Kise 2016.

Study characteristics
Methods	Study design: multicenter, parallel‐group, two‐arm, randomised controlled trial Setting: orthopaedic departments at two public hospitals and two physiotherapy clinics in Norway Trial time period: participants were enrolled between October 2009 and September 2012 Interventions: arthroscopic surgery versus supervised exercise Sample size calculations: the sample size calculation was based on the change in KOOS4 (defined as the average score for 4/5 KOOS subscale scores) from baseline to 2‐year follow‐up. To detect a 10‐point difference with a standard deviation of 15, with a level of power of 90%, level of significance of 0.05, and an estimated 15% dropout rate at two years, 56 participants were required in each group. To factor in a 20% cross‐over rate, 140 participants were recruited. Analysis: intention‐to‐treat
Participants	Number of participants Number of participants screened: 341 (115 not eligible) Number of participants at enrolment: 226 (85 declined participation, 1 ineligible) Number randomised: 140: 70 in the arthroscopic partial meniscectomy group and 70 in the supervised exercise therapy group Number included in analyses: 129 at 3 months (64 in the surgery group and 65 in exercise group), 129 at 12 months (66 in the surgery group and 63 in the exercise group), 126 at 24 months (64 in the surgery group and 62 in the exercise group), 120 at 5 years (62 in the surgery group and 58 in the exercise group). Fourteen out of 70 participants (20%) in the exercise group crossed over to the arthroscopic group and were analysed in the meniscectomy group in the 'as‐treated analysis' Definition of degenerative meniscal tear: degenerative meniscal tear was defined as an intrameniscal linear magnetic resonance imaging signal penetrating one or both surfaces of the meniscus. Inclusion criteria Age 33 to 60 years Knee pain for more than 2 months without a significant trauma Medial meniscal tear on MRI Eligible for arthroscopic partial meniscectomy Grade 0 to 2 radiographic severity (specification after Kellgren‐Lawrence) Exclusion criteria Those requiring acute trauma surgeries, including those treated as acute cases in the emergency room Ligament injuries Tumours (MRI) Pain or other musculoskeletal comorbidities severely affecting lower extremity muscle function overriding the symptoms from the knee Grade 3 or 4 radiographic severity (specification after Kellgren‐Lawrence) Comorbidities excluding physical activities and exercise Previous knee surgery within two years Not able to speak or read Norwegian, drug abuse or mental problems Baseline characteristics Arthroscopic partial meniscectomy (N = 70) Mean (SD) age: 48.9 (6.1) years No. (%) men: 43 (61) No. (%) right knee: 41 (59) Mean (SD) body‐mass index: 26.0 (3.7) No. (%) smokers: 10 (14.3) No. (%) use analgesics daily: 3 (4.2) Severity of radiographic osteoarthritis in knee ‐ Kellgren‐Lawrence classification: 0 ‐ 51 (73), 1 ‐ 16 (23), 2 ‐ 3 (4), 3 ‐ 0 No. (%): meniscal degeneration grade 1‐2: 6 (9), grade 3a‐3b: 64 (91) No. (%): meniscal extrusion: 35 (50) Mean (SD) pain duration (months): 12.0 (15.7) Mean (SD) knee function VAS: 63.8 (18.9) Mean (SD) KOOS scores: KOOS4 ‐ 59.6 (13.8); pain ‐ 67.6 (14.9); symptoms ‐ 77.4 (14.6); daily activities 79.6 (16.1); function in sport and recreation 47.8 (23.4); knee‐related quality of life 45.6 (15.5) Mean (SD) SF‐36: Physical component 47.4 (6.1), Mental component 56.0 (6.3) Mean (SD) Peak torque extension 163.1 (53.2), Total work extension 790.8 (254.8), Peak torque flexion 88.5 (25.7), Total work flexion 492.9 (158.7) Mean (SD) One leg hop test (cm) 83.2 (35.5) Mean (SD) 6‐metre timed hop test (sec) 2.7 (1.2) Mean (SD) Knee bends 30 sec test (No) 29.3 (10.6) Supervised exercise therapy (N = 70) Mean (SD) age: 50.2 (6.2) years No. (%) men: 43 (61) No. (%) right knee: 41 (59) Mean (SD) body‐mass index: 26.4 (4.3) No. (%) smokers: 3 (4.2) No. (%) use analgesics daily: 3 (4.2) Severity of radiographic osteoarthritis in knee ‐ Kellgren‐Lawrence classification: 0 ‐ 49 (70), 1 ‐ 18 (26), 2 ‐ 2 (3), 3 ‐ 1 (1) No. (%): meniscal degeneration grade 1‐2: 6 (9) No. (%): meniscal degeneration grade 3a‐3b: 63 (91) No. (%): meniscal extrusion: 45 (65) Mean (SD) pain duration (months): 17.3 (21.5) Mean (SD) knee function VAS: 57.9 (21.5) Mean (SD) KOOS scores: KOOS4 ‐ 54.3 (18.2); pain ‐ 63.4 (20.8); symptoms ‐ 69.8 (16.7); daily activities 75.0 (21.5); function in sport and recreation 44.0 (25.8); knee‐related quality of life 40.0 (17.5) Mean (SD) SF36: Physical component 45.4 (8.4), Mental component 55.0 (9.2) Mean (SD) Peak torque extension 157.5 (48.7), Total work extension 772.9 (245.1), Peak torque flexion 81.9 (27.2), Total work flexion 448.3 (187.8) Mean (SD) One leg hop test (cm) 76.6 (32.8) Mean (SD) 6‐metre timed hop test (sec) 3.1 (1.7) Mean (SD) Knee bends 30 sec test (No) 28.2 (10.6) Pre‐treatment group differences: there were no obvious differences in baseline characteristics between the groups.
