Blinded MRI analysis demonstrated that BST-CarGel®-treated patients showed a significantly greater treatment effect for lesion filling (P = ) over 5 years. BST-CarGel is an advanced bioscaffold technology for enhancing cartilage regeneration. BST-CarGel was developed to stabilize the blood clot in the cartilage lesion by dispersing a soluble and adhesive polymer scaffold containing chitosan.
|Published (Last):||19 May 2013|
|PDF File Size:||6.67 Mb|
|ePub File Size:||15.86 Mb|
|Price:||Free* [*Free Regsitration Required]|
This report was undertaken to investigate 5-year structural and clinical outcomes. The international randomized controlled trial enrolled 80 patients, aged 18 to 55 years, with grade III or IV focal lesions on the femoral condyles. General estimating equations were used for longitudinal statistical analysis of repeated measures. Safety was comparable for both groups. The search for a solution to problematic articular cartilage lesions continues despite decades of orthopedic experience in the knee.
None of the current repair procedures, which include bone marrow stimulation, cultured cell-based therapies, and grafting, have been studied sufficiently, particularly in the mid to long term yearsto fully understand which factors dictate longer term outcomes for this troublesome pathology. Microfracture MFXthe de facto standard of care and the most commonly used first-line surgical treatment 67 for small cartilage lesions, is the deliberate penetration of the subchondral bone below a cartilage lesion to elicit bleeding and a subsequent bone marrow—derived repair response.
Chitosan is an abundant glucosamine polysaccharide found in the exoskeleton of crustaceans and has many desirable biomaterial properties.
The full description of the methodology used in the original 1-year multicenter RCT https: The same follow-up procedures and outcome methodologies were applied in the 5-year extension protocol https: The initial 1-year trial 26 enrolled 80 patients at 26 clinical sites. Patients were randomized 1: The trial was single-blind since the independent third party carrying out the analyses of primary endpoints was unaware of patient treatment.
Investigators and patients were not blinded because of differences in incision size related to treatment. The extension protocol was originally designed dargel provide bsr term follow-up at 2, 3, 4, and 5 years and followed identical outcome measures.
All subjects who participated in the initial 1-year trial were asked to provide written informed consent prior to study activities to be part of this extension study, which was approved by the institutional review boards at each of the clinical sites prior caggel initiation of activities.
Repair tissue structure, defined as both the quantity and quality of new tissue, was assessed as the primary outcome. Customized high—spatial resolution pulse sequences specific for morphological or T2 relaxation time analyses of regions of interest were used.
For morphological carvel of cartilage, cartilage lesions and bone, both coronal and sagittal 3-dimensional fat-suppressed spoiled gradient echo SPGRand sagittal 3-dimensional gradient echo GRE sequences were used. Sagittal fat-suppressed dual echo fast hst echo sequences were used for transverse relaxation time T2 analyses. All blinded scans were sent to imaging core labs for centralized scan quality review and storage VirtualScopics, Rochester, NY and blinded quantitative analysis Qmetrics Technologies, Rochester, NY using validated techniques.
The quantification of lesion and repair biomarkers used proprietary, semiautomated radiologist-corrected morphological segmentation with a programmed anatomical atlas for all knee bone and cartilage structures. A musculoskeletal radiologist with expertise in cartilage repair manually traced the lesion boundaries on the 1-month posttreatment scan, which provided the reference for co-registration with 1- 3- 4- and 5-year scans.
Debrided lesions quantified using 1-month posttreatment scans represented baseline values for lesion surface area and volume. Further details and illustrations in Stanish et al.
Clinical benefit was evaluated as a secondary outcome at initiation, 2, 3, 4, and 5 years posttreatment using the WOMAC questionnaire consisting of 3 subscales: Pain, Stiffness, and Physical Function. Safety was assessed through recording of all adverse events AEs caegel to 5 years posttreatment. The safety definitions used during this trial conformed to international regulatory norms for clinical trials investigating medical devices. The tertiary endpoint was the Medical Outcomes Study Item Short-Form Health Survey version 2 SF30 which includes 2 aggregate measures, the physical and mental components, derived from 8 subscales.
