Toward designing human intervention studies to prevent osteoarthritis after knee injury: A report from an interdisciplinary OARSI 2023 workshop.

Objective: The global impact of osteoarthritis is growing. Currently no disease modifying osteoarthritis drugs/therapies exist, increasing the need for preventative strategies. Knee injuries have a high prevalence, distinct onset, and strong independent association with post-traumatic osteoarthritis (PTOA). Numerous groups are embarking upon research that will culminate in clinical trials to assess the effect of interventions to prevent knee PTOA despite challenges and lack of consensus about trial design in this population. Our objectives were to improve awareness of knee PTOA prevention trial design and discuss state-of-the art methods to address the unique opportunities and challenges of these studies. Design: An international interdisciplinary group developed a workshop, hosted at the 2023 Osteoarthritis Research Society International Congress. Here we summarize the workshop content and outputs, with the goal of moving the field of PTOA prevention trial design forward. Results: Workshop highlights included discussions about target population (considering risk, homogeneity, and possibility of modifying osteoarthritis outcome); target treatment (considering delivery, timing, feasibility and effectiveness); comparators (usual care, placebo), and primary symptomatic outcomes considering surrogates and the importance of knee function and symptoms other than pain to this population. Conclusions: Opportunities to test multimodal PTOA prevention interventions across preclinical models and clinical trials exist. As improving symptomatic outcomes aligns with patient and regulator priorities, co-primary symptomatic (single or aggregate/multidimensional outcome considering function and symptoms beyond pain) and structural/physiological outcomes may be appropriate for these trials. To ensure PTOA prevention trials are relevant and acceptable to all stakeholders, future research should address critical knowledge gaps and challenges.

Patient acceptable symptom state and treatment failure threshold values for work productivity and activity Impairment and EQ-5D-5L in osteoarthritis.

OBJECTIVE: To estimate patient acceptable symptom state (PASS) and treatment failure (TF) threshold values for Work Productivity and Activity Impairment (WPAI) measure and EQ-5D-5L among people with hip or knee osteoarthritis (OA) 3 and 12 months following participation in a digital self-management intervention (Joint Academy®). METHODS: Among the participants, we computed work and activity impairments scores (both 0-100, with a higher value reflecting higher impairment) and the Swedish hypothetical- (range: - 0.314 to 1) and experience-based (range: 0.243-0.976) EQ-5D-5L index scores (a higher score indicates better health status) at 3- (n = 14,607) and 12-month (n = 2707) follow-ups. Threshold values for PASS and TF were calculated using anchor-based adjusted predictive modeling. We also explored the baseline dependency of threshold values according to pain severity at baseline. RESULTS: Around 42.0% and 48.3% of the participants rated their current state as acceptable, while 4.2% and 2.8% considered the treatment had failed at 3 and 12 months, respectively. The 3-month PASS/TF thresholds were 16/29 (work impairment), 26/50 (activity impairment), 0.92/0.77 (hypothetical EQ-5D-5L), and 0.87/0.77 (the experience-based EQ-5D-5L). The thresholds at 12 months were generally comparable to those estimated at 3 months. There were baseline dependencies in PASS/TF thresholds with participants with more severe baseline pain considering poorer (more severe) level of WPAI/EQ-5D-5L as satisfactory. CONCLUSION: PASS and TF threshold values for WPAI and EQ-5D-5L might be useful for meaningful interpretation of these measures among people with OA. The observed baseline dependency of estimated thresholds limits their generalizability and values should be applied with great caution in other settings/populations.

Sex and age differences in the patient-reported outcome measures and adherence to an osteoarthritis digital self-management intervention.

