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Exercise and education vs intra-articular saline for knee osteoarthritis: a 1-year follow-up of a randomized trial

Open AccessPublished:January 16, 2023DOI:https://doi.org/10.1016/j.joca.2022.12.011

      Summary

      Objective

      To assess the longer-term effect of the Good Life with osteoarthritis in Denmark (GLAD) exercise and education program relative to open-label placebo (OLP) on changes from baseline in core outcomes in individuals with knee osteoarthritis (OA).

      Methods

      In this 1-year follow-up of an open-label, randomized trial, patients with symptomatic and radiographically confirmed knee OA were monitored after being randomized to either the 8-week GLAD program or OLP given as 4 intra-articular saline injections over 8 weeks. The primary outcome was the change from baseline in the Knee injury and Osteoarthritis Outcome Score questionnaire (KOOS) pain subscale after 1 year in the intention-to-treat population. Key secondary outcomes were the KOOS function and quality of life subscales, and Patients' Global Assessment of disease impact.

      Results

      206 adults were randomly assigned: 102 to GLAD and 104 to OLP, of which only 137 (63/74 GLAD/OLP) provided data at 1 year. At one year the mean changes in KOOS pain were 8.4 for GLAD and 7.0 for OLP (Difference: 1.5 points; 95% CI −2.6 to 5.5). There were no between-group differences in any of the secondary outcomes.

      Conclusions

      In this 1-year follow-up of individuals with knee OA, the 8-week GLAD program and OLP both provided minor longer-term benefits with no group difference. These results require confirmation given the significant loss to follow-up.

      Trial registration number

      NCT03843931.

      Keywords

      Introduction

      Knee osteoarthritis (OA) is a highly prevalent musculoskeletal condition mainly affecting older people, causing pain, physical disability, and reduced quality of life
      • Sharma L.
      Osteoarthritis of the knee.
      . Exercise combined with patient education is recommended as a primary treatment strategy
      • Bannuru R.R.
      • Osani M.C.
      • Vaysbrot E.E.
      • Arden N.K.
      • Bennell K.
      • Bierma-Zeinstra S.M.A.
      • et al.
      OARSI guidelines for the non-surgical management of knee, hip, and polyarticular osteoarthritis.
      • Kolasinski S.L.
      • Neogi T.
      • Hochberg M.C.
      • Oatis C.
      • Guyatt G.
      • Block J.
      • et al.
      2019 American College of Rheumatology/arthritis foundation guideline for the management of osteoarthritis of the hand, hip, and knee.
      • Fernandes L.
      • Hagen K.B.
      • Bijlsma J.W.
      • Andreassen O.
      • Christensen P.
      • Conaghan P.G.
      • et al.
      EULAR recommendations for the non-pharmacological core management of hip and knee osteoarthritis.
      and based on these recommendations, the Good Life with osteoarthritis in Denmark (GLAD) program has been developed and widely adopted in several countries globally
      • Roos E.M.
      • Barton C.J.
      • Davis A.M.
      • McGlasson R.
      • Kemp J.L.
      • Crossley K.M.
      • et al.
      GLA:D to have a high-value option for patients with knee and hip arthritis across four continents: Good Life with osteoArthritis from Denmark.
      .
      We have recently conducted a randomized controlled trial (RCT) comparing the effects of the GLAD program (8 weeks of exercise and education) with an open-label placebo (OLP) – given as inert intra-articular saline (IA saline) injections – in patients with knee OA
      • Bandak E.
      • Overgaard A.F.
      • Kristensen L.E.
      • Ellegaard K.
      • Guldberg-Moller J.
      • Bartholdy C.
      • et al.
      Exercise therapy and patient education versus intra-articular saline injections in the treatment of knee osteoarthritis: an evidence-based protocol for an open-label randomised controlled trial (the DISCO trial).
      . The results showed that the two interventions provided the same efficacy for symptomatic and functional improvements after 9 and 12 weeks from baseline
      • Bandak E.
      • Christensen R.
      • Overgaard A.
      • Kristensen L.E.
      • Ellegaard K.
      • Guldberg-Moller J.
      • et al.
      Exercise and education vs. saline injections for knee osteoarthritis: a randomised controlled equivalence trial.
      . However, the GLAD program includes encouragement of patients to a lifelong continuation of exercise on their own
      • Skou S.T.
      • Roos E.M.
      Good Life with osteoArthritis in Denmark (GLA:D): evidence-based education and supervised neuromuscular exercise delivered by certified physiotherapists nationwide.
      , and therefore we hypothesized that the GLAD program could be superior to OLP in the longer-term. Further, secondary analyses of our RCT suggested that patients who at baseline, take analgesics, have constant pain, or had an a priori preference for GLAD seem to benefit more from GLAD than from OLP in the short term
      • Henriksen M.
      • Nielsen S.M.
      • Christensen R.
      • Kristensen L.
      • Bliddal H.
      • Bartholdy C.
      • et al.
      Who are likely to benefit from the good life with osteoarthritis in Denmark (GLAD) exercise and education program? An effect modifier analysis of a randomised controlled trial.
      . It is, however, unknown if these subgroups also have benefits in the longer-term.
      Accordingly, the aim of this extension of our recently published trial
      • Bandak E.
      • Christensen R.
      • Overgaard A.
      • Kristensen L.E.
      • Ellegaard K.
      • Guldberg-Moller J.
      • et al.
      Exercise and education vs. saline injections for knee osteoarthritis: a randomised controlled equivalence trial.
      was twofold: (1) to assess if GLAD is superior to open-label placebo (IA saline) at a 1-year follow-up and (2) to assess whether the follow-up data corroborates our recent short term assertions regarding existence of subgroups of patients most likely to benefit from GLAD over OLP
      • Henriksen M.
      • Nielsen S.M.
      • Christensen R.
      • Kristensen L.
      • Bliddal H.
      • Bartholdy C.
      • et al.
      Who are likely to benefit from the good life with osteoarthritis in Denmark (GLAD) exercise and education program? An effect modifier analysis of a randomised controlled trial.
      .

