The Journal of Bone & Joint Surgery

The Journal of Bone & Joint Surgery, Volume 94, Issue 11

Scientific Articles | June 06, 2012

NeoCart, an Autologous Cartilage Tissue Implant, Compared with Microfracture for Treatment of Distal Femoral Cartilage Lesions: An FDA Phase-II Prospective, Randomized Clinical Trial After Two Years

Dennis C. Crawford, MD, PhD¹; Thomas M. DeBerardino, MD²; Riley J. Williams, III, MD³

¹ Department of Orthopaedics and Rehabilitation, Oregon Health and Science University, 3181 S.W. Sam Jackson Park Road, Mail Code OP31, Portland, OR 97239. E-mail address: crawfden@ohsu.edu
² Department of Orthopaedics, University of Connecticut Health Center, 263 Farmington Avenue, MARB 4, Farmington, CT 06034-4037
³ Sports Medicine and Shoulder Service, Hospital for Special Surgery, 535 East 70th Street, New York, NY 10021

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Investigation performed at Oregon Health and Science Center, Portland, Oregon; Keller Army Community Hospital, West Point, New York; Duke Sports Medicine Center, Durham North Carolina; University of California, San Francisco California; TRIA Orthopaedic Center, Bloomington, Minnesota; and the Hospital for Special Surgery, New York, NY

J Bone Joint Surg Am, 2012 Jun 06;94(11):979-989. doi: 10.2106/JBJS.K.00533

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Abstract

Background:

Despite introduction of autologous chondrocyte therapy for repair of hyaline articular cartilage injury in 1994, microfracture remains a primary standard of care. NeoCart, an autologous cartilage tissue implant, was compared with microfracture in a multisite prospective, randomized trial of a tissue-engineered bioimplant for treating articular cartilage injuries in the knee.

Methods:

Thirty patients were randomized at a ratio of two to one (two were treated with an autologous cartilage tissue implant [NeoCart] for each patient treated with microfracture) at the time of arthroscopic confirmation of an International Cartilage Repair Society (ICRS) grade-III lesion(s). Microfracture or cartilage biopsy was performed. NeoCart, produced by seeding a type-I collagen matrix scaffold with autogenous chondrocytes and bioreactor treatment, was implanted six weeks following arthroscopic cartilage biopsy. Standard evaluations were performed with validated clinical outcomes measures.

Results:

Three, six, twelve, and twenty-four-month data are reported. The mean duration of follow-up (and standard deviation) was 26 ± 2 months. There were twenty-one patients in the NeoCart group and nine in the microfracture group. The mean age (40 ± 9 years), body mass index (BMI) (28 ± 4 kg/m²), duration between the first symptoms and treatment (3 ± 5 years), and lesion size (287 ± 138 mm² in the NeoCart group and 252 ± 135 mm² in the microfracture group) were similar between the groups. Adverse event rates per procedure did not differ between the treatment arms. The scores on the Short Form-36 (SF-36), Knee Injury and Osteoarthritis Outcome Score (KOOS) activities of daily living (ADL) scale, and International Knee Documentation Committee (IKDC) form improved from baseline (p < 0.05) to two years postoperatively in both treatment groups. In the NeoCart group, improvement, compared with baseline, was significant (p < 0.05) for all measures at six, twelve, and twenty-four months. Improvement in the NeoCart group was significantly greater (p < 0.05) than that in the microfracture group for the KOOS pain score at six, twelve, and twenty-four months; the KOOS symptom score at six months; the IKDC, KOOS sports, and visual analog scale (VAS) pain scores at twelve and twenty-four months; and the KOOS quality of life (QOL) score at twenty-four months. Analysis of covariance (ANCOVA) at one year indicated that the change in the KOOS pain (p = 0.016) and IKDC (p = 0.028) scores from pretreatment levels favored the NeoCart group. Significantly more NeoCart-treated patients (p = 0.0125) had responded to therapy (were therapeutic responders) at six months (43% versus 25% in the microfracture group) and twelve months (76% versus 22% in the microfracture group). This trend continued, as the proportion of NeoCart-treated patients (fifteen of nineteen) who were therapeutic responders at twenty-four months was greater than the proportion of microfracture-treated participants (four of nine) who were therapeutic responders at that time.

Conclusions:

This randomized study suggests that the safety of autologous cartilage tissue implantation, with use of the NeoCart technique, is similar to that of microfracture surgery and is associated with greater clinical efficacy at two years after treatment.

