Research design
It is a pragmatic, multi-center, randomized managed trial with two parallel teams: [1] conservative therapy (consisting of rehabilitation + non-obligatory delayed surgical procedure) and [2] speedy ACL reconstruction in sufferers with an acute ACL damage.
The protocol is conform the Commonplace Protocol Objects: Suggestions for Interventional Trials (SPIRIT) tips [25] (the SPIRIT guidelines is supplied as Further file 1).
Individuals
Eligibility standards
Individuals eligible for inclusion on this trial should meet all the following standards:
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1.
Rotational trauma to a beforehand non-injured knee for which medical recommendation was sought inside 4 weeks after damage.
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2.
Medical prognosis of ACL insufficiency together with MRI (each partial and full ruptures).
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3.
Minimal of 16 years.
Individuals eligible for this trial should not meet any of the next standards:
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1.
Participant has a historical past of a earlier ACL damage or knee surgical procedure to the index knee.
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2.
Indication for acute surgical procedure due to associated accidents to the knee. (e.g. bucket deal with meniscal tear that ends in a locked knee or intra-articular fractures)
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3.
Feminine who’s pregnant or plans to turn out to be pregnant within the first 4 months of the trial, since MRI evaluation can’t be carried out.
Research setting
This research might be carried out in a number of Belgian hospitals: College Hospital of Leuven, Clinique Saint-Luc Bouge, Jessa Ziekenhuis Hasselt,, and College Hospital of Liège. Sufferers might be recruited on the Division of Orthopaedics and the Division of Bodily Drugs and Rehabilitation of the collaborating websites. Moreover, so as to make sure the requested pattern measurement, extra websites might be chosen in the middle of the research.
Affected person identification and screening
Sufferers launched to any of the collaborating websites with an acute ACL damage might be assessed for eligibility. In recurring follow, sufferers who might need an ACL damage typically current themselves on the emergency care unit and/or are referred to both (1) the Division of Bodily Drugs and Rehabilitation or (2) the Orthopaedic Division. The screening and identification technique might be carried out equally.
Like traditional follow, in the course of the preliminary session (V0), a bodily examination of the knee together with medical exams to diagnose ACL accidents and a affected person historical past might be taken by a medical physician. Based mostly on these findings the hypothesis of an ACL damage may be supported or rejected. If the medical exams had been constructive, an MRI is scheduled to verify the ACL tear. Moreover, if all different inclusion standards are checked, the medical physician will already inform the affected person in regards to the risk to be included within the research.
Through the second session (V1) with the medical physician, the findings of the MRI are mentioned. If the ACL tear is confirmed, the medical physician asks if there may be curiosity in collaborating within the research. If the affected person needs to be concerned on this research, he/she is referred to the appointed research assistant for additional eligibility checks and additional details about the research. If the medical physician confirms the eligibility and the affected person agrees upon participation, knowledgeable consent might be signed by each the investigator and the affected person.
To optimize recruitment and never miss potential candidates, the research nurse of the collaborating middle will weekly examine the planning of each the orthopedic and bodily medication division and remind the medical docs of all potential candidates. Moreover, common contact with the emergency division is important to make sure that all related sufferers on the emergency division are accurately referred to both a session on the Division of Bodily Drugs and Rehabilitation or the Division of Orthopedics.
Screening logs might be applied at every recruiting web site to doc the explanations for non-inclusion within the research (e.g., the rationale for decline or exclusion).
Interventions
The research compares two commonplace therapy choices for an acute ACL damage: [1] conservative therapy with non-obligatory delayed ACL reconstruction and [2] surgical therapy consisting of speedy ACL reconstruction and rehabilitation. We is not going to deviate from present follow, aside from the randomization, to maintain the trial pragmatic. Therefore, the research doesn’t predetermine the kind of ACL reconstruction and sufferers will select their very own physiotherapist for the rehabilitation. Nonetheless, to ensure a minimal high quality of rehabilitation, which is essential for the integrity of the comparability, we’ll present evidence-based tips and development standards for ACL rehabilitation to the physiotherapists.
