is associated with positive
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health outcomes such as increased life expectancy and reduced burden of major non-
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communicable diseases (3). For people with symptomatic knee osteoarthritis aerobic exercise
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programs, which could include walking programs, are recommended in clinical guidelines to
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reduce pain and disability (4-6). However, no specific guidelines regarding a safe and effective
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dosage of walking are available for people with severe knee osteoarthritis. For people with
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mobility restrictions due to the pain and disabilities associated with knee osteoarthritis,
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guidelines suggest these people be as physically active as their condition allows (3). Such
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recommendations create uncertainty for health professionals on how much physical activity is
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safe to recommend to their patients.
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We recently completed a systematic review that found about 1 in 10 people with knee
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osteoarthritis met current physical activity guidelines (7). While physical activity programs for
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people with osteoarthritis are recommended (4-6, 8-12) physical activity levels remain low in
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this population. One issue is that we do not know if the dosage recommended in physical activity
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guidelines (3) is safe and applicable for walking for people with severe knee osteoarthritis.
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Therefore, investigation of the highest dose that can be tolerated would provide information that
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could inform guidelines.
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To our knowledge a phase I dose response trial has not been investigated previously in people
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with knee osteoarthritis where the safety profile of a physical activity intervention, such as
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walking, can determine the highest dose that can be tolerated (maximum tolerated dose) without
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adverse events (13). An adverse event is defined as any unfavourable and unintended sign,
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symptom, or disease temporally associated with the use of an intervention or procedure that may
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or may not be considered related to the intervention or procedure (14). Possible short-term
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adverse events from increased levels of physical activity are temporary exacerbations of pain
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(12). Pain is a common symptom in people with knee osteoarthritis (15) and may be due to
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sensitised peripheral nociceptors, and this continuous nociceptive input may drive central
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sensitisation and increased pain response (16). While this pain response does not necessarily
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indicate a worsening of the osteoarthritic condition, substantial increases in pain may lead to
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modifications to physical activity (17).
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In the systematic review (7) we also found that people with knee osteoarthritis may not be much
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less physically active compared to people of similar age without osteoarthritis. One interpretation
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of these results is that a low level of physical activity is not solely related to disease factors such
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as pain, but could also be related to non-disease factors, such as demographic, physical, social,
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psychological and environmental factors (18). Therefore it is not known if it is feasible for
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people with knee osteoarthritis to complete recommended doses of physical activity.
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Therefore the primary research questions of the present study are: How much physical activity,
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in the form of walking, can be safely tolerated for people with severe knee osteoarthritis? How
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feasible is it for people with severe knee osteoarthritis in the community to complete doses of
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physical activity, in the form of walking? The secondary research question is to determine if
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there is a dose-response relationship for a change in pain, stiffness and activity limitation?
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METHOD
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Study design
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In this phase I dose-response study, an algorithm based (A+B) design (13, 19, 20) was used. The
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first cohort of 3 participants received the same dose. If no participant stopped due to an adverse
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event, the second cohort of 3 participants received the next higher dose and so on. However, if a
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participant stopped due to an adverse event, the second cohort of 3 participants was prescribed
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the same dose as the first cohort. If no further adverse events occurred the study continued at the
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next higher dose. However if another adverse event occurred the dose escalation stopped at that
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level and the previous dose was considered as the maximum tolerated dose (figure 1).
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If any participant elected to stop due to reasons related to feasibility, the next participant was
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recruited and received the same dose. For the purpose of this study, a lack of feasibility was
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defined as not completing the walking dose due to reasons other than safety. For example a
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participant may not have completed the walking dose due to unexpected time pressures.
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The health service and university ethics committees approved this trial in accordance with the
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Helsinki Declaration and all participants provided written informed consent. The trial was
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registered in the Australian New Zealand Clinical Trials Registry
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http://www.ANZCTR.org.au/ACTRN12614000098639.aspx.
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Insert figure 1 about here (Phase 1 design)
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Participants
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Adults with osteoarthritis of the knee were recruited consecutively from a metropolitan health
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service’s osteoarthritis hip and knee clinic between January and April 2014. Patients who
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attended the service were invited to participate provided they met the inclusion criteria: adult
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aged at least 50 years and living independently in the community; diagnosed with unilateral or
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bilateral severe knee osteoarthritis rated as grade III or IV determined radiographically (21);
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participants with contralateral knee replacement and unilateral severe knee osteoarthritis in
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remaining intact limb were eligible; able to understand English; able to participate safely in the
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moderate-intensity physical activity trial according to the 7-item Physical Activity Readiness
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Questionnaire (22).
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Participants were excluded if they: lived in supported accommodation such as a nursing home;
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reported daily resting level of pain to be 9 or 10 on a 0 (no pain) to 10 (worst possible pain)
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Numerical Pain Rating Scale (23). This level of pain may be indicative of a more serious
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pathology; had very high levels of psychological distress as measured by the Kessler 10
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questionnaire with a score > 29 (24); had an intellectual impairment as measured by the Short
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Portable Mental Status Questionnaire with a score of 7 or less (25); had a systemic arthritic
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condition such as rheumatoid arthritis; had a neurological condition that affected walking; had
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knee surgery or intra-articular corticosteroid injection within the past six months; had used oral
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corticosteroids within four weeks.
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Dose prescription
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Physical activity, in the form of walking, was chosen because of the importance of this type
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physical activity to health outcomes for people with osteoarthritis (1). The walking doses of 10,
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20, 35, 50, 70, 95, 120 and 150 minutes over one week, of at least moderate intensity, in a
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minimum of 10 minute sessions were selected so the doses could be compared with the current
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physical activity guidelines (table 1). Participants were aware the dose was between 10 minutes
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and 150 minutes over one week prior to participation. The initial dose of 10 minutes per week
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was based on data from previous research that found a relatively high proportion (49%) of
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people with knee osteoarthritis did not complete any bouts of physical activity at a moderate
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intensity for at least 10 minutes (26). The dose levels then approximated a modified Fibonacci
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scheme (27). For the maximum dose, the current physical activity guideline was selected as only
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a small proportion (10%) of people with knee osteoarthritis met this guideline (26).
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The participants completed the walking doses in the community using normal assistive devices,
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such as a walking stick. Each walking session was supervised individually by a physiotherapist
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to ensure any adverse events were managed appropriately and the dose was completed. The
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number of walking sessions to complete the walking dose was planned and agreed through
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discussion between the physiotherapist and the participant. For example the 50-minute dose
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could include 2x15 minute walking sessions and 1x20 minute session over 3 days. Participants
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were instructed to walk at a moderate intensity of 3 using the Rate of Perceived Exertion scale
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(0-10) and cadence monitored to ensure it was greater than 80 steps/minute (28). Participants
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continued taking their usual medications to manage their knee osteoarthritis. To reduce the risk
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of adverse events due to other physical activities, participants who were currently participating in
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physical activity of moderate intensity in bouts of 10 or more minutes were requested to refrain
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from this activity for 2 days prior to and during the test period. For example, physical activities
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like brisk walking or cycling were avoided. However, light everyday activities did not need to be
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avoided or modified.
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Insert table 1 about here (Walking doses)
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Outcomes
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The primary outcomes were: An estimation of the maximum tolerated dose of walking for people
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with severe knee osteoarthritis; and the proportion of people with severe knee osteoarthritis who
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did not complete the walking dose for feasibility reasons.
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The secondary outcomes were: Pain, stiffness and activity limitation using the Western Ontario
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and McMaster Universities Osteoarthritis Index (WOMAC) (29). The participants completed the
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WOMAC questionnaire at two times: day 1 prior to the first walking session; and day 7 after
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completion of the walking dose.