      Methods

      Study design

      We conducted an open-label, single-centre, RCT involving participants with knee OA at Bispebjerg-Frederiksberg Hospital in Copenhagen, Denmark
      • Bandak E.
      • Overgaard A.F.
      • Kristensen L.E.
      • Ellegaard K.
      • Guldberg-Moller J.
      • Bartholdy C.
      • et al.
      Exercise therapy and patient education versus intra-articular saline injections in the treatment of knee osteoarthritis: an evidence-based protocol for an open-label randomised controlled trial (the DISCO trial).
      ,
      • Bandak E.
      • Christensen R.
      • Overgaard A.
      • Kristensen L.E.
      • Ellegaard K.
      • Guldberg-Moller J.
      • et al.
      Exercise and education vs. saline injections for knee osteoarthritis: a randomised controlled equivalence trial.
      . All participants provided written informed consent before the commencement of the study. The study protocol was prospectively registered at www.clinicaltrials.gov (NCT03843931) and approved by the Health Research Ethics Committee of the Capital Region of Denmark (H-19012472) and the Danish Medicines Agency (EudraCT number 2019-000809-71). The present 1-year follow-up was not part of the a priori planning and hence not registered.

      Participants

      Eligible individuals were 50 years of age or older, had a Body Mass Index (BMI) ≤ 35 kg/m2, met the American College of Rheumatology clinical classification of knee OA,
      • Altman R.
      • Asch E.
      • Bloch D.
      • Bole G.
      • Borenstein D.
      • Brandt K.
      • et al.
      Development of criteria for the classification and reporting of osteoarthritis. Classification of osteoarthritis of the knee. Diagnostic and Therapeutic Criteria Committee of the American Rheumatism Association.
      with an average knee pain of at least 4/10 (10 = worst) in the last week during weight-bearing activities, and had radiographically verified tibiofemoral OA (Kellgren–Lawrence (KL) ≥ 2)
      • Kellgren J.H.
      • Lawrence J.S.
      Radiological assessment of osteo-arthrosis.
      . Major exclusion criteria included intra-articular treatments in either knee and/or participation in therapeutic exercise – both within 3 months of the baseline visit.
      Before randomization, participant information was delivered neutrally, ensuring that the descriptions of both interventions were equally accompanied by positive messages, including that the investigators had no treatment preference and expected beneficial effects from both interventions
      • Bandak E.
      • Overgaard A.F.
      • Kristensen L.E.
      • Ellegaard K.
      • Guldberg-Moller J.
      • Bartholdy C.
      • et al.
      Exercise therapy and patient education versus intra-articular saline injections in the treatment of knee osteoarthritis: an evidence-based protocol for an open-label randomised controlled trial (the DISCO trial).
      . Participants were assigned in a 1:1 ratio based on a computer-generated randomization list based on permuted random blocks of variable size (2–6 in each block) stratified by four baseline conditions: BMI ≥ 30 kg/m2 (yes/no), swollen study knee upon palpation
      • Maricar N.
      • Callaghan M.J.
      • Parkes M.J.
      • Felson D.T.
      • O'Neill T.W.
      Interobserver and intraobserver reliability of clinical assessments in knee osteoarthritis.
      , bilateral radiographic tibiofemoral OA (KL ≥ 2 bilaterally), and participation in sports activities as a young adult (20ies). Due to the open-label nature of the study design, neither the health professionals delivering the interventions, nor the participants were blinded after randomization. The most symptomatic knee at baseline was chosen as the study knee. In the original study, participants were evaluated in the clinic at baseline, and at 9, and 12 weeks. Further, online questionnaires were emailed to the participants weekly from baseline to week 8, and for this extension study, the participants were also emailed links to the online questionnaire again 1 year after baseline.

      Interventions

      The GLAD program consists of 8 weeks of patient education and supervised neuromuscular exercise
      • Skou S.T.
      • Roos E.M.
      Good Life with osteoArthritis in Denmark (GLA:D): evidence-based education and supervised neuromuscular exercise delivered by certified physiotherapists nationwide.
      . Two group-based educational sessions (1.5-h each) are provided once weekly for the first 2 weeks, followed by 12 group-based, supervised exercise sessions, provided twice weekly for 6 weeks. The GLAD program includes encouragement to continue to exercise after the 8-week intervention period. The OLP consisted of ultrasound-guided intra-articular saline injections of 5 mL isotonic solution of sodium chloride in sterile water (0.9% = 9 mg/mL) into the study knee in week 1, 3, 5 and 7 after baseline. Neither group received any attention or care from the study after the clinical visit at week 12.