Level of Evidence:

Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.

Figures in this Article

Introduction

Introduction | Materials and Methods | Results | Discussion

Articular cartilage has a poor capacity for repair, and articular cartilage injuries often result in pain and compromised joint function. In addition, injury to hyaline cartilage may be considered a primary risk factor for the development and progression of osteoarthritis^1,2. In 1994, Brittberg et al. reported using clonally expanded autogenous chondrocytes injected below a periosteal patch in sixteen patients³. Histological analysis of random biopsy specimens indicated the presence of type-II collagen within the healing tissue; this finding increased interest in this cell-based therapy and the potential for hyaline tissue repair. Subsequent clinical outcome trials have demonstrated the clinical benefit of this autologous chondrocyte implantation procedure; the clinical success of the technique appears to depend on anatomic location and associated comorbidity^4-8. However, temporal pain relief and functional improvements have been reported to be essentially equivalent to those after microfracture^9-12. Autologous chondrocyte implantation is both technically demanding and associated with a high percentage of reoperations¹³. Modification of this cell therapy designed to reduce complications by replacing the periosteal patch with a biocompatible matrix or selecting cells of potentially improved chondrogenic potential have been described and considered third and fourth-generation techniques¹⁴.

One strategy is the transition from implanting cells with putative chondrogenic potential to implantation of neocartilaginous tissue. NeoCart (Histogenics, Waltham, Massachusetts) is an autologous cartilage tissue-engineered implant that uniquely combines a bovine type-I collagen matrix scaffold with autogenous chondrocytes and bioreactor treatment. Previously, this technique was reported to generate increased glycosaminoglycan (GAG) and type-II collagen production in comparison with implants cultured without bioreactor treatment^15,16. The implant is then adhered with a novel collagen adhesive, creating a sutureless-fixation cartilage repair technique¹⁷. This cell-collagen construct is a matured tissue-like implant containing hyaline GAGs designed to provide a more rapid and potentially sustained therapeutic effect for articular cartilage repair. In an initial study, it safely repaired hyaline articular cartilage with sutureless application, integrated with native chondral tissue and to subchondral bone, and decreased pain and improved function for twenty-four months¹⁸.

Microfracture is recommended as a primary treatment for focal chondral lesions in the knee^19-21. Microfracture involves penetrating the subchondral bone after removing the damaged hyaline cartilage including the calcified layer²². This “marrow stimulation technique” provides cell elements to the area of injury, potentially forming a fibrin clot that may mature as repair tissue. The nature of this fibrocartilage repair includes a variable mixture of bone and disorganized matrix providing a mechanically inferior repair tissue as compared with native hyaline articular cartilage^12,23,24. Functional improvement and pain relief after microfracture have variably appeared to be most effective in patients with a new injury (symptoms of less than twelve months), a small focal injury (<2.5 cm²), a younger age (less than thirty years), and a lower body mass index (BMI) (<30 kg/m²)^23,24.

In this study, we compared the efficacy of a tissue-engineered, cell-seeded matrix scaffold (NeoCart) with that of microfracture at a minimum of two years after treatment of isolated symptomatic articular cartilage lesions of the knee. This report describes the clinical results and measures as required for phase II of a U.S. Food and Drug Administration (FDA)-regulated exploratory clinical trial (ClinicalTrials.gov, NCT00548119).

Materials and Methods

Introduction | Materials and Methods | Results | Discussion

Institutional review board approval was granted for this FDA-regulated phase-II prospective, randomized clinical trial designed to evaluate safety and clinical outcomes of the NeoCart implant compared with microfracture. Written consent was obtained from forty-nine subjects who were provisionally enrolled and screened for eligibility. The study was registered with ClinicalTrials.gov (#NCT00548119).

Eligible patients were between eighteen and fifty-five years of age, had a symptomatic International Cartilage Repair Society (ICRS) grade-III cartilage lesion of the femoral condyle, and satisfied the inclusion criteria (Table I). The final determination of eligibility was made at the time of knee arthroscopy, prior to randomization. Fourteen patients were excluded as a result of advanced degenerative osteoarthritis, nonqualifying lesion(s), withdrawal of consent, symptoms inconsistent with a femoral condyle cartilage lesion, or smoking status (Fig. 1). Five more patients were excluded at the time of arthroscopy (Fig. 1). A total of thirty patients were randomized at six investigational sites. Randomization was achieved by opening a sequentially numbered envelope in the operating room after arthroscopic determination of eligibility was made. A permuted block design, generated by a statistician independent of the study, was utilized to minimize the opportunity for guessing the next treatment assignment. These stringent precautions were taken to ensure that neither the surgeon nor the patient would know the treatment arm until the decision regarding eligibility was made at arthroscopy.

