Supplementary Appendix

Transcription

1 Supplementary Appendix This appendix has been provided by the authors to give readers additional information about their work. Supplement to: Skou ST, Roos EM, Laursen MB, et al. A randomized, controlled trial of total knee replacement. N Engl J Med 2015;373: DOI: /NEJMoa (PDF updated February 1, 2016.)

2 SUPPLEMENTARY APPENDIX FOR A Randomized, Controlled Trial of Total Knee Replacement Søren T. Skou, PT, PhD Ewa M. Roos, PT, PhD Mogens B. Laursen, MD, PhD Michael S. Rathleff, PT, PhD Lars Arendt-Nielsen, PhD, DMSc Ole Simonsen, MD, DMSc Sten Rasmussen MD, PhD 1

3 TABLE OF CONTENTS BLINDED REVIEW OF THE PRIMARY ENDPOINT RESULTS FROM THE STUDY... 3 DETAILS OF THE NON-SURGICAL TREATMENT... 7 Exercise... 7 Education Diet Insoles Pain medication FIGURES Fig. S1. Mean subscale scores for the five KOOS subscales TABLES Expanded Table 1. Baseline characteristics Expanded Table 3. Adverse Events Intention-to-treat results Table S1. Usage of pain medication at 12 months Table S2. Improvements of at least 15% and Number Needed to Treat (NNT) Per-protocol results Table S3. Outcome at 12 months Table S4. Usage of pain medication at 12 months Table S5. Adverse Events Table S6. Improvements of at least 15% and Number Needed to Treat (NNT) As-treated analysis Table S7. Adverse Events associated with treatment Treatment-related variables Table S8. Compliance Table S9. Other treatments or consultations during follow up REFERENCES

4 BLINDED REVIEW OF THE PRIMARY ENDPOINT RESULTS FROM THE STUDY: A Randomized Controlled Trial of Total Knee Replacement As described in the statistical analysis plan published before finishing the data collection and analyzing the data 1, the treatments were coded treatment A (Group A) and treatment B (Group B) by the database manager, who delivered the blinded data to the statistician in a data collection form. The statistician then conducted the primary and secondary endpoint intention-to-treat analyses (baseline to 12 months) before presenting the results to the first author, who was responsible for presenting it to the study group. Finally, the results underwent blinded interpretation by the study group (identical to the persons signing this document) before the treatment code was unveiled. This document presents the blinded interpretation of the results with one version assuming that Group A was the group receiving a total knee replacement (TKR) in addition to the 12-week nonsurgical treatment (neuromuscular exercise, patient education, weight loss (if needed), insoles and medicine) and the other version assuming that Group A was the group receiving the 12-week nonsurgical treatment alone. To keep the blinding of group allocation, neither adverse events nor possible crossovers from one group of randomization to the other were analyzed. Once the blinding was broken, both these aspects were analyzed and results taken into account for the overall interpretation of study results. 1 The statistical analysis plan is available from: 3

5 Results from the intention-to-treat analysis of the primary endpoint Between-group differences There was a statistically significant difference of 16.5 (crude) or 15.8 (adjusted) units between groups in the average score of four of the five subscale scores from the Knee Injury and Osteoarthritis Outcome Score (KOOS4) covering Pain, other Symptoms, Function in daily living (ADL), and knee-related Quality of Life (QOL). Group A had a median improvement of 72.9% from baseline to 12 months follow-up while Group B improved 31.5% in the KOOS4-score with a number needed to treat (NNT) of 5.7 for one patient to improve 15% in Group A compared to Group B. Results from the secondary intention-to-treat analysis Between-group differences Between-groups differences in change in the five KOOS subscales Pain, Symptoms, ADL, Sport/Rec and QOL, time to complete the Timed Up and Go test, time to complete the 20-meter walk test, the EQ-5D index, and EQ VAS supported the findings from the primary analysis showing statistically significant differences between groups in favor of Group A. Between-group change in body weight showed a statistically significant difference in favor of Group B, while usage of pain medication was not significantly different between groups. Within-group changes Both groups improved significantly in all primary and secondary outcomes with the exception of usage of pain medication, where Group B did not decrease their pain medication usage, and of body weight where Group A did not reduce their body weight. 4

