Treatment of Large Cartilage Defects in the Knee by Hydrogel-Based Autologous Chondrocyte Implantation: A 5-Year Follow-Up of a Prospective,Multicenter,Single-Arm Phase III Trial

Abstract

Objective

To evaluate efficacy and safety at 5 years after treatment with hydrogel-based autologous chondrocyte implantation (ACI) for large cartilage defects in the knee.

Design

Prospective, multicenter, single-arm, Phase III clinical trial. ACI was performed in 100 patients with focal full-thickness cartilage defects ranging from 4 to 12 cm² in size. The primary outcome measure was the responder rate (defined as improvement by ≥10 points) at 2 years using the Knee Injury and Osteoarthritis Outcome Score (KOOS).

Results

The preoperative overall KOOS was 39.8 points and continuously increased to 84.7 points at 5 years (mean increase 44.1 points, 95% CI = 40.4-47.9, P < 0.0001). The primary study endpoint (i.e., a KOOS responder rate of >40%) was descriptively met at each assessment timepoint from 3 months to 5 years (Month 3: 75.5%, 95% CI = 65.6-83.8; Year 2: 93.0%, 95% CI = 86.1-97.1, Year 5: 92.8%, 95% CI = 85.7-97.0). International Knee Documentation Committee (IKDC) subjective and objective scores and quality of life assessments (EQ-5D-5L) supported the results seen for the KOOS. The overall treatment failure rate at 5 years was 1%. All treatment-related adverse events were of mild or moderate intensity and mostly occurred within the first year after treatment.

Conclusions

Hydrogel-based ACI has been shown to be a safe and effective treatment option for patients with large knee cartilage defects with sustained efficacy up to 5 years as demonstrated by consistent and clinically relevant improvements in all investigated efficacy variables. No remarkable adverse events or safety issues were noted.

Keywords

cartilage repair large defects autologous chondrocyte implantation knee hydrogel

Introduction

Articular cartilage injuries cause pathological mechanical changes in the knee leading to non-resolving inflammation and metabolic stress on chondrocytes.¹ Furthermore, chondrocytes have only limited mitotic capabilities, and articular cartilage lacks innervation and a blood supply. Based on these characteristics, cartilage defects are extremely unlikely to heal on their own especially in adult individuals. When it does attempt to repair, particularly in the case of additional injury to the subchondral bone, it is generally a biomechanically inferior replacement tissue that develops, similar to the tissue laid down after microfracture (MFx) or other bone marrow stimulation techniques.^2-6

The optimal treatment for cartilage defects depends on several factors including defect size, type and severity of clinical symptoms. Small defects (<2 cm²) with limited or no clinical symptoms might make larger surgeries seem excessive and unjustified. But a wait-and-see approach especially for larger symptomatic lesions may have negative and devastating long-term consequences, as these defects are at significant risk of early osteoarthritis (OA) and poorer clinical outcomes in the natural course or when treated with an unsuitable procedure or too late.^7-9 Overall, there is consensus that symptomatic, full-thickness (ICRS grade III or IV), focal cartilage defects (in the absence of advanced OA) are the classic indication for cartilage repair surgery.^10-12

Several methods are available for the biological reconstruction of localized full-thickness cartilage defects, including bone marrow stimulating techniques, osteochondral transfer (OCT) or allografts, particulated or minced cartilage procedures and autologous chondrocyte implantation (ACI). Clinical studies have shown that successful treatment of full-thickness cartilage defects of the knee joint with a restorative procedure such as OCT or matrix-associated ACI (M-ACI) can significantly reduce premature degenerative changes compared with the untreated natural course, and that these methods therefore have the potential to prevent or at least delay early knee arthroplasty.^13-15

In this context, several studies, some at the highest level of evidence have documented that second- and third-generation ACI methods provide the best long-term results and the lowest failure and revision rates for both chondral and osteochondral lesions of the knee, in particular in defects larger than 2 to 4 cm² in size.¹¹,^16-20

Furthermore, compared with arthrotomy-based, more open surgical approaches, the arthroscopic application of ACI is associated with lower complication rates.²¹

For this reason, we have developed an in situ crosslinkable albumin-hyaluronan-based hydrogel as a carrier and delivery material for M-ACI. It can be applied either arthroscopically or by a mini-arthrotomy even in difficult defect locations without the need for additional fixation and anchoring of the implant.²²