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TABLE I Study Inclusion/Exclusion Criteria

	Inclusion Criteria	Exclusion Criteria*
Initial	Patient able and willing to give informed consentAge between 18 and 55 yrPatient presenting with symptomatic knee pain indicative of an articular cartilage injuryPatient medically able to undergo arthroscopic microfracture or biopsy and subsequent arthrotomy for NeoCart implantation	Any previous surgical treatment of lesion other than debridementBMI >35 kg/m²Joint space narrowing of >1/3 compared with normal knee, or <3 mm of joint space measured on radiographs, osteophytes, sclerosis, or degenerative conditions in treatment knee noted on radiographsMalalignment >3° outside mechanical axis of other knee, or need for surgery to correct malalignmentOther symptomatic pathology of contralateral kneeSurgery on contralateral knee within 8 wk prior to scheduled arthroscopyAny form of inflammatory arthritisAnkylosing spondylitisSynovioma, hemangioma, pigmented villonodular synovitis, or neoplasms in kneePatient on chemotherapyPatient unable to undergo MRIPatient who is pregnant or intends to become pregnant during yr following initial enrollmentKnown history of allergy to bovine products or to collagen or more than a minimal reaction to an intradermal collagen injection challengeHistory of autoimmune diseaseEvidence of HIV or chronic hepatitis-B or C viral infectionKnown allergy to gentamicinCurrent drug or alcohol abusePatient deemed by investigator as unlikely to comply with protocol
At arthroscopy	Patient with at least 1 treatable lesion located on either medial or lateral femoral condyle that would be a candidate for microfracture therapyICRS grade-III lesionLesions with a maximum linear dimension at least 1 cm and no more than 3 cm to healthy cartilage borderLesions with total area less than area of NeoCart (7-8 cm²)	Subchondral bone lossPatient requiring a concomitant procedure other than medial or lateral partial meniscectomy, removal of loose bodies, debridement of articular cartilage lesions other than that being treated and synovectomyUntreated ACL and/or PCL deficiency or ligamentous instability in involved kneeMeniscus with rim <50% of normal thicknessICRS grade-III or IV kissing lesionMore than slight anterior knee pain referable to patellofemoral joint and ICRS grade-III(B), III(C), or IV trochlear groove or patellar lesion

*MRI = magnetic resonance imaging, HIV = human immunodeficiency virus, ACL = anterior cruciate ligament, and PCL = posterior cruciate ligament.

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TABLE I Study Inclusion/Exclusion Criteria

	Inclusion Criteria	Exclusion Criteria*
Initial	Patient able and willing to give informed consentAge between 18 and 55 yrPatient presenting with symptomatic knee pain indicative of an articular cartilage injuryPatient medically able to undergo arthroscopic microfracture or biopsy and subsequent arthrotomy for NeoCart implantation	Any previous surgical treatment of lesion other than debridementBMI >35 kg/m²Joint space narrowing of >1/3 compared with normal knee, or <3 mm of joint space measured on radiographs, osteophytes, sclerosis, or degenerative conditions in treatment knee noted on radiographsMalalignment >3° outside mechanical axis of other knee, or need for surgery to correct malalignmentOther symptomatic pathology of contralateral kneeSurgery on contralateral knee within 8 wk prior to scheduled arthroscopyAny form of inflammatory arthritisAnkylosing spondylitisSynovioma, hemangioma, pigmented villonodular synovitis, or neoplasms in kneePatient on chemotherapyPatient unable to undergo MRIPatient who is pregnant or intends to become pregnant during yr following initial enrollmentKnown history of allergy to bovine products or to collagen or more than a minimal reaction to an intradermal collagen injection challengeHistory of autoimmune diseaseEvidence of HIV or chronic hepatitis-B or C viral infectionKnown allergy to gentamicinCurrent drug or alcohol abusePatient deemed by investigator as unlikely to comply with protocol
At arthroscopy	Patient with at least 1 treatable lesion located on either medial or lateral femoral condyle that would be a candidate for microfracture therapyICRS grade-III lesionLesions with a maximum linear dimension at least 1 cm and no more than 3 cm to healthy cartilage borderLesions with total area less than area of NeoCart (7-8 cm²)	Subchondral bone lossPatient requiring a concomitant procedure other than medial or lateral partial meniscectomy, removal of loose bodies, debridement of articular cartilage lesions other than that being treated and synovectomyUntreated ACL and/or PCL deficiency or ligamentous instability in involved kneeMeniscus with rim <50% of normal thicknessICRS grade-III or IV kissing lesionMore than slight anterior knee pain referable to patellofemoral joint and ICRS grade-III(B), III(C), or IV trochlear groove or patellar lesion

*MRI = magnetic resonance imaging, HIV = human immunodeficiency virus, ACL = anterior cruciate ligament, and PCL = posterior cruciate ligament.