6 Interpretation 1: Group A received a TKR in addition to the non-surgical treatment Our results show that TKR in addition to a combined non-surgical treatment program is more efficacious than the non-surgical treatment program alone in patients with knee osteoarthritis (OA) eligible for TKR in terms of self-reported pain, other symptoms, function in daily living, function in sport and recreation, quality of life, health status and physical performance (walking speed and timed up and go tests). The between-group differences were substantial and considered clinically relevant for several outcomes. The number needed to treat (NNT), defined as the number of patients needed to treat for one person to improve 15%, ranged from 2.4 (function in daily living) to 10.4 (quality of life) for the outcomes to be statistically significant in favor of TKR in addition to the non-surgical treatment program. This is the first study to investigate the effect of a TKR in addition to non-surgical treatment compared with non-surgical treatment alone. It provides high-quality evidence that TKR in combination with non-surgical treatment is superior to non-surgical treatment alone in improving symptoms after 1 year in patients with knee OA eligible for TKR. Both groups improved substantially in pain, function in daily living and quality of life, highlighting that a non-surgical treatment program is also efficacious in those eligible for a TKR. However, adding a TKR to this treatment program will improve the outcome further. Since the results are unambiguous in favor of TKR in addition to the non-surgical treatment program, this confirms our primary hypothesis described in the published study protocol 2. 2 Skou, ST ; Roos, EM; Laursen, MB; Rathleff, MS; Arendt-Nielsen, L; Simonsen, O; Rasmussen, S. Total knee replacement plus physical and medical therapy or treatment with physical and medical therapy alone: A randomised controlled trial in patients with knee osteoarthritis (the MEDIC-study). BMC Musculoskeletal Disorders 2012;13(1):67. 5

7 Interpretation 2: Group A received the non-surgical treatment alone Our results show that a non-surgical treatment program alone is more efficacious in reducing pain and improving function in daily living and quality of life than TKR in addition to the non-surgical treatment program in patients with knee OA eligible for a TKR. The results indicate that patients with knee OA eligible for TKR on average have an inferior outcome if a TKR is added to the nonsurgical treatment program, suggesting that adding a surgical treatment has a negative effect on their 12-month outcome. Since a non-surgical treatment program alone is more efficacious, cheaper and associated with fewer adverse events and no operative risks, TKR seems only applicable in a sub-group of patients with knee OA not able to participate in non-surgical treatment. Since the results are unambiguous in favor of the non-surgical treatment program alone, this means that our primary hypothesis cannot be confirmed. 6

8 DETAILS OF THE NON-SURGICAL TREATMENT Exercise The NEuroMuscular EXercise training program (NEMEX-TJR), previously demonstrated to be feasible in patients with moderate to severe knee OA assigned for TKR, 1 was given in 1-hour, group-based, supervised sessions twice weekly for 12 weeks. After 12 weeks of exercise, the patients underwent a transition period of 8 weeks, where the exercise program was increasingly performed at home. After the 12-week intervention period, and prior to the 12-month follow-up, a physiotherapist contacted the patients monthly by telephone to support their exercise adherence. The exercise program was previously published in: NEMEX-TJR training program: Ageberg E. et al. Feasibility of neuromuscular training in patients with severe hip or knee OA: The individualized goal-based NEMEX-TJR training program. BMC Musculoskeletal Disorders,

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16 Education The aim of the education was to encourage the patients to actively engage in the management of their knee OA. The two 60-min educational sessions, delivered in classes by the same physiotherapists delivering the exercise, was identical to the education given in the implementation initiative Good Life with osteoarthritis in Denmark (GLA:D) to more than 6,000 OA patients to date 2. The first session focused on the diagnosis, the etiology, symptoms and risk factors of knee OA with a short introduction to recommended treatment options. The second session gave an indepth description of treatment, with the main focus on exercise and physical activity, as well as guidance in self-help tools. The physiotherapist facilitated discussion and interaction among the patients during both sessions. Furthermore, all patients received a DVD containing the educational elements given in the education. Diet Patients with a Body Mass Index 25 at baseline participated in a 12-week dietary weight loss program (four 30-60min sessions) aimed at reducing body weight by at least 5% and sustaining that weight throughout the study period. The 5% reduction in body weight is sufficient to improve symptoms 3. The dietary intervention was delivered by the project dietician and was based on principles from Motivational Interviewing with instruction and guidance in relation to the diet of the individual patient. The patient s readiness to change was evaluated and formed the basis of the dietary intervention focusing on motivating the patient to take action on changing their diet 4. Based on the needs of the individual patient, this was supported by diet plans, written guides, recipes, etc. Session 1 took place in the first week of the intervention (60 min), while session 2-4 took place 3, 6 and 11 weeks after the start of the intervention (30 min). Patients participating in the dietary 15