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The following factors were collected to describe the participants: Age, gender, body mass index,
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severity of knee osteoarthritis including the compartments affected (21), presence of knee
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deformity using clinical observation, co-morbidities, medication use, physical activity level
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using the Incidental and Planned Activity Questionnaire (IPAQWA) (30), and physical activity
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measures of cadence, number of steps, distance covered and walking speed during each walking
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bout measured using an electronic pedometer worn by the participant (iPhone 4S: Footsteps,
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developed by Palm Shadow Apps LLC, http://palmshadow.com/index.php).
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Participants were followed up for 7 days after their first bout of walking. This period was
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selected to monitor any potential adverse effects from completing the walking dose; any
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potential adverse effects would be expected to have occurred by this time.
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Stopping rules - adverse events
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A stopping rule was defined as an adverse event or incident that stopped the participant from
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completing the walking dose for safety reasons and was likely related to the dose.
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Stopping rule 1: Substantial knee pain levels during a walking session
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Knee pain levels were recorded for each walking session, using the 0 to 10 point Numerical Pain
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Rating Scale (23), at the beginning, at 5-minute intervals during, immediately on completion,
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and at 2 hours after completion when resting. A participant who reported their knee pain level
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during the walk as unchanged or decreased compared with the beginning pain level would be
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expected to complete the walk. A participant who reported their knee pain level had increased
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during the walk but the level was less than 7/10 would be expected to complete the walk. A
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participant who reported their knee pain level had increased during the walk and the level was at
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least 7/10 were asked, “Are you prepared to continue?” This participant could continue or stop.
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Participants who stopped were expected to retry the walk on a subsequent day and the same rules
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were applied. If they stopped again, an adverse event was deemed to have occurred.
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Stopping rule 2: Substantial knee pain levels after a walking session
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Substantial increases in resting knee pain at the 2-hour mark after completion of a walking
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session relative to the beginning knee pain level resulted in stopping the dose due to safety
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reasons. Substantial increases in pain was defined as resting knee pain of at least 7/10 two hours
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after the walk which had increased by at least 3/10 if the pain level was between 0 to 6 at the
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beginning of the walk, or had increased by at least 2/10 if the pain level was 7 to 8 at the
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beginning of the walk. The thresholds of 3/10 and 2/10 were based on data that suggests that
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2/10 represents a clinically significant change in pain and varies depending on the initial level
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(31). If a participant reported to the investigator a substantial amount of pain more than 2 hours
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after the walk the dose was stopped and the participant was assisted to health professional
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management as appropriate.
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Stopping rule 3: Serious adverse events
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If any participant reported difficulty breathing that did not settle quickly with rest, new or
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unrelenting chest pain, or acute change in conscious level during the activity, this may precede a
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serious medical emergency such as cardiac arrest or stroke (32). In this event the session was
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stopped immediately with immediate emergency response. A potentially serious event was if the
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participant reported difficulty breathing but symptoms settled quickly with rest and their clinical
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signs (respiration rate, heart rate, oxygen saturation) remained normal. This participant could
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elect to complete the dose provided these symptoms settled quickly with rest and clinical signs
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remained normal.
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Data analysis
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The estimation of sample size was based on the algorithm based design and dose escalation (19)
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whereby a maximum 48 participants (8 dose levels with at maximum 6 patients, not including
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participants that stop due to feasibility). As it was hypothesised the maximal tolerated dose
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would be between doses 4 and 6, the expected sample size was between 21 and 45 participants.
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The primary analysis determined the maximum tolerated dose in minutes of moderate intensity
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walking per week (figure 1) (19). The primary analysis of feasibility was based on the proportion
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of participants not able to complete the walking dose for feasibility reasons.
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The secondary analyses were performed using IBM SPSS Statistics 21 and a p-value < 0.05 was
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considered statistically significant. Parametric tests were reported because parametric tests are
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relatively robust to minor violations of normality, and the results are easily interpretable by other
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researchers. Associations between the walking dose and baseline participant characteristics of
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age, body mass index, resting pain level, psychological distress (Kessler 10) and usual physical
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activity level (IPAQWA) were explored using Pearson’s correlation coefficient, r, to check for
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any bias in dose allocation. To test for a dose response relationship, associations between the
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walking dose, and changes in pain, stiffness and activity limitations over 7 days (WOMAC) were
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explored using linear and non-linear modelling. For the maximum tolerated dose or less, average
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knee pain levels recorded after completion of the walking sessions were compared to the
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beginning level of pain using paired t tests. Finally, physical activity parameters associated with
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the maximum tolerated dose were reported.
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RESULTS
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After screening 89 potentially eligible participants, 24 participants (13 women, 11 men) aged
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between 53 and 83 years, with an average body mass index of 34 kg/m2 (SD 9) met the selection
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criteria (figure 2). All participants had severe knee osteoarthritis with 23 participants (96%) rated
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as grade IV and one participant (4%) rated as grade III using Kellgren-Lawrence scale (21).
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Fifteen of the 24 subjects had bilateral severe knee osteoarthritis and nine of the 24 subjects had
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unilateral severe knee osteoarthritis. Two of the 24 subjects had a contralateral knee replacement.
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On average, participants self-reported participating in 2 hours per week (SD 2 hours) of planned
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physical activities such as home exercises and exercise classes. Seven participants (29%) self-
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reported no planned physical activity per week.
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The most common comorbidities were hypertension (n=11), and high cholesterol (n=11). There
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were no significant associations between the walking dose and baseline participant
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characteristics of age (r=.05), body mass index (r=.11), resting knee pain (r=.27), Kessler 10
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score (r=.06) and total physical activity (r=-.18). Table 2 summarises participants’
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characteristics.
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Insert figure 2 about here (Trial recruitment profile)
Insert table 2 about here (Participant characteristics)
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Maximum tolerated dose and adverse events
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For the first 5 walking doses (10 to 70 minutes), none of the 15 participants had adverse events
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(table 3). There was a small increase in average knee pain level at the immediate completion of
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each walking bout compared to the knee pain level at the beginning of each bout (mean
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increase=2.1 units, 95% CI=1.0,3.2); and knee pain level settled at 2 hours rest to levels
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comparable to knee pain level at the beginning of each bout (mean increase=0.3 units, 95% CI=-
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0.9,1.4).
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For the 95-minute walking dose, 1 of the first 3 participants did not complete the dose due to an
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adverse event. Of the next 3 participants prescribed the 95-minute dose, 1 participant had an
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adverse event. After discussion between the investigators it was decided that a further 3
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participants be prescribed the 95 minute dose. Of the final 3 participants, 1 participant had an
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adverse event. Therefore 3 out of 9 participants prescribed 95 minutes had an adverse event, all
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reporting substantial pain levels after 2 hours rest as per stopping rule 2. Therefore, the
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maximum tolerated dose was 70 minutes of walking over one week, at moderate intensity in at
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least 10-minute bouts. There were no serious adverse events from any of the participants (table
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3).
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Insert table 3 about here (Adverse events)
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Minor adverse events
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Four participants reported minor adverse events that were not considered a stopping event. One
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participant had an episode of momentary unsteadiness that resolved immediately; two
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participants stopped briefly during a walking session to rest their knee momentarily; one
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participant reported moderate hip pain that settled after each walk.
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Feasibility
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No participant stopped the dose of walking due to reasons of feasibility.
