Osteoarthritis, Knee
Conditions
Keywords
Cartilage, Knee, Osteoarthritis
Brief summary
The purpose of this study is to see if we can safely regenerate cartilage without invasive surgery using a biologic product called TissueGene-C.
Detailed description
Protocol TGC09201 is a multi-center, double-blind, placebo-controlled, randomized study. A total of one hundred (100) adults with grade 3 chronic degenerative joint disease (DJD) of the knee joint (as determined by radiographic examination) will be enrolled into the study. TissueGene-C will be administered intra-articularly once via x-ray guidance. TissueGene-C will be administered at a dose of 3 x 10e7 cells. Patients receiving control treatment will receive a single normal saline injection. The objectives of this study are to: 1. Evaluate the efficacy of TissueGene-C with regard to knee functionality and symptoms of knee osteoarthritis including pain. 2. Evaluate the safety of administration of a single intra-articular dose of TissueGene-C as evidenced by observation of the injection site for irritation or other abnormalities, the incidence and severity of adverse events, and the changes in physical examination findings and laboratory tests, including immune analyses. 3. Evaluate the incidence and dose of analgesia and/or anti-inflammatory medication. 4. Evaluate the regeneration of hyaline cartilage as determined by 3T magnetic resonance imaging (MRI). 5. Evaluate distribution of hChonJb#7 cells out of the injection site. 6. Evaluate the efficacy of TissueGene-C by evaluating the need for total knee arthroplasty after treatment
Interventions
BIOLOGICALTissueGene-C
Single intraarticular injection at 3 x 10e7 cells
DRUGNormal Saline
Single intraarticular injection of normal saline as a placebo control
Sponsors
Kolon TissueGene, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
1. Male or Female subject 2. Age 18 to 70 years 3. In general good health as evidenced by physical examination, normal hematology, serum chemistry, and urinalysis screening laboratory results, and a negative history of significant organ system disorders. All laboratory values must be within 20% of normal ranges. 1. Body Mass Index (BMI) should be between '18.5 - 45.5'. The applied scale is the same for both men and women. 2. Blood Pressure measurements - Systolic Blood Pressure should be between 90-160mm. Hg, and Diastolic Blood Pressure between 50-90mm.Hg, 4. Patients with Grade 3 chronic osteoarthritis of the knee as determined by the Radiographic Criteria of Kellgren and Lawrence. 5. Symptom of pain for more than four (4) consecutive months and intensity of ≥ 40 and ≤ 90 on the 100-mm scale. 6. Patients should be cleared to use protocol specified equipment: 3T MRI. 7. Patients providing written informed consent after the nature of the study is fully explained and understood by the patient.
Exclusion criteria
1. Age 71 or older 2. Patients with abnormal hematology, serum chemistry, or urinalysis screening laboratory results. 3. Patients taking non-steroidal anti-inflammatory medications within 14 days of baseline visit unless washed out as per section 3.6.4 above. 4. Patients taking steroidal anti-inflammatory medications within 2 months of baseline visit. 5. Patients with a recent (within 1 year) history of drug abuse and/or a positive urine drug test at the time of screening. 6. Patients receiving injections to the treated knee within 2 months prior to study entry 7. Patients who are contraindicated for 3T MRI. 8. Patients who are pregnant or currently breast-feeding children. 9. Patients with systemic, rheumatic or inflammatory disease of the knee or chondrocalcinosis, hemochromatosis, inflammatory arthritis, necrosis of the femoral condyle, arthropathy of the knee associated with juxta-articular Paget's disease of the femur or tibia, ochronosis, hemophilic arthropathy, infectious arthritis, Charcot's knee joint, villonodular synovitis, synovial chondromatosis, and/or history of inflammatory arthropathy. 10. Patients with ongoing infectious disease, including HIV and hepatitis B or C. 11. Patients with clinically significant cardiovascular, renal, hepatic, endocrine disease, cancer, or Type I diabetes. 12. Patients participating in a study of an experimental drug or medical device within 30 days of study entry. 13. Patients that will be unable to comply with the requisite study follow-up and are not able to complete all of the follow-up office visits and 3T MRI exams.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in the International Knee Documentation Committee (IKDC) Subjective Knee Evaluation Score at 1 Year | 1 Year | Symptoms, pain and function of the knee joint determined and scored using the International Knee Documentation Committee (IKDC) Subjective Knee Evaluation (Total Score, range 0-100 with higher scores better). Linear mixed model used for analysis. |