      Outcomes

      This extension study includes the core outcomes for trials in knee OA not involving putative structure-modifying OA drugs: Pain, physical function, Quality of life, and Patients global assessment
      • Smith T.O.
      • Hawker G.A.
      • Hunter D.J.
      • March L.M.
      • Boers M.
      • Shea B.J.
      • et al.
      The OMERACT-OARSI core domain set for measurement in clinical trials of hip and/or knee osteoarthritis.
      . The primary outcome was the change from baseline in the pain subscale of the Knee injury and Osteoarthritis Outcome Score questionnaire (KOOS)
      • Roos E.M.
      • Roos H.P.
      • Lohmander L.S.
      • Ekdahl C.
      • Beynnon B.D.
      Knee injury and osteoarthritis outcome score (KOOS) – development of a self-administered outcome measure.
      at 1 year. As key secondary outcomes, we used the other core outcomes as changes from baseline in the KOOS Physical function, Knee-related quality of life subscales, and the Participant's Global Assessment of the impact of OA on overall life assessed using a 100 mm visual analogue scale (higher is worse). Other secondary outcomes were changes from baseline in the Sports and Recreation, and Symptoms KOOS subscales, the treatment response according to the OMERACT-OARSI response criteria
      • Pham T.
      • Van Der Heijde D.
      • Lassere M.
      • Altman R.D.
      • Anderson J.J.
      • Bellamy N.
      • et al.
      Outcome variables for osteoarthritis clinical trials: the OMERACT-OARSI set of responder criteria.
      , the Intermittent and Constant Osteoarthritis Pain questionnaire (ICOAP)
      • Hawker G.A.
      • Davis A.M.
      • French M.R.
      • Cibere J.
      • Jordan J.M.
      • March L.
      • et al.
      Development and preliminary psychometric testing of a new OA pain measure--an OARSI/OMERACT initiative.
      with two domains; constant pain and intermittent pain experience (0–100 scale; 100 worst), and an average morning pain during the past week was assessed using a 100 mm visual analogue scale (higher is worse) after 1-year. For the 5 KOOS subscales, the minimal clinically important difference (MCID) was set to eight points as defined in the protocol and statistical analysis plan for the main trial
      • Bandak E.
      • Christensen R.
      • Overgaard A.
      • Kristensen L.E.
      • Ellegaard K.
      • Guldberg-Moller J.
      • et al.
      Exercise and education vs. saline injections for knee osteoarthritis: a randomised controlled equivalence trial.
      . For the 100 mm visual analogue scales (Patient Global Assessment and average morning pain) the MCID was set to 15 mm, and for the ICOAP it was set to 18 points
      • Bandak E.
      • Christensen R.
      • Overgaard A.
      • Kristensen L.E.
      • Ellegaard K.
      • Guldberg-Moller J.
      • et al.
      Exercise and education vs. saline injections for knee osteoarthritis: a randomised controlled equivalence trial.
      .
      Finally, the participants were asked about any treatments they had received for their knee OA since the end of the main trial (week 12) with the following options: Arthroscopy; Partial or total knee replacement; Exercise of the knee supervised by a physiotherapist; Exercise on their own; Injections; Massage or other manual treatment; No treatment received.

      Longer-term effect modification

      To confirm our previous short-term findings of effect modification
      • Henriksen M.
      • Nielsen S.M.
      • Christensen R.
      • Kristensen L.
      • Bliddal H.
      • Bartholdy C.
      • et al.
      Who are likely to benefit from the good life with osteoarthritis in Denmark (GLAD) exercise and education program? An effect modifier analysis of a randomised controlled trial.
      we subgrouped the study participants based on a range of baseline variables: BMI ≥30 kg/m2, swollen study knee upon palpation
      • Maricar N.
      • Callaghan M.J.
      • Parkes M.J.
      • Felson D.T.
      • O'Neill T.W.
      Interobserver and intraobserver reliability of clinical assessments in knee osteoarthritis.
      , bilateral radiographic tibiofemoral OA (K–L grade ≥ 2 in both knees), sports participation as a young adult (20ies), biological sex (male/female), age (using the median: 68.7 years), radiographic disease severity in study knee (K–L grade 4 vs 2 or 3), regular use of analgesics (paracetamol and ibuprofen), presence of constant pain (score >0 on the constant pain subscore of the ICOAP questionnaire), and presence of intermittent pain (score >0 on the intermittent pain ICOAP subscore). Finally, the participants were classified according to their a priori treatment preference at inclusion (before randomization). The participants were asked which of the interventions they would prefer if they could choose, for which the participants could choose between ‘GLAD’, ‘Saline’, or ‘Indifferent’. The preference did not affect the subsequent random allocation, which the participants were informed about.