17 intervention were telephoned twice (30 min calls) by the dietician to support their dietary intervention adherence. Insoles The patients received full-length Formthotics Original Dual Medium (perforated) insoles with medial arch support (Foot Science International, Christchurch, New Zealand) individually fitted by the same physiotherapists delivering the exercise. Furthermore, a 4 lateral wedge was added to the insoles of patients with a knee lateral-to-foot position (the knee moves over or lateral to the 5th toe in three or more of five trials) tested with the valid and reliable Single Limb Mini Squat Test. 5 The patients were advised to use their insoles bilaterally in all shoes every day. The insoles were provided by Foot Science International. The company was not involved in the study in any way. Pain medication The patients were offered pain medication if the orthopedic surgeon considered it necessary for the patient to participate in the exercise program. 1g paracetamol four times, 400 mg ibuprofen three times, and 20 mg pantoprazol were prescribed to those patients daily. The patient s use of the medication was assessed by self-report. Every 3 weeks, an orthopedic surgeon renewed the prescription if needed. If the patient experienced pain relief during a three-week period, they were urged to contact the research physiotherapist and discuss whether to discontinue the use of pain medication. 16

18 FIGURES Fig. S1. Mean subscale scores for the five KOOS subscales Mean subscale scores (0-100; worst to best) at all time points for the subscales of Pain (A), other Symptoms (B), Function in daily living (ADL; C), Function in sport and recreation (Sport/Rec; D), and knee-related Quality of life (QOL; E) for the groups randomized to Total Knee Replacement (TKR) followed by a 12-week non-surgical treatment of exercise, education, dietary advice, insoles, and pain medication (the TKR + non-surgical group) or non-surgical treatment alone (non-surgical group). The error bars indicate 95% confidence intervals. 17

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21 TABLES Expanded Table 1. Baseline characteristics 1 Baseline characteristics Non-surgical TKR + non-surgical Women, n (%) 30 (60) 32 (64) Age (years), mean (SD) 67.0 (8.7) 65.8 (8.7) Weight (kg), mean (SD) 91.1 (16.1) 89.4 (21.9) Body Mass Index, mean (SD) 32.0 (5.8) 32.3 (6.2) Study knee, n (right, %) 23 (46) 24 (48) Bilateral knee pain, n (%) 17 (34) 18 (36) Duration of knee symptoms, n (%) 0-6 months 6 (12) 0 (0) 6-12 months 2 (4) 5 (10) 1-2 years 8 (16) 8 (16) 2-5 years 10 (20) 15 (30) 5-10 years 12 (24) 11 (22) More than 10 years 12 (24) 11 (22) Radiographic knee OA severity (Kellgren-Lawrence), n (%) Grade 2 5 (10) 7 (14) Grade 3 21 (42) 21 (42) Grade 4 24 (48) 22 (44) Charlson Comorbidity Index, n (%) (32) 23 (46) 1 20 (40) 16 (32) 2 3 (6) 6 (12) 3 or above 1 (4) 5 (10) 20

22 Living alone, n (%)* 8 (16) 18 (36) College education or equivalent, n (%) 25 (50) 23 (46) Employment status, n (%)* Working full-time or part-time 9 (18) 9 (18) Unemployed 0 (0) 0 (0) Sick leave 0 (0) 7 (14) Retired 41 (82) 34 (68) Prior treatment of knee OA, n (%) Exercise 1 (2) 2 (4) Passive treatments 3 7 (14) 5 (10) Paracetamol* 11 (22) 21 (42) NSAIDs 15 (30) 12 (24) Opioids and opioid-like drugs 6 (12) 9 (18) Have used pain medication in the last week, n (%) 29 (58) 33 (67) Cortisone injection 2 (4) 2 (4) Surgery Arthroscopic surgery including meniscectomy and 15 (30) 17 (34) debridement Other knee surgery 1 (2) 3 (6) KOOS scores KOOS (11.4) 47.4 (13.4) Pain 49.5 (13.1) 48.6 (17.5) Symptoms 58.3 (15.2) 54.0 (15.0) ADL 53.5 (14.2) 55.0 (17.0) Sport/Rec 16.7 (15.1) 18.0 (14.7) QOL 32.7 (13.3) 32.3 (15.3) 21