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Dose response
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For the 15 participants completing up to the level of the maximum tolerated dose of 70 minutes,
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and who provided day 1 and day 7 WOMAC scores (n=13), linear modelling indicated no
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association between dose and changes in pain (R2=0.01), and a moderate association between
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dose and improved activity (R2=0.31) and reduced stiffness (R2=0.20). Non-linear modelling
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estimated U-shaped dose response curves suggesting a moderate dose might be associated with a
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reduction in pain (cubic R2 =0.32), activity limitation (cubic R2=0.69) and stiffness (cubic
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R2=0.52) (figure 3).
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Insert figures 3a, 3b and 3c about here (dose response graphs)
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Physical activity for the maximum tolerated dose
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For the maximum tolerated dose of 70 minutes per week (n=3), 7138 steps (SD 208) and 4770
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metres (SD 1185) were covered during the supervised sessions at a cadence of 99 steps per
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minute (SD 2.7) and average walking speed of 1.1m/s (SD 0.23).
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DISCUSSION
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This phase I dose response trial with escalating dose demonstrated up to 70 minutes per week of
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moderate intensity walking, in at least 10-minute sessions, in addition to baseline physical
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activity associated with daily life, was tolerated for people with severe knee osteoarthritis. For
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higher doses, adverse events occurred with knee pain levels that increased to severe levels during
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the walk and remained severe for at least 2 hours after the event.
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For the 15 participants who completed up to the maximum tolerated dose of 70 minutes, those
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who completed higher doses of walking did not experience increases in pain intensity at the end
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of the week compared to people who completed lower doses. While increased dynamic loading
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can predict progression of radiographic knee osteoarthritis, (33, 34) the preliminary findings in
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the current study are consistent with evidence that dynamic knee loading may not predict
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changes in pain intensity (35). Linear modeling also provided preliminary evidence that higher
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doses were associated with less limitation to daily activities and less knee stiffness; and non-
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linear modeling provided preliminary evidence suggesting the greatest benefits may have been
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observed with moderate doses of walking. Confidence bands around these estimates were wide
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suggesting uncertainty about the dose response in this small sample. While these effects were
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seen over one week, it remains to be tested whether a repeated weekly dose for people with
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severe knee osteoarthritis will demonstrate sustained positive changes to activity and pain levels.
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The results of our study may assist people with severe knee osteoarthritis to feel more confident
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of engaging in physical activity, and potentially benefit from a more active lifestyle. A previous
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study showed an association between negative pain perceptions by people with osteoarthritis to
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be associated with physical and psychological disability (36) which may prevent people with
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knee osteoarthritis from engaging in walking. Pain catastrophising, which is the tendency to
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focus on and magnify pain sensations, was found to have an association with physical disability
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(36). Moreover, pain related fear, which is the fear of re-injury due to movement, was also found
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to have an association with psychological disability (36). Our results suggest that in the short
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term people with severe knee osteoarthritis are capable of completing 70 minutes of moderate
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intensity walking in bouts of at least 10 minutes tolerating knee pain levels that settle quickly
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with rest.
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While 70 minutes per week was safely tolerated for participants with severe knee osteoarthritis
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this level of physical activity is less than half the level recommended in physical activity
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guidelines for older people (3). The question remains if this dosage is sufficient to provide longer
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term health benefits, such as reduced risk of cardiovascular disease that is associated with
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inactivity and is a notable concern for people with osteoarthritis (1). People without osteoarthritis
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who exercise for 15 minutes a day have a 14% reduced risk of all-cause mortality and a 3-year
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longer life expectancy compared to those who are inactive (37). Therefore the results for people
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without osteoarthritis suggests there may be relevant health benefits from prescribing 70 minutes
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per week for people with severe knee osteoarthritis, in addition to their usual physical activity.
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Further research investigating the medium term outcomes about reducing cardiovascular risk
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factors and long term outcomes about survival is warranted.
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The results of the current study are consistent with findings that a pre-operative intervention that
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primarily focuses on increasing levels of physical activity through walking may be safe, feasible
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and has the potential to be more beneficial compared to mixed pre-operative group program (38).
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A recent systematic review and meta-analysis of 48 randomised controlled trials found programs
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for people with osteoarthritis that focused on one type of exercise was more beneficial in
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reducing pain and patient reported disability compared to exercise programs that used mixed
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types of exercises with different exercise goals within the same session (39). With long wait
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times for joint replacement surgery, the maximum tolerated dose of walking for people with
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severe knee osteoarthritis may be an exercise option for people with severe knee osteoarthritis.
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The strength of our study was by applying a method that is typically used for testing the safety
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profile of a drug, to prescribing physical activity to people with osteoarthritis, which to our
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knowledge has not been done before. There are a number of limitations in our study. First, as
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part of the 3+3 phase I trial design, the estimate of the maximum tolerated dose is discontinuous
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and imprecise, but it could not fall outside the pre-specified dose levels. Second, we included a
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relatively small sample of participants and limited the dose to one week. However, our results
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from this phase I trial can inform planning for a phase II/III randomised controlled trial design,
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on a larger number of participants over a longer time period to test its efficacy. Third, the
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recruitment method and allocation of doses was at risk of selection bias as it was not randomised.
338
However there was no association between the walking doses and the baseline characteristics.
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Fourth, we did not monitor participant’s background physical activity level during the week
340
when they completed their walking dose. Finally, the adverse events were measured subjectively
341
with self-reported pain levels, whereas in drug trials adverse events can be measured objectively
342
using toxicity levels in the blood. However, there are no objective biological markers for the
343
presence of pain and self-report is the most accurate and reliable evidence of measuring pain and
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its intensity (31).
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CONCLUSION
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There is preliminary evidence that 70 minutes per week of moderate intensity supervised
348
walking was safe and feasible for people with severe osteoarthritis of the knee. For higher doses
349
there was a risk exacerbating knee pain levels.
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Authors’ contributions
352
All authors contributed to the conception and design, and contributed to the writing of the paper
353
by revising it critically for important intellectual content. JAW collected and assembled the data.
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JAW, NFT, KEW and PL performed the data analysis and interpretation of data. All authors read
355
and approved the manuscript.
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Acknowledgements
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None.
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Conflict of interest statement
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All authors declare that they do not have any potential conflict of interest.