Here we present the 5-year results of a prospective, international, multicenter Phase III study investigating hydrogel-based M-ACI for the treatment of large chondral or osteochondral defects of the knee (defect size 4–12 cm²) as a follow-up to the previously published 2-year results.²³

Method

Study Design and Participants

This single-arm Phase III clinical trial was conducted in full compliance with the principles laid down in the Declaration of Helsinki and met all legal and regulatory requirements. After approval by the local ethics committees, federal authorities, and study registration (ClinicalTrials.gov identifier: NCT03319797; EudraCT No.: 2016-002817-22) patients who consented in writing to participate in the trial were enrolled and treated between October 2017 and February 2019 at 6 Czech, 5 Hungarian, 3 Lithuanian, 2 German, and 1 Swiss centers.

Males and females aged 18 to 65 years (or ≥ 14 year-old minors with closed epiphyseal growth plates) with focal cartilage defects of the femoral condyle, trochlea, patella, or tibial plateau of the knee (defect grade of III or IV according to the International Cartilage Regeneration & Joint Preservation Society [ICRS] classification) were eligible for enrollment. The defect size range was between 4 and 12 cm², and the treatment of 2 defects as well as prior failed cartilage repair of the index lesion were allowed. Detailed inclusion and exclusion criteria were described previously²³ and are available at ClinicalTrials.gov.

Surgical Technique and Rehabilitation

M-ACI was performed as described earlier.²³ Briefly, in the first step, osteochondral biopsies were harvested from patients during arthroscopic surgery from a nonweightbearing area of the knee joint and were in vitro-culture expanded. In the second step, M-ACI was performed either arthroscopically or through a mini-arthrotomy approach using NOVOCART Inject (TETEC—Tissue Engineering Technologies AG, Reutlingen, Germany), a 2-component hydrogel-based M-ACI system, consisting of an autologous articular chondrocyte suspension (2-8 Mio. cells per mL) and a crosslinker solution. During injection using a dual chamber syringe application system, the cell containing component and the crosslinker solution are mixed, resulting in the formation of the cell-seeded hydrogel at the site of administration.

After surgery, all patients followed a defined rehabilitation protocol based on Hirschmüller et al.²⁴ Limitations on weightbearing for 6 weeks were recommended with stepwise increase to full weightbearing between 7 and 8 weeks after surgery. Continuous passive motion with increasing range of motion was started a day after surgery for 6 weeks. Within the first 6 weeks, physical therapy was aimed primarily at the reduction of swelling, isometric quadriceps activity, and mobilization. The phase from week 12 to 26 was characterized by strength training, maximum sensorimotor stimulation, and low-impact sports, such as cycling or Nordic Walking. After week 26, a stepwise return to sports was allowed, while high-impact sports were not recommended within the first year after treatment.

Main Assessment Criteria

Primary outcome measure was the Knee Injury and Osteoarthritis Outcome Score (KOOS), including the 5 subscales of symptoms, pain, activities of daily living (ADL), sports and recreation (sport/rec.) and quality of life (QoL).²⁵ Secondary outcome measures included the International Knee Documentation Committee (IKDC) score (IKDC-2000; including the Subjective Knee Evaluation Form and the Knee Examination Form) and the EQ-5D-5L (standardized measure of quality of life).²⁶ All patients were assessed preoperatively (baseline) and then at 3, 6, 12, 18, and 24 months after treatment, followed by annual assessments up to 5 years.

The assessment of repair tissue was performed at 1, 2, and 5 years after treatment in a subset of 25 patients by the Magnetic Resonance Observation of Cartilage Repair Tissue 2.0 (MOCART 2.0) score²⁷ and T2 mapping.^28-34 The MOCART 2.0 score quantifies graft maturation and lesion healing by morphological categorization, while T2 mapping provides information on the ultrastructural composition of the repair tissue. No baseline status was documented since both the MOCART 2.0 score and the T2 mapping characteristics mainly refer to the cartilage repair tissue and thus do not allow relevant preoperative assessment. For T2 mapping, the T2 relaxation time measured in the repair tissue set in relation to the T2 relaxation time measured in the surrounding healthy cartilage tissue results in a “global” T2 ratio (if only the full-thickness tissue areas are measured) and in a “zonal” T2 ratio (if, in addition, the differences in T2 relaxation times in the superficial and deep zones of the cartilage areas are considered). Ideal global and zonal T2 ratios are “1” (indicating no difference between regenerated tissue and normal tissue), and the ratio range of 0.8 to 1.2 is regarded as “normal” (and was therefore employed for the analyses of the T2 ratios). Safety assessment was mainly based on adverse events (AEs) and subsequent surgical procedures (SSIs, procedures performed on the target knee during the study).