      Statistical analyses

      The statistical analyses were performed according to an a priori statistical analysis plan that was written and closed before the analyses were commenced (see Supplement). The primary analyses were performed using the intention-to-treat population (ITT); patients were assessed and analysed as members of their randomized groups, irrespective of adherence to the treatments. Continuous outcomes were analysed as a change from baseline using repeated measures, mixed linear models, with fixed effect factors for group and time (including all timepoints to respect the ITT principle) and the corresponding interaction, while adjusting for baseline values (to increase precision) and the stratification factors (as part of the design). We included participant as random effect (random intercept with standard variance component covariance structure) and did not include random slope for time. A spatial Gaussian covariance structure was used to model the repeated measures covariance structure. For the primary analysis, missing data were not replaced but handled implicitly by the mixed linear models under the assumption that data were missing at random
      • Detry M.A.
      • Ma Y.
      Analyzing repeated measurements using mixed models.
      . Results are reported as least squares means and standard errors (SE), and differences between least squares means are reported with two-sided 95% confidence intervals (CI). No explicit adjustments for multiplicity were applied, rather the secondary outcome measures were analysed in a prioritized order (see Supplement).
      Sensitivity analyses were performed for the primary and key secondary outcomes at the 1-year follow-up, consisting of analysis of covariance with a baseline observation carried forward imputation of missing data (assuming nonignorable pattern of missingness) and a repetition of the primary analyses on the per-protocol population predefined as participants in both groups who did not have any major protocol deviation in the first 9 weeks of the trial (as defined in the main trial report
      • Bandak E.
      • Overgaard A.F.
      • Kristensen L.E.
      • Ellegaard K.
      • Guldberg-Moller J.
      • Bartholdy C.
      • et al.
      Exercise therapy and patient education versus intra-articular saline injections in the treatment of knee osteoarthritis: an evidence-based protocol for an open-label randomised controlled trial (the DISCO trial).
      ). Major protocol violations were defined as violations with direct bearing on the primary outcome (KOOS pain at week 9) and included lack of primary outcome assessment, non-adherence (defined as <75% of exercise/education sessions and 3 of 4 OLP injections), use of prohibited concomitant therapies during the initial 9 weeks of the trial (opioids, glucocorticoids, injection therapy outside protocol, non-pharmacological treatments outside protocol, surgery). In further post hoc sensitivity analyses, the primary analyses of primary and key secondary outcomes were repeated on a population consisting of participants who did not report any cross-over from the end of trial (week 12) to the 1-year follow-up, i.e., participants in the GLAD group that did not receive injections (of any kind) and participants in the OLP group who did not exercise (either supervised or on their own).
      For the subgroup analyses
      • Christensen R.
      • Bours M.J.L.
      • Nielsen S.M.
      Effect modifiers and statistical tests for interaction in randomized trials.
      , we took a conservative analytical approach in an attempt to avoid chance findings and due to the exploratory nature of the analyses: Missing outcome data (KOOS pain) at 1-year was replaced with the conservative baseline KOOS pain value assuming nonignorable missingness. The analyses of the potential effect modifiers focused only at the year 1 observation (i.e., without the repeated measurements at weeks 0–9, and 12) and were done using analysis of covariance models with group (GLAD vs OLP) and the moderator (with two levels) as main effects together with their interaction and the baseline KOOS pain value as a covariate. From these models, any group difference in the change from baseline in KOOS pain after 1 year between subgroups of participants based on the presence of the potential effect modifiers was estimated together with the associated 95% confidence interval (and the P-value) corresponding to the test of the hypothesis of no interaction between group and treatment modifier
      • Christensen R.
      • Bours M.J.L.
      • Nielsen S.M.
      Effect modifiers and statistical tests for interaction in randomized trials.
      . For sensitivity purposes, we repeated the subgroup analysis using a mixed linear model with implicit handling of missing data (i.e., no imputation of missing outcome data assuming missingness at random). All analyses were performed using the statistical software SAS version 9.4 (SAS Institute Inc., Cary, NC, USA).

