Protocol This trial protocol has been provided by the authors to give readers additional information about their work. Protocol for: Sihvonen R, Paavola M, Malmivaara A, et al. Arthroscopic partial meniscectomy versus sham surgery for a degenerative meniscal tear. N Engl J Med 2013;369:2515-24. DOI: 10.1056/NEJMoa1305189
Supplementary Material Arthroscopic Partial Meniscectomy vs. Sham for a Degenerative Meniscus Tear by Raine Sihvonen, Mika Paavola, Antti Malmivaara, Ari Itälä, Antti Joukainen, Heikki Nurmi, Juha Kalske and Teppo LN Järvinen On behalf of the FIDELITY (Finnish Degenerative Meniscal Lesion Study) Group CONTRIBUTORS, the FIDELITY Group: Jukka Nyrhinen, MD (Central Finland Central Hospital, Jyväskylä) Timo Järvelä, MD, PhD; Tero Järvinen MD, PhD; Janne Lehtinen, MD, PhD; Marko Raivio, MD (Hatanpää City Hospital, Tampere) Janne Karhunen, MD; Sikri Tukiainen, MD (Helsinki University Central Hospital/Jorvi Hospital, Espoo) Heikki Kröger, MD, PhD (Kuopio University Hospital, Kuopio) Ville Äärimaa, MD, PhD (Turku University Hospital, Turku) This supplement contains the following items 1. Protocol a. Original protocol b. Final protocol c. Summary of amendments 2. Statistical analysis plan a. Original statistical analysis plan b. Final statistical analysis plan c. Summary of amendments
1. PROTOCOL 1a. Original protocol Original protocol submitted to Clinical Trials.gov on October 24, 2007 can be accessed at: http://clinicaltrials.gov/archive/nct00549172/2007_10_24 This same information is copied below: First Received Date (At Clinical Trials.gov) October 24, 2007 Start Date October 2007 Estimated Primary Completion Date January 2013 (final data collection date for primary outcome measure) Primary Outcome Measures: The Lysholm knee score (Time Frame: One year) Pain at rest and activity (VAS) (Time Frame: One year) Secondary Outcome Measures WOMET (Western Ontario Meniscal Tear -disease specific quality of life -assessment tool) (Time Frame: One year) 15-D (general quality of life -assessment tool) (Time Frame: One year) Descriptive Information Brief Title: Arthroscopy in the Treatment of Degenerative Medial Meniscus Tear Official Title: Efficacy of Arthroscopic Partial Resection for the Degenerative Tear of the Medial Meniscus of a Knee Brief Summary Degenerative meniscal tears are the most common etiology for knee pain, swelling and loss of function. Partial arthroscopic meniscectomy is the most common orthopaedic procedure to treat meniscal tears. Improvements have been reported both after arthroscopy and with conservative treatment, however no direct comparison exist. Accordingly, the aim of this study is to assess the efficacy of arthroscopic partial meniscectomy for the treatment of degenerative tear of medial meniscus of the knee using a double-blind, placebo controlled, randomised trial. Detailed Description
Middle-aged men and women with degenerative meniscal tears constitute a large group of patients presenting with knee pain, sometimes accompanied with swelling and loss of function. Many meniscal tears occur without a trauma in physically active individuals as well as in older people and could be a part of early osteoarthritis. Partial arthroscopic meniscectomy is the most common orthopaedic procedure and is used to treat patients with meniscal tears. Many patients report improvement after arthroscopy referring especially to reduced knee pain, better knee function and improved quality of life. However, similar results have also been obtained with conservative treatment (physical therapy) of patients with degenerative meniscal tears. Accordingly, the aim of this study is to assess the efficacy of arthroscopic partial meniscectomy for the treatment of degenerative tear of medial meniscus of the knee using a double-blind, placebo controlled, randomised trial. The outcome of arthroscopic partial meniscectomy (vs. sham surgery) is assessed using the Lysholm knee score and pain at rest and activity (VAS) at 2, 6 and 12 months after the operation. In addition, the functional outcome is assessed using the WOMET knee score (a diseasespecific quality of life -knee score development on the assessment of meniscal pathology), the general quality of life score (15-D), and cost-effectiveness analysis. Study Type: Interventional Study Design: Allocation: Randomized Endpoint Classification: Efficacy Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor) Primary Purpose: Treatment Condition: Degenerative Tear of the Medial Meniscus of Knee Intervention: Procedure: Operative (partial arthroscopy): Partial arthroscopic resection of degenerative rupture of the medial meniscus Procedure: Conservative (diagnostic arthroscopy): Diagnostic arthroscopy Study Arms: Active Comparator: Operative (O): Partial resection of degenerative tear of medial meniscus Intervention: Procedure: Operative (partial arthroscopy) Sham Comparator: Conservative (K): Arthroscopy (diagnostic) Intervention: Procedure: Conservative (diagnostic arthroscopy) Estimated Enrollment: 140 Eligibility Criteria:
