Reduced knee adduction moments for management of knee osteoarthritis:

Gait & Posture 50 (2016) 60–68

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Full length article

Reduced knee adduction moments for management of knee osteoarthritis: A three month phase I/II randomized controlled trial Ryan T. Lewinson, Ph.D.a,b,c,* , Isabelle A. Vallerand, Ph.D.b , Kelsey H. Collins, B.S.a,c, J. Preston Wiley, M.D., M.P.E.b,c , Victor M.Y. Lun, M.D., M. Sc.b,c, Chirag Patel, M.D., M. Kinb , Linda J. Woodhouse, Ph.D., P.T.d , Raylene A. Reimer, Ph.D., R.D.b,c , Jay T. Worobets, Ph.D.c,e, Walter Herzog, Ph.D.a,b,c , Darren J. Stefanyshyn, Ph.D.a,c a

Schulich School of Engineering, University of Calgary, Calgary, Alberta, Canada Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada c Faculty of Kinesiology, University of Calgary, Calgary, Alberta, Canada d Faculty of Rehabilitation Medicine, University of Alberta, Edmonton, Alberta, Canada e Nike Sport Research Laboratory, Nike Inc., Beaverton, OR, USA b

A R T I C L E I N F O

Article history: Received 18 May 2016 Received in revised form 23 August 2016 Accepted 24 August 2016 Keywords: Loading Biomechanics Gait Clinical trial Wedged insole Footwear

A B S T R A C T

Wedged insoles are believed to be of clinical benefit to individuals with knee osteoarthritis by reducing the knee adduction moment (KAM) during gait. However, previous clinical trials have not specifically controlled for KAM reduction at baseline, thus it is unknown if reduced KAMs actually confer a clinical benefit. Forty-eight participants with medial knee osteoarthritis were randomly assigned to either a control group where no footwear intervention was given, or a wedged insole group where KAM reduction was confirmed at baseline. KAMs, Knee Injury and Osteoarthritis Outcome Score (KOOS) and Physical Activity Scale for the Elderly (PASE) scores were measured at baseline. KOOS and PASE surveys were readministered at three months follow-up. The wedged insole group did not experience a statistically significant or clinically meaningful change in KOOS pain over three months (p = 0.173). Furthermore, there was no association between change in KAM magnitude and change in KOOS pain over three months within the wedged insole group (R2 = 0.02, p = 0.595). Improvement in KOOS pain for the wedged insole group was associated with worse baseline pain, and a change in PASE score over the three month study (R2 = 0.57, p = 0.007). As an exploratory comparison, there was no significant difference in change in KOOS pain (p = 0.49) between the insole and control group over three months. These results suggest that reduced KAMs do not appear to provide any clinical benefit compared to no intervention over a follow-up period of three months. ClinicalTrials.gov ID Number: NCT02067208 ã 2016 Elsevier B.V. All rights reserved.

1. Introduction Osteoarthritis (OA) is a degenerative disease that commonly affects the medial tibiofemoral compartment of the knee [1]. As no cure exists for knee OA, and knee joint replacement is typically reserved for last line therapy, clinical management is often aimed at conservative non-surgical strategies [2,3]. Biomechanically, reduction of medial compartment load, often quantified as the knee adduction moment (KAM) [3,4], has been a goal of

* Corresponding author at: University of Calgary, 3330 Hospital Drive N.W Calgary, AB T2N 4N1, Canada. E-mail address: [email protected] (R.T. Lewinson). http://dx.doi.org/10.1016/j.gaitpost.2016.08.027 0966-6362/ã 2016 Elsevier B.V. All rights reserved.

conservative management. This biomechanical strategy is supported based on evidence that increased KAMs have been related to OA severity [5], pain [6], and disease progression [7]. Laterally wedged footwear insoles/orthotics tend to reduce KAMs [8–11], and have therefore been the subject of much research for management of knee OA over the past 15 years. Traditionally, lateral wedges were applied to all study participants without measuring their effects on KAMs at baseline [12,13], and it would simply be assumed that KAMs were reduced for all participants. However, recent evidence has shown that up to 33% of individuals receiving a lateral wedge insole experience increased KAMs during walking [10], and it has been suggested that perhaps wedged insoles may be best suited to only biomechanical responders [11].