| Change From Baseline in Visual Analog Scale (VAS) Score at 1 Year | 1 Year | Reduction in pain as measured by a 100 mm visual analog scale (0= no pain; 100 = extreme pain) from Baseline to 1 Year. Linear mixed model used for analysis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Comparative Evaluation of Knee Magnetic Resonance Images (MRIs) From Baseline to 1 Year | 1 Year | Comparison of pre-procedure 3T MRI scans to those obtained at months 12 following dose administration by an independent radiographic reviewer. Evaluations will be scored using Whole Organ Magnetic Resonance imaging Score (WORMS) Cartilage Morphology Subscore (Range 0-6, with higher scores being worse) |
| Change in Pain Severity From Baseline to 2 Years as Assessed by Questionnaire | 2 Years | Change in pain severity (on a scale from 1 to 4) from baseline to 2 years as measured by a questionnaire (lower scores better) |
| Number of Participants With Change in Pain Severity Measured by Incidence and Dose of Analgesia | 2 Years | The number of participants that had a change in pain severity as measured by the incidence and dose of analgesic medications |
| Change From Baseline in Knee Function as Determined by the Lower Extremity Functional Scale at 2 Years | 2 Years | Assessment of knee function as determined by the Lower Extremity Functional Scale (LEFS); change from baseline to 2 years (Range 0-80 with higher scores signifying lower difficulty in performing knee functions) |
| Change From Baseline in Knee Injury and Osteoarthritis Outcome Score (KOOS) at 2 Years | 2 Years | Symptoms, pain and functionality of the knee joint as determined by Total Score of the Knee Injury and Osteoarthritis Outcome Score (KOOS) (Range 0-100 with higher scores indicating healthier outcomes). Linear mixed model used for analysis. |
| The Number of Patients Experiencing Injection Site Reactions Related to Treatment | 2 Years | The number of patients with observations of the administration site deemed related to treatment with either active or placebo, including arthralgia, swelling, irritation, pain, stiffness or abnormalities |
| The Incidence and Severity of Adverse Events in Treated Patients | 2 Years | The incidence and severity of adverse events assessed through 104 weeks (2 years) after dose administration |
| Number of Participants With Adverse Events Due to Clinically Significant Changes in Hematology and Urinalysis Tests | 2 Years | The number of participants with changes in clinical hematology, chemistry, and urinalysis test results through 2 years that were considered Adverse Events |
| Change in SF-36 General Health Assessment Questionnaire (Overall Score) From Baseline to 2 Years | 2 Years | Overall assessment of general health as determined by scoring use an SF-36 Questionnaire (Range 0-100 with higher scores better - indicating less disability) |
| The Incidence of Total Knee Arthroplasty | 2 Years | Quantification of the incidence of total knee arthroplasty of the treated knee subsequent to treatment with TissueGene-C |
| Change From Baseline in Articular Cartilage Damage in the Knee as Determined by the Lysholm Knee Score at 2 Years | 2 Years | Measurement to assess outcomes of various chondral disorders of the knee determined by the Lysholm Knee Scale (Range 0-100 with higher scores better). Linear mixed model used for analysis. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| TissueGene-C TissueGene-C at 3 x 10e7 cells per injection (intraarticular)
TissueGene-C: Single intraarticular injection at 3 x 10e7 cells | 67 |
| Placebo Control Normal Saline injection
Normal Saline: Single intraarticular injection of normal saline as a placebo control | 35 |
| Total | 102 |
Baseline characteristics
| Characteristic | TissueGene-C | Placebo Control | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 28 Participants | 15 Participants | 43 Participants |
| Age, Categorical Between 18 and 65 years | 39 Participants | 20 Participants | 59 Participants |
| Age, Continuous | 56.7 Years STANDARD_DEVIATION 7.89 | 56.5 Years STANDARD_DEVIATION 8.62 | 56.6 Years STANDARD_DEVIATION 8.21 |
| Body Mass Index (BMI) | 29.6 kg/m^2 STANDARD_DEVIATION 5.87 | 29.6 kg/m^2 STANDARD_DEVIATION 5.62 | 29.6 kg/m^2 STANDARD_DEVIATION 5.7 |
| Race/Ethnicity, Customized Black | 12 participants | 4 participants | 16 participants |
| Race/Ethnicity, Customized Caucasian/White | 53 participants | 29 participants | 82 participants |
| Race/Ethnicity, Customized Hispanic | 2 participants | 2 participants | 4 participants |
| Region of Enrollment United States | 67 participants | 35 participants | 102 participants |
| Sex: Female, Male Female | 43 Participants | 21 Participants | 64 Participants |
| Sex: Female, Male Male | 24 Participants | 14 Participants | 38 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 45 / 67 | 8 / 35 |
| serious Total, serious adverse events | 7 / 67 | 4 / 35 |
Outcome results
Primary
Change From Baseline in the International Knee Documentation Committee (IKDC) Subjective Knee Evaluation Score at 1 Year
Symptoms, pain and function of the knee joint determined and scored using the International Knee Documentation Committee (IKDC) Subjective Knee Evaluation (Total Score, range 0-100 with higher scores better). Linear mixed model used for analysis.