Fig. 1

Enrollment diagram, including patient randomization through clinical assessment.

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All potential study patients were evaluated preoperatively with use of cartilage-sequence magnetic resonance imaging to assess both the lesion and the surrounding articular cartilage. Only patients with one or two isolated articular cartilage lesions of the femoral condyle(s) were included. The patients underwent diagnostic arthroscopy. Following confirmation of the eligibility of the chondral lesion(s), the patient was randomized either to NeoCart treatment and, therefore, immediate biopsy of uninjured hyaline cartilage from the proximal trochlea or to microfracture treatment.

The patients randomized to the microfracture treatment arm underwent that procedure at the index arthroscopy. Microfracture included lesion debridement to a stable cartilage margin, removal of the calcified cartilage layer, and the homogeneous creation of subchondral osseous penetrations within the base of the cartilage defect with use of 2 to 4-mm awls^21,24.

The patients randomized to NeoCart treatment were allowed immediate unrestricted activity after the arthroscopic biopsy and returned for implantation approximately six weeks later. During the six-week period, the NeoCart was produced via collagenase extraction of chondrocytes, followed by seeding of these cells onto a bovine type-I collagen matrix. The seeded matrix construct was then incubated in a bioreactor with conditions simulating the knee environment—e.g., low oxygen tension and varying pressure. The implant was released after sterility and glycoprotein-composition quality-control confirmation. One specimen was discarded following a manufacturing process error, after which a repeat arthroscopic biopsy was performed.

Implantation was carried out during a second outpatient surgical procedure via mini-arthrotomy, debridement, and preparation of the defect bed in a manner analogous to microfracture, without subchondral penetration³. The NeoCart was secured without suture by using a proprietary collagen-based polymer (CT-3; Histogenics) to anneal the implant to the prepared condyle defect bed and adjacent tissue¹⁸.

The rehabilitation protocol, standardized to that recommended after microfracture, was identical for both groups following the index procedure²¹. The protocol included six weeks of toe-touch weight-bearing, six to eight hours of continuous passive motion daily beginning on postoperative day 1, and restriction of sports activity for six months. One patient began immediate unrestricted weight-bearing ten days after NeoCart implantation in concurrence with the rehabilitation protocol, which allowed accelerated weight-bearing by individuals with small, contained lesions.

Clinical measurements included the following self-reported patient surveys: the International Knee Documentation Committee (IKDC) form (subjective); Knee Injury and Osteoarthritis Outcome Score (KOOS) pain, symptoms, activities of daily living (ADL), quality of life (QOL), and sports scales; Short Form-36 (SF-36) questionnaire; and a visual analog scale (VAS) pain score. The IKDC is a combined outcomes assessment of objective clinician and subjective patient measures validated to assess short and long-term knee function^25,26. The KOOS contains five separately scored components designed and validated to assess short and long-term function in subjects with knee injury. These scores were obtained preoperatively and at three, six, twelve, and twenty-four months postoperatively. IKDC objective data were collected and reported to the study sponsor by one physician (not an author), blinded to the treatment, for nineteen of the thirty patients (patients of the first author) or by clinicians (not authors) blinded to all patient-reported subjective data scores. The study sponsor collected and managed all data and provided this information to the authors after all patients had completed two years of follow-up. Subsequent calculations and application of statistical methods are the work of the first author.

Statistical Analyses

All data were collected prospectively, with data entry, edit checks, and query tracking supported by a data management service (Synteract, Carlsbad, California). Descriptive statistics (mean and standard deviation) and the responder rate were calculated for each time point for the intent-to-treat population with the significance level set at p < 0.05 (two-sided). The intent-to-treat population included all patients who had been randomized, with the patients classified by the group to which they had been randomized, regardless of the treatment received and follow-up status. The mean change from baseline to the three, six, twelve, and twenty-four-month follow-up points was calculated. The analysis included the IKDC (subjective) score, all five KOOS subscores (pain, symptoms, ADL, sports, and knee-related QOL), the VAS score for knee pain (maximum), and the SF-36 score. A paired t test was applied to each group to assess the score change from baseline. Changes in IKDC and KOOS scores from baseline to twelve months were evaluated with an analysis of covariance (ANCOVA), with the baseline scores used as the covariate.