Statistical Analysis

All statistical analyses were performed using the software package SAS, Version 9.4 or higher.

The primary study outcome was the overall KOOS responder rate (R) defined as the proportion of patients with a ≥10-points improvement from baseline at Year 2. An improvement of 8 to 10 points in the KOOS represents the minimal clinically important difference (MCID),³⁵ i.e. the smallest change score needed for the effect to be considered clinically relevant.³⁶

The threshold for clinical relevance was set to 40% responders, thereby resulting in the confirmatory study hypothesis:

H₀: R ≤ 40% versus H₁: R > 40%

The H₀ hypothesis was tested using a 1-sided exact binomial test at a significance level of 0.025, or, equivalently, using the lower bound of the 2-sided 95% Clopper-Pearson confidence interval (CI).

Patients classified as treatment failures were handled as non-responders irrespective of their KOOS response, including missing KOOS data.

The change in the overall KOOS from baseline and other continuous secondary efficacy endpoints to Year 5 were analyzed by a linear mixed effect model for repeated measurements (MMRM). The model used all the longitudinal observations of the overall KOOS score after implantation up to and including Year 5 (except observations obtained after surgical intervention in patients classified as treatment failures) and included the effects of “country,” “visit,” and “baseline score.” The treatment effect at each postbaseline timepoint was estimated using least squares (LS) means for changes from baseline, as well as associated 95% CIs and P values. The ordinal secondary endpoints were analyzed by non-parametric methods based on ranks.

In addition to clinically relevant improvement, the substantial clinical benefit (SCB), that is, an improvement in clinical outcome that is needed for a patient to feel substantially better, was assessed for the individual KOOS subscores as defined by Ogura et al.³⁷

Accordingly, SCBs for the KOOS subscores were ≥27.7 points improvement compared with the preoperative level for pain, ≥14.28 points for symptoms, ≥29.4 points for ADL, ≥30.0 points for sports/rec., and ≥37.5 points for QoL.

All efficacy analyses were done on the intent-to-treat (ITT) population (i.e., patients who have received M-ACI treatment).

Sensitivity analyses were performed considering concomitant analgesic medication and surgeries performed concomitantly with or after M-ACI implantation.

Two-sided statistical tests were performed at a significance level of α=0.05 and corresponding 2-sided 95% CIs were calculated.

For the MOCART 2.0, summary statistics including 95% CIs for the mean sum of scores are presented. In terms of T2 mapping, the number and percentage of lesions are summarized by T2 global and zonal index categories (<0.8, 0.8-1.2, and >1.2). The association of the MOCART 2.0 score and quantitative T2 mapping analyses with overall KOOS response and KOOS change from baseline were explored using logistic or linear models.

Results

Patient Population

Of the 132 patients screened, 102 patients were assessed as eligible to participate and were included in the study. Two patients discontinued participation after harvest of the cartilage biopsy but prior to implantation. As these 2 patients had undergone tissue biopsy, they were included for the safety analysis but were not assessed for efficacy. At Year 2, all 100 ITT patients were available for efficacy assessment and 97 were assessed for efficacy at 5 years (2 patients were lost to follow-up, 1 patient withdrew consent).

Patient demographic and baseline characteristics are summarized in Table 1.

Table 1.

Patient Demographic and Baseline Characteristics.