Objective: To explore sex and age differences in Patient-Reported Outcomes Measures (PROMs) and adherence to digital osteoarthritis (OA) self-management intervention. Methods: A register-based study with data from an OA digital self-management intervention. PROMs and adherence were collected at baseline and/or 3 â€‹month follow-up: 'pain intensity' in hip/knee (best/worst: 0-10), 'activity impairments' (best/worst: 0-10), 'overall health' perception (worst/best: 0-10), 'physical function' (30-s chair stand test), 'health-related quality of life' (EQ-5D-5L index score; worst/best: 0.243-0.976), the subscales and total scores of the Knee Injury/Hip Disability and Osteoarthritis Outcome Score (KOOS/HOOS-12; worst/best: 0-100), 'fear of movement' (yes/no), 'walking difficulties' (yes/no), 'programme adherence' (0-100 â€‹% and ≥80 â€‹% [yes/no]), 'patient acceptable symptom state' (PASS; yes/no), and 'treatment failure' (those who answered no to PASS question and thought the treatment failed [yes/no]). We used linear/logistic regression to calculate mean/risk differences in the PROMs and adherence levels among sex and age groups at 3-month follow-up. We employed entropy balancing to explore the contributions of baseline characteristics and different covariates to the sex/age differences. Results: We included 14,610 participants (mean (SD) age: 64.1 (9.1), 75.5 â€‹% females). Females generally reported better outcomes than males. Participants aged ≥70 had greater activity impairments, lower KOOS/HOOS-pain/function scores, more walking difficulties, less fear of movement and higher adherence than those <70. However, these differences were small and not likely clinically relevant. Conclusion: No clinically relevant differences in PROMs and adherence were found among sex/age groups in this digital OA programme, suggesting that sex/age seemed not to impact the outcomes of this intervention.

EULAR recommendations for the non-pharmacological core management of hip and knee osteoarthritis: 2023 update.

INTRODUCTION: Hip and knee osteoarthritis (OA) are increasingly common with a significant impact on individuals and society. Non-pharmacological treatments are considered essential to reduce pain and improve function and quality of life. EULAR recommendations for the non-pharmacological core management of hip and knee OA were published in 2013. Given the large number of subsequent studies, an update is needed. METHODS: The Standardised Operating Procedures for EULAR recommendations were followed. A multidisciplinary Task Force with 25 members representing 14 European countries was established. The Task Force agreed on an updated search strategy of 11 research questions. The systematic literature review encompassed dates from 1 January 2012 to 27 May 2022. Retrieved evidence was discussed, updated recommendations were formulated, and research and educational agendas were developed. RESULTS: The revised recommendations include two overarching principles and eight evidence-based recommendations including (1) an individualised, multicomponent management plan; (2) information, education and self-management; (3) exercise with adequate tailoring of dosage and progression; (4) mode of exercise delivery; (5) maintenance of healthy weight and weight loss; (6) footwear, walking aids and assistive devices; (7) work-related advice and (8) behaviour change techniques to improve lifestyle. The mean level of agreement on the recommendations ranged between 9.2 and 9.8 (0-10 scale, 10=total agreement). The research agenda highlighted areas related to these interventions including adherence, uptake and impact on work. CONCLUSIONS: The 2023 updated recommendations were formulated based on research evidence and expert opinion to guide the optimal management of hip and knee OA.

Weekly pain trajectories among people with knee or hip osteoarthritis participating in a digitally delivered first-line exercise and education treatment.

OBJECTIVE: Digital self-management programs are increasingly used in the management of osteoarthritis (OA). Little is known about heterogeneous patterns in response to these programs. We describe weekly pain trajectories of people with knee or hip OA over up to 52-week participation in a digital self-management program. METHODS: Observational cohort study among participants enrolled between January 2019 and September 2021 who participated at least 4 and up to 52 weeks in the program (n = 16 274). We measured pain using Numeric Rating Scale (NRS 0-10) and applied latent class growth analysis to identify classes with similar trajectories. Associations between baseline characteristics and trajectory classes were examined using multinomial logistic regression and dominance analysis. RESULTS: We identified 4 pain trajectory classes: "mild-largely improved" (30%), "low moderate-largely improved" (34%), "upper moderate-improved" (24%), and "severe-persistent" (12%). For classes with decreasing pain, the most pain reduction occurred during first 20 weeks and was stable thereafter. Male sex, older age, lower body mass index (BMI), better physical function, lower activity impairment, less anxiety/depression, higher education, knee OA, no walking difficulties, no wish for surgery and higher physical activity, all measured at enrolment, were associated with greater probabilities of membership in "mild-largely improved" class than other classes. Dominance analysis suggested that activity impairment followed by wish for surgery and walking difficulties were the most important predictors of trajectory class membership. CONCLUSIONS: Our results highlight the importance of reaching people with OA for first-line treatment prior to developing severe pain, poor health status and a wish for surgery.