Conservative therapy consisting of rehabilitation and non-obligatory delayed ACL reconstruction
Rehabilitation
Sufferers on this therapy arm will full rehabilitation with their physiotherapist. As talked about above, the physiotherapist will obtain evidence-based tips and standards for ACL rehabilitation. Nonetheless, there may be sufficient flexibility in how the physiotherapist needs to use these tips in medical follow. The rules are primarily based on present literature [26,27,28]. The rehabilitation protocol includes three phases (see under), and development relies on goal-based standards, not time primarily based. If the particular objectives of the earlier section are achieved, sufferers can progress to the following section. We ask the participant to fill in a modified model of the Train Adherence Score Scale (EARS) [29] (see outcomes) to judge the standard of the rehabilitation, at each follow-up go to (go to 3–7, see Desk 1). The EARS consists of a number of questions on completely different workouts carried out, the depth and frequency of the rehabilitation program, and limitations and facilitators for adherence to the predefined workouts.
Indications for delayed surgical procedure
If a affected person of the conservative therapy group complains about constant symptomatic instability of the knee that stops rehabilitation development, a delayed surgical procedure may be thought of. A constructive pivot shift together with ACL insufficiency-induced instability and an extra MRI are wanted to verify the reason for instability (Standards primarily based on the KANON trial [1]). In accordance with present follow, delayed surgical procedure is not going to be carried out throughout the first 12 weeks post-injury.
Quick ACL reconstruction and rehabilitation
ACL reconstructive surgical procedure
We is not going to impose any tips on the kind of ACL reconstruction to maintain the trial pragmatic. The choice on graft sort and surgical procedure method is a medical determination made by the orthopedic surgeon of the collaborating middle. All surgical procedure particulars might be famous within the affected person register and may be retrieved if vital. Though the research doesn’t predetermine the kind of surgical procedure, we’ll impose strict standards for the timing of the surgical procedure. The speedy ACL reconstruction have to be carried out inside 12 weeks after the ACL damage. This to keep away from that sufferers of the speedy ACL reconstruction already had a substantial quantity of pre-operative physiotherapy classes, thus retaining a transparent distinction between each teams.
Rehabilitation
The identical goal-based rehabilitation protocol might be utilized as within the intervention group (see Desk 2). Nonetheless, relying on the kind of surgical procedure, a while restrictions relating to vary of movement and weight-bearing may be imposed by the surgeon. In that case, the physiotherapist has to barely adapt the rehabilitation protocol. Rehabilitation begins the primary days after surgical procedure. Moreover, additionally preoperative rehabilitation classes may be carried out.
Outcomes
Major outcomes
The Knee Harm and Osteoarthritis End result Rating (KOOS) QOL is the first final result of this research. The KOOS collects information on 5 knee-specific patient-centered outcomes: ache, signs, ADL, sport and leisure operate (Sport/Rec), and knee-related QOL. Since most ACL sufferers report no or solely small points with ache, signs, and ADL operate preoperatively there may be much less room for enchancment on these subscales, and due to this fact the subscales Sport/Rec and QOL are advisable for follow-up ACL sufferers [30, 31]. We selected the subscale QOL as the first final result since not all individuals might be concerned in sports activities, and due to this fact the Sport/Rec is much less helpful in our trial. Standardized reply choices are given on a Likert scale, and every query is assigned a rating from 0 to 4. A normalized rating is calculated for every subscale (100 indicating no signs and 0 indicating excessive signs). Take a look at-retest reliability of the KOOS [32] is excessive with ICC values between 0.83 and 0.95 for KOOS QOL and between 0.61 and 0.95 for the opposite subscales. The minimal detectable change is 7-7.2 for the KOOS QOL and between 5 and 12 for the opposite subscales [32].
Secondary outcomes
The Knee Harm and Osteoarthritis End result Rating (KOOS)
subscales: ache, signs, ADL, sport and leisure operate [22].
Worldwide Knee Documentation Committee Subjective Knee Type (IKDC subjective)
this questionnaire administers affected person’s notion of knee signs throughout actions of every day dwelling and sports activities actions. This questionnaire consists of 18 objects and a complete rating is calculated (vary 0-100, with larger scores representing decrease ranges of signs, larger ranges of operate and participation) [33].
Modified Tegner Rating
this scale might be used to grade the exercise degree of the sufferers [34]. A rating is given from 1 (sick go away or incapacity pension due to knee issues) to 10 (aggressive sports activities) primarily based on the very best degree of actions the affected person performs recurrently. Beside the present exercise degree, we may also ask the pre-injury exercise degree to find out when the affected person returned to regular actions.
Sickness notion questionnaire (IPQ-R)
the sickness perceptions questionnaire measures sufferers’ beliefs and emotions about their sickness (resembling whether or not they suppose the sickness may be cured or managed by their therapy) [35].