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Minutes per week
Intensity
Increment
1
10
moderate
-
2
20
moderate
100%
3
35
moderate
75%
4
50
moderate
43%
5
70
moderate
6
95
moderate
7
120
moderate
8
150
40%
35%
26%
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Dose
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Table 1: Walking doses
25%
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Table 2: Participant characteristics 20 mins (n=3)
35 mins (n=3)
50 mins (n=3)
70 mins (n=3)
95 mins (n=9)
All participants (n=24)
Age (yrs) mean (SD) range [min-max]
65 (11) [53-74]
70 (7) [62-76]
68 (7) [61-75]
66 (12) [55-78]
67 (15) [53-83]
66 (6) [57-76]
67 (8) [53-83]
Sex, n (%) women
3 (100)
1 (33)
0 (0)
2 (67)
1 (33)
6 (67%)
13 (54)
2 Body mass index (kg/m ) mean (SD) range [min-max]
33 (7) [27-40]
29 (4) [25-32]
38 (2) [36-39]
29 (8) [21-37]
40 (19) [26-62]
34 (9) [24-48]
34 (9) [21-62]
3 (100) 0 (0)
3 (100) 0 (0)
3 (100) 0 (0)
2 (67) 1 (33)
3 (100) 0 (0)
9 (100) 0 (0)
23 (96) 1 (4)
Unilateral or bilateral knee OA n (%) unilateral knee OA n (%) bilateral knee OA
2 (33) 1 (67)
1 (33)* 2 (67)
1 (33) 2 (67)
1 (33) 2 (67)
1 (33) 2 (67)
3 (33)* 6 (67)
9 (37)* 15 (63)
Main knee compartments affected by OA n (%) medial n (%) medial and patellofemoral n (%) lateral
2 (67) 1 (33) 0 (0)
2 (67) 1 (33) 0 (0)
3 (100) 0 (0) 0 (0)
3 (100) 0 (0) 0 (0)
3 (100) 0 (0) 0 (0)
7 (78) 0 (0) 2 (22)
20 (83) 2 (8) 2 (8)
1 (33) 0 (0) 1 (33) 1 (33)
3 (100) 0 (0) 0 (0) 0 (0)
2 (67) 0 (0) 0 (0) 1 (33)
2 (67) 0 (0) 1 (33) 0 (0)
2 (67) 0 (0) 1 (33) 0 (0)
5 (56) 2 (22) 1 (11) 1 (11)
15 (63) 2 (8) 4 (17) 3 (13)
18 (4) [14-21]
17 (6) [12-24]
14 (2) [13-16]
11 (1) [10-12]
15 (9) [10-26]
17 (5) [12-25]
16 (5) [10-26]
Physical activity – incidental (hours/week) mean (SD) range [min-max]
28 (15) [11-41]
25 (16) [15-44]
26 (19) [8-46]
18 (4.3) [13-22]
29 (23) [14-56]
20 (14) [7-46]
23 (14) [7-56]
Physical activity – planned (hours/week) mean (SD) range (min-max)
5 (2) [3–7]
3 (1) [2-5]
0.8 (1) [0-2]
0.5 (0.9) [0-2]
0.4 (0.7) [0-1]
2 (3) [0-8]
2 (2) [0-8]
32 (17) [15-48]
28 (16) [18-46]
27 (20) [8-48]
18 (5) [13-22]
30 (23) [14-56]
23 (16) [7-53]
25 (15) [7-56]
8 (2) [7-10]
11 (3) [9-14]
10 (2) [8-11]
7 (4) [3-9]
7 (7) [0-14]
10 (3) [5-14]
9 (4) [0-14]
WOMAC stiffness (0-8) mean (SD) range [min-max]
4 (2) [3-5]
4 (2) [3-6]
4 (1) [4-5]
3 (2) [2-6]
4 (2) [2-5]
5 (2) [0-7]
4 (2) [0-7]
WOMAC activity limitation (0-68) mean (SD) range [min-max]
18 (10) [11-30]
36 (8) [30-45]
35 (3) [32-38]
23 (9) [14-31]
26 (21) [2-43]
37 (13) [11-59]
31 (13) [2-59]
Single point stick, n (%)
0 (0)
0 (0)
1(33)
1 (33)
0 (0)
4 (44)
6 (25)
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Presence of knee deformity (mild) n (%) varus +/- fixed flexion n (%) valgus +/- fixed flexion n (%) fixed flexion only n (%) nil deformity b Kessler 10 (10-50) mean (SD) range [min-max]
b c
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c Physical activity – total (hours/week) mean (SD) range [min-max] d WOMAC pain (0-20) mean (SD) range [min-max]
a
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a
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Osteoarthritis (OA) score n (%) grade IV n (%) grade III
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10 mins (n=3)
Osteoarthritis score rated using Kellgren Lawrence scale (14). Kessler 10 score: 10-15 low, 16-21 moderate, 22-29 high, 30-50 very high level of psychological distress
Total physical activity in hours per week is the sum of incidental physical activity (e.g. housework, gardening or walking to the shops) AND planned physical activity (e.g. walking for exercise, home exercises or exercise classes). d WOMAC pain: 0 (best) to 20 (worst); stiffness: 0 (best) to 8 (worst), activity limitation: 0 (best) to 68 (worst). *2 participants with unilateral knee OA had a contralateral TKA.
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Table 3: Adverse events
20 mins (n=3)
35 mins (n=3)
50 mins (n=3)
70 mins (n=3)#
95 mins (n=9)
All doses (n=24)
0
0
0
0
0
3*
3*
0
0
0
0
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Serious adverse 0 0 0 events # Maximum tolerated dose, * Substantial pain levels after walking
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Adverse events
10 mins (n=3)
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Figure 1: Phase 1 dose response trial, 3+3 design
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Figure 2: Trial recruitment profile
Figure 3a: Linear and non-linear dose response relationships (95% CI) for change in pain (WOMAC) after completion of the walking dose (a negative score indicates a
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decrease in pain)
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Figure 3b: Linear and non-linear dose response relationships (95% CI) for change in activity limitation (WOMAC) after completion of the walking dose (a negative score indicates a decrease in activity limitation)
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Figure 3c: Linear and non-linear dose response relationships (95% CI) for change in stiffness (WOMAC) after completion of the walking dose (a negative score indicates
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a decrease in stiffness)
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3 participants
Add 3 more participants
≥1 adverse event or not able to tolerate
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0 adverse events/ all able to tolerate
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Escalate dose
>1 adverse event or not able to tolerate
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1 adverse event or not able to tolerate
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0 adverse events/ all able to tolerate
Maximum tolerated dose reached
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Potentially eligible participants
Excluded (n = 65):
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n = 89
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Declined to participate (n = 15) Did not meet the selection criteria (n = 35) - Limited English (n = 12) - Other condition that affected walking (n = 10) - Not severe osteoarthritis (n = 8) - Resting pain level > 8/10 (n = 1) - Aged < 50 years (n = 4) Eligible but study concluded (n = 15)
Recruited
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n = 24
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S1063-4584(15)01121-8
DOI:
10.1016/j.joca.2015.04.001
Reference:
YJOCA 3450
To appear in:
Osteoarthritis and Cartilage
Received Date: 22 October 2014 Revised Date:
10 February 2015
Accepted Date: 2 April 2015
Please cite this article as: Wallis JA, Webster KE, Levinger P, Singh PJ, Fong C, Taylor NF, Maximum tolerated dose of walking for people with severe osteoarthritis of the knee: a phase I trial, Osteoarthritis and Cartilage (2015), doi: 10.1016/j.joca.2015.04.001. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Maximum tolerated dose of walking for people with severe osteoarthritis of the knee: a phase I trial Authors
Physiotherapy, Eastern Health. 2. Kate E Webster, PhD, School of Allied Health, La Trobe University.
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1. Jason A Wallis, B.Phty, M.Phty (MSK), PhD Candidate La Trobe University; Department of
3. Pazit Levinger, PhD, Institute of Sport, Exercise & Active Living (ISEAL), Victoria University.
Eastern Health; Lecturer Monash and Deakin University.
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4. Parminder J Singh, MBBS, MRCS, FRCS (Tr&Orth), MS, FRACS. Department of Orthopaedics,
University.
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5. Chris Fong, MBBS, FRACP. Department of Rheumatology, Eastern Health; Lecturer Monash
6. Nicholas F Taylor, PhD, School of Allied Health, La Trobe University. Allied Health Clinical Research Office, Eastern Health.
Correspondence (for review and publication): Mr Jason A Wallis
Department
Physiotherapy Department
Institution
Eastern Health, Box Hill, Victoria 3128
Country
Australia
Tel
(work) +61 3 9895 3463 (work) +61 3 9895 4852 [email protected]; [email protected]
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Name
Running Title: Maximum tolerated dose of walking for severe knee osteoarthritis Key words: osteoarthritis; knee; physical activity; maximum tolerated dose of walking Word Count: Abstract: 250; Manuscript: 3990 References: 39 Tables: 3 Figures: 5
Appendices: 0
Ethics Committee approval: La Trobe University and Eastern Health
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Abstract: Objective: To determine how much physical activity, in the form of walking, can be safely
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and feasibly tolerated for people with severe knee osteoarthritis.