Interventions	Arthroscopic surgery Arthroscopic partial meniscectomy. Six orthopaedic surgeons with at least 10 years of clinical experience performed the operations. Surgery was performed with the participant under general anaesthesia, with or without thigh tourniquet, antibiotic prophylaxis, or antithrombotic prophylaxis. Arthroscopes with 30 degree optics and standard arthroscopic instruments were used. Ringer acetate was used for lavage. Normal procedure involved two portals: anteromedial and anterolateral. Additional injuries (ligaments, cartilage) preceded systematic probing of both menisci, and finally, all unstable meniscal tissue was resected. The participants were discharged from hospital on the day of surgery and were advised to use two crutches post‐operatively until gait normalised and no swelling or discomfort occurred during weight bearing. Before hospital discharge, the participants were given written and oral instructions for simple home exercises, aimed at regaining knee range of motion and reducing swelling. They were encouraged to perform the exercises two to four times daily. Exercise The supervised exercise therapy programme consisted of progressive neuromuscular and strength exercises over 12 weeks, performed during a minimum of two and a maximum of three sessions each week (24 to 36 sessions). Each session lasted approximately 60 to 80 minutes. About 20 minutes was spent warming up and cooling down on a stationary cycle, 20 to 30 minutes was spent on neuromuscular exercise, and 20 to 30 minutes was spent on strength training.
Outcomes	Outcomes were measured at baseline and at 3, 12 and 24 months and 5 years of follow‐up. Primary outcomes KOOS4 defined as the average score for 4/5 KOOS subscale scores on pain, symptoms, function in sport and recreation, and knee‐related quality of life at 24 months. Subscale scores are calculated separately and transformed to a scale from 0 to 100 where 0 = worst, 100 = best Isokinetic muscle strength at 3 months (including peak torque flexion, peak torque extension, total work flexion and total work extension) for knee extensors and flexors Incident and enlarging marginal tibiofemoral osteophyte at 5 years (co‐primary outcome pre‐specified in trial registration record) Secondary outcomes Five KOOS subscales ‐ pain, symptoms, ADL, sports/rec, QoL. Subscale scores are calculated separately and transformed to a scale from 0 to 100 where 0 = worst, 100 = best SF‐36 Physical and Mental Component Summaries (scores range from 0 = worst to 100 = best) 3 performance tests to evaluate lower extremity function: the one leg hop test for distance (measuring length in centimetres, higher score indicative of better function) the 6‐metre timed hop test (measuring time in seconds, lower time indicative of better function), the knee bends test (measuring maximum number in 30 seconds, higher score = better function). Adverse events ‐ any situations where participants sought health care Serious adverse events ‐ death, cardiovascular or gastrointestinal events, deep vein thrombosis, pulmonary embolism, systemic or local infection Progression of osteophytes and tibiofemoral joint space narrowing at 5 years assessed by the Osteoarthritis Research Society International (OARSI) atlas ‐ scored separately for the medial and lateral tibiofemoral compartments on a 0 (normal) to 3 (severe changes) scale (half‐grades were used when progression had occurred but without achieving a full grade; participants undergoing subsequent tibial osteotomy were given joint space narrowing score of 3) Total radiographic progression score at 5 years ‐ sum of medial and lateral compartment joint space narrowing and osteophyte score Severity of knee osteoarthritis at 5 years ‐ using the modified Kellgren‐Lawrence classification from 0 (normal) to 4 (severe), including a grade with definite osteophyte only (grade 2/ost) Radiographic knee osteoarthritis at 5 years ‐ assessed as Grade 2 (definite osteophyte and possible joint space narrowing) or above using Kellgren‐Lawrence classification (grade 1 (doubtful): doubtful joint space narrowing and possible osteophytic lipping; grade 2 (minimal): definite osteophytes and possible joint space narrowing; grade 3 (moderate): moderate multiple osteophytes, definite narrowing of joint space and some sclerosis and possible deformity of bone ends; grade 4 (severe): large osteophytes, marked narrowing of joint space, severe sclerosis and definite deformity of bone ends) in knees graded as 0 or 1 at baseline. Those receiving total knee arthroplasty also categorised as having radiographic knee osteoarthritis Symptomatic knee osteoarthritis at 5 years ‐ participants reporting knee pain at least weekly (question P1 from KOOS Pain subscale) in addition to incident radiographic knee osteoarthritis Knee surgery (replacement or osteotomy) Outcomes included in this review at 3 and 24 months and 5 years Pain measured on KOOS Pain subscale (0 to 100, higher score = less pain) (we multiplied the mean values by –1 so that lower scores = less pain, as per Cochrane Handbook guidance, so direction was consistent across pain scales) Function measured on KOOS ADL subscale(0 to 100, higher score = better) Knee‐specific health‐related quality of life measured on KOOS QoL subscale(0 to 100, higher score = better) Generic health‐related quality of life measured on SF‐36 Mental Component Summary (0 to 100, higher score = better) (24 months only) Serious adverse events Total adverse events Progression of knee osteoarthritis Knee surgery (replacement or osteotomy)