Tampa Scale for Kinesiophobia
this questionnaire measures the worry of motion. It’s a 11 merchandise scale that makes use of a 4-point likert scale. Psychological components resembling worry of motion is likely to be an essential predictor of final result after ACL damage, no matter surgical therapy or not. Hartigan et al. (2013) confirmed for instance that kinesiophobia is expounded to knee operate after surgical procedure [36].
The EQ-5D-5 L questionnaire
this questionnaire measures generic well being standing in 5 dimensions: mobility, self-care, traditional actions, ache/discomfort and nervousness/despair. Every dimension has 3 ranges: no issues, average issues and excessive issues. The sum of the rating on the 5 dimensions describes the affected person’s well being state. We are going to administer this questionnaire for the financial analysis to compute quality-adjusted life years (QALYs).
Practical exams
The one leg hop for distance. This useful take a look at assesses knee useful efficiency. The affected person might be requested to leap so far as potential on one leg (push-off and touchdown on similar leg). After the touchdown, the affected person has to maintain steadiness for 3 s with out shuffling on the stance leg. The affected person will performs 3 trials on the injured leg and three trials on the unhurt leg. Subsequently the limb symmetry index (LSI) might be calculated by dividing the gap jumped on the injured leg by the gap jumped on the contralateral, unhurt leg [37]. This take a look at is usually used to resolve on return-to-sport, with an LSI > 90% as criterium for readiness for return-to-sport [38].
Isokinetic power of the quadriceps and hamstrings. Isokinetic power of the quadriceps and hamstrings might be measured on an isokinetic dynamometer (Biodex or Cybex). This to evaluate restoration of power. For each the quadriceps and hamstrings maximal concentric power might be measured at 60°/sec and 240°/sec. Much like the only leg hop for distance, the symmetry between the power of the injured leg and unhurt leg might be calculated. Once more an LSI of > 90% is usually used as criterium for readiness for return-to-sport as a rating < 90% is correlated with elevated threat for re-injury threat after ACL reconstruction [38, 39].
Adversarial occasions
Adversarial occasions resembling surgical issues, arthrofibrosis, an infection and any extra acute damage to the ipsilateral or contralateral knee (resembling re-injury, graft-rupture or contralateral ACL damage, laesions of menisci, cartilage or ligament,… ) might be registered at each follow-up go to.
Return to work/ return to pre-injury exercise degree
A custom-made questionnaire might be developed to manage the next information: days of sick-leave, earlier and present occupational degree, sort of job, job-related actions, pre-injury sport degree and time to return to pre-injury exercise degree.
Rehabilitation
A custom-made questionnaire is developed to gather details about the rehabilitation: the frequency (quantity of classes per week) and depth of physiotherapy classes, whether or not the rehabilitation concerned energetic train remedy, the kind of workouts and whether or not the affected person carried out workouts at dwelling or within the health club. An inventory of workouts is supplied. The affected person has to examine which workouts had been carried out in the course of the rehabilitation. and whether or not the affected person carried out workouts at dwelling or power coaching (in a health middle).
The anterior cruciate ligament OsteoArthritis rating (ACLOAS)
This scoring system might be used to attain and monitor structural knee joint injury on MRI [40]. The next joint options are assessed with this scoring system: acute osteo-chondral accidents, traumatic and degenerative bone marrow lesions, meniscus morphology and extrusion, osteophytes, collateral and cruciate ligaments together with ACL graft, Hoffa-synovitis and effusion-synovitis. Along with the MRI options assessed with the ACLOAS, the next MRI options might be assessed to detect restoration of the ACL: slope of ACL with respect to the Blumensaat line, distance between the Blumensaat line and the ACL, bounderies and pressure of the ACL [16].
Central MRI studying
All pseudonymized MRI pictures might be scored by one central reader. This central reader might be a doctor with experience in musculoskeletal imaging. The central reader scores the photographs in keeping with ACLOAS.
Timeline
An summary of all assessments that might be carried out on the completely different research visits may be present in Desk 1. 5 follow-up visits are deliberate: at 4 and seven, 12, 24 and 36 months after randomization see Fig. 1.