      Results

      The trial flow is illustrated in Fig. 1. Of the 544 screened patients, 206 underwent randomization; 102 were assigned to GLAD and 104 to OLP. At the 1-year follow-up, 69 participants (33.5%) were lost (39 [38.2%] GLAD; 30 [28.8%] OLP) (Fig. 1). The baseline characteristics of the two groups were similar for age, sex, BMI, radiographic disease severity, and primary and secondary outcomes (Table I). The baseline characteristics of the participants who were lost to follow-up at 1 year were comparable to those of the participants who provided data at year 1 (Supplement Table S1).
      Fig. 1
      Fig. 1Study flow chart. The per-protocol population was defined based on protocol adherence in the initial 9 weeks of the trial (see text for details).
      Table IDemographics and Baseline Characteristics in the intention to treat population
      GLADOLP
      n = 102n = 104
      Demographics
      Age, years70.1 (8.3)66.7 (8.3)
      Age, older than median, n(%)59 (57.8%)44 (42.3%)
      Female sex, n(%)45 (44.1%)49 (47.1%)
      Body mass, kg80.7 (14.2)81.5 (13.9)
      Height, cm172.0 (9.5)172.1 (9.5)
      Body mass index, kg/m227.2 (3.7)27.4 (3.6)
      Radiographic disease severity (K/L grade)
      2, n(%)25 (24.5%)31 (29.8%)
      3, n(%)36 (35.3%)30 (28.9%)
      4, n(%)41 (40.2%)43 (41.4%)
      Stratification factors
      Body mass index ≥ 30, n(%)25 (24.5%)25 (24.0%)
      Swollen study knee, n(%)35 (34.3%)37 (35.6%)
      Bilateral tibiofemoral OA (K/L ≥ 2), n(%)92 (90.2%)93 (89.4%)
      Active as a young adult, n(%)66 (64.7%)68 (65.4%)
      Core outcomes
      KOOS pain score, 0–100
      Primary outcome measure.
      56.3 (14.9)57.6 (13.1)
      KOOS physical function score, 0–10065.7 (15.0)67.8 (14.7)
      KOOS quality of life score, 0–10039.7 (15.5)40.8 (14.6)
      Patient global assessment, VAS 0–10061.4 (20.9)59.2 (20.5)
      Other outcomes
      KOOS symptoms score, 0–10064.0 (17.1)62.8 (16.3)
      KOOS sports & recreation score, 0–10035.3 (21.3)31.8 (19.6)
      Morning pain, VAS 0–10044.7 (25.4)44.5 (23.4)
      ICOAP constant pain score, 0–10023.6 (28.4)15.4 (23.8)
      ICOAP intermittent pain score, 0–10040.9 (22.4)42.9 (18.1)
      ICOAP total score, 0–10033.0 (19.2)30.4 (15.0)
      Other potential effect modifiers
      ICOAP constant score of 0, n(%)47 (46.1%)35 (33.7%)
      ICOAP intermittent score of 0, n(%)89 (87.3%)98 (94.2%)
      Analgesics use (paracetamol or ibuprofen), n(%)34 (33.3%)43 (41.4%)
      Treatment preference
      Missing data from 13 participants (GLAD 8; IA saline 5).
      GLAD, n(%)37 (36.3%)27 (26.0%)
      IA Saline, n(%)33 (32.4%)46 (44.2%)
      Indifferent, n(%)24 (23.5%)26 (25.0%)
      Data is mean (standard deviation) unless otherwise specified.
      VAS: visual analogue scale. KOOS: knee injury and osteoarthritis outcome score. ICOAP: intermittent and constant osteoarthritis pain questionnaire. K/L: Kellgren Lawrence radiographic disease severity grading. GLAD: GOOD LIFE with osteoArthritis in Denmark. IA: intra-articular.
      Primary outcome measure.
      Missing data from 13 participants (GLAD 8; IA saline 5).
      Both groups showed minor improvements in the primary outcome after 1 year (Table II). However, for the primary outcome, the mean difference between the two groups was 1.5 KOOS pain points that did not reach statistical significance (test for superiority, P = 0.48) and the two-sided 95% CI (−2.6 to 5.5) excluded clinically relevant differences over the course of the 1-year follow-up (Table II and Fig. 2(A)). Similarly, there were no significant group differences in the other core outcomes (Table II and Fig. 2(B)) and the other secondary outcomes over the 1-year follow-up, and the 95% CI excluded clinically relevant differences (Table II).
      Table IIChange from baseline in primary and secondary outcomes at 1 year in the intention to treat population
      GLAD (N = 102)OLP (N = 104)Estimated treatment difference
      LS mean (SE)LS mean (SE)Mean difference (95% CI)P-value
      Primary outcome
      Change in KOOS pain score – score8.4 (1.8)7.0 (1.7)1.5 (−2.6 to 5.5)0.48
      Key secondary outcomes
      Change in KOOS function score2.1 (1.8)3.1 (1.7)−1.1 (−5.0 to 2.8)0.56
      Change in KOOS quality of life score5.1 (1.8)4.0 (1.7)1.0 (−3.1 to 5.2)0.62
      Change in PGA – VAS (mm)−12.9 (3.2)−11.4 (2.9)−1.6 (−8.8 to 5.6)0.66
      Other secondary outcomes
      Change in KOOS sports and recreation – score2.0 (2.4)3.8 (2.3)−1.8 (−7.2 to 3.6)0.51
      Change in KOOS symptoms – score−4.5 (1.9)−5.3 (1.8)0.9 (−3.6 to 5.3)0.39