	All Patients (N=100)
Sex, n (%)
Male	63 (63.0)
Female	37 (37.0)
Age (years), mean ± SD (range)	39.8 ± 11.5 (15-62)
Body mass index (kg/m²), mean ± SD (range)	27.0 ± 4.1 (20.2-34.4)
Patients with at least 1 prior surgery^a, n (%)	52 (52.0)
Meniscus removal	27 (27.0)
Joint debridement	16 (16.0)
Ligament operation	15 (15.0)
Chondroplasty	7 (7.0)
Time since first symptoms (months), mean ± SD	22.7 ± 26.8 (0.5-126.6)
Concomitant surgeries^b, n (%)	22 (22.0)
Ligament operation	11 (11.0)
Osteotomy	5 (5.0)
Meniscus removal	3 (3.0)
Tenoplasty	3 (3.0)
Defect location, n defects (%)
Femoral condyle	80 (61.5)
Patellofemoral	45 (34.6)
Tibial plateau	5 (3.8)
Lesion etiology, n defects (%)
Traumatic	78 (60.0)
OCD	6 (4.6)
Focal degenerative	46 (35.4)
Defect size (cm²), mean ± SD (range)
All lesions	4.8 ± 1.9 (1.0-10.4)
Main lesion^c	5.4 ± 1.6 (3.0-10.4)
Total^d	6.3 ± 2.1 (4.0-12.5)

n = number of patients; n defects = number of defects; SD = standard deviation; OCD = osteochondritis dissecans.

Only surgeries performed in more than 3 patients.

Performed concomitantly to tissue harvest or product implantation. Only surgeries performed in more than 1 patient.

Lesions were classified into larger (main) lesions and smaller lesions, i.e., in patients with 2 lesions (n = 30), the classification was based on the size of the respective lesions, while in patients with 1 lesion only, this lesion was classified as the larger (main) lesion.

All lesions per patient added to 1 single value.

KOOS Results

Overall KOOS response rate based on MCID (primary outcome)

The KOOS responder rate of 93.0% (95% CI = 86.1-97.1, P < 0.0001) observed at Year 2 was maintained out to Year 5, where the rate was 92.8% (95% CI = 85.7-97.0, P < 0.0001). The analysis of the KOOS responder rates over time up to Year 5 indicated statistically significant rates (i.e., KOOS responder rates of >40%) at all timepoints from as early as Month 3 (75.5%, 95% CI = 65.6-83.8, P < 0.0001) (Fig. 1). Thus, the primary study endpoint (i.e., a KOOS responder rate of >40%) was descriptively met at each assessment time point from Month 3 to Year 5. The sensitivity analyses (based on adjustment for increased pain medication given within 7 days prior to the assessment time point and for patients without concomitant and/or subsequent surgeries), showed results that were almost identical to the main analysis and thus supported its validity.

Figure 1.

Overall KOOS responder rates (≥10 points improvement) over time. Vertical error bars indicate the 95% confidence intervals. The horizontal line indicates the 40% threshold for clinical relevance. KOOS, Knee Injury and Osteoarthritis Outcome Score.

KOOS subscore SCB rates

The SCB rates according to the definition by Ogura et al.³⁷ at 2 years were 72.0% for KOOS pain (95% CI = 62.1-80.5), 84.0% for symptoms (95% CI = 75.3-90.6), 62.0% for ADL (95% CI = 51.7-71.5), 84.0% for sports/recreation (95% CI = 75.3-90.6), and 73.0% for quality of life (95% CI = 63.2-81.4). These SCB rates were maintained at the same level up to 5 years (Table 2).

Table 2.

Substantial Clinical Benefit Responder Rates at Year 2 and Year 5.

			SCB Response Rate% [95% CI]
Score	SCB (points)	Baseline Score ± SD	Year 2	Year 5
KOOS Pain	≥27.7	50.1 ± 17.1	72.0 [62.1-80.5]	70.1 [60.0-79.0]
KOOS Symptoms	≥14.28	52.7 ± 17.6	84.0 [75.3-90.6]	83.5 [74.6-90.3]
KOOS ADL	≥29.4	52.5 ± 19.0	62.0 [51.7-71.5]	61.9 [51.4-71.5]
KOOS Sports/Rec.	≥30	21.0 ± 16.4	84.0 [75.3-90.6]	83.5 [74.6-90.3]
KOOS QoL	≥37.5	22.5 ± 14.0	73.0 [63.2-81.4]	74.2 [64.3-82.6]

SCB = substantial clinical benefit; SD = standard deviation; ADL = activities of daily living; QoL = quality of life; Sport/Rec = sports and recreation; KOOS = Knee Injury and Osteoarthritis Outcome Score.

Notably, the lower limits of the 95% CIs at 2 years and 5 years were all well above the assumed threshold for clinical relevance of 40% defined for the overall KOOS.