Design: Phase I dose response trial with escalating walking doses of 10, 20, 35, 50, 70, and 95 minutes over one week, were prescribed non-randomly to people with severe knee
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osteoarthritis. The primary stopping rule was a substantial increase in knee pain. The primary outcomes were an estimation of the maximum tolerated dose of walking; and the proportion
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of people who did not complete the dose for feasibility reasons. The secondary outcomes were pain, stiffness and activity limitation (WOMAC).
Results: Twenty-four participants (13 women) aged 53 to 83 years, and average body mass index of 34 kg/m2 (SD 9) were recruited. Three participants were assigned to each dose
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between 10 and 70 minutes, and nine participants assigned to the 95-minute dose. The trial was stopped at 95 minutes due to the maximum number of adverse events occurring at this dose. Therefore, the maximum tolerated dose was 70 minutes. No participant stopped due to
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reasons related to feasibility. There was a moderate association between dose and increased activity (linear R2=0.31, cubic R2=0.69) and reduced stiffness (linear R2=0.20, cubic
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R2=0.52), with increased benefits at moderate to higher doses.
Conclusions: There is preliminary evidence that 70 minutes per week of moderate intensity supervised walking was safe and feasible for people with severe osteoarthritis of the knee; for higher doses there was a risk of exacerbating knee pain levels.
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The maximum tolerated dose of walking for people with severe osteoarthritis of the knee: a
2
phase I trial
3
INTRODUCTION
5
Increasing physical activity is important for people with osteoarthritis of the knee as their risk of
6
mortality from cardiovascular causes is substantially increased (1). Physical activity is defined as
7
any bodily movement produced by the skeletal muscles that requires energy expenditure
8
including recreational tasks as well as structured activities like exercise and is categorised into
9
light, moderate and vigorous intensity (2). Physical activity guidelines for older adults
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4
recommend at least 150 minutes per week of at least moderate physical activity in a minimum of
11
10 minute bouts (3). Maintaining these levels of physical activity is associated with positive
12
health outcomes such as increased life expectancy and reduced burden of major non-
13
communicable diseases (3). For people with symptomatic knee osteoarthritis aerobic exercise
14
programs, which could include walking programs, are recommended in clinical guidelines to
15
reduce pain and disability (4-6). However, no specific guidelines regarding a safe and effective
16
dosage of walking are available for people with severe knee osteoarthritis. For people with
17
mobility restrictions due to the pain and disabilities associated with knee osteoarthritis,
18
guidelines suggest these people be as physically active as their condition allows (3). Such
19
recommendations create uncertainty for health professionals on how much physical activity is
20
safe to recommend to their patients.
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10
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We recently completed a systematic review that found about 1 in 10 people with knee
23
osteoarthritis met current physical activity guidelines (7). While physical activity programs for
Maximum tolerated dose of walking for knee osteoarthritis
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people with osteoarthritis are recommended (4-6, 8-12) physical activity levels remain low in
25
this population. One issue is that we do not know if the dosage recommended in physical activity
26
guidelines (3) is safe and applicable for walking for people with severe knee osteoarthritis.
27
Therefore, investigation of the highest dose that can be tolerated would provide information that
28
could inform guidelines.
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24
29
To our knowledge a phase I dose response trial has not been investigated previously in people
31
with knee osteoarthritis where the safety profile of a physical activity intervention, such as
32
walking, can determine the highest dose that can be tolerated (maximum tolerated dose) without
33
adverse events (13). An adverse event is defined as any unfavourable and unintended sign,
34
symptom, or disease temporally associated with the use of an intervention or procedure that may
35
or may not be considered related to the intervention or procedure (14). Possible short-term
36
adverse events from increased levels of physical activity are temporary exacerbations of pain
37
(12). Pain is a common symptom in people with knee osteoarthritis (15) and may be due to
38
sensitised peripheral nociceptors, and this continuous nociceptive input may drive central
39
sensitisation and increased pain response (16). While this pain response does not necessarily
40
indicate a worsening of the osteoarthritic condition, substantial increases in pain may lead to
41
modifications to physical activity (17).
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In the systematic review (7) we also found that people with knee osteoarthritis may not be much
44
less physically active compared to people of similar age without osteoarthritis. One interpretation
45
of these results is that a low level of physical activity is not solely related to disease factors such
46
as pain, but could also be related to non-disease factors, such as demographic, physical, social,
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psychological and environmental factors (18). Therefore it is not known if it is feasible for
48
people with knee osteoarthritis to complete recommended doses of physical activity.
49
Therefore the primary research questions of the present study are: How much physical activity,
51
in the form of walking, can be safely tolerated for people with severe knee osteoarthritis? How
52
feasible is it for people with severe knee osteoarthritis in the community to complete doses of
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physical activity, in the form of walking? The secondary research question is to determine if
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there is a dose-response relationship for a change in pain, stiffness and activity limitation?
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METHOD
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Study design
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In this phase I dose-response study, an algorithm based (A+B) design (13, 19, 20) was used. The
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first cohort of 3 participants received the same dose. If no participant stopped due to an adverse
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event, the second cohort of 3 participants received the next higher dose and so on. However, if a
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participant stopped due to an adverse event, the second cohort of 3 participants was prescribed
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the same dose as the first cohort. If no further adverse events occurred the study continued at the
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next higher dose. However if another adverse event occurred the dose escalation stopped at that
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level and the previous dose was considered as the maximum tolerated dose (figure 1).
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If any participant elected to stop due to reasons related to feasibility, the next participant was
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recruited and received the same dose. For the purpose of this study, a lack of feasibility was
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defined as not completing the walking dose due to reasons other than safety. For example a
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participant may not have completed the walking dose due to unexpected time pressures.
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The health service and university ethics committees approved this trial in accordance with the
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Helsinki Declaration and all participants provided written informed consent. The trial was
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registered in the Australian New Zealand Clinical Trials Registry
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http://www.ANZCTR.org.au/ACTRN12614000098639.aspx.
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Insert figure 1 about here (Phase 1 design)
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Participants
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Adults with osteoarthritis of the knee were recruited consecutively from a metropolitan health
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service’s osteoarthritis hip and knee clinic between January and April 2014. Patients who
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attended the service were invited to participate provided they met the inclusion criteria: adult
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aged at least 50 years and living independently in the community; diagnosed with unilateral or
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bilateral severe knee osteoarthritis rated as grade III or IV determined radiographically (21);
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participants with contralateral knee replacement and unilateral severe knee osteoarthritis in
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remaining intact limb were eligible; able to understand English; able to participate safely in the
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moderate-intensity physical activity trial according to the 7-item Physical Activity Readiness
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Questionnaire (22).
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Participants were excluded if they: lived in supported accommodation such as a nursing home;
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reported daily resting level of pain to be 9 or 10 on a 0 (no pain) to 10 (worst possible pain)
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Numerical Pain Rating Scale (23). This level of pain may be indicative of a more serious
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pathology; had very high levels of psychological distress as measured by the Kessler 10
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questionnaire with a score > 29 (24); had an intellectual impairment as measured by the Short
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Portable Mental Status Questionnaire with a score of 7 or less (25); had a systemic arthritic
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condition such as rheumatoid arthritis; had a neurological condition that affected walking; had
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knee surgery or intra-articular corticosteroid injection within the past six months; had used oral
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corticosteroids within four weeks.