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This may partly explain why clinical pain responses to lateral wedges have been mixed across trials and highlights the notion that the influence of reduced KAMs on reduced pain is not known, because it has not been controlled for. One study failed to show an association between KAM reduction and immediate, same-day pain reduction [14]; however, it is not known if this finding also holds for longer follow-up durations. Like lateral wedges, medial wedges affect KAMs during gait [15–17], and may increase or decrease KAMs depending on the individual. Consequently, medial wedges may also serve as an appropriate intervention for patients who experience KAM reductions with this wedge type. Considering the lack of longitudinal evidence regarding the effects of reduced KAMs on pain for individuals with medial knee OA, a three-month randomized controlled trial was performed, comparing wedged insoles (KAM reduction) to usual footwear (no KAM change) to test the hypothesis that pain reduction over three months is associated with individuals experiencing reduced KAMs. Moreover, it was hypothesized that pain reduction would have a dose-response relationship to KAMs, where larger KAM reductions would be associated with larger reductions in pain. As these questions have not been studied previously, this study was intended as a phase I/II trial to assess the hypotheses related to reduced KAMs and the mechanism of pain reduction, and to provide general insight to possible clinical benefit. 2. Methods 2.1. Study design The detailed protocol of this study has been described previously [18]. Any modifications to the previously described protocol have been outlined in this manuscript. The study was a single-blind, parallel groups, randomized controlled trial conducted at the University of Calgary between January 2015 and October 2015. The study was approved by the Conjoint Health Research Ethics Board of the University of Calgary. Written informed consent was obtained from all participants prior to any data collection, testing, or evaluation of medical histories. The study was registered with ClinicalTrials.gov (ID# NCT02067208). Study participants consisted of individuals from the greater Calgary, Alberta area. Inclusion criteria were age between 40 and 85 years, Knee Injury and Osteoarthritis Outcome Score (KOOS) of 75 or lower on the pain subscale on initial contact, confirmed diagnosis of unilateral or bilateral knee OA based on the American College of Rheumatology criteria [19], and confirmation that medial compartment disease was the primary location of symptoms based on clinical exam by a physician. Contrary to our original proposal [20], individuals of any Kellgren-Lawrence (KL) grade 1 were included in the study. The original criteria of KL grade 1–3 was modified since individuals with KL grades of 4 may still preferentially select conservative therapy over surgery. Full inclusion and exclusion criteria, as well as details regarding assigning Kellgren-Lawrence radiographic severity grades are provided in the Supplementary file. 2.2. Footwear 2.2.1. Usual footwear Usual footwear was defined as the footwear that the participant had used most regularly over the past two months. Although use of an orthotic/insole was described as an exclusion criteria previously [18], this approach was modified to consider previous orthotic/ insole use as acceptable under the assumption that if this is what

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the individual was used to wearing, a reduction in KAMs relative to this usual footwear should still be beneficial. 2.2.2. Wedged insoles The wedged insoles evaluated were 6 mm laterally wedged insoles, and 6 mm medially wedged insoles. For both insole types, wedges ran the length of the foot [21], and were fabricated using a 3D printer (New Balance Athletic Shoe Inc., Boston, MA). The material used was stiff in compression, but flexible along the anterior-posterior and medial-lateral axes of the insole, similar to ethylene vinyl acetate (EVA), which has been used for insoles previously [17]. When evaluating insoles at baseline, and when utilizing insoles during the three month study period, insoles were applied bilaterally in the participant’s usual footwear. If this footwear had a sock liner, insoles were placed beneath the sock liner. If no sock liner was present, the insole was placed within the shoe without any further sock liner added. If the usual footwear included an orthotic/insole that the individual was already using, this orthotic/insole was removed when the experimental insoles were applied. 2.3. Procedures & measurements 2.3.1. Baseline testing All participants meeting clinical eligibility underwent baseline testing, which included completion of the KOOS full-version (relative to most symptomatic knee) [22], physical activity scale for the elderly (PASE) [23], and UCLA physical activity scale surveys [24]. Additionally, a report of co-intervention use over the past week was provided. History of surgery to the most symptomatic knee was also recorded. Finally, participant baseline characteristics such as sex, age, height and body mass were recorded, and dual xray absorptiometry (DXA) testing was performed to quantify total body fat percentage, and whole body bone density (Hologic QDR 4500, Hologic Inc., Bedford, MA). Biomechanical gait analysis during walking was performed on all participants while wearing their usual footwear, usual footwear with the lateral wedge insole, and usual footwear with the medial wedge insole. For each participant and condition, the first peak knee adduction moment (KAM) was determined, and participants rated their perceived overall comfort using a 100 mm visual analogue scale. Participants who were found to experience KAM increases with both the lateral wedge and medial wedge were then eliminated from further study. Thus the study consisted of only biomechanical responders to wedged insoles. Since the minimum clinically relevant reduction in KAM is not known, this study considered any KAM reduction as a valid reduction. The first peak KAM was selected as the primary biomechanical variable of interest to maintain consistency with most other studies on knee OA [3,14,25,26], and since a number of other biomechanical variables were calculated to provide a better representation of total knee load. Specifically, the additional biomechanical variables calculated for each footwear condition included the knee adduction angular impulse (KAAI) during stance phase, the 3D resultant knee moment, the amount of varus thrust during stance phase, and the frontal-plane ankle joint angle, frontal-plane knee joint angle, and left to right frontal-plane knee joint spacing. Detailed descriptions of the procedures used to collect and process all baseline survey and biomechanical data are available in the Supplementary file and elsewhere [18]. 2.3.2. Randomization, blinding and allocation Following baseline data collection, participants were randomized using block-randomization sequences in a 1:1 ratio that were generated using a computer program, and stratified based on sex, to either an insole (KAM reduction) group, or a waitlist control