KOOS change from baseline

The overall KOOS among the 100 ITT patients was 39.8 points at baseline and continuously increased to 84.7 points at Year 5 (least squares [LS] mean increase 44.1 points, 95% CI = 40.4-47.9, P < 0.0001). The largest improvement occurred within the first year after treatment (Table 3). Accordingly, stable or slightly higher values between Year 1 and Year 5 were seen in all KOOS subscores. The mean changes from baseline were significant in the overall KOOS and in all 5 KOOS subscores at all timepoints measured from Month 3 to Year 5 (P < 0.0001). The greatest improvements in KOOS subscores at Year 5 (i.e., an increase of more than 50 points) were found for sports/rec. (LS mean increase: 58.2, 95% CI = 53.2-63.2) and QoL (LS mean increase: 50.5; 95%, CI = 45.2-55.8) (Table 3).

Table 3.

Patient-Reported Outcome Scores and Changes From Baseline Over Time.

Score^a	Mean ± SD	LS Mean Change From Baseline [95% CI]^b
KOOS overall
Baseline	39.8 ± 14.3
Month 3	66.3 ± 15.8	26.0 [22.6; 29.3]
Year 1	78.8 ± 15.0	38.6 [35.3; 41.8]
Year 2	82.4 ± 16.4	41.8 [38.2; 45.4]
Year 5	84.7 ± 17.1	44.1 [40.4; 47.9]
KOOS pain
Baseline	50.1 ± 17.1
Month 3	77.9 ± 14.3	27.2 [24.3, 30.1]
Year 1	86.2 ± 13.0	35.7 [32.9, 38.4]
Year 2	88.6 ± 13.5	37.6 [34.7; 40.6]
Year 5	89.9 ± 14.3	38.9 [35.9; 42.0]
KOOS symptoms
Baseline	52.7 ± 17.6
Month 3	76.2 ± 15.8	22.2 [18.9, 25.4]
Year 1	84.3 ± 12.7	30.6 [28.0, 33.3]
Year 2	86.4 ± 14.7	32.2 [29.0; 35.3]
Year 5	88.3 ± 15.8	34.1 [30.8; 37.5]
KOOS ADL
Baseline	52.5 ± 19.0
Month 3	81.1 ± 13.5	28.1 [25.3, 30.9]
Year 1	89.9 ± 13.1	37.0 [34.2, 39.7]
Year 2	91.3 ± 13.4	37.9 [34.9; 41.0]
Year 5	92.5 ± 13.9	39.0 [35.9; 42.1]
KOOS sports/rec.
Baseline	21.0 ± 16.4
Month 3	49.0 ± 24.7	27.9 [22.6, 33.2]
Year 1	68.9 ± 22.1	48.0 [43.2, 52.8]
Year 2	75.7 ± 22.8	54.6 [49.7; 59.6]
Year 5	79.2 ± 22.9	58.2 [53.2; 63.2]
KOOS QoL
Baseline	22.5 ± 14.0
Month 3	47.2 ± 20.8	24.5 [20.0, 28.9]
Year 1	63.8 ± 23.5	41.2 [36.3, 46.2]
Year 2	69.8 ± 24.1	46.8 [41.6; 51.9]
Year 5	73.7 ± 24.7	50.5 [45.2; 55.8]
IKDC subjective
Baseline	34.3 ± 12.8
Month 3	55.7 ± 15.6	21.6 [18.3, 24.9]
Year 1	70.8 ± 16.5	36.8 [33.3, 40.3]
Year 2	75.8 ± 17.5	41.3 [37.6; 45.1]
Year 5	79.4 ± 18.2	44.6 [40.6; 48.5]
EQ-5D-5L index
Baseline	0.61 ± 0.28
Month 3	0.88 ± 0.11	0.27 [0.25, 0.29]
Year 1	0.92 ± 0.12	0.31 [0.29, 0.34]
Year 2	0.93 ± 0.11	0.32 [0.30; 0.35]
Year 5	0.94 ± 0.14	0.32 [0.29; 0.35]
EQ-5D-5L VAS
Baseline	59.5 ± 19.2
Month 3	75.5 ± 13.2	15.8 [13.1, 18.5]
Year 1	81.3 ± 14.4	21.9 [18.9, 24.9]
Year 2	84.1 ± 15.5	24.7 [21.5; 27.9]
Year 5	87.4 ± 15.7	27.7 [24.4; 30.9]

KOOS = Knee injury and Osteoarthritis Outcome Score; SD = standard deviation; ADL = Activities of Daily Living; Sports/rec = Sports and recreation; QoL = quality of life; IKDC = International Knee Documentation Committee score; EQ-5D-5L = EuroQoL-5 dimensions-5 levels; VAS = visual analog scale; LS = least squares.