23 Functional performance, mean (SD) Time (s) for the Timed Up and Go test 8.6 (2.1) 9.4 (2.4) Time (s) for the 20-meter walk test 12.2 (2.6) 13.4 (3.7) EQ-5D, mean (SD) EQ-5D Index (0.147) (0.156) EQ VAS 66.8 (16.5) 66.3 (19.1) 1 The proportion living alone (p=0.02), employment status (p=0.02) and the proportion using paracetamol (p=0.03) were significantly different (p < 0.05; *) between groups at baseline. No other significant differences between groups were found at baseline. 2 Charlson Comorbidity Index is a sum score (ranging from 0 to 37) of 19 disorders each assigned a score of 1, 2, 3 or 6 based on the risk of dying associated with the disease. 6 3 Passive treatments included massage, stretching, acupuncture, short-wave therapy, therapeutic gold injection, therapeutic ultrasound, and manipulation. 22

24 Expanded Table 3. Adverse Events Adverse events 1 Non-surgical TKR + non-surgical P Value Number of events Serious events Site other than index knee Musculoskeletal Skin Gastrointestinal Other Subtotal Index knee During total knee replacement surgery 0 0 Postoperatively Stiffness leading to brisement forcé 1 3 Deep infection 0 1 Deep venous thrombosis requiring 0 3 anticoagulant treatment Supra-condylar femur fracture 0 1 Subtotal All serious events Non-serious events Sites other than index knee 6 Subtotal Index knee 23

25 Pain Swelling 2 8 Subjective instability 3 0 Decreased range of motion 1 6 Joint distortion 2 1 Other Subtotal All non-serious events This table includes all serious and non-serious adverse events that occurred during the 12-month study period, but which did not necessarily have a causal relationship with the treatment administered. Serious adverse events include those having the potential to significantly compromise the clinical outcome, result in significant disability or incapacity, requiring inpatient or outpatient hospital care, and those considered to prolong hospital care, to be life-threatening, or to result in death. Non-serious adverse events comprise all other adverse events. Categories for adverse events during surgery and postoperative adverse events were chosen on the basis of categories from the Danish Knee Arthroplasty Registry ( 2 In the TKR + non-surgical group this included pain in the opposite knee leading to TKR (n=3) and back pain leading to spinal fusion. 3 A melanoma. 4 Carcinoid tumor in the small intestine; abdominal pain with outpouching of the colon; and hiatal hernia. 5 In the non-surgical group, this included a cerebral thrombosis; coronary thrombosis; hospitalization due to suspicion of cerebral thrombosis caused by neurological symptoms in the legs; and metastatic breast cancer. In the TKR + non-surgical group, this included hospitalization due to depression and anxiety; malignant breast cancer (n=2); atrial fibrillation; leukemia; pneumonia; hospitalization due to retinal detachment; trauma to the cranium from a fall leading to hospitalization; and myelomatosis. 6 In the non-surgical group, this included serious illness in the family (n=2); lack of motivation/time (n=2); eye surgery; impaired balance; medication intake resulting in fatigue; advised by doctor to reduce the intensity of exercise due to hypertension; advised by doctor to exercise only once a week due to a lack of 24