Trial movement chart
V1 = go to 1
Pattern measurement
The end result(s) on which the pattern measurement calculation relies upon is the KOOS QOL, a self-administered questionnaire. The end result for the non-inferiority evaluation is the change on the KOOS QOL between the baseline measurement and 1 yr after randomization. The pattern measurement was calculated utilizing the ability process in SAS 9.4 to indicate with 80% of energy that conservative therapy isn’t inferior to plain therapy, the place a non-inferiority margin of seven (change-points) was adopted primarily based on the research of Collins et al. who report a minimal detectable change in KOOS QOL of seven factors [33]. The evaluation consists in estimating the distinction in imply change-scores between each therapy arms with a one-sided 95% confidence interval (Akin to a 5% significance degree). Non-inferiority might be concluded when the decrease restrict of the arrogance interval might be above the non-inferiority margin of -7. An equal therapy impact in each arms and an ordinary deviation for the change-score of 19 had been assumed for the pattern measurement calculation [1]. Assuming a drop-out of 10%, a complete variety of 260 sufferers is required for randomization. For the superiority evaluation the pattern measurement was calculated to display with a two-sample t-test a distinction between the 2 therapy teams with respect to the change in KOOS QOL rating at 7 months follow-up in comparison with post-injury. Contemplating equal group sizes, a two-sided 5% significance degree, 90% energy, the smallest essential distinction as 13.5 change-points [31] an ordinary deviation of 18 for the change in KOOS QOL versus baseline [31], and a ten% drop-out fee, the calculation signifies a complete pattern measurement of 88 sufferers. Moreover, the 5% significance degree was adopted since a hierarchy of statistical testing might be used. Provided that the non-inferiority take a look at is important at 12 months, the take a look at of superiority at 7 months might be carried out since superiority is judged vital to alter follow. Moreover, a prediction mannequin might be constructed within the intervention group (rehabilitation and non-obligatory delayed ACL reconstruction) with the occasion of delayed surgical procedure as binary final result and the place an preliminary set of the 5 predictor variables described above might be thought of. Following the rule of thumb of together with at the least 10 occasions per parameter within the mannequin, this evaluation requires at the least 50 occasions (i.e. delayed surgical procedures within the experimental group). Assuming that 1/3 of sufferers within the experimental group will want delayed surgical procedure (KANON Trial), a minimal of 150 sufferers might be wanted within the intervention group so as to develop such a prediction mannequin.
Randomization
Random sequence era (laptop generated, utilizing block randomisation) might be carried out and allocation might be hid. An allocation ratio of 1:1.15 might be utilized (130 sufferers allotted to speedy ACL reconstruction and 150 sufferers allotted to conservative therapy). With this we adjust to the pattern measurement calculation. We could have (1) minimal 130 sufferers per arm for the first evaluation and (2) 150 sufferers within the conservative arm for the secondary evaluation. At every collaborating web site, the accountable research nurse/principal investigator could have entry to the randomisation device in REDCap.
To make sure the integrity of the Trial: the randomization listing might be ready by a statistician not concerned within the trial. The randomization listing might be integrated within the information administration device ‘REDCap’. In spite of everything sufferers have completed the Trial and the database is locked, the randomization code might be damaged for evaluation of response information.
Blinding
Given the character of the trial, blinding of individuals and care suppliers isn’t possible.
Information collectors and information analysts might be blinded to the extent potential. Outcomes might be collected in the identical means in each teams, e.g. by electronical questionnaires for which assessors and collectors may be blinded. Nonetheless, due to the subjective and self-reported nature of the outcomes being assessed, detection bias could also be a possible threat of bias. In spite of everything individuals have accomplished the Trial, the database might be locked and the collected Trial information might be unblinded to permit evaluation of the Trial information.
Statistical analyses
The first analyses might be carried out on the intention-to-treat (ITT) inhabitants (topics are included within the teams to which they had been randomly assigned, even when they didn’t full their therapy). For instance, topics within the conservative group that underwent ACL reconstruction or topics within the early reconstruction group that didn’t bear reconstruction. This alternative was primarily based on the primary goal of this trial: informing medical docs which technique (speedy ACL reconstruction or conservative with non-obligatory delayed surgical procedure) is most applicable after acute ACL damage and due to this fact assist them in decision-making to bear speedy ACL reconstruction or not. This ITT evaluation will carefully mirror on a regular basis follow as in actual life; sufferers is not going to at all times adhere to both remedy’s recommendation.
The as-treated inhabitants contains topics in teams as to how they had been handled. This post- hoc as-treated evaluation will lead to 3 teams: rehabilitation alone, rehabilitation plus early ACL reconstruction, and rehabilitation plus delayed ACL reconstruction. Nonetheless, this evaluation will solely be explorative as this might be a non-randomized comparability that may in all probability be biased.
