ChondroCelect - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

ChondroCelect 10,000 cells/mi­crolitre implantation suspension

2. QUALITATIVE AND QUANTITATIVE COMPOSITION2.1 General description

Characterised viable autologous cartilage cells expanded ex vivo expressing specific marker proteins.

2.2 Qualitative and quantitative composition

Each vial of product contains 4 million autologous human cartilage cells in 0.4 ml cell suspension, corresponding to a concentration of 10,000 cells/mi­crolitre.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Implantation suspension

Before re-suspension the cells are settled to the bottom of the container forming an off-white layer and the excipient is a clear colourless liquid.

4. CLINICAL PARTICULARS4.1 Therapeutic indications

Repair of single symptomatic cartilage defects of the femoral condyle of the knee (International Cartilage Repair Society [ICRS] grade III or IV) in adults. Concomitant asymptomatic cartilage lesions (ICRS grade I or II) might be present. Demonstration of efficacy is based on a randomised controlled trial evaluating the efficacy o f Chondrocelect in patients with lesions between 1–5cm2

4.2 Posology and method of administration

ChondroCelect must be administered by an appropriately qualified surgeon and is restricted to hospital use only. ChondroCelect is solely intended for autologous use and should be administered in conjunction with debridement (preparation of the defect bed), a physical seal of the lesion (placement of a biological membrane, preferentially a collagen membrane) and rehabilitation.

Posology

The amount of cells to be administered is dependent on the size (surface in cm2) of the cartilage defect. Each product contains an individual treatment dose with sufficient number of cells to treat the predefined lesion size, as measured at biopsy procurement. The recommended dose of ChondroCelect is 0.8 to 1 million cells/cm2, corresponding with 80 to 100 microlitre of product/cm2 of defect.

Elderly population

The use of ChondroCelect has not been studied in this age group.

Paediatric population

The safety and efficacy in children and adolescents (aged less than 18) have not been established.

ChondroCelect is therefore not recommended for use in children and adolescents below 18 years.

Method of administration

For implantation.

ChondroCelect is intended solely for use in autologous cartilage repair and is administered to patients in an Autologous Chondrocyte Implantation procedure (ACI).

Implantation of ChondroCelect is to be performed during arthrotomy under sterile conditions and requires both preparation of the defect bed and a seal (biological membrane) to secure the implant. Complete joint haemostasis must be achieved prior to membrane fixation and cell implantation. During the ACI procedure it is important to ensure that a good, direct contact of the implanted cells with the defect bed is obtained as such contact is of paramount importance for optimal tissue regeneration. In clinical studies with ChondroCelect a periosteal flap was used as a biological membrane. Scientific publications have shown that commercially available collagen membranes can be used as an alternative to the periost in ACI procedures. However, ChondroCelect has not been evaluated in combination with collagen membranes in clinical studies, although a commercially available collagen membrane has been used in patients treated with ChondroCelect under compassionate use. The safety data obtained in these patients do not indicate a particular safety concern, and confirm a lower incidence of hypertrophy as suggested by scientific literature on the use of collagen membranes versus periost.

A technical variant of the ACI procedure is the cell seeding method, whereby the cells are seeded onto a collagen membrane prior to implantation. In this technique, a good fixation using stitches on the edges of the collagen membrane is required, in order to assure a direct contact of the implanted cells with the defect bed. Using fibrin glue only, instead of stitches, to secure the implant is not recommended.

The implantation should be followed by an appropriate rehabilitation schedule for approximately one year, as recommended by the physician (see section 4.4).

Full technical details on the procedures associated with this implantation technique are provided in the ChondroCelect user manual.

For information on preparation and handling of ChondroCelect, please refer to section 6.6.

4.3 Contraindications

Hypersensitivity to any of the excipients listed in section 6.1, or to bovine serum. ChondroCelect must not be used in case of advanced osteoarthritis of the knee.

Patients with femoral epiphyseal growth plate that is not fully closed

4.4 Special warnings and precautions for use

General

ChondroCelect is an autologous product and should under no circumstances be administered to other patients.

Patients with acute or recent history of bone or joint infections should be temporary deferred until documented recovery.