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group (usual footwear). Neither investigators nor participants were aware of which group the participant was randomized to during baseline data collection, as randomization occurred at the end of the laboratory testing session. At this time, both the participant and investigator were aware of the randomization. Once participants were randomized to either insole or control, those allocated to the insole group were given either a medial or lateral wedge – whichever was found to reduce KAMs the most, thereby maximizing KAM reduction for the insole group. Participants in the waitlist control group were informed that they would be receiving either the medial or lateral wedge (whichever reduced KAMs the most) in three months. All entry of survey and biomechanical data into spreadsheets was done by a blinded investigator. Investigators involved in data analyses were blinded to which group the participant was allocated. 2.3.3. Follow-up Following randomization, participants were asked to use their assigned footwear as much as possible over the next three months, and to avoid transferring the insole (if in insole group) to other footwear during that time. Both groups were asked to avoid the use of any new co-interventions. The KOOS, PASE, UCLA and cointervention survey were completed by the participant and returned to the investigators by email at three months followup. Additionally at three months, participants responded to questions regarding frequency of use of their assigned footwear over the past week, as well as whether new injuries had developed. A follow-up biomechanical assessment was not performed. The rationale for this was based on the fact that the primary objective was to assess the relationship between KAM reduction at baseline and change in pain over 3-months. This approach is also generalizable to other studies, where KAMs are measured only at baseline, and generalizable to clinical practice, where it would not be feasible to continuously monitor KAMs.

bone density) were compared across groups using ANOVA, while categorical variables were compared across groups using a chisquare test with Yates correction for continuity. Biomechanical and clinical outcome data were compared between the insole and control group at baseline using MANOVA with two-tailed independent samples t-tests for post-hoc assessment. Within the insole group, biomechanical effects of the intervention insole were determined by calculating mean differences between usual and intervention footwear and 95% confidence intervals. Differences in KOOS pain over the three month period between groups were assessed using ANCOVA, adjusting for baseline KOOS pain score [29]. To account for missing follow-up data (n = 5/38 participants), multiple imputation was utilized to fill missing data, and a sensitivity analysis was performed by comparing ANCOVA results with imputation to ANCOVA results obtained from exclusively completed cases [28]. As results were unchanged, results are presented for cases with completed data only. Assessments between groups for all follow-up variables including KOOS, PASE and UCLA scores are expressed as mean differences with 95% confidence intervals. To assess the effects of the intervention on KOOS pain exclusively for the insole group, a two-tailed paired samples t-test was used. To assess whether a difference existed between groups in terms of the number of participants experiencing a clinically relevant improvement in KOOS pain of 13.4 points, a chi-square test with Yates correction for continuity was used. Multivariable linear regressions were conducted on the insole group to evaluate whether changes in KAM, KAAI, 3D resultant moment induced by the intervention footwear were associated with change in KOOS pain over three months. Covariates assessed in these models included adiposity by DXA scan, KellgrenLawrence grade, baseline KOOS pain and change in PASE score over three months. 3. Results

2.4. Outcomes

3.1. Demographics

The primary outcome variable was KOOS pain. Secondary variables included biomechanical effects at baseline (KAM, KAAI, 3D moment, varus thrust), other KOOS components (symptoms, function during daily living, function during sport and recreation, quality of life),and physical activity surveys (PASE, UCLA).

Of the 367 volunteers interested in the study, 49 met all eligibility criteria and 48 completed baseline testing (Fig. 1). Of the 48 participants tested at baseline, 10 (20.4%) did not experience KAM reductions with either insole type and so were excluded on the basis of biomechanical ineligibility, resulting in 19 individuals being randomized to the insole group and 19 to the control group. Participant baseline characteristics are shown in Table 1, which includes characteristics of the 10 participants who were biomechanically ineligible for further participation.

