Phase 3 Clinical Trial of CartiLife® in Korea

Study Overview
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Brief Summary
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To evaluate the safety and efficacy of pellet-type extracellular matrix-associated autologous chondrocytes (CartiLife®) obtained by cultivating costal chondrocytes of the subject implanted into articular cartilage defects of the knee resulting from trauma or degeneration.

Detailed Description
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This open-label, phase 3 study is being conducted to evaluate the safety and efficacy of pellet-type extracellular matrix-associated autologous chondrocytes (CartiLife®) compared with microfracture surgery in adults with articular cartilage defects due to trauma or degeneration of the knee. It is hypothesized that CartiLife® treatment will demonstrate structural regeneration and improvement in function and pain at Week 48 compared to baseline.

Official Title
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A Multi-Center, Active-Controlled, Open-Label, Phase III Trial to Compare the Efficacy and Safety for Treatment of Autologous Chondrocytes Implantation With CartiLife Versus Microfracture for Patients With Knee Chondral Defects

Conditions
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Articular Cartilage Defect, Articular Cartilage Degeneration

Intervention / Treatment
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* Drug: Autologous Chondrocyte Implantation (CartiLife®)
* Procedure: Microfracture Surgery


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: In order to be eligible to participate in this study, an individual must meet all of the following: Patients over the age of 18. Defect size: 2 to 10 cm^2 on the unilateral knee cartilage (up to 4 ㎤ in volume). Defect: isolated ICRS (International Cartilage Repair Society) grade III or IV single defect chondral lesion on articular cartilage with comparatively healthy cartilage present near the lesion site (ICRS Grade 1   2). Patients with a KOOS total score below 55. Patients able to walk without aid. Patients who agree to abide by rehabilitation protocols and follow-up programs, including residential exercise routines. Patients who provide written consent to the application of the clinical trial. Exclusion Criteria: Individuals who meet any of the following will be excluded from participation in this study: Patients with inflammatory articular diseases such as rheumatoid arthritis or gouty arthritis. Patients scoring 3 or above on the Kellgren-Lawrence Grading Scale. Patients with inflammatory articular diseases related to autoimmune diseases. Patients hypersensitive to bovine derived proteins or any of the components in this product. Patients hypersensitive to Gentamycin. Patients with Haemophilia or markedly reduced immune function. Patients with arterial bleeding and severe venous bleeding. Patients with other diseases including tumors except for cartilaginous defects of joints. Patients with a history of radiation treatment and chemotherapy within the past two years. Patients who are pregnant, or nursing a baby. Patients who participate in concurrent clinical trials or previous clinical trials within 30 days of administration. Other cases where the investigator deems the patient ineligible for participation.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Investigational Group : CartiLife® Procedure: Extracellular matrix-associated autologous chondrocytes comprise CartiLife®, composed as pellets (1.1 to 1.8 mm in diameter) in suspension. One pre-filled syringe is implanted per 1 cm^3 of defect volume, and fibrin adhesive is applied to fix pellets in place through minimal arthrotomy. Active comparator: Microfracture Surgery Procedure : Microfracture surgery, performed by arthroscopy after the joint is cleaned of calcified cartilage, will be conducted using an awl or drill to create tiny fractures in the subchondral bone plate.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CartiLife®<br>Extracellular matrix-associated autologous chondrocytes comprise CartiLife®, composed as pellets (1.1 to 1.8 mm in diameter) in suspension. One pre-filled syringe is implanted per 1 cm^3 of defect volume, and fibrin adhesive is applied to fix pellets in place through minimal arthrotomy. | Drug: Autologous Chondrocyte Implantation (CartiLife®)<br>* CartiLife consists of small beads (1 mm in diameter) in suspension, developed from pellet culture of autologous costal chondrocytes after multiplication. The beads are implanted in an injective manner with fibrin glue through minimal arthrotomy. The dose depends on the size (volume) of the defect, recommended dose is 480 pellets/cm^3 defect<br>* Other names: CartiLife;|
| Active Comparator: Microfracture Surgery<br>Microfracture surgery, performed by arthroscopy after the joint is cleaned of calcified cartilage, will be conducted using an awl or drill to create tiny fractures in the subchondral bone plate. | Procedure: Microfracture Surgery<br>* Microfracture surgery, performed by arthroscopy after the joint is cleaned of calcified cartilage, will be conducted using an awl or drill to create tiny fractures in the subchondral bone plate<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MOCART (Magnetic Resonance Observation of Cartilage Repair Tissue) | MOCART is a validated tool that provides reliable, reproducible, and accurate assessment of cartilage repair tissue (Marlovits et al, 2006 that; Trattnig et al, 2011). | At Week 48, post-operation | 