Precautions for use

Concomitant knee problems like early osteoarthritis, osteochondritis dissecans (OCD), instability of the knee, cartilage lesions at other locations than the femoral condyle, lesions of knee ligaments or of the meniscus, varus or valgus malalignment (abnormal weight distribution in the knee), and inflammatory joint disease are potential complicating factors. In the pivotal study of ChondroCelect, patients with these_comorbidities of the knee were excluded from treatment. Where possible, concomitant knee problems should be corrected prior to or at the latest at the time of ChondroCelect implantation.

In the pivotal study there was no influence of Body Mass Index (BMI) on outcome but bibliographic data shows that a BMI over 30 may adversely affect the success of the procedure.

Rehabilitation

Upon implantation, the patient should follow an appropriate rehabilitation schedule and physical activity should be resumed as recommended by the physician. Depending on the location, the size of the lesion and the patient’s profile, appropriate rehabilitation instructions have been developed. Too early and vigorous activity may compromise the grafting and the durability of clinical benefit from ChondroCelect. Therefore the treated knee should be protected according to the recommendations as outlined in the appropriate rehabilitation schedule, to avoid early damage which might lead to graft failure.

Details and information on the appropriate rehabilitation schedule is provided in the ChondroCelect user manual.

Cases in which ChondroCelect cannot be supplied

In some cases it can be possible that the source chondrocytes of the patient are not expandable or that the release criteria are not met, due to poor biopsy quality, patient characteristics, or manufacturing failure. Therefore it can occur that ChondroCelect cannot be delivered. The surgeon will be informed as early in the process as possible, and should hence select an alternative treatment for the patient concerned.

4.5 Interaction with other medicinal products and other forms of interaction

Fibrin glues are routinely used in ACI procedures to seal the outside margins and to improve the water-tightness of the compartment of the biological membrane used to cover the defect. The use of fibrin glue inside the cartilage defect bed is not recommended as this may result in a significantly poorer outcome (see section 5.3).

Fibrin sealant products differ significantly in their quantitative and qualitative composition. In vitro interaction studies were performed with a commercially available fibrin glue containing aprotinin (a fibrinolysis inhibitor of bovine origin). These studies have demonstrated that this type of fibrin sealant can be safely used with ChondroCelect. No interaction studies with any other type of fibrin glues were performed. However, the concomitant use of another type of fibrin glue with a synthetic fibrinolysis inhibitor (tranexamic acid) in the pivotal clinical trial did not reveal any safety signal.

Pain relief medicinal products should be used according to the recommendations of the responsible surgeon.

4.6 Fertility, pregnancy and lactation

Pregnancy

Limited clinical data on exposed pregnancies are available. Conventional reproductive and developmental toxicity studies are not considered relevant, given the nature and the intended clinical use of the autologous cell therapy product. As ChondroCelect is used to repair a cartilage defect of the knee and is implanted with the ACI procedure using open-knee surgery, it is not recommended during pregnancy.

Breast-feeding

There are no data on the use of ChondroCelect during breast-feeding. Given the local nature of ChondroCelect adverse reactions on the nursing infant are not anticipated. A decision should be made whether to discontinue breast-feeding taking into account the potential benefits of the treatment for the woman and the potential risk to the infant.

Fertility

There are no data on possible effects of ChondroCelect treatment on fertility.

4.7 Effects on ability to drive and use machines

Due to the surgical nature of the underlying procedure, implantation with ChondroCelect has a major influence on the ability to drive and use machines. During the rehabilitation period that follows treatment with ChondroCelect, patients should refer to their treating physician and follow their advice strictly.

Driving cars and using machines may be limited during the rehabilitation period.

4.8 Undesirable effects

Summary of the safety profile

In a randomized, controlled study in the target population, 51 patients were treated with ChondroCelect. In these patients, a periosteal flap was used to secure the implant.

Adverse reactions occurred in 78.4% of the patients over a 36-months postoperative follow-up period..

Related to ChondroCelect:

• • arthralgia
• • cartilage hypertrophy
• • joint crepitation
• • joint effusion
• • treatment failure
• • delamination

The adverse reactions listed are those that occurred most frequently, with treatment failure and delamination being the most serious.