Quantification of chondroitin sulfate, hyaluronic acid and N-glycans in synovial fluid - A technical performance study.

Objective: To validate a quantitative high performance liquid chromatography (HPLC) assay for chondroitin sulfate (CS) and hyaluronic acid (HA) in synovial fluid, and to analyze glycan-patterns in patient samples. Design: Synovial fluid from osteoarthritis (OA, n â€‹= â€‹25) and knee-injury (n â€‹= â€‹13) patients, a synovial fluid pool (SF-control) and purified aggrecan, were chondroitinase digested and together with CS- and HA-standards fluorophore labelled prior to quantitative HPLC analysis. N-glycan profiles of synovial fluid and aggrecan were assessed by mass spectrometry. Results: Unsaturated uronic acid and sulfated-N-acetylgalactosamine (ΔUA-GalNAc4S and ΔUA-GalNAc6S) contributed to 95% of the total CS-signal in the SF-control sample. For HA and the CS variants in SF-control the intra- and inter-experiment coefficient of variation was between 3-12% and 11-19%, respectively; tenfold dilution gave recoveries between 74 and 122%, and biofluid stability test (room temperature storage and freeze-thaw cycles) showed recoveries between 81 and 140%. Synovial fluid concentrations of the CS variants ΔUA-GalNAc6S and ΔUA2S-GalNAc6S were three times higher in the recent injury group compared to the OA group, while HA was four times lower. Sixty-one different N-glycans were detected in the synovial fluid samples, but there were no differences in levels of N-glycan classes between patient groups. The CS-profile (levels of ΔUA-GalNAc4S and ΔUA-GalNAc6S) in synovial fluid resembled that of purified aggrecan from corresponding samples; the contribution to the N-glycan profile in synovial fluid from aggrecan was low. Conclusions: The HPLC-assay is suitable for analyzing CS variants and HA in synovial fluid samples, and the GAG-pattern differs between OA and recently knee injured subjects.

Interpretation threshold values for patient-reported outcomes in patients participating in a digitally delivered first-line treatment program for hip or knee osteoarthritis.

Objective: Establish proportions of patients reporting important improvement, acceptable symptoms and treatment failure and define interpretation threshold values for pain, patient-reported function and quality-of-life after participating in digital first-line treatment including education and exercise for hip and knee osteoarthritis (OA). Methods: Observational study. Responses to the pain Numeric Rating Scale (NRS, 0-10 best to worst), Knee injury and Osteoarthritis Outcome Score 12 (KOOS-12) and Hip disability and Osteoarthritis Outcome Score 12 (HOOS-12, both 0-100 worst to best) were obtained for 4383 (2987) and 2041 (1264) participants with knee (hip) OA at 3 and 12 months post intervention. Threshold values for Minimal Important Change (MIC), Patient Acceptable Symptom State (PASS) and Treatment Failure (TF) were estimated using anchor-based predictive modeling. Results: 70-85% reported an important improvement in pain, function and quality of life after 3 and 12 months follow-up. 42% (3 months) and 51% (12 months) considered their current state as satisfactory, whereas 2-4% considered treatment failed. MIC values were -1 (NRS) and 0-4 (KOOS/HOOS-12) across follow-ups and joint affected. PASS threshold value for NRS was 3, and 53-73 for the KOOS/HOOS-12 subscales Corresponding values for TF were 5 (NRS) and 34-55 (KOOS/HOOS-12). Patients with more severe pain at baseline had higher MIC scores and accepted poorer outcomes at follow-ups. Conclusion: Threshold estimates aid in the interpretation of outcomes after first-line OA interventions assessed with NRS Pain and KOOS/HOOS-12. Baseline pain severity is important to consider when interpreting threshold values after first-line interventions in these patients.

Within-person change in patient-reported outcomes and their association with the wish to undergo joint surgery during a digital first-line intervention for osteoarthritis.