All scores range from 0 (worst) to 100 points (best score) except for EQ-5D-5L index (-0.661 to 1 points).

Changes from baseline were analyzed via a linear mixed model for repeated measures, with country and visit as fixed factors, and baseline value as a covariate. All patients with postbaseline data were included. Changes from baseline were highly significant for all outcome measures at all assessment time points (P < 0.0001).

Other Clinical Efficacy Results

The IKDC subjective score and the EQ-5D-5L (index value and VAS) showed highly consistent outcomes in line with the KOOS outcomes, i.e., early, increasing, and nominally significant improvements from (including) Month 3 onwards until Year 1 and sustained or even further slightly increasing improvements through Year 5 (Table 3).

After 5 years, 94.6% of patients were rated as “normal” (91.4% at Year 2) and 4.3% as “nearly normal” in the IKDC objective knee examination. Only 1 patient was assessed as “abnormal” at the 5-year follow-up (3 patients at Year 2) and none of the patients as “severely abnormal.”

Structural Outcomes

Magnetic resonance imaging (MRI) outcomes were assessed in a subgroup of patients treated at clinical sites equipped with a 3 Tesla MRI. Among the 25 patients (with 30 lesions) in the MRI population, the mean MOCART 2.0 sum score was 72.3 ± 21.0 points (95% CI = 64.2-80.5, median: 75.0) at Year 2 and 64.6 ± 21.8 points (95% CI = 56.2-73.1, median: 70.0) at Year 5. However, this slight decrease of median 5 points occurred over 3 years and was driven by changes in smaller defects (9 defects ≤4 cm², mean defect size 3.4 cm²) where the median MOCART 2.0 score decreased from 90 to 75 points from Year 2 to 5. The median MOCART 2.0 score in larger defects (19 defects >4 cm², mean defect size 6.5 cm²) remained stable over time (70 points at both timepoints).

In terms of T2 mapping, the proportion of lesions within the “ideal” range of 0.8 to 1.2 observed at Year 2 (73.9% for global ratio and 78.3% for the zonal ratio) remained widely stable out to Year 5 (69.6% and 78.3% for global and zonal ratio, respectively).

In terms of correlation between the MOCART 2.0 score or the T2 mapping parameters with KOOS outcomes (responder rate or change from baseline), a positive association of the MOCART 2.0 subscore “subchondral changes” with KOOS change from baseline (i.e., better KOOS with less subchondral changes) was observed at 5 years.

Safety Results

AEs were assessed in the safety population (i.e., patients with cartilage biopsies taken) comprising 102 patients. The most common treatment-related AEs occurring in >5% of patients were arthralgia (18 patients, 17.6%), joint effusion (18 patients, 17.6%) and joint swelling (10 patients, 9.8%). None of the related AEs were severe; 8 patients (7.8%) experienced moderate and 36 patients (35.3%) mild related AEs.

Unplanned subsequent surgical interventions (SSIs) on the target knee were performed in 7 patients (6.9%). The most common AEs leading to an unplanned SSI was meniscus injury in 4 patients (3.9%). Only 2 AEs requiring an SSI were classified as treatment-related: 1 case of graft failure and 1 case of lateral patellar compression syndrome (most probably caused by overtightened sutures of the knee joint capsule during transplantation surgery). Both events recovered after corrective surgery.

Most related AEs occurred within the first year post treatment, while no related AEs or SSIs on the target knee were documented between 2 and 5 years.

The treatment failure rate (defined as proportion of patients requiring surgical re-interventions affecting the closed surface of the transplant area) was 1% (1 patient with graft failure).