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Dose prescription
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Physical activity, in the form of walking, was chosen because of the importance of this type
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physical activity to health outcomes for people with osteoarthritis (1). The walking doses of 10,
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20, 35, 50, 70, 95, 120 and 150 minutes over one week, of at least moderate intensity, in a
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minimum of 10 minute sessions were selected so the doses could be compared with the current
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physical activity guidelines (table 1). Participants were aware the dose was between 10 minutes
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and 150 minutes over one week prior to participation. The initial dose of 10 minutes per week
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was based on data from previous research that found a relatively high proportion (49%) of
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people with knee osteoarthritis did not complete any bouts of physical activity at a moderate
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intensity for at least 10 minutes (26). The dose levels then approximated a modified Fibonacci
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scheme (27). For the maximum dose, the current physical activity guideline was selected as only
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a small proportion (10%) of people with knee osteoarthritis met this guideline (26).
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The participants completed the walking doses in the community using normal assistive devices,
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such as a walking stick. Each walking session was supervised individually by a physiotherapist
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to ensure any adverse events were managed appropriately and the dose was completed. The
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number of walking sessions to complete the walking dose was planned and agreed through
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discussion between the physiotherapist and the participant. For example the 50-minute dose
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could include 2x15 minute walking sessions and 1x20 minute session over 3 days. Participants
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were instructed to walk at a moderate intensity of 3 using the Rate of Perceived Exertion scale
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(0-10) and cadence monitored to ensure it was greater than 80 steps/minute (28). Participants
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continued taking their usual medications to manage their knee osteoarthritis. To reduce the risk
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of adverse events due to other physical activities, participants who were currently participating in
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physical activity of moderate intensity in bouts of 10 or more minutes were requested to refrain
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from this activity for 2 days prior to and during the test period. For example, physical activities
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like brisk walking or cycling were avoided. However, light everyday activities did not need to be
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avoided or modified.
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Outcomes
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The primary outcomes were: An estimation of the maximum tolerated dose of walking for people
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with severe knee osteoarthritis; and the proportion of people with severe knee osteoarthritis who
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did not complete the walking dose for feasibility reasons.
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The secondary outcomes were: Pain, stiffness and activity limitation using the Western Ontario
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and McMaster Universities Osteoarthritis Index (WOMAC) (29). The participants completed the
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WOMAC questionnaire at two times: day 1 prior to the first walking session; and day 7 after
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completion of the walking dose.
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The following factors were collected to describe the participants: Age, gender, body mass index,
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severity of knee osteoarthritis including the compartments affected (21), presence of knee
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deformity using clinical observation, co-morbidities, medication use, physical activity level
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using the Incidental and Planned Activity Questionnaire (IPAQWA) (30), and physical activity
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measures of cadence, number of steps, distance covered and walking speed during each walking
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bout measured using an electronic pedometer worn by the participant (iPhone 4S: Footsteps,
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developed by Palm Shadow Apps LLC, http://palmshadow.com/index.php).
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Participants were followed up for 7 days after their first bout of walking. This period was
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selected to monitor any potential adverse effects from completing the walking dose; any
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potential adverse effects would be expected to have occurred by this time.
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Stopping rules - adverse events
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A stopping rule was defined as an adverse event or incident that stopped the participant from
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completing the walking dose for safety reasons and was likely related to the dose.
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Stopping rule 1: Substantial knee pain levels during a walking session
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Knee pain levels were recorded for each walking session, using the 0 to 10 point Numerical Pain
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Rating Scale (23), at the beginning, at 5-minute intervals during, immediately on completion,
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and at 2 hours after completion when resting. A participant who reported their knee pain level
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during the walk as unchanged or decreased compared with the beginning pain level would be
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expected to complete the walk. A participant who reported their knee pain level had increased
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during the walk but the level was less than 7/10 would be expected to complete the walk. A
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participant who reported their knee pain level had increased during the walk and the level was at
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least 7/10 were asked, “Are you prepared to continue?” This participant could continue or stop.
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Participants who stopped were expected to retry the walk on a subsequent day and the same rules
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were applied. If they stopped again, an adverse event was deemed to have occurred.
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Stopping rule 2: Substantial knee pain levels after a walking session
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Substantial increases in resting knee pain at the 2-hour mark after completion of a walking
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session relative to the beginning knee pain level resulted in stopping the dose due to safety
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reasons. Substantial increases in pain was defined as resting knee pain of at least 7/10 two hours
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after the walk which had increased by at least 3/10 if the pain level was between 0 to 6 at the
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beginning of the walk, or had increased by at least 2/10 if the pain level was 7 to 8 at the
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beginning of the walk. The thresholds of 3/10 and 2/10 were based on data that suggests that
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2/10 represents a clinically significant change in pain and varies depending on the initial level
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(31). If a participant reported to the investigator a substantial amount of pain more than 2 hours
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after the walk the dose was stopped and the participant was assisted to health professional
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management as appropriate.
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Stopping rule 3: Serious adverse events
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If any participant reported difficulty breathing that did not settle quickly with rest, new or
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unrelenting chest pain, or acute change in conscious level during the activity, this may precede a
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serious medical emergency such as cardiac arrest or stroke (32). In this event the session was
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stopped immediately with immediate emergency response. A potentially serious event was if the
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participant reported difficulty breathing but symptoms settled quickly with rest and their clinical
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signs (respiration rate, heart rate, oxygen saturation) remained normal. This participant could
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elect to complete the dose provided these symptoms settled quickly with rest and clinical signs
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remained normal.
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Data analysis
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The estimation of sample size was based on the algorithm based design and dose escalation (19)
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whereby a maximum 48 participants (8 dose levels with at maximum 6 patients, not including
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participants that stop due to feasibility). As it was hypothesised the maximal tolerated dose
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would be between doses 4 and 6, the expected sample size was between 21 and 45 participants.
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The primary analysis determined the maximum tolerated dose in minutes of moderate intensity
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walking per week (figure 1) (19). The primary analysis of feasibility was based on the proportion
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of participants not able to complete the walking dose for feasibility reasons.
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The secondary analyses were performed using IBM SPSS Statistics 21 and a p-value < 0.05 was
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considered statistically significant. Parametric tests were reported because parametric tests are
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relatively robust to minor violations of normality, and the results are easily interpretable by other
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researchers. Associations between the walking dose and baseline participant characteristics of
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age, body mass index, resting pain level, psychological distress (Kessler 10) and usual physical
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activity level (IPAQWA) were explored using Pearson’s correlation coefficient, r, to check for
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any bias in dose allocation. To test for a dose response relationship, associations between the
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walking dose, and changes in pain, stiffness and activity limitations over 7 days (WOMAC) were
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explored using linear and non-linear modelling. For the maximum tolerated dose or less, average
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knee pain levels recorded after completion of the walking sessions were compared to the
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beginning level of pain using paired t tests. Finally, physical activity parameters associated with
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the maximum tolerated dose were reported.
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RESULTS
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After screening 89 potentially eligible participants, 24 participants (13 women, 11 men) aged
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between 53 and 83 years, with an average body mass index of 34 kg/m2 (SD 9) met the selection
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criteria (figure 2). All participants had severe knee osteoarthritis with 23 participants (96%) rated
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as grade IV and one participant (4%) rated as grade III using Kellgren-Lawrence scale (21).
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Fifteen of the 24 subjects had bilateral severe knee osteoarthritis and nine of the 24 subjects had
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unilateral severe knee osteoarthritis. Two of the 24 subjects had a contralateral knee replacement.
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On average, participants self-reported participating in 2 hours per week (SD 2 hours) of planned
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physical activities such as home exercises and exercise classes. Seven participants (29%) self-
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reported no planned physical activity per week.
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The most common comorbidities were hypertension (n=11), and high cholesterol (n=11). There
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were no significant associations between the walking dose and baseline participant
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characteristics of age (r=.05), body mass index (r=.11), resting knee pain (r=.27), Kessler 10
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score (r=.06) and total physical activity (r=-.18). Table 2 summarises participants’
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characteristics.