All questionnaires were sbt to patients during on-site study visits or by mail as needed.
There was a problem providing the content you requested
Sample size determination for the 1-year trial was previously reported. The bootstrap method was used to account for sample size differences. Data were analyzed using the Statistical Analysis System software version 9. All reported P values are 2-sided. P values of less than 0.
Screening and enrollment for the initial 1-year trial took place from May to Januaryand 1-year follow-up was concluded in February Screening and enrollment into the extension study took place from March to October and the 5-year follow-up was concluded in February The extension study suffered patient loss to follow-up at all planned time points due to several factors, including extremely protracted enrolment periods for both the initial 12 month trial and the extension study, compounded by financial bankruptcy of the original trial sponsor BioSyntech Canada Inc.
The delayed initiation of the extension study regretfully allowed all but 4 patients to surpass their 2-year follow-up time point, and many others to pass their 3- 4- and 5-year time points prior to enrolling into the extension study. Only 2 patients had complete data for 1, 2, 3, 4, and 5 years. A statistical comparison of baseline characteristics of those patients who did not enroll into the extension enrolment with those who did, found that enrolled patients had significantly higher BMIs, larger treated lesion areas, and attended more posttreatment physiotherapy sessions than those that did not enroll, but were similar for all other parameters.
Longitudinal analysis of repeated measures using general estimating equations GEE for the quantity and quality of repair cartilage over 5 years posttreatment. Values represent least squares means adjusted for lesion volume and the standard error. B Repair tissue T2 relaxation times: Mean T2 is derived from the entire repair cartilage volume. Dashed line represents mean ipsilateral native cartilage T2 value.
Values represent means and standard errors. Lower numbers represent better outcomes. Values represent mean change from baseline adjusted for baseline and standard errors. Overall, both trial treatments were well tolerated and the safety profiles were considered comparable. During the 5-year follow-up period, 54 AEs were reported in 31 individual patients, 13 One 1 serious AE SAE was reported by 1 subject in the MFX group, which was moderate in severity and not related in any way to the study treatment or index knee but required surgery and radiotherapy.
Limited information was released by the patient except that the SAE was ongoing at the time of the 5-year follow-up period.
No patient in either treatment group was discontinued from the study because of an AE, SAE, or incident. There were no deaths over the 5-year period of the study.
BST-CarGel ® – Smith & Nephew – PDF Catalogs | Technical Documentation
The baseline characteristics for the patients included in this 5 year analysis were generally well-balanced, except for a few notable exceptions: None of the characteristics were found to be significant covariates leading to bias during sensitivity analyses, despite reports that clinical outcomes after microfracture are age dependent.
Unique to this trial was the new level of evidence brought by the use of validated 3-dimensional quantitative MRI, which assessed the structural outcomes of repair tissue quantity and quality over 5 years with a high level of standardization and precision not previously achieved in a Good Clinical Practice—compliant RCT for cartilage repair.
T2 or transverse relaxation time is well known to be sensitive to, and highly dependent on, the extracellular cartilage matrix and particularly the collagen network structure, orientation, as well as macromolecular concentration, and tissue hydration. This interpretation for T2 MRI and its relationship to collagen organization is substantiated by a previous statistical correlation between T2 and polarized light microscopy scoring of 38 repair tissue biopsies retrieved at 1 year posttreatment in this same study.
The equivalent clinical improvement between groups was an expected finding for 2 predictable reasons. First, the study was not powered for a clinical benefit endpoint. Second, optimal MFX surgical technique was strictly obeyed in both groups. The equivalent clinical improvements found in this trial add to accumulating evidence that when performed properly, 9 microfracture can effectively improve clinical pain and function for the mid- to long-term despite the widely purported clinical outcome expectancy of 2 to 3 years linked to a mechanically deficient fibrocartilaginous repair tissue and excessive intralesional bony overgrowth.