Discussion

The final efficacy analyses after 5 years showed that clinical improvements in patients with large cartilage knee defects (mean lesion size for the main lesion 5.4 cm²) achieved with hydrogel-based M-ACI at Year 2²³ were fully sustained through Year 5 in all investigated clinical variables (KOOS, IKDC subjective and objective, and EQ-5D-5L). Significant mean improvements from the preoperative status were apparent as early as 3 months after treatment (first measurement time point), and the primary study endpoint (i.e., a KOOS responder rate based on a 10-point improvement of >40% at Year 2) was descriptively met from Month 3 through Year 5. The clinical relevance of these improvements is also supported by stable SCB rates³⁷ between 2 and 5 years.

Persistence of efficacy up to 5 years and for more than 5 and 10 years after M-ACI/ACI has also been reported in numerous other clinical studies^38-50 and reviews.²⁰,^51-53

Overall KOOS values in the NOVOCART Inject Phase III trial remained stable between 2 and 5 years (82.4 and 84.7 points, respectively) and are higher than those reported for spheroid-based M-ACI/Spherox (CO.DON AG, Teltow, Germany) in a Phase II study in patients with similar mean defect sizes of 5.6 cm² (73.8 and 76.9 points after 2 and 5 years, respectively). The same holds true for the IKDC results (NOVOCART Inject: 75.8 and 79.4; Spherox: 70.3 and 71.6 points at 2 and 5 years, respectively).^54,55

Another study comparing the M-ACI product MACI (Vericel, Inc., Cambridge, MA, USA) versus MFx in patients with similarly larger defects as in the NOVOCART Inject study (MACI = 5.1 cm², MFx 4.9 cm²), reported lower IKDC values in both treatment groups (Year 2: 65.3 vs. 60.1; Year 5: 68.5 vs. 61.8 for MACI and MFx, respectively) compared with those reported in the NOVOCART Inject study (Year 2: 75.8 points; Year 5: 79.4 points). In this study, no overall KOOS values were reported.⁵⁶

In the present study, a very high proportion of patients were found to be KOOS responders with 93.0%, 93.9%, and 92.8% after 2, 3 and 5 years, respectively. These responder rates are comparable with those reported for Spherox (90% at 3 and 5 years) and higher than reported for MFx (84% at 3 and 5 years) based on an RCT reported by Hoburg et al.^59,58 However, the definition of responders in the Spherox study was less strict (improvement of ≥ 8 instead of 10 points) and the defects treated were smaller (Spherox: 2.7 cm²; NOVOCART Inject: 5.4 cm² for the main lesion).

For the MACI study, a responder was defined as having at least a 10-point improvement in both the KOOS pain and function (sports/rec.) subscales.⁵⁶ Applying the same responder criterion, NOVOCART Inject showed numerically higher responder rates compared with MACI (90.0% vs. 86% at Year 2 and 89.7% vs. 78% at Year 5) and MFx (68% at Year 2 and 73% at Year 5), with both studies treating similar defect sizes.

Although comparison of data from different studies is not entirely unproblematic, it nevertheless shows that the KOOS and IKDC outcomes in the NOVOCART Inject trial favorably compare to results up to 5 years reported for other M-ACI products in the treatment of large cartilage defects of the knee.

Direct comparisons of NOVOCART Inject to other cartilage repair modalities are provided in 2 matched pair analyses with a 2-year follow-up.

The first analysis, based on data from the German Cartilage Registry, compared NOVOCART Inject to Spherox in 90 patients with large (≥4 cm²) knee cartilage defects.⁵⁹ Mean defect size was 5.5 cm², similar to the NOVOCART Inject Phase III trial. NOVOCART Inject showed significantly higher IKDC scores after 1 and 2 years compared with Spherox, with no significant differences in overall KOOS. NOVOCART Inject patients demonstrated significantly higher improvements in overall KOOS (21.5 vs. 14.8 points, P = 0.047), KOOS pain (20.6 vs. 12.2 points, P = 0.037), and IKDC score (24.3 vs. 16.0 points, P = 0.039) after 2 years. Response rates were nominally higher in the NOVOCART Inject group, however not statistically significant. Patient satisfaction was significantly higher in the NOVOCART Inject group (P = 0.016).