2.5. Sample size Given the nature of this phase I/II study, sample sizes were planned based on analyses for the insole group – between group analyses were exploratory. All calculations were done using Stata version 13 (Stata Corp., College Station, TX) with a significance level of 0.05 and power of 80%. Based on our calculations on changes in KOOS pain [18], 20 participants in each group were required to detect clinically meaningful KOOS changes of 13.4 points over 3-months within each group [22,27]. To account for a potential dropout/exclusion rate of 15% [12], recruitment of a minimum of 46 participants across both the insole and control groups was planned. 2.6. Statistical analysis All data were analyzed on an intention-to-treat basis using Stata version 13 [28]. Through visual inspection of boxplots for each variable, all data were determined to be normally distributed, and thus parametric tests were used for all data analysis. For all tests, a significance level of 0.05 was used. At baseline, participant characteristics that were continuous variables (eg. age, height, mass, BMI, DXA body fat percentage,

3.2. Footwear, biomechanics & baseline measures Of the 48 participants who underwent baseline testing, 37/48 (77.1%) experienced KAM reductions with the lateral wedge, and 20/48 (41.7%) experienced KAM reductions with the medial wedge. Additionally, 10/48 (20.8%) did not experience KAM reductions with either wedge, while 18/48 (37.5%) experienced KAM reductions with both wedge types. In the insole group, lateral wedges were found to reduce KAMs the most for each of these participants. Since wedge allocation was based on the insole that most greatly reduced KAMs, the insole group consisted entirely of lateral wedges and by experimental design all 19 had KAM reductions. Responses were less consistent for other biomechanical variables, where some participants experienced increases while others experienced decreases (Supplemental file). Differences in baseline usual footwear biomechanics between the wedged insole and control groups were not found to be statistically significant (F (8,29) = 0.87, p = 0.56). All biomechanical and footwear data can be found in Table 2.

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Fig. 1. Participant flow through the study.

When assessing baseline KOOS, PASE and UCLA scores between groups by MANOVA, a significant difference was detected (F (7,30) = 2.52, p = 0.036); however, post-hoc assessments were not found to be statistically significant (baseline KOOS ADL was bordering on significant difference between groups at p = 0.050). 3.3. Follow-up outcomes All follow-up clinical data can be found in Table 3. Change in KOOS pain over 3-months was not significantly different nor clinically relevant between the insole and control group when

adjusted for baseline pain (F(1,30) = 0.49, p = 0.49). The model was unchanged when adjusting for sex, BMI, DXA Body fat, KellgrenLawrence grade, PASE change over three months, or total assigned intervention usage at three months (calculated as days per week multiplied by hours per day). When assessing change in KOOS pain exclusively for the insole group, there was no statistical difference between scores at baseline and three months (p = 0.173), and this change was also not clinically relevant. In the insole group, 5/19 individuals experienced a clinically meaningful improvement in KOOS pain, and in the control group 2/19 individuals experienced a clinically meaningful improvement in KOOS pain; this was not a

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Table 1 Baseline characteristics for the two study groups, as well as the group of participants excluded following biomechanical testing are shown as number (%) unless denoted by *, where these values are means (SD). P-values are shown for between group comparisons from chi-square tests with Yates correction for continuity for proportion data, and one-way ANOVA for continuous data (denoted by *). Variable

Wedged Insole Group (n = 19)

Control Group (n = 19)

Excluded (n = 10)

P-Value

Female *Age (years) *Height (m) *Body mass (kg) *BMI (kg/m2) *Body fat (%) *Bone density (g/cm2) Bilateral OA

13 (68) 59.9 (7.4) 1.69 (0.12) 93.3 (23.8) 32.5 (8.0) 37.4 (8.5) 1.12 (0.14) 18 (95)

11 (58) 59.6 (7.7) 1.73 (0.09) 87.6 (20.8) 29.2 (6.7) 33.0 (8.9) 1.10 (0.12) 16 (84)

7 (70) 59.7 (9.9) 1.64 (0.10) 77.6 (20.0) 28.5 (5.9) 35.3 (8.8) 1.05 (0.15) 7 (70)

0.634 0.989 0.100 0.199 0.243 0.299 0.396 0.821

OA Compartments Uni-compartmental Bi-compartmental Tri-compartmental

2 (11) 3 (16) 14 (74)

2 (11) 2 (11) 15 (79)

1 (10) 1 (10) 8 (80)

Radiographic Severity K-L Grade 1 K-L Grade 2 K-L Grade 3 K-L Grade 4

5 2 3 9

(26) (11) (16) (47)