In the responder analysis, a patient was classified as a responder if he or she had at least a 12-point improvement in the pain score of the KOOS assessment and a 20-point improvement in the IKDC subjective score. This combination of two validated patient-reported outcome measures for cartilage repair (IKDC function and KOOS pain scores) to define a responder was derived conservatively from reports indicating the ability of each score to detect a minimal clinically important difference^27,28. Roos and Lohmander suggested 10 points as a cutoff for clinical improvement or decline and described the minimal perceptible clinical improvement as 8 points for KOOS measures²⁹. Similarly, Irrgang et al. and others showed that the IKDC was responsive with a change of 6 points and had reliable sensitivity and specificity for patients perceiving improvement with score changes ranging from 11 to 20 points^25,26.

Patients were dichotomized as either “responders” or “nonresponders” if they met the dual-threshold criteria³⁰. The FDA panel indicated a preference for a single functional and separate pain measure for primary outcome determination. Thus, our definition of a therapeutic responder was both a change in the KOOS pain score of ≥12 points and a change in the IKDC function score of ≥20 points. Patients with a high baseline KOOS pain score (>80 points) were classified as responders if the improvement in their IKDC score met the 20-point criterion and their KOOS pain score had not deteriorated >8 points (the minimal perceptible clinical limit); this was done to account for potential confounding by ceiling effects or the phenomenon where measuring patient response to treatment is no longer influenced by their treatment.

Source of Funding

Institutional financial support was provided by Histogenics Corporation (Waltham, Massachusetts). The funding source provided data management and monitoring services as required by the FDA and had no authorship role.

Results

Introduction | Materials and Methods | Results | Discussion

Study Group

Of the forty-nine subjects who provided consent, fourteen did not meet all inclusion criteria prior to arthroscopy. Of the thirty-five patients undergoing diagnostic arthroscopy, thirty were confirmed as eligible and randomized to treatment groups. Five patients were deemed ineligible at arthroscopy; three of them had confirmed inflammatory arthropathy, one required a concomitant procedure, and another had an ICRS grade-III or IV kissing lesion. Of the patients randomized to the study arm, one had two femoral condyle lesions that satisfied the eligibility criteria; therefore, both lesions were treated with the study implant. All randomized patients received treatment to which they had been assigned, and none were lost to follow-up prior to the twelve-month time point. Two patients were lost to clinical follow-up before the twenty-four-month time point for unknown reasons. Demographic characteristics of the study population and for each treatment arm are summarized in Table II.

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TABLE II Patient Characteristics*

	NeoCart (N = 21)	Microfracture (N = 9)	Total (N = 30)
Age (yr)	41 ± 9	39 ± 10	40 ± 9
% male	90% (19 of 21)	67% (6 of 9)	83% (25 of 30)
BMI†(kg/m2)	29 ± 3	25 ± 4	28 ± 4
Time since first symptoms (yr)	3 ± 5	2 ± 4	3 ± 5
Baseline IKDC score (points)	44 ± 13	52 ± 12	47 ± 13
Baseline KOOS pain score (points)	65 ± 12	73 ± 16	67 ± 14
Post-debridement lesion size (mm2)	287 ± 138	252 ± 135	278 ± 135

*The values are given as the mean and standard deviation, except for % male.
†There was a significant difference between arms (p < 0.05).

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TABLE II Patient Characteristics*

	NeoCart (N = 21)	Microfracture (N = 9)	Total (N = 30)
Age (yr)	41 ± 9	39 ± 10	40 ± 9
% male	90% (19 of 21)	67% (6 of 9)	83% (25 of 30)
BMI†(kg/m2)	29 ± 3	25 ± 4	28 ± 4
Time since first symptoms (yr)	3 ± 5	2 ± 4	3 ± 5
Baseline IKDC score (points)	44 ± 13	52 ± 12	47 ± 13
Baseline KOOS pain score (points)	65 ± 12	73 ± 16	67 ± 14
Post-debridement lesion size (mm2)	287 ± 138	252 ± 135	278 ± 135

*The values are given as the mean and standard deviation, except for % male.
†There was a significant difference between arms (p < 0.05).