Inclusion Criteria: 1. Age: 35 to 65 years of age. 2. A pain located on the medial joint line of the knee that has persistent at least for 3 months. 3. Pain that can be provoked by palpation or compression of the joint line or a positive McMurray sign. 4. Tear of the medial meniscus on MRI. 5. Degenerative rupture of the medial meniscus confirmed at arthroscopy. Exclusion Criteria: 1. Acute, trauma-induced onset of symptoms. 2. Locking or painful snapping of the knee joint. 3. A surgical operation performed on the affected knee. 4. Osteoarthritis of the medial compartment of the knee (determined by clinical criteria of the ACR). 5. Osteoarthritis on knee radiographs (Kellgren-Lawrence > 1). 6. Acute (within the previous year) fractures of the knee. 7. Decreased range of motion of the knee. 8. Instability of the knee. 9. MRI assessment showing a tumor or any other complaint requiring surgical or other means of treatment. 10. Arthroscopic assessment showing anything other than a degenerative tear of the medial meniscus requiring surgical intervention. Gender: Both Ages: 35 Years to 65 Years Location, Countries: Hatanpää City Hospital, Tampere, Finland Data Monitoring Committee: Yes Study Chair: Teppo LN Jarvinen, MD, PhD, University of Tampere Principal Investigator: Raine TA Sihvonen, MD, Tampere City Hospital Study Director: Mika Paavola, MD, PhD, Helsinki University Study Director: Antti Malmivaara, MD, PhD, Helsinki
1b. Final protocol Amended sections only (the final protocol was published in its entirety in Sihvonen et al 1 ) Primary Outcome Measures: (Changes in the score) The Lysholm knee score (Time Frame: One year) WOMET (Western Ontario Meniscal Tear -disease specific quality of life -assessment tool) (Time Frame: One year) Pain after exercise (NRS) (Time Frame: One year) Secondary Outcome Measures (Time Frame: One year) 15-D (general quality of life -assessment tool)(time Frame: One) Pain at rest (NRS) (Time Frame: One year) Eligibility Criteria: Inclusion Criteria: 1. Age: 35 to 65 years of age. 2. A pain located on the medial joint line of the knee that has persistent at least for 3 months. 3. Pain that can be provoked by palpation or compression of the joint line or a positive McMurray sign. 4. Tear of the medial meniscus on MRI. 5. Degenerative rupture of the medial meniscus confirmed at arthroscopy. Exclusion Criteria: 1. Acute, trauma-induced onset of symptoms. 2. Locked knee (that cannot be straightened normally). 3. A surgical operation performed on the affected knee. 4. Osteoarthritis of the medial compartment of the knee (determined by clinical criteria of the ACR). 5. Osteoarthritis on knee radiographs (Kellgren-Lawrence > 1). 6. Acute (within the previous year) fractures of the knee. 7. Decreased range of motion of the knee. 8. Instability of the knee.
9. MRI assessment showing a tumor or any other complaint requiring surgical or other means of treatment. 10. Arthroscopic assessment showing anything other than a degenerative tear of the medial meniscus requiring surgical intervention. Location, Countries: (Changed at January 19, 2010) Hatanpää City Hospital, Tampere, Finland Helsinki University Central Hospital, Helsinki, Finland Kuopio University Hospital, Kuopio, Finland Turku University Hospital, Turku, Finland Central Hospital of Central Finland Hospital District, Jyväskylä, Finland Data Monitoring Committee: Yes Study Chair: Teppo LN Jarvinen, MD, PhD, University of Tampere Principal Investigator: Raine TA Sihvonen, MD, Tampere City Hospital Study Director: Mika Paavola, MD, PhD, Helsinki University Study Director: Antti Malmivaara, MD, PhD, Helsinki University Collaborators Helsinki University Central Hospital Kuopio University Hospital Turku University Hospital Central Finland Hospital District
1c. Summary of amendments 1) Primary and secondary outcomes WOMET upgraded as a primary outcome Pain assessment o Pain after exercise specified as a primary outcome o Pain at rest specified as a secondary outcome When we registered the trial in ClinicalTrials.com, our two primary outcome measures were the Lysholm knee score and the Pain at rest and activity (using the visual analogue scale, VAS) at 12 months after surgery. The secondary outcomes were the WOMET score and a cost-utility analysis (based on the patients general quality of life using the 15D score and the utilization of healthcare resources), both also at 12 months after surgery. The Lysholm score was chosen as our primary outcome as it was validated for meniscus injury and it was (and still is) the most often used knee outcome instrument. However, during the recruitment phase of our trial, we validated the WOMET in this particular patient population (patients with a degenerative meniscus injury), 2 and as the WOMET is a disease-specific QoL instrument and showed at least comparable (if not better) psychometric properties to the Lysholm score, we decided to add it as our third primary outcome. Finally, we initially registered both Pain at rest and activity (VAS) as primary outcome(s). However, after realizing that this was somewhat ambiguous, we chose to specify that Pain after exercise was a primary outcome (as being more important of the two to patients with degenerative meniscus tear) and Pain at rest a secondary outcome. On this note, our method to query pain was actually NRS (Numerical rating scale), rather than VAS (visual analogue scale). As per the request of the NEJM, this amendment was also updated to the ClinicalTrials.com database (August 1, 2013) to make the registration concordant with the paper/reported outcomes. 