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Insert figure 2 about here (Trial recruitment profile)
Insert table 2 about here (Participant characteristics)
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Maximum tolerated dose and adverse events
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For the first 5 walking doses (10 to 70 minutes), none of the 15 participants had adverse events
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(table 3). There was a small increase in average knee pain level at the immediate completion of
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each walking bout compared to the knee pain level at the beginning of each bout (mean
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increase=2.1 units, 95% CI=1.0,3.2); and knee pain level settled at 2 hours rest to levels
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comparable to knee pain level at the beginning of each bout (mean increase=0.3 units, 95% CI=-
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0.9,1.4).
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For the 95-minute walking dose, 1 of the first 3 participants did not complete the dose due to an
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adverse event. Of the next 3 participants prescribed the 95-minute dose, 1 participant had an
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adverse event. After discussion between the investigators it was decided that a further 3
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participants be prescribed the 95 minute dose. Of the final 3 participants, 1 participant had an
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adverse event. Therefore 3 out of 9 participants prescribed 95 minutes had an adverse event, all
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reporting substantial pain levels after 2 hours rest as per stopping rule 2. Therefore, the
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maximum tolerated dose was 70 minutes of walking over one week, at moderate intensity in at
244
least 10-minute bouts. There were no serious adverse events from any of the participants (table
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3).
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Insert table 3 about here (Adverse events)
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Minor adverse events
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Four participants reported minor adverse events that were not considered a stopping event. One
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participant had an episode of momentary unsteadiness that resolved immediately; two
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participants stopped briefly during a walking session to rest their knee momentarily; one
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participant reported moderate hip pain that settled after each walk.
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Feasibility
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No participant stopped the dose of walking due to reasons of feasibility.
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Dose response
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For the 15 participants completing up to the level of the maximum tolerated dose of 70 minutes,
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and who provided day 1 and day 7 WOMAC scores (n=13), linear modelling indicated no
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association between dose and changes in pain (R2=0.01), and a moderate association between
262
dose and improved activity (R2=0.31) and reduced stiffness (R2=0.20). Non-linear modelling
263
estimated U-shaped dose response curves suggesting a moderate dose might be associated with a
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reduction in pain (cubic R2 =0.32), activity limitation (cubic R2=0.69) and stiffness (cubic
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R2=0.52) (figure 3).
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Physical activity for the maximum tolerated dose
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For the maximum tolerated dose of 70 minutes per week (n=3), 7138 steps (SD 208) and 4770
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metres (SD 1185) were covered during the supervised sessions at a cadence of 99 steps per
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minute (SD 2.7) and average walking speed of 1.1m/s (SD 0.23).
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DISCUSSION
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This phase I dose response trial with escalating dose demonstrated up to 70 minutes per week of
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moderate intensity walking, in at least 10-minute sessions, in addition to baseline physical
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activity associated with daily life, was tolerated for people with severe knee osteoarthritis. For
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higher doses, adverse events occurred with knee pain levels that increased to severe levels during
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the walk and remained severe for at least 2 hours after the event.
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For the 15 participants who completed up to the maximum tolerated dose of 70 minutes, those
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who completed higher doses of walking did not experience increases in pain intensity at the end
284
of the week compared to people who completed lower doses. While increased dynamic loading
285
can predict progression of radiographic knee osteoarthritis, (33, 34) the preliminary findings in
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the current study are consistent with evidence that dynamic knee loading may not predict
287
changes in pain intensity (35). Linear modeling also provided preliminary evidence that higher
288
doses were associated with less limitation to daily activities and less knee stiffness; and non-
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linear modeling provided preliminary evidence suggesting the greatest benefits may have been
290
observed with moderate doses of walking. Confidence bands around these estimates were wide
291
suggesting uncertainty about the dose response in this small sample. While these effects were
292
seen over one week, it remains to be tested whether a repeated weekly dose for people with
293
severe knee osteoarthritis will demonstrate sustained positive changes to activity and pain levels.
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The results of our study may assist people with severe knee osteoarthritis to feel more confident
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of engaging in physical activity, and potentially benefit from a more active lifestyle. A previous
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study showed an association between negative pain perceptions by people with osteoarthritis to
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be associated with physical and psychological disability (36) which may prevent people with
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knee osteoarthritis from engaging in walking. Pain catastrophising, which is the tendency to
300
focus on and magnify pain sensations, was found to have an association with physical disability
301
(36). Moreover, pain related fear, which is the fear of re-injury due to movement, was also found
302
to have an association with psychological disability (36). Our results suggest that in the short
303
term people with severe knee osteoarthritis are capable of completing 70 minutes of moderate
304
intensity walking in bouts of at least 10 minutes tolerating knee pain levels that settle quickly
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with rest.
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While 70 minutes per week was safely tolerated for participants with severe knee osteoarthritis
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this level of physical activity is less than half the level recommended in physical activity
309
guidelines for older people (3). The question remains if this dosage is sufficient to provide longer
310
term health benefits, such as reduced risk of cardiovascular disease that is associated with
311
inactivity and is a notable concern for people with osteoarthritis (1). People without osteoarthritis
312
who exercise for 15 minutes a day have a 14% reduced risk of all-cause mortality and a 3-year
313
longer life expectancy compared to those who are inactive (37). Therefore the results for people
314
without osteoarthritis suggests there may be relevant health benefits from prescribing 70 minutes
315
per week for people with severe knee osteoarthritis, in addition to their usual physical activity.
316
Further research investigating the medium term outcomes about reducing cardiovascular risk
317
factors and long term outcomes about survival is warranted.
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The results of the current study are consistent with findings that a pre-operative intervention that
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primarily focuses on increasing levels of physical activity through walking may be safe, feasible
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and has the potential to be more beneficial compared to mixed pre-operative group program (38).
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A recent systematic review and meta-analysis of 48 randomised controlled trials found programs
323
for people with osteoarthritis that focused on one type of exercise was more beneficial in
324
reducing pain and patient reported disability compared to exercise programs that used mixed
325
types of exercises with different exercise goals within the same session (39). With long wait
326
times for joint replacement surgery, the maximum tolerated dose of walking for people with
327
severe knee osteoarthritis may be an exercise option for people with severe knee osteoarthritis.
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328
The strength of our study was by applying a method that is typically used for testing the safety
330
profile of a drug, to prescribing physical activity to people with osteoarthritis, which to our
331
knowledge has not been done before. There are a number of limitations in our study. First, as
332
part of the 3+3 phase I trial design, the estimate of the maximum tolerated dose is discontinuous
333
and imprecise, but it could not fall outside the pre-specified dose levels. Second, we included a
334
relatively small sample of participants and limited the dose to one week. However, our results
335
from this phase I trial can inform planning for a phase II/III randomised controlled trial design,
336
on a larger number of participants over a longer time period to test its efficacy. Third, the
337
recruitment method and allocation of doses was at risk of selection bias as it was not randomised.
338
However there was no association between the walking doses and the baseline characteristics.
339
Fourth, we did not monitor participant’s background physical activity level during the week
340
when they completed their walking dose. Finally, the adverse events were measured subjectively
341
with self-reported pain levels, whereas in drug trials adverse events can be measured objectively
342
using toxicity levels in the blood. However, there are no objective biological markers for the
343
presence of pain and self-report is the most accurate and reliable evidence of measuring pain and
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its intensity (31).
345
CONCLUSION
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There is preliminary evidence that 70 minutes per week of moderate intensity supervised
348
walking was safe and feasible for people with severe osteoarthritis of the knee. For higher doses
349
there was a risk exacerbating knee pain levels.