Safety

There were three serious adverse events, as defined by the U.S. Department of Health and Human Services Office for Human Research Protections, across treatment groups. Two adverse events occurred in the NeoCart group, both in the same patient. The first event was a case of septic arthritis in the contralateral knee after meniscectomy, which subsequently required a total knee arthroplasty (the second event). In the microfracture group, there was one adverse event: cancer of gynecologic origin. None of these events were considered to be related to the treatment of the cartilage defect. No patients were dropped from the study because of an adverse event. One patient elected to undergo repeat arthroscopic biopsy when an autologous cartilage tissue implant was lost to contamination. A total of eighty-six adverse events were reported during the study period, with sixty-two in the twenty-one patients in the NeoCart group and twenty-four in the nine patients in the microfracture group. These events included a repeat arthroscopic biopsy; an arthroscopic microfracture of a lesion in the ipsilateral knee; an arthroscopic anterior cruciate ligament (ACL) reconstruction of the contralateral knee after the patient had returned to full activity; and postoperative pain, stiffness, swelling, back pain, arm pain, and peri-incisional numbness. Adverse events considered related to the study interventions were consistent with those associated with routine outpatient arthroscopy or mini-knee arthrotomy, with the exception of the repeat biopsy.

Efficacy Analysis

In the NeoCart arm, improvement compared with baseline was significant for all measures at six, twelve, and twenty-four months. In contrast, improvement over baseline measures in the microfracture arm was limited to the IKDC and SF-36 scores at six months and the IKDC, KOOS ADL, and SF-36 scores at twelve and twenty-four months. The NeoCart group had more improvement in the KOOS pain and symptom scores at six months than the microfracture group. At twelve months, the patients treated with the NeoCart showed more improvement in the IKDC, KOOS pain, KOOS sports, and VAS pain scores than the microfracture cohort. At twenty-four months, the improvements in the IKDC, KOOS pain, KOOS sports, KOOS QOL, and VAS pain scores in the NeoCart group were significantly greater than those in the microfracture group (p < 0.05). The mean baseline data in the two groups, although not identical, were not significantly different. ANCOVA was performed to adjust for any variation in baseline scores. Changes in both the IKDC function (Fig. 2-A) and KOOS pain (Fig. 2-B) scores were evaluated with use of the baseline score as the covariant. The IKDC score changes from baseline differed significantly between the microfracture and NeoCart study arms (p = 0.028), when the scores were adjusted. The difference in the adjusted means (NeoCart minus microfracture) was 11.59 with a 95% confidence interval (CI) of 1.353, 21.82. The KOOS pain score changes from baseline also differed significantly between the microfracture and NeoCart study arms (p = 0.016). The difference in the adjusted KOOS pain score means (NeoCart minus microfracture) was 12.06 with a 95% CI of 2.388, 21.74.

Fig. 2

ANCOVA analysis of change in IKDC (Fig. 2-A) and KOOS pain (Fig. 2-B) outcome scores at one year, as a function of baseline. Mfx = microfracture and Neo = NeoCart.

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Temporal improvement, reflected as the changes in the KOOS pain and IKDC function scores, is represented in Figure 3. Direct comparison by applying an unpaired t test indicated significantly greater improvement from baseline in the NeoCart arm compared with the microfracture arm for the KOOS pain score at six months and both the KOOS pain and the IKDC function score at twelve and twenty-four months.

Fig. 3

Temporal representation of IKDC and KOOS pain score means (Figs. 3-A and 3-C) and mean changes from baseline (Figs. 3-B and 3-D). All thirty patients (twenty-one in the NeoCart group and nine in the microfracture group) are represented at three, six, and twelve months; twenty-eight patients (nineteen in the NeoCart group and nine in the microfracture group) are represented at twenty-four months. Standard deviation bars are shown. Asterisks represent significant differences, as shown by the unpaired t test, between the NeoCart and microfracture arms (p < 0.05).