26 leukocytes; a neuropathic wound on the foot; an abscess in the gluteal region; pain in the opposite knee; pain in the opposite knee with previous TKR; pain in the hip (n=2); hand/finger surgery/fracture (n=3); painful pes planus; sciatic nerve pain (n=2); low back pain (n=2); rib, head and hip pain following two falls; shortlasting restless legs; paresthesia of the foot; shoulder surgery due to rupture of m. supraspinatus; spinal stenosis; lateral ankle pain; pain in the hamstrings muscles; groin pain; Ankylosing Spondylitis; shoulder injury from a fall; muscle strain in the upper thigh; and plantar fasciitis. In the TKR + non-surgical group, this included lack of motivation/time; low haemoglobin percentage (n=2); abnormal swelling of the whole leg in the days after surgery; nausea (n=2); nerve pain; tranexamic acid given pre-surgery by mistake (unintended event); puncture of the synovial membrane during lateral release; mental unstability; impaired balance; loss of consciousness leading to a fall; lack of skin under the foot resulting in pain and limping; low back pain; hand surgery following fracture; increased need of insulin; short-lasting restless legs (n=3); Achilles tendinopathy; foot pain (n=4); ankle sprain (n=2); iliotibial band syndrome; swelling of the left foot; plantar fasciitis; pain in the opposite knee (n=2); arm pain; muscle cramps; quadriceps strain; back and hip pain following a fall; swelling of the foot; pain in the hamstrings muscle; short-lasting vertigo; reduced walking distance; and serious illness in the family. 7 In the non-surgical group, this included a sensation of the knee locking up; and calor and rubor around the knee. In the TKR + non-surgical group, this was soft tissue calcification; hospital care due to liquid oozing from the scar; superficial infection; bleeding from the wound; numbness around the scar; increased soreness around the knee; and pruritus around the knee. 25

27 Intention-to-treat results Table S1. Usage of pain medication at 12 months Outcome Non-surgical group (95 % CI) TKR + non-surgical group (95 % CI) Proportion of users of pain medication 1 (n non-surgical, n TKR+non-surgical) Baseline (50, 49) 0.58 (0.44 to 0.71) 0.67 (0.53 to 0.79) 12 months (49, 46) 0.41 (0.28 to 0.55) 0.26 (0.15 to 0.41) Risk ratio for taking pain medication at 12 months vs. baseline Adjusted estimate 2, (0.53 to 0.94) 0.39 (0.23 to 0.64) Risk ratio for taking pain medication at 12 months in the non-surgical group vs. the TKR + non-surgical group Adjusted estimate (0.87 to 2.85) User of pain medication was defined as a patient taking pain medication of any kind on a regular basis during the previous week. 2 The estimates were adjusted for site. 3 The crude estimate was similar to the adjusted estimate (data not shown) 26

28 Table S2. Improvements of at least 15% and Number Needed to Treat (NNT) Outcome Proportion improving at Proportion improving at NNTB (95% CI) (n non-surgical, n TKR+non-surgical) least 15% in non-surgical group (95% CI) least 15% in TKR + non-surgical group (95% CI) KOOS 4 from baseline to 1 yr 0.67 (0.53 to 0.79) 0.85 (0.71 to 0.93) 5.7 (2.9 to 143.2) (49, 46) Mean change in KOOS subscales score Pain (49, 46) 0.69 (0.55 to 0.81) 0.83 (0.69 to 0.91) 7.6 (NNTB 3.3 to to NNTH 27.0) Symptoms 0.45 (0.31 to 0.59) 0.85 (0.71 to 0.93) 2.5 (1.7 to 4.4) (49, 46) ADL 0.59 (0.45 to 0.72) 0.89 (0.76 to 0.96) 3.3 (2.2 to 7.4) (49, 46) Sport/Rec 0.65 (0.51 to 0.77) 0.89 (0.76 to 0.96) 4.2 (2.5 to 12.9) (49, 46) QOL 0.69 (0.55 to 0.81) 0.89 (0.76 to 0.96) 5.1 (2.8 to 24.9) (49, 46) 1 NNT was estimated using the formula 1/(TER - MER), TER being the event rate (proportion of responders, i.e., patients improving at least 15%) in the TKR + non-surgical group and MER the event rate in the nonsurgical group. 95% CIs were derived from the reciprocal transformation of the CIs for the difference in proportions. 7 CIs that include both positive and negative values can be difficult to understand and interpret. To address this, we used NNTB (NNT Benefit) and NNTH (NNT Harms) if the 95% CI included both positive and negative values (e.g. a 95% CI going from 5 to -10 would be NNTB 5 to to NNTH 10). 8 27

