Randomized, multi-center phase II clinical trial for the regeneration of cartilage lesions in the knee using nasal chondrocyte-based tissue (N-TEC) or nasal chondrocyte-based cell-therapies (N-CAM)
The clinical trial “Nose to Knee II” is a phase II multicenter clinical trial based on the phase I study described above, which focuses on efficacy and the comparison of grafts in different maturation stages and therefore requires higher patient numbers to be statistically significant. Patients, between 18 and 65 years old, suffering from articular cartilage lesions not related to an inflammatory state, are treated in four different countries: Croatia, Germany, Italy and Switzerland and will be followed for up to 2 years.
We are currently recruiting.
The ultimate goal in the treatment of articular cartilage lesions is to achieve the regeneration of organized functional hyaline cartilage. However, current therapeutic options such as arthroscopic debridement, microfracture, autologous osteochondral grafting and use of allografts suffer from major drawbacks, such as defect-size limitations, long and complex rehabilitation times, donor-site morbidity and limited graft material. Even the more advanced cell-based therapies, in addition to involving technically challenging operations associated with donor-site morbidity and highly variable outcome, do not provide entirely satisfactory treatment. Moreover, due to the use of Articular Chondrocytes (AC) in these therapies, their applicability for older patients is limited, due to the age-dependent properties of articular chondrocytes. Such techniques, although improving symptoms in short-term follow-up, cannot offer predictable and reproducible restoration of cartilage structure and function and have yet to prove cost effectiveness.
However, a tissue-therapy based on the use of autologous Nasal Chondrocytes (NC) could overcome these drawbacks and lead to a measurable benefit for the patient. A phase-I study using an engineered nasal cartilage tissue performed to evaluate the safety and feasibility of the procedure, showed promising clinical results (see above: “Nose to Knee phase I”). Despite the known advantages and disadvantages a direct comparison of the efficacy of a mature graft (active ingredient is cells and matrix) vs an immature graft (active ingredient only cells) is difficult due to the paucity of well-designed randomized and controlled trials, especially for the more recently developed techniques such as ACI, MACI and Tissue Engineering. Thus in this trial we aim at carrying out a phase II clinical trial for cartilage repair, introducing the following two main innovations: 1) the use of autologous nasal chondrocytes (NC) as cell source superior to articular chondrocytes (AC) (as in phase I) and 2) the delivery of a mature graft (Nasal chondrocytes Tissue Engineered Cartilage (N-TEC) as opposed to an immature graft (Nasal chondrocyte Cell Activated Matrix (N-CAM) see Figure below).
The main objective of the trial is the comparison of a mature versus an immature graft in order to determine the impact of graft maturation on the clinical outcome:
=> Determine whether implantation of a more mature graft is beneficial for the quality and durability of the repair tissue and the clinical outcome, measured by a superiority of at least 10 points in the main primary outcome (self-assessed KOOS score)
In addition, since the integration with the surrounding cartilage might be less efficient for a mature graft than for an immature graft (cell-seeded scaffold) as described in vitro by Obradovic et al, 2001, we want to assess this integration using the non-invasive MRI technique. Further we want to evaluate the quality of the repair tissue in order to determine its influence on the clinical outcome as experienced by the patient.
=> Determine the potential of the mature graft to integrate with the adjacent cartilage (MOCART) and the formation of hyaline cartilage as repair tissue as assessed by dGEMRIC analysis
Recent studies have indicated that ‘acute’ cartilage lesions have a more favorable prognosis following cellular therapy than those defined as ‘chronic’. Although a threshold time to distinguish between acute and chronic defects after onset of the traumatic event has not yet been defined, there is increasing consensus on the fact that 2-3 years after the trauma the joint starts displaying homeostatic changes and possible traits of early degeneration. On one hand, a more mature cartilage graft, due to the higher mechanical stability and superior cell protection, could play a critical role in the repair of chronic cartilage lesions. On the other hand, an immature graft could be sufficient to trigger anabolic regenerative processes in the case of acute defects. Therefore, it is necessary to compare efficacy of N-TEC and N-CAM in the clinical settings of acute (defined as <1 years) vs chronic (defined as >1) cartilage lesions. This analysis will be performed retrospectively.
=> determine whether the efficacy of each treatment has a correlation to the characteristics of the defect (e.g. “acute” versus “chronic” setting) possibly allowing the most promising treatment in relation to the time after the initial cartilage injury (onset of symptoms) to be selected
In order to achieve this we will enroll 108 patients in four different countries in the study and divide them in two groups, one receiving the immature graft (N-CAM) and the other the mature graft (N-TEC). Patients must display a symptomatic, isolated cartilage lesion grade III-IV (according to the grading by the International Cartilage Repair Society (ICRS)) from 2 to 8 cm2 on the femoral condyle and/or the trochlea, have to be between 18-65 years old and must consent in oral and written manner in order to be enrolled in the study. After written informed consent has been obtained, the patients will be tested to see if they comply with all other inclusion and exclusion criteria. Subsequently blood (72ml) and a cartilage biopsy (tissue sample) from the nasal septum of the patient will be taken. The cartilage cells (Chondrocytes) are isolated from the tissue, expanded for 2 weeks and placed on a collagen matrix. For the immature graft the resulting construct will be cultured for 2 more days to allow the cells to adhere to the matrix. For the mature graft the construct will be cultured for 2 more weeks, to allow the cells to form cartilage tissue. After performing the quality tests the implant will be released by the manufacturer based on the sterility, cell viability and in case of the mature graft the deposition of matrix. Subsequently, the construct will be implanted in the knee. At 6 weeks as well as 3, 12 and 24 months after the operation follow-ups will be performed. During the follow-ups at 12 and 24 months questionnaires (KOOS, EQ-5d) will be filled out by the patient and MRIs will be performed at 3,12 and 24 months.
While the questionnaires (especially the Knee injury and Osteoarthritis Outcome Score (KOOS-Score)) provide subjective information about the efficacy of the treatment, the MRIs will shed light on the integration of the implant in the defect and give information about the quality of the repair tissue. Retrospectively the data will be analyzed in correlation to the status of the defect at time of treatment: acute (symptoms since less than 2 years) or chronic (symptoms since more than 2 years). This will give an indication whether one treatment (immature or mature graft) is more effective for a defined indication (acute or chronic) than the other.
The possibility to extend indications of engineered grafts to stages of early osteoarthritis, to delay or eliminate the need for prosthetic implants, represents a major challenge for the developed method and a good opportunity for this area of research.
The study is currently recruiting patients in all clinical centers:
- University Hospital Basel, Basel, Switzerland
- Medical Center - University of Freiburg, Freiburg, Germany
- University Hospital Sveti Duh, Zagreb, Croatia
- Istituto Ortopedico Galeazzi (IOG), Milan, Italy