2) Exclusion criteria: (locking to locked) The terminology related to mechanical symptoms of the knee is vague, at best. When planning our trial, we were advised by the local IRB that our sham surgery controlled design cannot pose a medical risk to the patients, and accordingly, patients with an absolute indication for knee arthroscopy have to be operated on (i.e., excluded). To conform to this requirement, we listed a painful snapping or locking as one of our exclusion criterion. However, as patients with a degenerative meniscus tear (even without radiographic or clinical OA) quite frequently report of various mechanical symptoms (such as sensations of catching, snapping or locking), but rarely have (episodes of) locked knee (meaning that they cannot extend their knee fully), patients with mechanical symptoms were enrolled right from the beginning. When extending our trial from the initial study center (Tampere) to four other centers, this particular exclusion criterion (expression) was discussed in detail to make sure that all doctors enroll identical patients. It was subsequently agreed that we should rephrase the exclusion criterion as follows: Locked knee (that cannot be straightened normally). As you can appreciate, our study sample includes patients with mechanical
symptoms (locking or catching, Table 2.), but those with (episodes of) locked knee were excluded (Figure 1.). 3) Sites: The trial began in only one center (Tampere), but once the study protocol had been thoroughly refined, it was expanded to four additional sites to increase the enrollment rate and also, to minimize possible bias and criticism for having only one surgeon performing all operations. This amendment was made to the ClinicalTrials.com database on January 19, 2010. Be it reiterated here that all the above noted amendments to the original protocol were made prior to completion of the trial and have been elaborated in detail in our published protocol paper 1.
2. STATISTICAL ANALYSIS PLAN 2a. Original statistical analysis plan A description of our original statistical analysis plan was published 1 as follows: The trial was designed to ascertain the superiority of APM over placebo at 12 months with primary outcome measures by the means of statistically significant differences between the groups. Baseline characteristics will be analysed by descriptive statistics. For the primary analysis, the change in scores (Lysholm and WOMET) and pain (NRS) at 12 months will be compared between the two study groups. A secondary analysis of the primary endpoint will adjust for those prerandomisation variables which might reasonably be expected to influence the outcome (ie, sex, age, radiological OA and baseline score). A two-sided p value of 0.05 will be considered to indicate statistical significance. We will use the Bonferroni method to appropriately adjust the overall level of significance for multiple (three) primary outcomes. Analyses of the outcome measures score will also be performed at 2 and 6 months. Additionally, the number and percentage of satisfied patients, those subjectively improved, and those whose allocation was unsealed will be calculated and compared between the two groups. All statistical analyses will be performed on an intention-to-treat basis, meaning that data from patients will be analysed according to the initial study-group assignment regardless of compliance with randomisation. However, as the potential for treatment conversion exists, but only from placebo surgery to APM, per-protocol analysis will also be carried out. We plan to conduct a subgroup analysis to compare the result based on the degree of radiographic OA (K&L 0 vs I). The serious adverse event rates occurring within 12 months of surgery for both study arms will be evaluated descriptively in aggregate and separately. If the number of events is large enough to allow more sophisticated analysis, the rates between the APM and placebo arms will be compared. The data will be presented by the total number of events and the total number of individuals with at least one event. 2b. Final statistical analysis plan A detailed description of the execution of the statistical analysis can be found in our Blinded Data Analyses Statement of Interpretation -document (Supplementary Appendix of our submission). Be it reiterated here that the entire statistical analysis was carried out blinded and the randomization code was broken only after the main findings/interpretation of the results were mutually agreed on (and documented) by the entire manuscript writing committee. 2c. Summary of amendments We used medians (range) to carry out the statistical analysis/data interpretation (as the data of our primary outcomes is not normally distributed), but reported it using means with 95% confidence
intervals to conform with the apparent policy of the New England Journal of Medicine to prefer this format. References 1. Sihvonen R, Paavola M, Malmivaara A, Jarvinen TL. Finnish Degenerative Meniscal Lesion Study(FIDELITY): a protocol for a randomised, placebo surgery controlled trial on the efficacy of arthroscopic partial meniscectomy for patients with degenerative meniscus injury with a novel 'RCT within-a-cohort' study design. BMJ open 2013;3. 2. Sihvonen R, Jarvela T, Aho H, Jarvinen TL. Validation of the Western Ontario Meniscal Evaluation Tool (WOMET) for patients with a degenerative meniscal tear: a meniscal pathologyspecific quality-of-life index. The Journal of bone and joint surgery American volume 2012;94:e65.