| KOOS Total Score | The KOOS is a reliable and valid patient-reported outcome measurement tool that evaluates both short-term and long-term consequences of knee injury. The 5 separately scored subscales of Pain, other Symptoms, Function in daily living (ADL), Function in Sport and Recreation (Sport/Rec), and knee-related QOL may enrich clinical and research data interpretation (Roos and Lohmander, 2003; Collins et al, 2011). In the 'Knee injury and Osteoarthritis Outcome Score', scores range from 0 to 100 with a score of 0 indicating the worst possible knee symptoms and 100 indicating no knee symptoms. | From Week 0 to Week 48, post-operation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MOCART Score | MOCART is a validated tool that provides reliable, reproducible, and accurate assessment of cartilage repair tissue (Marlovits et al, 2006 that; Trattnig et al, 2011). In the 'Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) Score', the total score ranges from 0 to 100, with a score of 0 indicating the worst possible knee symptoms and 100 indicating no knee symptoms. | At Week 24 and Week 96, post-operation | 
| Lysholm Score | The Lysholm scale is a broadly applicable, validated tool for measuring changes following nonsurgical and surgical intervention, as well as deterioration over time in patients with various knee pathologies (Collins et al, 2011). In the 'Lysholm score', the total score ranges from 0 to 100, with a score of 0 indicating the worst possible knee symptoms and 100 indicating no knee symptoms. | At Week 0 to Week 8, 24, 48 and 96, post-operation | 
| IKDC Score | The IKDC Knee form covers domains likely to be important to patients and has adequate consistency and broad applicability across mixed groups of patients (Collins et al, 2011). In the 'International Knee Documentation Committee Subjective Knee Form', the total score ranges from 0 to 100, with a score of 0 indicating the worst knee symptoms(lowest level of function or highest level of symptoms) and 100 indicating no knee symptoms(highest level of function and lowest level of symptoms). | At Week 0 to Week 8, 24, 48 and 96, post-operation | 
| KOOS Score (Pain, Other symptoms, Function in daily living, Function in sport and recreation, and knee-related QOL subscales) | The KOOS is a reliable and valid patient-reported outcome measurement tool that evaluates both short-term and long- term consequences of knee injury. The 5 separately scored subscales of Pain, other Symptoms, Function in daily living (ADL), Function in Sport and Recreation (Sport/Rec), and knee-related QOL may enrich clinical and research data interpretation (Roos and Lohmander, 2003; Collins et al, 2011). KOOS Score (Pain, Other symptoms, Function in daily living, Function in sport and recreation, and knee-related QOL subscales) are measured between 0, 1, 2, 3 and 4. The KOOS subscales are scored separately: Pain (9 items); Symptoms (7 items); Function in daily living (17 items); Function in sport and recreation (5 items); knee-related QOL (4 items). Each scale is scored between 0 to 4. The total score ranges from 0 to 100, with a score of 0 indicating the worst possible knee symptoms and 100 indicating no knee symptoms. | At Week 0 to Week 8, 24, 48 and 96, post-operation | 
| VAS (100mm Pain Visual Analogue Scale) | The VAS is a validated, ubiquitous tool for patient-reported measurement of pain at a given point in time (Kersten et al, 2014). Visual Analogue Scale (VAS) is a measurement instrument that measures a specified characteristic which is deemed difficult to quantify across a continuous line of value to determine its representative value. The VAS scale ranges from 0 to 100 mm, with 0 indicating absence of pain and 100 indicating the worst pain experienced. | At Week 0 to Week 8, 24, 48 and 96, post-operation | 
| Tegner Activity Scale | The Tegner activity score is a frequently used patient-administered activity rating system for patients with various knee activity functions. The instrument scores a person's activity level between 0 and 10 where 0 is 'on sick leave/disability' and 10 is 'participation in competitive sports such as soccer at a national or international elite level' (Karen Hambly, 2011). A level of 0 indicates that the patient is unable to participate in activities barring 'Sick leave or disability pension because of knee problems', and a level of 10 indicates that the patient is capable of participating in activities which at its most intense include 'Competitive sports - soccer, football, rugby at a national elite level'. | At Week 0 to Week 8, 24, 48 and 96, post-operation | 
| Pain medication history | Pain medication history is an indicator of patient pain. Pain medication history is an indicator of patient pain. The frequency of analgesic ingestion is measured for the specified duration over the course of the clinical trial, and changes in analgesic ingestion in terms of frequency are assessed to analyze the efficacy of the clinical trial product. | At Week 0 to Week 8, 24, 48 and 96, post-operation | 
| Treatment related adverse events | Number of subjects with treatment related adverse events as assessed by analysis of adverse events including symptoms, abnormal findings on physical examination, vital signs, ECG, and standard laboratory examination results. The total number of patients who exhibit symptoms identified as an adverse event will be cumulatively combined to obtain a whole digit number representing the number of patients who have suffered an adverse event throughout the course of the clinical trial. | At Week 0 (pre-operation), and up to 24 Months (post-operation) |