Related to surgical intervention of the knee

• • (postoperative) joint swelling
• • arthralgia
• • pyrexia
• • arthrofibrosis
• • decreased range of motion of the knee

Most of the reported adverse reactions were expected as related to the open-knee surgical procedure.. These were generally mild and disappeared in the weeks following surgery.

Tabulated list of adverse re actions

They are listed by System Organ Class and frequency. Frequencies are defined according to the following convention: very common (> 1/10); common (> 1/100 to < 1/10); uncommon (> 1/1,000 to < 1/100); rare (> 1/10,000 to < 1/1,000); very rare (< 1/10,000). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Description of selected adverse reactions

Arthrofibrosis

In the compassionate use patients, a higher incidence of arthrofibrosis and decreased joint range of motion was observed in a subgroup of patients with a patellar lesion (8.2% and 13.1% respectively) compared to non-patellar lesions (0.6% and 2.6% respectively).

Cartilage hypertrophy

In the majority of the 370 patients included in the Compassionate Use Program, a collagen membrane instead of a periosteal flap was used to seal the defect. According to current literature the incidence of cartilage hypertrophy can be reduced by using a collagen membrane to cover the lesion site instead of using a periosteal flap (Gooding et al., 2006; Niemeyer et al., 2008). When a collagen membrane was used to seal the lesion site after application of ChondroCelect, the incidence of cartilage hypertrophy was reported to be 1.8% compared to 25% in the randomized, controlled trial alone.

Synovitis and subchondral bone injuries have been reported in animal models and are possible risks with the use of ChondroCelect.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. V

4.9 Overdose

No case of overdose has been reported.

5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Other drugs for disorders of the musculo-skeletal system, ATC code: M09AX02

Conventional pharmacodynamic studies for ChondroCelect have not been performed.

Clinical efficacy

The efficacy of ChondroCelect was studied in a phase III, multicenter, randomized, controlled trial (TIG/ACT/01/2000) and the first two years of its 4-year extension phase (TIG/ACT/01/2000EX­T). ChondroCelect was compared to the procedure of microfracture in the repair of symptomatic single cartilage lesions of the femoral condyles of the knee. 51 patients were treated with ChondroCelect, 61 patients were treated with microfracture. Patients aged between 18 and 50 years, who had a single symptomatic cartilage lesion between 1 and 5 cm2 of the femoral condyles met the inclusion criteria. Patients could be treatment-naïve or might have undergone previous arthroscopic or other surgical repair procedure(s). Patients with patellofemoral cartilage lesion, OCD, depth of lesion >0.5 cm, prior meniscal transplant, prior mosaicplasty and prior microfracture within the last 12 month were excluded. Patients had to agree to actively participate in a strict rehabilitation protocol and follow-up program.

The median time since onset of knee injury was slightly longer in the ChondroCelect group than in the microfracture group (2.0 years versus 1.6 years). More patients in the ChondroCelect treatment group, compared to patients in the microfracture group, had undergone previous knee surgery (88% versus 77%). In the ChondroCelect group 77% of patients had a medial and 23% a lateral condyle defect.

Histological examination of the repair biopsy at 12 months showed superior structural repair in the ChondroCelect arm compared to the microfracture arm. There was continuous improvement up to 36 months in the clinical outcome measure KOOS (the Knee Injury and Osteoarthritis Outcome Score) in both treatment arms. The estimated benefit was larger in the ChondroCelect group but the results did not reach statistical significance. At this time point 41 patients were evaluated in the ChondroCelect arm and 49 were evaluated in the microfracture arm. Patients with less than 3 years since onset of symptoms (n=27 in the ChondroCelect arm and n=32 in the microfracture arm) benefited most from ChondroCelect. For the group with a longer time since onset of symptoms there were no apparent differences between the 2 groups. Re-intervention on the treated lesion for graft delamination or periost loosening occurred in 2 of 51 patients within 36 months after ChondroCelect implantation, compared to 7 of 61 patients treated with microfracture having generally insufficient or inadequate cartilage repair.