4 4 2 9

(21) (21) (11) (47)

1 2 1 6

(10) (20) (10) (60)

Symptom duration 0 to <5 years 5 to <10 years 10 years Hx of knee surgery

9 5 5 2

(47) (26) (26) (11)

10 (53) 6 (32) 3 (16) 5 (26)

2 2 6 5

(20) (20) (60) (50)

1.0

1.0

0.480

significant difference (X2(1) = 0.70, p = 0.403). When comparing the insole and control groups in terms of KOOS symptoms, KOOS function during daily living, KOOS function during sport and recreation, KOOS quality of life, PASE physical activity and UCLA physical activity, no significant differences were observed (Table 3). When assessing variables related to KOOS pain change over three months for the insole group (n = 15), the best model (as a balance of maximizing the R2 while minimizing the number of predictor

0.865

variables) was found to include baseline KOOS pain and change in PASE score over three months as independent variables (R2 = 0.57, p = 0.007), with the majority of the variance explained by baseline pain. Specifically, the relationship was such that improved KOOS pain over three months was associated with worse baseline pain (i.e. a lower KOOS pain score) and reduction in physical activity (i.e. a lower PASE score) over three months. When testing this model for the control group, no association was found (R2 = 0.04,

Table 2 Biomechanics and footwear comfort data are shown as means (SD) between groups for the usual footwear condition, and also within the wedged insole group, where usual footwear is compared to the intervention insole. Mean differences (95% confidence interval) are shown for the wedged insole group, where negative values indicate a lower wedged insole result vs usual footwear. Variable

Wedged Insole Group (n = 19) Usual Footwear

Wedged Insole

Control Group (n = 19) Mean Difference (95% CI) *

Usual Footweara

KAM, Nm

68.1 (21.6)

60.2 (18.6)

7.9 ( 10.6 to

5.1)

KAAI, Nms

30.5 (10.7)

28.1 (10.0)

2.4 ( 3.6 to

1.1)**

25.5 (8.5)

3D Resultant, Nm

72.4 (19.9)

66.4 (17.7)

6.0 ( 9.5 to

2.6)***

61.4 (18.9)

Varus Thrust, mm

41.5 (16.9)

38.0 (17.4)

3.5 ( 9.2 to 2.3)

Static Ankle Angle, deg

174.7 (15.5)

182.6 (15.9)

7.9 ( 0.1 to 16.0)

175.6 (15.1)

Static Knee Angle, deg

179.9 (4.7)

181.1 (4.8)

1.1 ( 0.6 to 2.8)

178.5 (4.6)

Static Left to Right Knee Joint Spacing, mm

311.6 (134.3)

311.9 (137.5)

0.3 ( 3.9 to 4.6)

264.5 (128.8)

Footwear comfort, mm

66.1 (21.2)

57.5 (32.6)

a

No significant differences were found between control and wedged insole groups for usual footwear. p < 0.001. ** p = 0.002. *** p = 0.003. *

8.6 ( 25.2 to 8.1)

59.2 (18.2)

36.3 (20.9)

66.7 (24.9)

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Table 3 Clinical outcome data at baseline and 3 months follow-up. Mean differences within groups are based on complete cases only (n = 15 wedge group, n = 18 control group) as per the approach described in the statistical analysis section of this manuscript, and thus the difference observed between the baseline and three months columns may not equate to those in the mean differences column. Between group mean differences were adjusted by baseline values, and so values may not equate to difference seen between the two within groups columns. Variable

Wedged Insole Group Mean (SD)

Control Group Mean (SD)

Mean (SD) Difference (3 months – Between Groups Mean Differencea (95% CI) (Insole – Baseline) Control)

Baseline (n = 19)

3 Months (n = 15)

Baseline (n = 19)

3 Months (n = 18)

Wedged Insole (n = 15)

Control (n = 18)

KOOS (0–100) Pain

51.5 (17.1)

56.6 (13.1)

55.4 (13.5)

55.6 (16.7)

6.6 (17.7)

1.0 (12.8)

3.3 ( 6.3 to 12.9)

Symptoms

55.5 (16.7)

61.9 (13.5)

57.0 (14.5)

58.5 (16.0)

5.7 (17.3)

1.4 (15.1)

3.8 ( 6.1 to 13.7)

ADL

60.1 (16.2)

64.0 (15.2)

70.2 (14.5)

64.0 (17.8)

5.9 (14.9)

5.4 (16.8)

6.1 ( 4.9 to 17.1)

Sport/Rec

45.0 (27.5)

44.0 (18.7)