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Responder analysis was applied to assess efficacy with use of the dual-criteria threshold of improvement that included both the KOOS pain and the IKDC score (Fig. 4). The proportion of responders in the NeoCart group was 43% (nine of twenty-one) at six months, 76% (sixteen of twenty-one) at twelve months, and 79% (fifteen of nineteen) at twenty-four months. In contrast, a minority of patients treated with microfracture were considered responders: 25% (two of eight) at six months, 22% (two of nine) at twelve months, and 44% (four of nine) at twenty-four months. The proportion of responders in NeoCart group was found to be significantly greater than that in the microfracture group (p = 0.0125) when a Fisher exact test was applied to the data at both six months and twelve months after treatment. At twenty-four months, 79% of NeoCart-treated and 44% of the microfracture-treated patients were considered responders (p = 0.097), with two microfracture-treated patients considered responders when the correction for a possible ceiling effect was applied. Similarly, 81% (seventeen) of the twenty-one patients in the NeoCart group responded to treatment compared with 44% (four) of the nine in the microfracture cohort at the time of final follow-up (Fig. 4-B).

Fig. 4

Responder analysis at twelve months postoperatively (Fig. 4-A) and the time of the last follow-up (Fig. 4-B), at an average of 25.6 months postoperatively. Responders (shown in the shaded areas) are defined by improvement in the IKDC score of ≥20 points and the KOOS pain score of ≥12 points. The proportion of responders in the NeoCart group is greater than that in the microfracture group at twelve months (sixteen of twenty-one and two of nine, respectively) and at the time of the last follow-up (seventeen of twenty-one and four of nine, respectively). The circled symbols indicate subjects considered therapeutic responders on the basis of a single criterion due to a potential KOOS pain ceiling effect (two in the microfracture group and one in the NeoCart group).

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Discussion

Introduction | Materials and Methods | Results | Discussion

Currently, microfracture is the standard surgical treatment for isolated cartilage lesions in the U.S.^19-21. Microfracture results include inconsistent fibrocartilage formation within the lesion and a highly variable therapeutic response^{12,21,23,24,27}. We describe an exploratory multisite randomized trial that evaluated a tissue-engineered bioimplant for treatment of hyaline cartilage knee injury in comparison with microfracture.

The pathogenesis of osteoarthritis is poorly understood. One putative etiology for osteoarthritis involves focal damage to the articular cartilage in a localized, nonuniform manner with altered joint biomechanics, tissue loss, and subsequent remodeling of subchondral bone^1,2. The chondral injury, when painful and focal, is potentially managed with a variety of surgical techniques. Microfracture is widely recommended as a primary treatment, but it requires compromise of the normal subchondral bone by multiple 3-mm awl penetrations in an effort to supply mesenchymal cells to the chondral injury. Clinically, outcome measures are reported to plateau between twelve and twenty-four months after microfracture treatment, and the procedure appears less efficacious for larger, more chronic lesions in older patients and those with a higher BMI^11,23,24.

Surgical therapies designed to improve the clinical efficacy of cartilage injury treatments by improving the potential for a hyaline healing response have followed the original report by Brittberg et al.^3,7,31,32. However, among well-tested alternatives to microfracture, none have provided a significant clinical improvement when directly compared with microfracture up to two years after treatment^11,12. One recent report indicated a significant improvement, after thirty-six months, in one measure, the group mean of a combined KOOS score (excluding the KOOS sports score), for patients treated with an autologous chondrocyte implant variant, ChondroCelect (TiGenix, Brussels, Belgium) as compared with those treated with microfracture³³. These investigators applied a heterogeneous compound symmetry structure mode analysis to a partially combined KOOS score and found a statistical difference (p < 0.05). Prior reports on this study population demonstrated no clinical differences at either one or two years, despite showing improved histological quality of the repair tissue. Other investigators have found minimal distinction in clinical outcomes between autologous chondrocyte implantation and microfracture treatment after either two or five years^10,11,34.

NeoCart is a bioengineered tissue patch containing an autologous chondrocyte population matured in a biodegradable collagen matrix with use of bioreactor technology. The bioreactor culture technique (hydrostatic pressure with modified flow rates and low oxygen) has been previously shown to stimulate extracellular matrix accumulation and suppress long-term degradation of matrix accumulated by isolated chondrocytes in in vitro studies^15,16,35. Using an in vivo porcine model, Kusanagi et al. showed improved temporal and absolute integration and matrix production with bioreactor-treated human chondrocyte constructs (chondrocytes in a type-I-collagen honeycomb matrix), in comparison with untreated constructs, when applied to femoral chondral defects^36,37. This is a unique approach for providing potentially improved replacement tissue to the damaged articular surface in comparison with that produced by currently available clinical therapy in the U.S. The initial clinical report on the use of NeoCart for treatment of cartilage injury indicated an ability to integrate with adjacent normal tissue and an associated progressive collagen organization within the treatment area¹⁸. Perhaps these biologic distinctions are responsible for the findings reported in our small prospective randomized study. Trends through the first two years indicate not only improved pain and function scores, but also a more rapid onset of improvement in the NeoCart group. Similarly, a larger percentage of patients appear to respond to the NeoCart treatment at six, twelve, and twenty-four months. This difference appears to be a result of the response to NeoCart, rather than some failure of the microfracture technique, as the outcomes in this study are comparable with those reported in other studies for microfracture treatment^11,23,34,38.