AIM: To study the association between within-person changes in patient-reported outcomes (PROMs) and wish for joint surgery during participation in a digital first-line intervention comprising exercise and education for knee/hip osteoarthritis (OA). METHODS: Retrospective observational registry study. Participants enrolled between June 1, 2018 and October 30, 2021, with follow-up data at three months (n = 13,961). We used asymmetric fixed effect (conditional) logistic regressions to study the association between change in wish to undergo surgery at last available time point (3, 6, 9, or 12 months) and improvement or worsening of PROMs pain (0-10), quality of life (QoL) (EQ5D-5L, 0.243-0.976), overall health (0-10), activity impairment (0-10), walking difficulties (yes/no), fear of movement (yes/no), and Knee/Hip injury and Osteoarthritis Outcome Score 12 Items (KOOS-12/HOOS-12, 0-100) function and QoL subscales. RESULTS: The proportion of participants wishing to undergo surgery declined by 2% (95% CI: 1.9, 3.0), from 15.7% at the baseline to 13.3% at 3 months. Generally, improvements in PROMs were associated with reduced likelihood of wishing for surgery, while worsening was associated with increased likelihood. For pain, activity impairment EQ-5D and KOOS/HOOS QoL, a worsening led to a change in the probability of wish for surgery of larger absolute magnitude than an improvement in the same PROM. CONCLUSIONS: Within-person improvements in PROMs are associated with reduced wish for surgery while worsenings with an increased wish for surgery. Larger improvements in PROMs may be needed to match the magnitude of the change in wish for surgery associated with a worsening in the same PROM.

A scoping review of how early-stage knee osteoarthritis has been defined.

BACKGROUND: Early-stage knee osteoarthritis (KOA) classification criteria will enable consistent identification and trial recruitment of individuals with knee osteoarthritis (OA) at an earlier stage of the disease when interventions may be more effective. Toward this goal, we identified how early-stage KOA has been defined in the literature. METHODS: We performed a scoping literature review in PubMed, EMBASE, Cochrane, and Web of Science, including human studies where early-stage KOA was included as a study population or outcome. Extracted data included demographics, symptoms/history, examination, laboratory, imaging, performance-based measures, gross inspection/histopathologic domains, and the components of composite early-stage KOA definitions. RESULTS: Of 6142 articles identified, 211 were included in data synthesis. An early-stage KOA definition was used for study inclusion in 194 studies, to define study outcomes in 11 studies, and in the context of new criteria development or validation in six studies. The element most often used to define early-stage KOA was Kellgren-Lawrence (KL) grade (151 studies, 72%), followed by symptoms (118 studies, 56%), and demographic characteristics (73 studies, 35%); 14 studies (6%) used previously developed early-stage KOA composite criteria. Among studies defining early-stage KOA radiographically, 52 studies defined early-stage KOA by KL grade alone; of these 52, 44 (85%) studies included individuals with KL grade 2 or higher in their definitions. CONCLUSION: Early-stage KOA is variably defined in the published literature. Most studies included KL grades of 2 or higher within their definitions, which reflects established or later-stage OA. These findings underscore the need to develop and validate classification criteria for early-stage KOA.

Digital self-management of hip and knee osteoarthritis and trajectories of work and activity impairments.

OBJECTIVE: To investigate the trajectories of work and activity impairments among people participating in a digital self-management program for osteoarthritis (OA). METHODS: We conducted an observational longitudinal study using data for baseline, 3, 6, 9 and 12 months follow ups from people participating in a digital OA treatment between June 2018 and September 2021. The Work Productivity and Activity Impairment-Osteoarthritis (WPAI-OA) questionnaire was used to measure work and activity impairments. We applied linear mixed models and group-based trajectory modelling (GBTM) to assess the trajectories of work and activity impairments and their variability. Dominance analysis was performed to explore the relative importance of baseline characteristics in predicting the trajectory subgroup membership. RESULTS: A total of 14,676 participants with mean (± standard deviation) age 64.0 (± 9.1) years and 75.5% females were included. The adjusted mean improvements in work impairment from baseline were 5.8% (95% CI 5.3, 6.4) to 6.1% (95% CI 5.5, 6.8). The corresponding figures for activity impairment were 9.4% (95% CI 9.0, 9.7) to 11.3% (95% CI 10.8, 11.8). GBTM identified five (low baseline-declining, moderate baseline-declining, high baseline-declining, very high baseline-substantially declining, and very high baseline-persistent) and three (low baseline-declining, mild baseline-declining, high baseline-declining) subgroups with distinct trajectories of activity and work impairments. Dominance analysis showed that baseline pain was the most important predictor of membership in trajectory subgroups. CONCLUSION: While participation in a digital self-management program for OA was, on average, associated with improvements in work and activity impairments, there were substantial variations among the participants. Baseline pain may provide useful insights to predict trajectories of work and activity impairments.