      OMERACT-OARSI responders – no. (%)
      For the dichotomous outcome OMERACT-OARSI responders, a simplistic non-responder imputation technique was used to handle missing data (assuming non-response).
      21 (20.6%)18 (17.3%)OR: 1.25 (0.62–2.55)0.53
      Change in average morning pain – VAS (mm)−7.9 (2.9)−8.2 (2.7)0.4 (−6.3 to 7.0)0.91
      Change in ICOAP total score−8.9 (2.1)−7.9 (1.9)−1.0 (−5.8 to 3.8)0.69
      Change in ICOAP constant pain score−8.2 (2.9)−3.9 (2.7)−4.3 (−11.0 to 2.4)0.21
      Change in ICOAP intermittent pain score−8.9 (2.7)−11.0 (2.5)2.1 (−4.1 to 8.3)0.50
      Values are least-squares means (standard error) unless otherwise stated and based on repeated measures mixed linear models, where missing data for continuous outcomes are modelled implicitly.
      KOOS: knee injury and osteoarthritis outcome score.
      PGA: patient global assessment.
      VAS: visual analogue scale. CI: 95% confidence interval. OR: odds ratio.
      For the dichotomous outcome OMERACT-OARSI responders, a simplistic non-responder imputation technique was used to handle missing data (assuming non-response).
      Fig. 2
      Fig. 2A: Trajectories for the primary efficacy outcome measure (i.e., KOOS pain) in the ITT population. Based on repeated measures mixed linear models, where missing data is modelled implicitly. Error bars indicate standard error of the estimate. B: Forest plot illustrating the contrast between GLAD and Open-Label Placebo (OLP) after 1 year in the improvements from baseline in the core outcomes for the intention-to-treat population. Error bars indicate 95% confidence interval.
      The distributions of the types of treatments received since the final clinical trial visit (at week 12) were similar in both groups (Table III). In the GLAD group, 24 participants (23.5%) reported that they had not received any treatment, whereas 40 participants (38.5%) in the OLP group reported no treatments. The risk difference was −0.15 (95% CI −0.27 to −0.02). In the GLAD group 27 participants (26.5%) had received 1 type of treatment, and 6 (5.9%) had received 2 treatment types. In the OLP group 24 participants (23.0%) had received 1 type of treatment, and 8 (7.7%) had received 2 treatment types.
      Table IIITreatments received from the last clinical trial assessment (week 12) to the 1-year follow-up
      GLAD (N = 102)OLP (N = 104)Risk difference (95% CI)
      No treatment received, n(%)24 (23.5%)40 (38.5%)−0.15 (−0.27 to −0.02)
      Arthroscopy, n(%)0 (0%)1 (1.0%)−0.01 (−0.03 to 0.01)
      Partial or total knee replacement, n(%)2 (2.0%)4 (3.8%)−0.02 (−0.06 to 0.03)
      Exercise of the knee supervised by a physiotherapist, n(%)4 (3.9%)5 (4.8%)−0.01 (−0.06 to 0.05)
      Exercise on their own, n(%)26 (25.5%)21 (20.2%)0.05 (−0.06 to 0.17)
      Injections, n(%)5 (4.9%)6 (5.8%)−0.01 (−0.07 to 0.05)
      Massage or other manual treatment, n(%)5 (4.9%)3 (2.9%)0.02 (−0.03 to 0.07)
      Missing responses, n(%)44 (43.1%)32 (30.8%)0.12 (−0.01 to 0.25)
      In the exploratory subgroup analyses (Fig. 3), the participants who used analgesics at baseline seemed to benefit from the GLAD program over OLP at the 1-year follow-up, compared to those who did not use analgesics at baseline. The subgroup difference was 9.9 KOOS pain points (95% CI 2.4 to 17.4; P = 0.0099) and potentially clinically relevant. Also, participants with a priori preference for the GLAD program might potentially benefit from the GLAD program after 1 year compared to participants with preference for OLP with a subgroup difference of −8.5 KOOS pain points (95% CI −17.3 to 0.4) that did not reach statistical significance (P = 0.0599) (Fig. 3).
      Fig. 3
      Fig. 3Forest plot of the treatment effect (GLAD vs open-label placebo (OLP)) on the primary outcome change from baseline in the KOOS pain subscale after 1 year across subgroups based on dichotomised baseline information (effect modifiers) in the ITT population. Analysed using analysis of covariance with missing outcome data (KOOS pain) at year 1 replaced with the baseline value.
      The pre-specified sensitivity analyses confirmed the robustness of the primary analyses (see Supplement Tables S2 and S3) and the subgroup analyses (see Supplement Fig. S1). The post hoc analyses of the non-cross-over population also confirmed the primary analyses showing statistically non-significant group differences in the primary and key secondary outcomes with 95% CI excluding the possibility of clinically relevant differences (Supplement Table S4).