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Authors’ contributions
352
All authors contributed to the conception and design, and contributed to the writing of the paper
353
by revising it critically for important intellectual content. JAW collected and assembled the data.
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JAW, NFT, KEW and PL performed the data analysis and interpretation of data. All authors read
355
and approved the manuscript.
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Acknowledgements
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None.
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Conflict of interest statement
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All authors declare that they do not have any potential conflict of interest.
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Minutes per week
Intensity
Increment
1
10
moderate
-
2
20
moderate
100%
3
35
moderate
75%
4
50
moderate
43%
5
70
moderate
6
95
moderate
7
120
moderate
8
150
40%
35%
26%
M AN U moderate
TE D EP AC C
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Dose
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Table 1: Walking doses
25%
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Table 2: Participant characteristics 20 mins (n=3)
35 mins (n=3)
50 mins (n=3)
70 mins (n=3)
95 mins (n=9)
All participants (n=24)
Age (yrs) mean (SD) range [min-max]
65 (11) [53-74]
70 (7) [62-76]
68 (7) [61-75]
66 (12) [55-78]
67 (15) [53-83]
66 (6) [57-76]
67 (8) [53-83]
Sex, n (%) women
3 (100)
1 (33)
0 (0)
2 (67)
1 (33)
6 (67%)
13 (54)
2 Body mass index (kg/m ) mean (SD) range [min-max]
33 (7) [27-40]
29 (4) [25-32]
38 (2) [36-39]
29 (8) [21-37]
40 (19) [26-62]
34 (9) [24-48]
34 (9) [21-62]
3 (100) 0 (0)
3 (100) 0 (0)
3 (100) 0 (0)
2 (67) 1 (33)
3 (100) 0 (0)
9 (100) 0 (0)
23 (96) 1 (4)
Unilateral or bilateral knee OA n (%) unilateral knee OA n (%) bilateral knee OA
2 (33) 1 (67)
1 (33)* 2 (67)
1 (33) 2 (67)
1 (33) 2 (67)
1 (33) 2 (67)
3 (33)* 6 (67)
9 (37)* 15 (63)
Main knee compartments affected by OA n (%) medial n (%) medial and patellofemoral n (%) lateral
2 (67) 1 (33) 0 (0)
2 (67) 1 (33) 0 (0)
3 (100) 0 (0) 0 (0)
3 (100) 0 (0) 0 (0)
3 (100) 0 (0) 0 (0)
7 (78) 0 (0) 2 (22)
20 (83) 2 (8) 2 (8)
1 (33) 0 (0) 1 (33) 1 (33)
3 (100) 0 (0) 0 (0) 0 (0)
2 (67) 0 (0) 0 (0) 1 (33)
2 (67) 0 (0) 1 (33) 0 (0)
2 (67) 0 (0) 1 (33) 0 (0)
5 (56) 2 (22) 1 (11) 1 (11)
15 (63) 2 (8) 4 (17) 3 (13)
18 (4) [14-21]
17 (6) [12-24]
14 (2) [13-16]
11 (1) [10-12]
15 (9) [10-26]
17 (5) [12-25]
16 (5) [10-26]
Physical activity – incidental (hours/week) mean (SD) range [min-max]
28 (15) [11-41]
25 (16) [15-44]
26 (19) [8-46]
18 (4.3) [13-22]
29 (23) [14-56]
20 (14) [7-46]
23 (14) [7-56]
Physical activity – planned (hours/week) mean (SD) range (min-max)
5 (2) [3–7]
3 (1) [2-5]
0.8 (1) [0-2]
0.5 (0.9) [0-2]
0.4 (0.7) [0-1]
2 (3) [0-8]
2 (2) [0-8]
32 (17) [15-48]
28 (16) [18-46]
27 (20) [8-48]
18 (5) [13-22]
30 (23) [14-56]
23 (16) [7-53]
25 (15) [7-56]
8 (2) [7-10]
11 (3) [9-14]
10 (2) [8-11]
7 (4) [3-9]
7 (7) [0-14]
10 (3) [5-14]
9 (4) [0-14]
WOMAC stiffness (0-8) mean (SD) range [min-max]
4 (2) [3-5]
4 (2) [3-6]
4 (1) [4-5]
3 (2) [2-6]
4 (2) [2-5]
5 (2) [0-7]
4 (2) [0-7]
WOMAC activity limitation (0-68) mean (SD) range [min-max]
18 (10) [11-30]
36 (8) [30-45]
35 (3) [32-38]
23 (9) [14-31]
26 (21) [2-43]
37 (13) [11-59]
31 (13) [2-59]
Single point stick, n (%)
0 (0)
0 (0)
1(33)
1 (33)
0 (0)
4 (44)
6 (25)
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Presence of knee deformity (mild) n (%) varus +/- fixed flexion n (%) valgus +/- fixed flexion n (%) fixed flexion only n (%) nil deformity b Kessler 10 (10-50) mean (SD) range [min-max]
b c
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c Physical activity – total (hours/week) mean (SD) range [min-max] d WOMAC pain (0-20) mean (SD) range [min-max]
a
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a
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Osteoarthritis (OA) score n (%) grade IV n (%) grade III
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10 mins (n=3)
Osteoarthritis score rated using Kellgren Lawrence scale (14). Kessler 10 score: 10-15 low, 16-21 moderate, 22-29 high, 30-50 very high level of psychological distress
Total physical activity in hours per week is the sum of incidental physical activity (e.g. housework, gardening or walking to the shops) AND planned physical activity (e.g. walking for exercise, home exercises or exercise classes). d WOMAC pain: 0 (best) to 20 (worst); stiffness: 0 (best) to 8 (worst), activity limitation: 0 (best) to 68 (worst). *2 participants with unilateral knee OA had a contralateral TKA.
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Table 3: Adverse events
20 mins (n=3)
35 mins (n=3)
50 mins (n=3)
70 mins (n=3)#
95 mins (n=9)
All doses (n=24)
0
0
0
0
0
3*
3*
0
0
0
0
AC C
EP
TE D
M AN U
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Serious adverse 0 0 0 events # Maximum tolerated dose, * Substantial pain levels after walking
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Adverse events
10 mins (n=3)
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Figure 1: Phase 1 dose response trial, 3+3 design
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Figure 2: Trial recruitment profile
Figure 3a: Linear and non-linear dose response relationships (95% CI) for change in pain (WOMAC) after completion of the walking dose (a negative score indicates a
SC
decrease in pain)
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Figure 3b: Linear and non-linear dose response relationships (95% CI) for change in activity limitation (WOMAC) after completion of the walking dose (a negative score indicates a decrease in activity limitation)
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Figure 3c: Linear and non-linear dose response relationships (95% CI) for change in stiffness (WOMAC) after completion of the walking dose (a negative score indicates
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a decrease in stiffness)
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3 participants
Add 3 more participants
≥1 adverse event or not able to tolerate
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0 adverse events/ all able to tolerate
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Escalate dose
>1 adverse event or not able to tolerate
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1 adverse event or not able to tolerate
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0 adverse events/ all able to tolerate
Maximum tolerated dose reached
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Potentially eligible participants
Excluded (n = 65):
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n = 89
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Declined to participate (n = 15) Did not meet the selection criteria (n = 35) - Limited English (n = 12) - Other condition that affected walking (n = 10) - Not severe osteoarthritis (n = 8) - Resting pain level > 8/10 (n = 1) - Aged < 50 years (n = 4) Eligible but study concluded (n = 15)
Recruited
AC C
EP
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n = 24
AC C
EP
TE D
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AC C
EP
TE D
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AC C
EP
TE D
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