Incipient dementia and avoidable hospital admission in persons with osteoarthritis.

Objective: To investigate the associations between incipient dementia (ID) and hospitalization for ambulatory care sensitive conditions (ACSCs) among people with osteoarthritis (OA) of the peripheral joints. Methods: Among individuals aged 51-99 years residing in Skåne, Sweden, in 2009, we identified those with a doctor-diagnosed OA and no dementia during 1998-2009 (n â€‹= â€‹57,733). Treating ID as a time-varying exposure, we followed people from January 1, 2010 or their 60th birthday (whichever occurred last) until hospitalization for ACSCs, death, 100th birthday, relocation outside Skåne, or December 31, 2019 (whichever occurred first). Using age as time scale, we applied flexible parametric survival models, adjusted for confounders, to assess the associations between ID and hospitalization for ACSCs. Results: There were 58 and 33 hospitalizations for ACSCs per 1000 person-years among OA people with and without ID, respectively. The association between ID and hospitalization for any ACSCs was age-dependent with higher risk in ages<86 years and lower risks in older ages. Between ages 60 and 100 years, persons with ID had, on average, 5.8 (95% CI 0.9, 10.7), 1.6 (-2.6, 5.9) and 3.1 (2.3, 4.0) fewer hospital-free years for any, chronic and acute ACSCs, respectively, compared with persons without ID. Conclusions: Among persons with OA, while ID was associated with increased risks of hospitalization for ACSCs in younger ages, it was associated with decreased risk in oldest ages. These results suggest the need for improvement in quality of ambulatory care including the continuity of care for people with OA having dementia.

Assessing the importance of predictors of adherence to a digital self­management intervention for osteoarthritis.

OBJECTIVE: Treatment adherence is suggested to be associated with greater improvement in patient outcomes. Despite the growing use of digital therapeutics in osteoarthritis management, there is limited evidence of person-level factors influencing adherence to these interventions in real-world settings. We aimed to determine the relative importance of factors influencing adherence to a digital self-management intervention for hip/knee osteoarthritis. METHODS: We obtained data from people participating in a digital OA treatment, known as Joint Academy, between January 2019 and September 2021. We collected data on the participants' adherence, defined as the percentage of completed activities (exercises, lessons, and quizzes), at 3 (n = 14,610)- and 12-month (n = 2682) follow-up. We used dominance and relative weight analyses to assess the relative importance of sociodemographic (age, sex, place of residence, education, year of enrolment), lifestyle (body mass index, physical activity), general health (comorbidity, overall health, activity impairment, anxiety/depression), and osteoarthritis-related (index joint, fear of moving, walking difficulties, pain, physical function, wish for surgery, Patient Acceptable Symptom State) factors, measured at baseline, in explaining variations in adherence. We used bootstrap (1000 replications) to compute 95% confidence intervals. RESULTS: Mean (SD) adherences at 3 and 12 months were 86.3% (16.1) and 84.1% (16.7), with 75.1% and 70.4% of participants reporting an adherence ≥ 80%, respectively. The predictors included in the study explained only 5.6% (95% CI 5.1, 6.6) and 8.1% (7.3, 11.6) of variations in 3- and 12-month adherences, respectively. Sociodemographic factors were the most important predictors explaining more variations than other factors altogether. Among single factors, age with a nonlinear relationship with adherence, was the most important predictor explaining 2.3% (95% CI 1.9, 2.8) and 3.7% (2.4, 5.3) of variations in 3- and 12-month adherences, respectively. CONCLUSION: Person-level factors could only modestly explain the variations in adherence with sociodemographic characteristics, mainly age, accounting for the greatest portion of this explained variance.