36.5 (22.9)

39.9 (23.7)

0.7 (28.2)

4.6 (23.3)

0.8 ( 13.7 to 15.3)

QOL

37.2 (18.1)

42.1 (14.3)

36.5 (15.2)

36.1 (17.1)

6.7 (14.5)

0.3 (17.2)

6.1 ( 4.0 to 16.2)

PASE, points

173.9 (80.2)

173.5 (77.9)

216.3 (112.5)

190.2 (93.9)

3.4 (70.4)

28.3 (77.3)

12.4 ( 34.1 to 59.0)

UCLA, 1–10

5.1 (1.4)

5.3 (1.5)

6.3 (2.1)

5.6 (2.0)

0.3 (1.6)

0.7 (1.4)

0.5 ( 0.5 to 1.6)

a

Adjusted for baseline value of variable.

p = 0.737). No relationships were found between KOOS change in pain and KAM reduction (R2 = 0.02, p = 0.594), KAAI reduction (R2 = 0.003, p = 0.844), or 3D resultant moment reduction (R2 = 0.004, p = 0.815). Scatter plots showing the loading vs. change in pain analyses are displayed in the Supplemental File. 3.4. Co-interventions, adherence & adverse events The two study groups were well matched in terms of co-intervention use at baseline (F(4,33) = 0.90, p = 0.476) and co-intervention use and adherence at follow-up (F(6,25) = 1.07, p = 0.408) (Table 4). However, the insole group tended to develop more new injuries than the control group during the study, bordering on statistical significance (13 vs. 6; X2(1) = 3.79, p = 0.052) (Supplemental file shows itemized injuries). 4. Discussion The purpose of this phase I/II trial was to evaluate the relationship between KAM reduction and pain reduction over three months in individuals with medial knee osteoarthritis. Based

on existing literature, it was hypothesized that (1) pain reduction over three months would be associated with individuals experiencing reduced KAMs, and (2) pain reduction would have a dose-response relationship to KAMs, where larger KAM reductions would result in greater pain reductions. The results from this study do not support either hypothesis, since no differences were observed between or within the insole and control group in terms of clinical outcomes, and none of the knee loading variables were associated with change in KOOS pain score over three months. While the study recruited more individuals than originally planned for baseline testing, the exclusion/dropout rate (31%) was greater than anticipated (15%). A post-hoc power and sample size calculation was conducted based on the mean difference in change in KOOS pain over 3 months between the insole and control groups (Table 3), and it was found that the present study achieved only 17% power. Based on the results from this study in terms of difference in KOOS pain between groups, it was further calculated that to identify a significant difference in KOOS pain between groups at 80% power, an estimated 242 participants total would be required. It should be emphasized that even with statistical significance, the

Table 4 Co-intervention use and adherence characteristics are shown for both study groups. Variable

Wedged Insole Group

Control Group

Baseline (n = 19)

3 Months (n = 15)

Baseline (n = 19)

3 Months (n = 18)

Co-Intervention (days/week) NSAID/Acetaminophen Physiotherapy/Targeted Exercise Compression/Tensor brace Narcotic medication Unloader brace

3.2 (2.9) 1.9 (2.6) 0.8 (2.2) 0.1 (0.3) 0 (0)

3.2 (3.0) 1.5 (2.2) 1.3 (2.6) 0.1 (0.5) 0 (0)

3.1 (2.8) 0.9 (2.2) 0.3 (0.8) 0 (0) 0 (0)

2.9 (2.8) 0.6 (1.8) 0.2 (0.7) 0.8 (2.0) 0 (0)

Adherence Use of assigned footwear (days/week) Use of assigned footwear (hours/day)

– –

5.5 (2.4) 6.4 (4.0)

– –

4.4 (3.3) 5.1 (4.9)