29 Per-protocol results Table S3. Outcome at 12 months 1 Outcome Improvement Improvement Between-Group Between-Group (number of data points non- in non-surgical in TKR + non- difference difference surgical, number of data group surgical group (crude) (adjusted) 3 points TKR+non-surgical) 2 (95% CI) (95% CI) (95% CI) (95% CI) Mean (months) follow-up after start of non-surgical (12.2 to 12.7) (11.9 to 12.3) treatment Primary endpoint: mean change in KOOS 4 from (10.8 to 25.3) (24.4 to 40.5) (-23.2 to -5.5) (-22.0 to -5.9) baseline to 1 yr (99, 103) Secondary Endpoints Mean change in KOOS subscales score Pain (99, 103) (11.4 to 29.3) (26.2 to 44.7) (-25.9 to -4.4) (-24.8 to -5.9) Symptoms (99, 103) (9.0 to 24.5) (17.8 to 32.2) (-17.6 to 1.0) (-15.3 to 1.7) ADL (99, 103) (8.4 to 25.0) (19.8 to 40.8) (-23.4 to -3.7) (-21.8 to -4.4) Sport/Rec

30 (98, 101) (9.1 to 30.9) (23.1 to 40.0) (-23.5 to 0.4) (-24.4 to -0.1) QOL (99, 103) (10.1 to 27.4) (28.4 to 49.0) (-30.9 to -9.0) (-30.6 to -10.4) Mean change in time (s) for the Timed Up and Go test (-2.3 to -0.8) (-3.0 to -1.7) (-0.0 to 1.6) (0.3 to 1.7) (97, 96) Mean change in time (s) for the 20-meter walk test (97, (-2.1 to -0.4) (-3.4 to -1.7) (0.2 to 2.4) (0.3 to 2.4) 97) Mean change in EQ-5D EQ-5D Index (99, 102) (0.059 to 0.198) (0.167 to 0.320) ( to ) ( to ) EQ VAS (98, 103) (2.0 to 17.9) (12.4 to 26.1) (-18.7 to 0.2) (-17.7 to -1.1) Mean weight change (kg) (84, 79) (-5.1 to -1.1) (-2.3 to 1.0) (-4.3 to -0.8) (-4.3 to -0.7) 1 The per protocol population was defined as those participating in the non-surgical treatment with at least 75% compliance with the exercise during the 12-week intervention period and who stayed in the treatment arm allocated by randomization during the 12 months. 2 n refers to the number of data points out of 100 in the non-surgical group and 104 in the TKR + nonsurgical group in each group (25 in the non-surgical group and 26 in the TKR + non-surgical group at baseline, 3, 6 and 12 months) 3 The results were adjusted for follow up (baseline, 3, 6, and 12 months), site (Frederikshavn, Farsoe), baseline values and interaction between follow-up and treatment arm. 4 Only for the 22 and 21 patients with a BMI 25 at baseline in the non-surgical group and the TKR + nonsurgical group, respectively. 29

31 Table S4. Usage of pain medication at 12 months 1 Outcome Non-surgical group (95 % CI) TKR + non-surgical group (95 % CI) Proportion of users of pain medication 2 (n non-surgical, n TKR+non-surgical) Baseline (25, 26) 0.52 (0.33 to 0.71) 0.69 (0.49 to 0.84) 12 months (25, 26) 0.44 (0.26 to 0.64) 0.27 (0.13 to 0.47) Risk ratio for taking pain medication at 12 months vs. baseline Adjusted estimate 3, (0.61 to 1.18) 0.39 (0.20 to 0.77) Risk ratio for taking pain medication at 12 months in the non-surgical group vs. the TKR + non-surgical group Adjusted estimate (0.78 to 3.79) The per protocol population was defined as those participating in the non-surgical treatment with at least 75% compliance with the exercise during the 12-week intervention period and who stayed in the treatment arm allocated by randomization during the 12 months. 2 User of pain medication was defined as a patient taking pain medication of any kind on a regular basis during the previous week. 3 The estimates were adjusted for site. 4 The crude estimate was similar to the adjusted estimate (data not shown) 30