      Discussion

      In this extension of our recently published trial
      • Bandak E.
      • Christensen R.
      • Overgaard A.
      • Kristensen L.E.
      • Ellegaard K.
      • Guldberg-Moller J.
      • et al.
      Exercise and education vs. saline injections for knee osteoarthritis: a randomised controlled equivalence trial.
      we found no differences between the GLAD program and OLP for symptomatic patients with knee OA in any of the outcome measures at the 1-year follow-up. No evidence could be found to support the prevailing idea that the GLAD program, including encouragement to continue exercise, has longer-term beneficial effects that exceed those of OLP for all patients with symptomatic knee OA. The results rather suggest that only patients who use analgesics at baseline may seem to have a sustainable and clinically relevant beneficial effect of GLAD over OLP in the longer-term, confirming the short-term results
      • Henriksen M.
      • Nielsen S.M.
      • Christensen R.
      • Kristensen L.
      • Bliddal H.
      • Bartholdy C.
      • et al.
      Who are likely to benefit from the good life with osteoarthritis in Denmark (GLAD) exercise and education program? An effect modifier analysis of a randomised controlled trial.
      .
      A widely held assertion is that the effect of GLAD should be assessed in the long term as this is more relevant for a chronic condition such as knee OA. This is based on the rationale that the patients are encouraged as a part of the GLAD program to continue to exercise on their own after the completion of the initial 8 weeks GLAD program, and that the initial effect in an observational study is sustainable in the long term
      • Skou S.T.
      • Roos E.M.
      Good Life with osteoArthritis in Denmark (GLA:D): evidence-based education and supervised neuromuscular exercise delivered by certified physiotherapists nationwide.
      . The effect of intra-articular saline has been suggested to last for up to 6 months
      • Saltzman B.M.
      • Leroux T.
      • Meyer M.A.
      • Basques B.A.
      • Chahal J.
      • Bach Jr., B.R.
      • et al.
      The therapeutic effect of intra-articular normal saline injections for knee osteoarthritis: a meta-analysis of evidence level 1 studies.
      , but there is no proof of longer-term effects. Therefore, it was reasonable to hypothesize that GLAD would be superior to OLP after 1 year. Our main trial
      • Bandak E.
      • Christensen R.
      • Overgaard A.
      • Kristensen L.E.
      • Ellegaard K.
      • Guldberg-Moller J.
      • et al.
      Exercise and education vs. saline injections for knee osteoarthritis: a randomised controlled equivalence trial.
      showed that GLAD and OLP were equivalent in the short term (9–12 weeks), and the present 1-year results corroborate the short-term findings. Further, the present results show a remarkable attrition from the short-term effects
      • Bandak E.
      • Christensen R.
      • Overgaard A.
      • Kristensen L.E.
      • Ellegaard K.
      • Guldberg-Moller J.
      • et al.
      Exercise and education vs. saline injections for knee osteoarthritis: a randomised controlled equivalence trial.
      in several of the secondary outcomes – in particular, the KOOS symptom subscale (Table II).
      Despite the encouragement to continue exercise after termination of GLAD program, only 30 participants (29.4%) self-reported doing so. This poor carryover calls for means to improve adherence to continued exercise, e.g., via supervised booster sessions, although this has been sparsely studied
      • Nicolson P.J.A.
      • Bennell K.L.
      • Dobson F.L.
      • Van Ginckel A.
      • Holden M.A.
      • Hinman R.S.
      Interventions to increase adherence to therapeutic exercise in older adults with low back pain and/or hip/knee osteoarthritis: a systematic review and meta-analysis.
      . In the OLP group, 26 participants reported having exercised after the initial 12 weeks main trial phase. This “cross-over” from OLP to exercise did not, however, have a significant impact on our results as the sensitivity analysis of the non-cross-over population did not differ from the primary ITT results. However, it should be noted that 30–40% of the participants did not respond to the 1-year questionnaire about treatments received, and therefore the actual cross-over-population may be larger.
      The longer-term effect modification by the baseline use of analgesics corroborates the short-term results
      • Henriksen M.
      • Nielsen S.M.
      • Christensen R.
      • Kristensen L.
      • Bliddal H.
      • Bartholdy C.
      • et al.
      Who are likely to benefit from the good life with osteoarthritis in Denmark (GLAD) exercise and education program? An effect modifier analysis of a randomised controlled trial.
      , and this interaction has not been investigated by others. This makes it difficult to confirm from the literature and it is not possible to explain the underlying mechanisms based on the present data. However, it could be speculated that patients taking analgesics have a preconception that their pain can be treated, and that the GLAD program provides them with the means to do so, although the education does not include details on how to use analgesics. As previously described
      • Henriksen M.
      • Nielsen S.M.
      • Christensen R.
      • Kristensen L.
      • Bliddal H.
      • Bartholdy C.
      • et al.
      Who are likely to benefit from the good life with osteoarthritis in Denmark (GLAD) exercise and education program? An effect modifier analysis of a randomised controlled trial.
      the stratification of patients based on our data is very easily implemented in clinical practice as it related to a short interview about regular usage of NSAIDS or paracetamol. The a priori preference for GLAD was not a robust treatment modifier in the longer-term but with a similar precision as in the short term results
      • Henriksen M.
      • Nielsen S.M.
      • Christensen R.
      • Kristensen L.
      • Bliddal H.
      • Bartholdy C.
      • et al.
      Who are likely to benefit from the good life with osteoarthritis in Denmark (GLAD) exercise and education program? An effect modifier analysis of a randomised controlled trial.
      . Patients' preferences are also easy to assess in a clinical setting. The presence of constant pain at baseline seems to modify the short-term effect
      • Henriksen M.
      • Nielsen S.M.
      • Christensen R.
      • Kristensen L.
      • Bliddal H.
      • Bartholdy C.
      • et al.
      Who are likely to benefit from the good life with osteoarthritis in Denmark (GLAD) exercise and education program? An effect modifier analysis of a randomised controlled trial.
      , but the present results show that it does not modify the 1-year effect. This could be speculated to be due to a suggested association between pain variability and placebo response
      • Treister R.
      • Honigman L.
      • Lawal O.D.
      • Lanier R.K.
      • Katz N.P.
      A deeper look at pain variability and its relationship with the placebo response: results from a randomized, double-blind, placebo-controlled clinical trial of naproxen in osteoarthritis of the knee.
      that may mainly be at play in the short-term.
      The major strengths and limitations of our trial have been elaborated on previously
      • Bandak E.
      • Christensen R.
      • Overgaard A.
      • Kristensen L.E.
      • Ellegaard K.
      • Guldberg-Moller J.
      • et al.
      Exercise and education vs. saline injections for knee osteoarthritis: a randomised controlled equivalence trial.
      , but this 1 year extension study is mainly limited by a relatively large attrition of 30–40%. On the other hand, our 1-year retention is similar to the real-word GLAD registries as the clinical GLAD registry also has 30–40% attrition at their 1-year follow-up
      • Skou S.T.
      • Roos E.M.
      Good Life with osteoArthritis in Denmark (GLA:D): evidence-based education and supervised neuromuscular exercise delivered by certified physiotherapists nationwide.
      ,
      • Skou S.T.
      • Bricca A.
      • Roos E.M.
      The impact of physical activity level on the short- and long-term pain relief from supervised exercise therapy and education: a study of 12,796 Danish patients with knee osteoarthritis.
      ,
      • Pihl K.
      • Roos E.M.
      • Taylor R.S.
      • Gronne D.T.
      • Skou S.T.
      Associations between comorbidities and immediate and one-year outcomes following supervised exercise therapy and patient education - a cohort study of 24,513 individuals with knee or hip osteoarthritis.
      GLAD. The appropriateness of OLP as a control for the GLAD program has been questioned as the saline injections are claimed to be associated with other contextual factors and greater placebo responses than GLAD
      • Kloppenburg M.
      • Rannou F.
      • Berenbaum F.
      What evidence is needed to demonstrate the beneficial effects of exercise for osteoarthritis?.
      , although the placebo response magnitude in GLAD has not been estimated previously. While the contextual factors associated with GLAD and OLP in our study are not all the same, some are shared. These include attention given by clinicians, the provision of an actual intervention, and the positive messages about the expected benefit given in relation to the intervention deliveries. Hence, our results reflect a less biased estimate of the effects of GLAD than those arising from either no-attention control group comparators, or observational studies of GLAD without control groups. The 18-month START trial applied an attention control group as comparator to high and low-intensity muscle strengthening exercises and found no group differences in knee OA pain improvements
      • Messier S.P.
      • Mihalko S.L.
      • Beavers D.P.
      • Nicklas B.J.
      • DeVita P.
      • Carr J.J.
      • et al.
      Effect of high-intensity strength training on knee pain and knee joint compressive forces among adults with knee osteoarthritis: the START randomized clinical trial.
      , which supports our results. Further, a systematic review showed that exercise therapy with or without other physical therapy interventions was not superior to placebo for pain and function in the longer-term (approximately 6 months)
      • Dean B.J.F.
      • Collins J.
      • Thurley N.
      • Rombach I.
      • Bennell K.
      Exercise therapy with or without other physical therapy interventions versus placebo interventions for osteoarthritis – systematic review.
      .
      There are also limitations related to our subgroup analyses as the study was not specifically designed for these, and there was no formal subgroup power calculation. However, the analyses were planned a priori and corroborate the short-term assertions about analgesics and treatment preference as possible effect modifiers. However, the subgroup results need to be replicated in future studies – not only for the GLAD program but also for other exercise and education interventions.