Our purpose, as with most FDA phase-II trials, is to continue to assess safety and, preliminarily, efficacy. Although the current study is limited by size and not powered to detect differences in the group mean, a secondary goal is to assess the range of treatment-effect differences in the NeoCart group, to allow sample size calculation for the definitive phase-III study. Similarly, use of the 2:1 randomization format, common for clinical trials with novel therapeutics, allowed this smaller-scale pilot study to accumulate an adequate number of patients for such calculations while providing the necessary control cohort of microfracture-treated patients^27,39.

The four adverse events requiring surgery, unrelated to the study treatment, and the minor complications that we observed were typical of outpatient surgical procedures and did not differ between the two small cohorts. Despite randomization, the study groups were similar, although not identical. The observed responders in the NeoCart group had lower mean baseline IKDC and KOOS pain scores, indicating NeoCart-treated patients had more room to improve than those treated with microfracture. In fact, three patients (two in the microfracture group and one in the NeoCart group) were considered responders at the time of final follow-up as they met the IKDC threshold and had improvement in the KOOS pain score but may have been limited by a ceiling effect. Application of ANCOVA, however, indicated that differences in the change in the reported outcomes from baseline between the NeoCart and microfracture groups were not disproportionately influenced by the different baseline scores. Notably, the lesions were slightly smaller; BMI, lower; symptom duration, shorter; and age at the time of injury, lower in the microfracture population. These circumstances are known to be associated with more favorable outcomes of microfracture treatment and are associated with higher Patient Reported Outcome scores^23,24. The larger, properly statistically powered phase-III study should control and account for these potentially confounding issues and identify the superior treatment.

In randomized clinical trials, assessment of clinical effectiveness is frequently determined by quantifying the average change within a population and comparing group means with control treatment. Alternatively, responder analysis has been applied as a method of allowing a more discrete assessment of clinically relevant treatment efficacy, failure, and applicability to individual patient care^40,41. In this analysis, we reported positive responders exclusively and required an improvement above the reported perceptible clinical improvement for both metrics for a patient to be considered a therapeutic responder. We recognize a potential limitation to dichotomizing continuous or ordinal variables into a binary variable³⁰. However, recent FDA guidance on patient-reported outcomes specifically endorses responder analysis as a preferred alternative to assessing clinical relevance⁴². Also, it is recognized that applying responder analysis assessments to randomized clinical trials is suitable when comparing new techniques with standard-of-care therapy^43-46.

Our preliminary findings strongly suggest that using the NeoCart autologous cartilage tissue implant significantly decreases knee pain and improves function within six months after treatment and provides significantly greater improvements than microfracture. Collectively, this report on NeoCart may represent a potentially important evolution in the treatment of cartilage injury and joint-specific chondral pathology. Concomitant application of responder analysis to identify individuals` or subpopulations most likely to benefit may further define therapeutic application. A larger-scale, confirmatory study comparing NeoCart safety and efficacy with those of the microfracture technique has been sanctioned by the FDA under special protocol assessment.

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Disclosure: One or more of the authors received payments or services, either directly or indirectly (i.e., via his or her institution), from a third party in support of an aspect of this work. In addition, one or more of the authors, or his or her institution, has had a financial relationship, in the thirty-six months prior to submission of this work, with an entity in the biomedical arena that could be perceived to influence or have the potential to influence what is written in this work. No author has had any other relationships, or has engaged in any other activities, that could be perceived to influence or have the potential to influence what is written in this work. The complete Disclosures of Potential Conflicts of Interest submitted by authors are always provided with the online version of the article.

Topics

cartilage ; femur ; pain ; united states food and drug administration ; pain score

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Dennis C. Crawford, Thomas M. DeBerardino, Riley J. Williams, III; NeoCart, an Autologous Cartilage Tissue Implant, Compared with Microfracture for Treatment of Distal Femoral Cartilage LesionsAn FDA Phase-II Prospective, Randomized Clinical Trial After Two Years. The Journal of Bone & Joint Surgery. 2012 Jun;94(11):979-989.

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