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observed difference in KOOS change between groups would not be clinically meaningful. Thus, while our sample was underpowered to detect a significant difference, it is unlikely that meeting our originally intended sample size would alter the outcomes or interpretations of this study given differences between groups would still be unlikely to be statistically or clinically significant. Consequently, the results of this study would be expected to be similar even with a larger sample size. This study is the first to suggest that KAM reduction may not contribute to a greater therapeutic effect than a control group over short-term follow-up. Evidence regarding the benefit of wedged insoles for knee OA is currently quite conflicted [12,30–32]. In a recent systematic review, it was suggested that part of the discrepancy may be due to the fact that some trials did not use a sham insole in their control group, which could result in the interpretation of placebo effects as actual insole effects in the experimental group [33]. However, recent evidence has also highlighted that sham insoles can actually increase KAMs [34]. Others have highlighted that the disparity in trial results may be associated with an unintended increase in KAMs with the wedged insole, potentially washing out actual effects of KAM reduction [35]. In the present trial, KAM reduction was confirmed at baseline for the insole group and KAMs were unaltered in the control group, yet still no difference was observed between study groups at three months follow-up, and no relationship between KAM reduction and change in pain over three months was observed. These results are in agreement with those of Jones et al. [14], who assessed the relationship between KAM reduction and pain at baseline without follow-up. While regression analyses found no association between change in KAM and change in pain, the results from the current study do not discount the potential long-term importance of knee joint load reductions for individuals with knee OA. There is research to suggest that altered joint loading may contribute to osteoarthritis, both in human and animal models [4,5,36,37], and thus load reduction may serve an important role. In terms of joint structure, Bennell et al. [26], have shown that the amount of medial tibial cartilage volume loss over one year for individuals with knee OA was positively associated with magnitude of the KAAI during walking. Additionally, it has been shown that KAM magnitude predicts radiographic disease progression over six years [7]. Therefore, it may be possible that beneficial effects of load reduction are not apparent in the short-term, and instead require long-term (1 year) follow-up for detection. Consequently, further studies should be considered that assess the effects of confirmed KAM reduction on long term outcomes such as structural maintenance of the joint. Reductions in KOOS pain over three months for the insole group were associated with a more severe baseline pain (lower KOOS), and a reduced physical activity level (reduced PASE). In a metaanalysis, it was shown that placebo effects in OA trials are often largest for individuals whose baseline pain is more severe [38] – it is possible these patients have more to gain, or may be more prone to day-to-day fluctuation. Thus, in the present study, the finding that changes in pain were related to a more severe baseline KOOS pain score may suggest that effects of the insoles in the short-term may be similar to what might be expected from a placebo. Since the control group did not receive a sham insole, it would therefore make sense that a similar effect was not seen in the control group. In regards to the association with change in PASE score, it has been highlighted recently that physical activity must always be accounted for in OA trials [39]. One reason for this is that physical activity may induce positive psychological and/or physiological changes that ultimately alter the processing of pain [40]. Another possibility is that with altered physical activity levels, total cumulative joint loading may be altered, which could contribute

towards a lack of association between KAM reduction and pain change [41]. Finally, it is possible that the finding of KOOS pain change being associated with baseline pain in the insole group represents regression towards the mean; however, this is less likely than other possibilities above given the two study groups were well matched at baseline, and that the association was observed in the insole group only and not in the control group. Co-intervention use was unchanged over the duration of the trial for either group. Previous trials have found that in some cases, pain may not change, but a reduction in co-intervention use may occur, which ultimately may indicate a therapeutic effect [32]. Contrary to this, the present trial found that wedged insoles may produce more adverse events compared to the control group. It should be noted that these findings were of borderline significance, and may be associated with the fact that only the wedged insole group actually received a new intervention. While these adverse events were generally no more than foot or leg discomfort or cramping, three individuals did drop-out from the trial due to foot discomfort. There are a number of limitations to this study. Primarily, the study included a relatively short follow-up, and thus the long-term effects of load reduction using wedged insoles remain unknown. While a relatively small sample size was utilized, our data suggest that no clinically meaningful association between load reduction and change in pain exists in the short-term. Supporting this point, the results presented here are in agreement with a larger study assessing baseline changes in pain from reduced KAMs [14]. Since biomechanical variables were not assessed at follow-up, it was assumed that the biomechanical changes induced in the laboratory at baseline would be maintained throughout the trial duration and during prolonged activity, as has been shown to be the case in other studies [42,43]. It remains a possibility that the effects of the wedged insoles on KAMs changed over time, or that the individual’s own shoes had different effects over time with shoe wear. Despite this, KAM reduction was confirmed at baseline, which has not been done previously in any knee OA clinical trial with follow-up to date. Of particular importance is the fact that any reduction in KAM was considered a valid reduction at baseline. It is possible that results may differ if a larger sample size was attained and participation was restricted to only those individuals with a pre-defined magnitude of KAM reduction. While medial knee OA was predominant in the study sample, some participants also had OA in other compartments, which could potentially affect clinical responses to altered knee mechanics and wedged insoles. Moreover, individuals of any OA severity were included, and thus it is not known if specific knee OA subgroups may benefit more from a KAM reduction intervention. 5. Conclusion This phase I/II trial evaluated the effects of reduced KAMs via wedged insoles on clinical outcomes over time in patients with knee OA. After three-months follow-up, no differences were observed between the insole group and control group in terms of pain, physical activity, or co-intervention use. Additionally, reduced KAMs were not found to be associated with reduced pain over the duration of the study. These results suggest a nonclinically meaningful, and non-statistically significant effect of wedged insoles on KOOS pain, and pain changes that did occur over three-months did not appear to be related to KAM reduction. Longer-duration studies may be needed to evaluate whether KAM reduction confers any structural benefit to the joint.