Analysis of Rates of Completion, Delays, and Participant Recruitment in Randomized Clinical Trials in Surgery.

Importance: Discontinuation and nonpublication are established sources of avoidable waste among surgical trials, but rates of delayed completion and recruiting shortfalls remain unclear. Objectives: To examine the rate of delayed completion, incomplete enrollment, and discontinuation among randomized clinical trials in surgical populations and the duration of delays and extent of recruiting shortfalls among these trials. Design, Setting, and Participants: This cross-sectional study examined randomized clinical trials in surgical populations registered on ClinicalTrials.gov between January 1, 2010, and December 31, 2014. Analysis was conducted between October 27, 2021, and June 30, 2022. Main Outcomes and Measures: The main outcomes were the percentages of trials completed on time or with full enrollment. Delays and recruiting shortfalls were identified by comparing projected enrollment and study timeframes prespecified at the time of registration with the actual study duration and enrollment reported on completion or discontinuation. Absolute and relative differences between planned and actual trial conduct were presented for discontinued trials and those completed with delays or recruiting shortfalls. Results: In total, 2542 randomized clinical trials in surgical populations were included in the study sample, of which 370 (14.6%; 95% CI, 13.2%-15.9%) were completed both on time and with full enrollment. Approximately 1 in 5 trials (20.4%; 95% CI, 18.9%-22.0%) were completed within their planned timeframe, and 1166 trials (45.9%; 95% CI, 43.9%-47.8%) met their prespecified enrollment target. The median delay among completed trials was 12.2 months (IQR, 5.1-24.3 months) or 66.7% (IQR, 30.1%-135.8%) longer than planned. Among completed trials that did not meet their prespecified enrollment target, the median recruiting shortfall was equivalent to 31.0% (IQR, 12.7%-55.5%) of the planned study sample. A total of 546 trials (21.5%; 95% CI, 19.9%-23.1%) were discontinued. The median time to discontinuation was 26.4 months (IQR, 15.2-45.7 months), and the median recruiting shortfall among discontinued trials was equivalent to 92.7% (IQR, 65.0%-100.0%) of the trial's prespecified enrollment target. Conclusions and Relevance: This cross-sectional study found that delayed completion, recruiting shortfalls, and untimely discontinuation were common among surgical trials. These findings highlight the importance of ensuring that investigators and funders do not overestimate the feasibility of planned trials.

Association of Traumatic Knee Injury With Radiographic Evidence of Knee Osteoarthritis in Military Officers.

OBJECTIVE: The association between knee injury and knee osteoarthritis (OA) is understudied relative to its importance, particularly in younger populations. This study was undertaken to examine the association of knee injury with radiographic features of knee OA in military officers, who have a physically demanding profession and high rates of knee injury. METHODS: Participants were recruited in 2015-2017 from an existing program that enrolled 6,452 military officers during 2004-2009. Officers with a history of knee ligament or meniscal injuries (n = 117 via medical record review) were compared to officers with no history of knee injury (n = 143). Bilateral posteroanterior knee radiographs were obtained using a standardized fixed-flexion positioning frame. All images were read for Kellgren/Lawrence (K/L) grade, osteophyte (OST), and joint space narrowing (JSN) scores. Data were analyzed using linear-risk regression models with generalized estimating equations. RESULTS: Injured and noninjured participants were similar (mean age 28 years, mean body mass index 25 kg/m2 , ~40% female). The mean time from first knee injury to imaging among injured participants was 9.2 years. Compared with noninjured knees, greater prevalence of radiographic OA (K/L grade ≥ 2), OST (grade ≥ 1), and JSN (grade ≥ 1) was observed among injured knees, with prevalence differences of +16% (95% confidence interval [95% CI] 10%, 22%), +29% (95% CI 20%, 38%), and + 17% (95% CI 10%, 24%), respectively. Approximately 1 in 6 officers with prior knee injury progressed to radiographic OA by age 30 years. CONCLUSION: At the midpoint of a projected 20-year military career, officers with a history of traumatic knee injury have a markedly increased prevalence of knee radiographic OA compared to officers without injury.

An Economic Model for Estimating Trial Costs with an Application to Placebo Surgery Trials.