In the second matched pair analysis (144 patients), NOVOCART Inject was compared with the MFx control group from another RCT after 2 years. NOVOCART Inject showed significantly higher KOOS changes from baseline and responder rates (improvement ≥10 points) (KOOS LS mean change: 36.9 versus 26.9 points, P = 0.0026; responder rate 94.4% vs. 65.3%, P < 0.0001).²⁵ NOVOCART Inject also demonstrated superior SCB as defined by Ogura et al.³⁸ for KOOS pain, symptoms, sports/rec., and QoL.⁶¹ Furthermore, the MOCART 1.0 score was significantly higher in the NOVOCART Inject group compared with the MFx group (LS mean 86.9 vs. 69.1 points, P = 0.0096).⁶⁰ These results are notable as defect size (a parameter that could not be matched) in the NOVOCART Inject group was larger (main lesion size 5.4 vs. 3.5 cm²).

In the present study, MRI assessments using the MOCART 2.0 sum score showed predominately unchanged favorable morphological conditions at 1, 2, and 5 years after surgery, with slight numerical deterioration at Year 5 driven by smaller defects. These findings are likely artifactual, as smaller defects generally achieve better MRI outcomes, supported by numerous publications.²³,^62-67

T2 mapping showed good-quality repair tissue in the majority of cases. Increases were observed in the T2 global and zonal ratios from 1 to 2 years with the proportion of lesions within an “ideal” range of 0.8 to 1.2 reaching 69.6% for the T2 global and 78.3% for the T2 zonal ratio after 5 years, the latter being an indicator of hyaline-like cartilage structure.^68,69

A correlation between clinical and MRI outcomes was only observed for the MOCART 2.0 subscore “subchondral changes” which was positively associated with KOOS change from baseline (i.e., better KOOS with less subchondral changes) after 5 years. Of note, a decrease in ”subchondral changes“ was observed between 2 and 5 years, indicating that the subchondral bone benefited from treatment with NOVOCART Inject.

The stable T2 mapping results at 5-years together with the decrease in the MOCART 2.0 subscore “subchondral changes” and the observation of Janacova et al.⁷⁰ that successful cartilage defect treatment also leads to recovering of perilesional tissue align with the durable 5-year clinical outcome of NOVOCART Inject and may be beneficial for the further prognosis.

However, the lack in correlation between most MRI variables and clinical outcome which is in agreement with systematic reviews and meta-analyses showing that correlations are variable, with no correlation of MRI parameters and clinical outcome in the majority of clinical trials, indicates that MRI assessments are no validated surrogates for clinical effects in patients with cartilage defects.^71-73

The safety profile of NOVOCART Inject observed in the Phase III study up to 5 years was consistent with the established safety experience from published studies with other M-ACI products where arthralgia, joint effusion and joint swelling represented the most commonly reported treatment-related adverse events.^55,74,75 Most of these events occurred within the first year post treatment, were of mild or moderate intensity and resulted from the respective surgical procedure.

Limitations

The lack of a control group is certainly a limitation of this study, however a suitable comparator treatment for this study in patients with large (≥4 cm²) cartilage defects of the knee was not available at the time of study initiation as discussed previously.²³ Nevertheless, proof of efficacy of NOVOCART Inject is provided by clinically meaningful and stable improvement in clinical parameters up to 5 years in a broad population of patients with large knee cartilage defects (including patients with different defect etiologies, multiple defects and prior failed cartilage repair) and supported by sensitivity analyses addressing potential confounding factors as well as favorable comparisons to other cartilage repair methods.

Conclusion

M-ACI with NOVOCART Inject has shown to be a safe and effective treatment option for patients with large (4-12 cm²) symptomatic full-thickness cartilage defects of the knee and has shown sustained efficacy up to 5 years as demonstrated by consistent and clinically relevant improvements in all investigated efficacy variables. No remarkable adverse events or safety issues were noted.

Footnotes

Acknowledgments and Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The study was funded by TETEC—Tissue Engineering Technologies AG.

Declaration of Conflicting Interests

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: P.N. received consulting or advisory, and speaking and lecture fees from TETEC AG. S.T. received payment for central MRI assessment by TETEC AG. C.G., A.Kö., and A.Ki. are employees of TETEC AG. R.S. is an employee of Octane Biotherapeutics, Inc. All other authors received an investigator fee as outlined in the initial clinical trial authorization documents and accepted by the corresponding ethics committees.

Ethical Approval

The trial was approved by the ethics committees responsible for the respective centers and by the local regulatory authorities. The main ethics committee was the Bayerische Landesärztekammer, Germany (No. 17012).

ORCID iD

A. Kirner

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