When it did occur, it was linked to a predisposing factor e. A possible explanation of the reported short-term success MFX could be the fact that orthopedic surgeons practicing MFX are often not performing critical steps of the technique as published originally by Steadman et al.
Ultimately, the determination of what factors are predictive of clinical outcome following cartilage repair will be multivariate, considering the numerous patient-specific and cartilage lesion—specific variables.
Patient age, 31505556 BMI, 3257 time from onset of symptoms, 3456 gender, lesion size, and location are all relevant, 58 although other procedure-based parameters such as technical aspects of the surgical treatment and postoperative rehabilitation 5859 could also play critical roles.
Consequently, the correlation between repair tissue structure and clinical outcomes has been elusive. Several studies have reported relationships between structural assessments and long-term clinical outcomes, but these studies suffer from small sample sizes, statistical rigor, and subjective scoring of both the structural and the clinical components.
Previous studies have been limited to subjective semiquantitative MRI analysis using MOCART 64 or Henderson scores 65 and none used quantitative 3-dimensional analysis cargfl structural assessments as described in this study. There is currently no consensus regarding the optimal patient-based instruments for outcome assessments in cartilage repair. Some have been validated but are insensitive and incomplete. Clearly, more and longer studies are required both with structural tools and patient-reported clinical measures that are specific enough to detect improvements following cartilage repair before the relationship between clinical and structural outcomes will emerge.
Thus, with clinical benefit being shown at acceptable levels for most cartilage repair therapies 33346768 and for significantly long follow-up periods, superiority of one therapy or technique falls to the structure of the replaced or regenerated cartilage within the lesion, such as was found in this trial. It can be easily argued that a sufficient quantity of repair cartilage with hyaline features enables appropriate articulation, biomechanical loading, and tissue metabolism, which would be necessary for long-term durability and function.
Furthermore, repair tissue structure represents a reliable clinical trial endpoint since hyaline cartilage has an exquisite structure characterized by hallmark features, including collagen content and zonal organization, glycosaminoglycan, and cell population, 69 which can be easily discriminated by highly accurate quantitative measures sensitive to early changes in cartilage structure under reasonable clinical trial time frames.
Furthermore, the trial outcomes reported here at 5 years are likely conservative estimates since 2 negative prognosticators, higher BMIs and larger lesions, were bsr in the enrolled patients compared with those who did not enroll in the extension study, although neither were found to be significant statistical covariates.
This investigation was bdt at 26 clinical sites in Carvel, Spain, and South Korea complete list is given in the Acknowledgments section. Declaration of Conflicting Interests: One or more of the authors received payments, either directly or indirectly i. Piramal Healthcare Canada Ltd. Data collection and blinded analyses were conducted by third parties as described herein. The extension study protocol https: National Center for Biotechnology InformationU.
Journal List Cartilage v. Shive1 William D. Shive 1 Piramal Healthcare Canada Ltd. Author information Copyright and License information Disclaimer. This article has been cited by other articles in PMC.
Trial Detail – UK Clinical Trial Gateway
Design The international randomized controlled trial enrolled 80 patients, aged 18 to 55 years, with grade III or IV focal lesions on the carge condyles. Introduction The search for a solution to problematic articular cartilage lesions continues despite decades of orthopedic experience in the knee. Materials and Methods The full description of the methodology used in the original 1-year multicenter RCT https: Study Design and Participants The initial 1-year trial 26 enrolled 80 patients at 26 clinical sites.
Outcome Measures Primary Outcome Repair tissue structure, defined as both the quantity and quality of new tissue, was assessed as the primary outcome. Secondary and Tertiary Outcomes Clinical benefit was evaluated as cargwl secondary outcome at initiation, 2, 3, 4, and carvel years posttreatment using the WOMAC questionnaire consisting of 3 subscales: Statistical Analysis Sample size determination for the 1-year trial was previously reported.
Results Enrollment and Baseline Characteristics of the Patients Screening and enrollment for the initial 1-year trial took place from May to Januaryand 1-year follow-up was concluded in February