BACKGROUND AND OBJECTIVE: Waste in clinical trials remains rife. We developed an economic model to predict the cost of trials based on input costs, duration, power, number of sites, recruitment eligibility and consenting rates. METHODS: We parameterised the model for three proxy placebo-controlled surgical trials using data from a systematic review, a bespoke cost survey, and from the literature. We used the model to compare target and actual trial performance for (i) a trial that was completed on time but with more sites, (ii) a trial that completed after a time extension, and (iii) an incomplete trial. RESULTS: Successful trials more accurately anticipated the true recruitment rate that they achieved and those that overestimated this were most likely to fail. The costs of overestimating recruitment rates were dramatic: all proxy trials had significantly higher costs than planned, with additional funding of at least AUD$600,000 (50% above budget) required for trials that completed after adding more sites or more time, and over AUD$2 million (260% above budget) for incomplete trials. CONCLUSIONS: This model shows the trade-offs between time and cost, or both, when recruitment is lower than anticipated. Greater consideration is needed to improve trial planning, reviewing, and funding of these trials to avoid costly overruns and incomplete trials.

Evidence of ACL healing on MRI following ACL rupture treated with rehabilitation alone may be associated with better patient-reported outcomes: a secondary analysis from the KANON trial.

OBJECTIVES: Evaluate the natural course of anterior cruciate ligament (ACL) healing on MRI within 5 years of acute ACL rupture and compare 2-year and 5-year outcomes based on healing status and treatment group. METHODS: Secondary analysis of 120 Knee Anterior Cruciate Ligament Nonsurgical vs Surgical Treatment (KANON) trial participants randomised to rehabilitation and optional delayed ACL reconstruction (ACLR) or early ACLR and rehabilitation. ACL continuity on MRI (Anterior Cruciate Ligament OsteoArthritis Score 0-2) was considered evidence of ACL healing. Outcomes included Knee Injury and Osteoarthritis Outcome Score (KOOS), KOOS patient acceptable symptomatic state (PASS) and treatment failure criteria. Linear mixed models were used to estimate adjusted mean differences (95% CIs) in patient-reported sport and recreational function (KOOS-Sport/Rec) and quality of life (KOOS-QOL) at 2 and 5 years, between participants with MRI evidence of ACL healing and those who had (1) no evidence of ACL healing, (2) delayed ACLR or (3) early ACLR. RESULTS: MRI evidence of ACL healing at 2-year follow-up was observed in 16 of 54 (30%, 95% CI 19 to 43%) participants randomised to optional delayed ACLR. Excluding participants who had delayed ACLR, 16 of 30 (53%, 36-70%) participants managed with rehabilitation-alone displayed MRI evidence of ACL healing. Two-year outcomes were better in the healed ACL group (n=16) compared with the non-healed (n=14) (mean difference (95% CI) KOOS-Sport/Rec: 25.1 (8.6-41.5); KOOS-QOL: 27.5 (13.2-41.8)), delayed ACLR (n=24) (KOOS-Sport/Rec: 24.9 (10.2-39.6); KOOS-QOL: 18.1 (5.4-30.8)) and early ACLR (n=62) (KOOS-Sport/Rec: 17.4 (4.1-30.7); KOOS-QOL: 11.4 (0.0-22.9)) groups. Five-year KOOS-QOL was better in the healed versus non-healed group (25.3 (9.4-41.2)). Of participants with MRI evidence of ACL healing, 63-94% met the PASS criteria for each KOOS subscale, compared with 29-61% in the non-healed or reconstructed groups. CONCLUSIONS: MRI appearance of ACL healing after ACL rupture occurred in one in three adults randomised to initial rehabilitation and one in two who did not cross-over to delayed ACLR and was associated with favourable outcomes. The potential for spontaneous healing of the ACL to facilitate better clinical outcomes may be greater than previously considered. TRIAL REGISTRATION NUMBER: ISRCTN84752559.

Treatment for Acute Anterior Cruciate Ligament Tear in Young Active Adults.

KANON Follow-up AnalysisThis was an extended follow-up analysis from the KANON trial examining the management of acute ACL tears in young active adults. There was no difference in patient-reported outcomes at the 11-year follow-up among patients treated with early surgery versus an initial nonsurgical approach.