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Competing interests RTL has a filed a U.S. Provisional Patent 62/183,055 and held a Footwear Research Award from New Balance Athletic Shoe Inc. during this project. IAV has nothing to disclose. KHC has nothing to disclose. JPW has nothing to disclose. VMYL has nothing to disclose. CP has nothing to disclose. LJW has nothing to disclose. RAR has nothing to disclose. JTW has nothing to disclose. WH has nothing to disclose. DJS has a filed a U.S. Provisional Patent 62/ 183,055. Role of the funding source RTL was funded to conduct this project by a Vanier Canada Graduate Scholarship from the Canadian Institutes of Health Research, a MD/PhD Studentship from Alberta Innovates Health Solutions, a Doctoral Scholarship from the Killam Trusts, and a Footwear Research Award from New Balance Athletic Shoe Inc. Funding agencies had no role in study design, data analysis, or writing of this manuscript. Contributions Conception and design (RTL, KHC, DJS); Analysis and interpretation of the data (RTL, IAV, JPW, JTW, WH, DJS); Drafting of the article (RTL); Critical revision of the article for important intellectual content (IAV, KHC, JPW, VMYL, CP, LJW, RAR, JTW, WH, DJS); Final approval of the article (IAV, KHC, JPW, VMYL, CP, LJW, RAR, JTW, WH, DJS); Statistical expertise (IAV); Obtaining of funding (RTL); Technical, or logistic support (KHC, LJW, RAR); Collection and assembly of data (RTL, JPW, VMYL, CP). Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j. gaitpost.2016.08.027. References [1] D.T. Felson, Clinical practice. Osteoarthritis of the knee, N. Engl. J. Med. 354 (2006) 841–848. [2] K.L. Bennell, D.J. Hunter, R.S. Hinman, Management of osteoarthritis of the knee, BMJ 345 (2012) e4934. [3] N.D. Reeves, F.L. Bowling, Conservative biomechanical strategies for knee osteoarthritis, Nat. Rev. Rheumatol. 7 (2011) 113–122. [4] T.P. Andriacchi, A. Mündermann, R.L. Smith, E.J. Alexander, C.O. Dyrby, S. Koo, A framework for the in vivo pathomechanics of osteoarthritis at the knee, Ann. Biomed. Eng. 32 (2004) 447–457. [5] L. Sharma, D.E. Hurwitz, E.J.M.A. Thonar, J.A. Sum, M.E. Lenz, D.D. Dunlop, et al., Knee adduction moment, serum hyaluronan level, and disease severity in medial tibiofemoral osteoarthritis, Arthritis Rheum. 41 (1998) 1233–1240. [6] S. Amin, N. Luepongsak, C.A. McGibbon, M.P. LaValley, D.E. Krebs, D.T. Felson, Knee adduction moment and development of chronic knee pain in elders, Arthritis Rheum. 51 (2004) 371–376. [7] T. Miyazaki, Dynamic load at baseline can predict radiographic disease progression in medial compartment knee osteoarthritis, Ann. Rheum. Dis. 61 (2002) 617–622. [8] R.S. Hinman, C. Payne, B.R. Metcalf, T.V. Wrigley, K.L. Bennell, Lateral wedges in knee osteoarthritis: what are their immediate clinical and biomechanical effects and can these predict a three-month clinical outcome, Arthritis Rheum. 59 (2008) 408–415. [9] W. Kakihana, M. Akai, K. Nakazawa, T. Takashima, K. Naito, S. Torii, Effects of laterally wedged insoles on knee and subtalar joint moments, Arch. Phys. Med. Rehabil. 86 (2005) 1465–1471. [10] G.J. Chapman, M.J. Parkes, L. Forsythe, D.T. Felson, R.K. Jones, Ankle motion influences the external knee adduction moment and may predict who will respond to lateral wedge insoles? An ancillary analysis from the SILK trial, Osteoarthr. Cartilage 23 (2015) 1316–1322. [11] J.B. Arnold, D.X. Wong, R.K. Jones, C.L. Hill, D. Thewlis, Lateral wedge insoles for reducing biomechanical risk factors for medial knee osteoarthritis progression: a systematic review and meta-Analysis, Arthritis Care Res. 68 (2016) 936–951.

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