Major final result evaluation
The first evaluation will evaluate the intervention group with the management group on their imply change in KOOS QOL at 2 main endpoints:
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1)
Non-inferiority testing at 1 yr post-injury.
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2)
Superiority testing at 7 months post-injury.
A one-sided 95% confidence interval for the imply distinction between teams excluding 7 models within the drawback of the conservative therapy might be thought of as an indication of non-inferiority at 1 yr. A two-sided 95% confidence interval for the imply distinction between teams excluding 13.5 models within the benefit of the conservative therapy might be thought of as an indication of superiority at 7 months.
Estimation and testing of those imply variations might be primarily based on a single evaluation mannequin. A linear mannequin for repeated measurements might be used, utilized to final result measures in any respect time factors, modelling an unstructured residual variance-covariance matrix to cope with correlations as a result of longitudinal information construction. In comparison with separate cross-sectional analyses, this strategy improves the ability and minimizes the consequences of potential bias resulting from drop-out. All sufferers with at the least one final result measurement are included within the evaluation, even when they’d no final result measured at 7 or 12 months. The mannequin contains group, time-point and group by time-point interplay as results. The imply variations between the teams at 7 and 12 months and their confidence intervals might be estimated as post-hoc exams primarily based on this mannequin. Given the hierarchical strategy of statistical testing (superiority testing provided that non-inferiority is demonstrated), no correction for a number of testing might be carried out.
The first evaluation might be utilized to the ITT inhabitants. Sufferers with out final result measures aside from baseline might be excluded.
Secondary final result evaluation
Imply variations at different time-points are obtained as extra post-hoc exams from the mannequin used for the first evaluation. The evaluation of secondary final result variables might be carried out analogously to the first evaluation. A sensitivity evaluation might be carried out, repeating the first evaluation utilizing a number of imputation to cope with sufferers that don’t have any final result measures aside from baseline.
Prediction evaluation
A prediction mannequin might be ran on the intervention group (rehabilitation with non-obligatory delayed ACL reconstruction). Based mostly on 5 variables we need to assess whether or not it’s potential to foretell whether or not the sufferers within the intervention group will want surgical procedure or not (binary final result). The occasion of ‘delayed surgical procedure’ was thought of as binary final result and never as time-to-event for the reason that principal query is to analyze whether or not it’s potential to foretell who will want a delayed surgical procedure. The timing of the delayed surgical procedure is much less related because the timing is usually influenced by a number of private components resembling work, college, vacation and likewise by the supply of the surgeon and so forth.
A logistic regression mannequin might be used and a backward choice process might be utilized for mannequin choice. The efficiency of the mannequin might be quantified by the world below the ROC curve (AUC). Inner validation might be carried out by the use of a leave-one-out cross validation technique to acquire a extra real looking estimate of the mannequin efficiency.
Explorative evaluation
The same technique of research as described for the first evaluation (intention-to-treat) might be utilized to the as-treated analyses.
Information monitoring
Entry to information
The investigator will allow trial-related monitoring, audits, ethics committee evaluate, and regulatory inspection, offering direct entry to all associated supply information/paperwork.
On the finish of the trial, the funder (KCE) could have entry to the research information. This can solely be the pseudonymized research information.
Security recording and reporting
The chance of hostile occasions (AE) occurring as a result of intervention on this trial is unlikely. Due to this fact, security reporting might be restricted to the security reporting vital for routine care. The participant might be requested to report any hostile occasion associated to the study-specific intervention to the research group. The next hostile occasions might be registered at each follow-up go to: surgical issues, arthrofibrosis, an infection, any extra acute damage to the ipsilateral or contralateral knee (resembling re-injury, graft-rupture or contralateral ACL damage, lesions of menisci, cartilage or ligament,… ).
These reported occasions might be documented by the investigator within the supply paperwork. As well as, the next minimal data must be recorded for every hostile response by the reporting investigator (AE description, begin and cease date of the AE, severity, seriousness, causality evaluation to the research interventions, and final result). The sponsor will hold detailed information of all AEs reported to him by the investigators and can consider for seriousness, causality, and expectedness.
Protocol amendments
Any modifications to the protocol which can influence the conduct of the research, the potential advantage of the affected person, or might have an effect on affected person security, together with modifications in research targets, research design, affected person inhabitants, pattern sizes, research procedures, or important administrative facets would require a proper modification to the protocol. The trial steering committee will agree upon such modification, add to the trial registration on medical trials.gov, and approve by the Ethics Committees earlier than implementation.