32 Table S5. Adverse Events 1 Adverse events 2 Non-surgical TKR + non-surgical P Value Number of events Serious events Site other than index knee Subtotal Index knee Subtotal 0 2 <0.001 All serious events Non-serious events Sites other than index knee Subtotal Index knee Subtotal All non-serious events The per protocol population was defined as those participating in the non-surgical treatment with at least 75% compliance with the exercise during the 12-week intervention period and who stayed in the treatment arm allocated by randomization during the 12 months. 2 This table includes all serious and non-serious adverse events that occurred during the 12-month study period, but which did not necessarily have a causal relationship with the treatment administered. Serious adverse events include those having the potential to significantly compromise the clinical outcome, result in significant disability or incapacity, requiring inpatient or outpatient hospital care, and those considered to prolong hospital care, to be life-threatening, or to result in death. Non-serious adverse events comprise all other adverse events. See Expanded Table 3 for elaboration on the specific adverse events. 31

33 Table S6. Improvements of at least 15% and Number Needed to Treat (NNT) 1 Outcome Proportion Proportion NNTB (95% CI) (n non-surgical, n TKR+non-surgical) improving at least 15% in non-surgical improving at least 15% in TKR + non- group (95% CI) surgical group (95% CI) KOOS 4 from baseline to 1 yr (25, 26) 0.64 (0.43 to 0.81) 0.81 (0.60 to 0.92) 6.0 (NNTB 2.4 to to NNTH 13.5) Mean change in KOOS subscales score Pain (25, 26) 0.68 (0.47 to 0.84) 0.85 (0.64 to 0.94) 6.0 (NNTB 2.5 to to NNTH 15.8) Symptoms 0.52 (0.32 to 0.71) 0.81 (0.60 to 0.92) 3.5 (1.9 to 24.9) (25, 26) ADL 0.56 (0.36 to 0.74) 0.96 (0.76 to 1.00) 2.5 (1.6 to 5.2) (25, 26) Sport/Rec (25, 26) 0.64 (0.43 to 0.81) 0.85 (0.64 to 0.94) 4.9 (NNTB 2.3 to to NNTH 36.2) QOL (25, 26) 0.72 (0.51 to 0.87) 0.92 (0.73 to 0.98) 4.9 (NNTB 2.5 to to NNTH ) 1 The per protocol population was defined as those participating in the non-surgical treatment with at least 75% compliance with the exercise during the 12-week intervention period and who stayed in the treatment arm allocated by randomization during the 12 months. 32

34 2 NNT was estimated using the formula 1/(TER - MER), where TER is the event rate (proportion of responders, i.e., patients improving at least 15%) in the TKR + non-surgical group and MER the event rate in the non-surgical group. 95% CIs were derived from the reciprocal transformation of the CIs for the difference in proportions. 35 CIs that include both positive and negative values can be difficult to understand and interpret. To address this, we used NNTB (NNT Benefit) and NNTH (NNT Harms) if the 95% CI included both positive and negative values (e.g. a 95% CI going from 5 to -10 would be NNTB 5 to to NNTH 10). 7,8 33

35 As-treated analysis Table S7. Adverse Events associated with treatment Adverse events 1 Before TKR 2 After TKR 2 P Value Number of events Serious events Site other than index knee Musculoskeletal 0 4 Skin 1 0 Gastrointestinal 1 2 Other 4 9 Subtotal Index knee During TKR surgery 0 0 Postoperatively Stiffness leading to brisement forcé 0 4 Deep infection 0 1 Deep venous thrombosis requiring 0 3 anticoagulant treatment Supra-condylar femur fracture 0 1 Subtotal 0 9 <0.001 All serious events Non-serious events Sites other than index knee Subtotal

36 Index knee Pain Swelling 2 8 Subjective instability 2 1 Decreased range of motion 1 6 Joint distortion 2 1 Other 1 8 Subtotal All non-serious events This table includes all serious and non-serious adverse events (AEs) that occurred during the 12-month study period, but which did not necessarily have a causal relationship with the treatment administered. Serious adverse events include those having the potential to significantly compromise the clinical outcome, result in significant disability or incapacity, requiring inpatient or outpatient hospital care, and those considered to prolong hospital care, to be life-threatening, or to result in death. Non-serious adverse events comprise all other adverse events. Categories for adverse events during surgery and postoperative adverse events were chosen on the basis of categories from the Danish Knee Arthroplasty Registry ( See Expanded Table 3 for elaboration on the specific AEs. 2 This as-treated analysis assessed AEs before total knee replacement (TKR; including those remaining in the non-surgical group throughout the follow-up period; and all treatment-dependent AE reported prior to the TKR in those who had TKR even though randomized to the non-surgical treatment alone) and after TKR (including AEs in those receiving TKR by randomization; and all treatment-dependent AE reported after TKR in those who had TKR even though randomized to the non-surgical treatment alone throughout the follow-up period). 35