After the 5 year follow-up period, 37 patients were evaluated in the ChondroCelect arm and 40 in the microfracture arm. Overall, the clinically relevant benefit of ChondroCelect implantation observed over baseline after 36 months was maintained up to 60 months after treatment. No statistically significant difference could be observed in clinical benefit between ChondroCelect and microfracture at that point in time. In the subgroup of patients with recent symptom onset (< 3 years) the clinical benefit of ChondroCelect over microfracture was significantly larger, confirming the results at 36 months after treatment. In patients with a longer time since onset of symptoms, both treatments performed equally. Seven patients treated with ChondroCelect needed re-intervention, compared to 10 patients in the microfracture group. Treatment failure in the ChondroCelect group was generally related to delamination of the graft.

Patients with lesions larger than 5 cm2 have been treated under compassionate use only. The safety data obtained in these patients do not indicate a particular safety concern. Further clinical data in patients with larger lesions are foreseen to be collected in the future.

Sixteen patients below 18 years have been treated with ChondroCelect under compassionate use. No specific safety signal was detected in these patients. If, based on the benefit/risk assessment of the responsible surgeon treatment of patients below 18 years is considered, special attention should be given to ensure that the growth plate is completely closed.

5.2 Pharmacokinetic properties

The product is implanted locally.

The nature and intended clinical use of ChondroCelect are such that conventional studies on pharmacokinetics, absorption, distribution, metabolism and elimination are not applicable.

5.3 Preclinical safety data

Non-clinical data based on implantation of expanded cartilage cells in goats and mice did not reveal special hazard for humans.

In studies in goats, mild signs of synovitis were observed in the majority of the animals, including controls at 10 weeks post surgery. Inflammation resolved with time and parameters returned to baseline levels with only some very mild and local signs of synovitis remaining in a few animals. Although it is thought that these reactions are mostly surgery-related, a potential influence of the expanded chondrocytes cannot be completely excluded.

In a study in sheep, the majority of animals showed penetration of the transplanted cells in subchondral bone; in two of these cases complete penetration of underlying bone marrow was observed. This finding might be related to the inability to perform a progressive loading under nonweight bearing conditions post-surgery in these models and therefore cannot be fully extrapolated as such to the human situation.

A technical variant of the ACI procedure is the cell seeding method, whereby the cells are seeded onto a collagen membrane prior to implantation. From a pre-clinical study in the orthotopic goat model it appeared that this technique provided comparable results as the Brittberg technique, on condition that a good fixation is established using stitches on the edges of the collagen membrane. Using fibrin glue in the defect bed instead of stitches to secure the implant resulted in an overall poor outcome, suggesting the need for a direct contact of the implanted cells with the defect bed

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Dulbecco’s Modified Eagles Medium (DMEM) (containing amino acids, vitamins, salts and carbohydrates).

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3 Shelf life

6.4 Special precautions for storage

Store between 15°C – 25 °C.

Do not refrigerate or freeze.

Keep the product vial(s) within the falcon tube in the outer plastic screw top container in order to protect from light and bacterial/fungal contamination.

Do not irradiate.

6.5 Nature and contents of container and special equipment for use, administration or implantation

ChondroCelect is supplied as one individual treatment dose (falcon tube) contained in 1 to 3 Type I glass vials of 1 ml. Each vial contains 0.4 ml of autologous human cartilage cells suspension and is closed with a chlorobutyl stopper and aluminium seal.

The vials are placed in a sterile falcon tube with a plastic screw top.

The falcon tube is placed in a plastic screw top container together with surgery materials (one sterile syringe of 1 ml, one 18G intravenous catheter and two pieces of Vicryl 6.0) and a temperature monitor.

6.6 Special precautions for disposal and other handling

ChondroCelect is intended solely for autologous use. Prior to implantation match the patient name to the patient/donor identification on the shipment documentation and product vial.

Before administration, ChondroCelect should be resuspended by gently tapping the vial to bring the cells back into suspension.

ChondroCelect should not be sterilised. If the ChondroCelect vial is damaged or its sterility has been compromised, the product must not be used and must be shipped back to TiGenix.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDER

TiGenix N.V.

Romeinse straat 12/2 3001 LEUVEN Belgium

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/09/563/001

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 5 October 2009

Date of latest renewal: 22 August 2014