Notes	Funding: this study was funded by Sophies Minde Ortopedi AS, Swedish Rheumatism Association, Swedish Scientific Council, Region of Southern Denmark, Danish Rheumatism Association, and the Health Region of South‐East Norway. Trial Registration: www.clinicaltrials.gov (NCT01002794) Adverse events: Arthroscopic partial meniscectomy Serious adverse events Serious knee‐related adverse events: 1 participant in the surgery group received a total knee arthroplasty 34 months after the index surgery. 2 participants (one allocated to surgery and one cross‐over) received an osteotomy 4 to 6 months after the index procedure. 4 participants (three allocated to surgery and one cross‐over) underwent another partial meniscectomy at 6, 12, 15 and 36 months after the index operation. Other serious adverse events: none reported Other adverse events Pain, swelling, instability, stiffness, decreased range of motion in the index knee ‐ 16 (23%) Similar symptoms in the contralateral knee ‐ 10 (14%) Total other adverse events ‐ 26 (37%) Total ALL adverse events: 31/64 (48.4%) Supervised exercise therapy Serious adverse events Serious knee‐related adverse events: none reported Other serious adverse events: none reported Other adverse events Pain, swelling, instability, stiffness,decreased range of motion in the index knee ‐ 16 (23%) Similar symptoms in the contralateral knee ‐ 15 (21%) Total other adverse events ‐ 31 (44%) Total ALL adverse events: 31/60 (51.7%) Knee surgery (replacement or osteotomy) (5 year follow‐up): 1 participant in the surgery group received a total knee arthroplasty 34 months after the index surgery. 2 participants (one allocated to surgery and one cross‐over) received an osteotomy 4 to 6 months after the index procedure Progression of knee OA: 10/58 (17.2%) participants from the exercise group and 13/62 (21.0%) participants from the arthroscopy group had radiographic knee OA consistent with grade 2 or more on the Kellgren‐Lawrence classification at five years. Withdrawals: 6/70 in the arthroscopic partial meniscectomy group and 8/70 in the supervised exercise therapy group Cross‐overs: in the final report (Berg 2020, secondary publication of Kise 2016), 14/70 crossed over from exercise to arthroscopy group in contrast to earlier report (Kise 2016) which reported 13/70 cross‐overs. Report of study results: 3‐month study findings reported in Stensrud 2015 (secondary publication of Kise 2016). Data analysis: the authors supplied outcome data for knee‐related quality of life measured on KOOS QoL subscale (0 to 100, higher score = better) upon request
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated randomisation sequence was used.
Allocation concealment (selection bias)	Low risk	The allocations were kept in sequentially‐numbered, opaque envelopes.
Blinding of participants and personnel (performance bias) All outcomes	High risk	Participants were not blinded to the group assignments; however, strength and function test assessors were blinded.
Blinding of outcome assessor Self‐reported outcomes	High risk	Participants were not blinded to group assignments, thus, there was a risk of bias in the measurement of pain, function and knee‐related quality of life.
Blinding of outcome assessor Assessor‐reported outcome (knee replacement)	Low risk	The outcome assessors were blinded to group allocation.
Incomplete outcome data (attrition bias) All outcomes	Low risk	8/70 in the exercise group and 6/70 in the arthroscopic group did not have outcome data (questionnaires not returned).
Selective reporting (reporting bias)	Unclear risk	One outcome (incident and enlarging marginal tibiofemoral osteophytes at 5 years) was pre‐specified as a co‐primary outcome but moved to secondary outcome and redefined as progression of both osteophytes and tibiofemoral joint space narrowing separately at 5 years. The rationale for the change was provided (to describe radiographic changes in knee osteoarthritis development) and the change was made before 5‐year data collection and analysis. Additional secondary outcomes that were not pre‐specified were reported (e.g. total radiographic progression score, severity of knee OA using modified Kellgren‐Lawrence classification, adverse events, knee surgery). Although the paper did not publish the KOOS summary data for each treatment group, the authors provided them upon request and they were used in the analysis.
Other bias	Low risk	No other bias apparent