37 Treatment-related variables Table S8. Compliance Variable 1 Non-surgical TKR + non-surgical Compliance with exercise during 17.3 (5.7) 15.7 (7.5) the 12 weeks, mean no. of sessions out of 24 (SD) Received insoles, n (%) 48 (96) 41 (82) Compliance with insoles, n (%) 2 Never use them 9 (21) 16 (40) Use them every month 0 (0) 1 (3) Use them every week 8 (19) 5 (13) Use them every day 11 (26) 9 (23) Use them all the time 15 (35) 9 (23) Patient education, n sessions (%) out of (18) 12 (24) 1 0 (0) 1 (2) 2 41 (82) 37 (74) Compliance with aspects learned in the education, n (%) 3 Never use it 4 (10) 4 (11) Use it every month 0 (0) 0 (0) Use it every week 11 (28) 10 (27) Use it every day 20 (50) 20 (54) Use it all the time 5 (13) 3 (8) 36

38 Dietary advice, n sessions (%) out of (5) 2 (5) 1 2 (5) 3 (8) 2 0 (0) 4 (10) 3 2 (5) 1 (3) 4 37 (86) 29 (74) Compliance with aspects learned from the dietician, n (%) 5 Never use it 4 (10) 2 (6) Use it every month 3 (8) 2 (6) Use it every week 7 (18) 8 (24) Use it every day 17 (44) 16 (47) Use it all the time 8 (21) 6 (18) 1 The numbers in this table include data on compliance during the 12-week intervention period and at the 12- month follow up. 2 At the 12-month follow up, 43 out of 48 in the non-surgical group (90%) and 40 out of 41 in the TKR + non-surgical group (98%) receiving insoles answered this question. 3 At the 12-month follow up, 40 out of 41 in the non-surgical group (98%) and 37 out of 38 (97%) in the TKR + non-surgical group participating in at least one of the two sessions of patient education answered this question patients in the non-surgical group (86%) and 39 in the TKR + non-surgical group (78%) had a BMI of 25 or above and were offered dietary advice. 5 At the 12-month follow up, 39 out of 41 in the non-surgical group (95%) and 34 out of 37 in the TKR + non-surgical group (92%) participating in at least one of the sessions with the dietician answered this question. 37

39 Table S9. Other treatments or consultations during follow up Variable 1 Non-surgical TKR + non-surgical Surgery during follow up TKR Months from start of 6.9 (2.6 to 11.5) non-surgical treatment, mean (range) Brisement forcé 1 3 Arthroscopic knee surgery 1 0 Other surgery Total number of knee surgeries Other treatments or consultations during follow up Supervised exercise Passive treatments Paracetamol NSAIDs Opioids and opioid-like 3 3 drugs 6 Other pain killers Cortisone injection 4 5 Patients consulting general 2 17 practitioner or orthopedic surgeon 7 Total number of other

40 treatments or consultations 1 This included all treatments or consultations other than those given as study treatment reported by the patient to the project physiotherapist and at follow ups at 3, 6 or 12 months. Furthermore, public hospital records in the North Denmark Region were examined for those undergoing total knee replacement (TKR). 2 This included surgery due to supra-condylar femur fracture; debridement with liner exchange; debridement with insertion of spacer; cicatrice surgery due to infection (n=2); revision surgery with removal of prosthesis; split-skin transplant; knee fusion. 3 Number of patients reporting exercise (yes/no) supervised by a physiotherapist, but not specified regarding number of sessions or content. 4 In the non-surgical group, this was acupuncture. In the TKR + non-surgical group, it was acupuncture; therapeutic ultrasound; massage; manipulation; mobilization; and taping. 5 Patient report of current intake at the 12-month follow up dichotomized into yes/no. 6 In the non-surgical group, this was tricyclic antidepressants. 7 This only included consultations not resulting in any of the mentioned treatments. 39

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