      Conclusion

      In conclusion, the results of this randomized, OLP-controlled trial with a 1-year follow-up showed that GLAD and OLP both provided minor benefit with no group difference in patients with knee OA. The results indicate however, that there may be beneficial effects of GLAD over OLP for a subgroup of patients with knee OA who take analgesics at baseline. These results require confirmation given the considerable loss to follow-up and exploratory nature of the study.

      Contributions

      E. Bandak, R. Christensen, H. Bliddal, L.E. Kristensen, and M. Henriksen conceived and designed the trial and the protocol that was reviewed and adjusted following important scientific and practical advice from K. Ellegaard, C. Bartholdy, D.J. Hunter, and R. Altman. E. Bandak was the trial manager. M. Henriksen and R. Christensen did statistical analyses. J. Guldberg-Møller and H. Bliddal had clinical responsibility. M. Henriksen drafted the first version of the manuscript. All authors read and critically revised the manuscript, and all authors approved the final manuscript and submission of the Article. E. Bandak and M. Henriksen had full access to all data in the trial and take responsibility for the data and the accuracy of the data analysis. M. Henriksen is the guarantor.

      Declaration of competing interest

      All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/and declare: support for the submitted work as detailed above; no financial relationships with any organisations that might have an interest in the submitted work in the previous 3 years; no other relationships or activities that could appear to have influenced the submitted work.

      Funding

      This study was supported by grants from The Lundbeck Foundation, The Danish Physiotherapists Association, and Aase og Ejnar Danielsens Fund. The Parker Institute, Bispebjerg and Frederiksberg Hospital, is supported by a core grant from the Oak Foundation (OCAY-18-774-OFIL).
      The funders had no role in the design and conduct of the study; collection, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication.

      Acknowledgements

      We thank the participants for their involvement in the study. We thank the patient research partners, intervention physiotherapists, the research assistants, the Parker Institute secretariat and data management team, and all other staff engaged in the project for their important contributions.

      Appendix A. Supplementary data

      The following are the Supplementary data to this article.

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