Time frame: 1 Year
Population: Patients with available baseline IKDC scores
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| TissueGene-C | Change From Baseline in the International Knee Documentation Committee (IKDC) Subjective Knee Evaluation Score at 1 Year | 23.3 scores on a scale |
| Placebo Control | Change From Baseline in the International Knee Documentation Committee (IKDC) Subjective Knee Evaluation Score at 1 Year | 9.9 scores on a scale |
Comparison: The primary efficacy evaluation based on IKDC and the VAS were tested at week 52 evaluated 100 mm VAS with the following superiority hypothesis:~HO: μTG = μPC vs. HA: μTG ≠ μPC, where μTG and μPC are the mean change from baseline in IKDC or VAS scores at week 52 for patients in the TG-C and placebo control groups, respectively. If the null hypotheses for both the IKDC and the VAS are rejected, it the clinical effect of TG-C is concluded to be superior to that of the control.p-value: <0.01Mixed Models Analysis
Primary
Change From Baseline in Visual Analog Scale (VAS) Score at 1 Year
Reduction in pain as measured by a 100 mm visual analog scale (0= no pain; 100 = extreme pain) from Baseline to 1 Year. Linear mixed model used for analysis.
Time frame: 1 Year
Population: Patients with available baseline and 1 year VAS score
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| TissueGene-C | Change From Baseline in Visual Analog Scale (VAS) Score at 1 Year | -39.7 units on a scale |
| Placebo Control | Change From Baseline in Visual Analog Scale (VAS) Score at 1 Year | -24.3 units on a scale |
Comparison: The primary efficacy evaluation based on IKDC and the VAS were tested at week 52 evaluated 100 mm VAS with the following superiority hypothesis:~HO: μTG = μPC vs. HA: μTG ≠ μPC, where μTG and μPC are the mean change from baseline in IKDC or VAS scores at week 52 for patients in the TG-C and placebo control groups, respectively. If the null hypotheses for both the IKDC and the VAS are rejected, it the clinical effect of TG-C is concluded to be superior to that of the control.p-value: <0.01Mixed Models Analysis
Secondary
Change From Baseline in Articular Cartilage Damage in the Knee as Determined by the Lysholm Knee Score at 2 Years
Measurement to assess outcomes of various chondral disorders of the knee determined by the Lysholm Knee Scale (Range 0-100 with higher scores better). Linear mixed model used for analysis.
Time frame: 2 Years
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| TissueGene-C | Change From Baseline in Articular Cartilage Damage in the Knee as Determined by the Lysholm Knee Score at 2 Years | 20.1 scores on a scale |
| Placebo Control | Change From Baseline in Articular Cartilage Damage in the Knee as Determined by the Lysholm Knee Score at 2 Years | 11.4 scores on a scale |
Comparison: The efficacy evaluation at week 104 evaluated Lysholm score with the following superiority hypothesis:~HO: μTG = μPC vs. HA: μTG ≠ μPC, where μTG and μPC are the mean change from baseline in KOOS scores at week 104 for patients in the TG-C and placebo control groups, respectively. If the null hypotheses for Lysholm score is rejected, it the clinical effect of TG-C is concluded to be superior to that of the control.p-value: <0.01Mixed Models Analysis
Secondary
Change From Baseline in Knee Function as Determined by the Lower Extremity Functional Scale at 2 Years
Assessment of knee function as determined by the Lower Extremity Functional Scale (LEFS); change from baseline to 2 years (Range 0-80 with higher scores signifying lower difficulty in performing knee functions)
Time frame: 2 Years
Population: Patients that completed 2-year follow-up
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| TissueGene-C | Change From Baseline in Knee Function as Determined by the Lower Extremity Functional Scale at 2 Years | 16.7 scores on a scale |
| Placebo Control | Change From Baseline in Knee Function as Determined by the Lower Extremity Functional Scale at 2 Years | 13.8 scores on a scale |
Secondary
Change From Baseline in Knee Injury and Osteoarthritis Outcome Score (KOOS) at 2 Years
Symptoms, pain and functionality of the knee joint as determined by Total Score of the Knee Injury and Osteoarthritis Outcome Score (KOOS) (Range 0-100 with higher scores indicating healthier outcomes). Linear mixed model used for analysis.
Time frame: 2 Years
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| TissueGene-C | Change From Baseline in Knee Injury and Osteoarthritis Outcome Score (KOOS) at 2 Years | 10.0 scores on a scale |
| Placebo Control | Change From Baseline in Knee Injury and Osteoarthritis Outcome Score (KOOS) at 2 Years | 10.5 scores on a scale |
Comparison: The efficacy evaluation at week 104 evaluated KOOS with the following superiority hypothesis:~HO: μTG = μPC vs. HA: μTG ≠ μPC, where μTG and μPC are the mean change from baseline in KOOS scores at week 104 for patients in the TG-C and placebo control groups, respectively. If the null hypotheses for KOOS is rejected, it the clinical effect of TG-C is concluded to be superior to that of the control.p-value: <0.01Mixed Models Analysis
Secondary
Change in Pain Severity From Baseline to 2 Years as Assessed by Questionnaire
Change in pain severity (on a scale from 1 to 4) from baseline to 2 years as measured by a questionnaire (lower scores better)
Time frame: 2 Years
Population: Patients that completed 2 year follow-up
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| TissueGene-C | Change in Pain Severity From Baseline to 2 Years as Assessed by Questionnaire | -0.87 scores on a scale | Standard Deviation 0.844 |
| Placebo Control | Change in Pain Severity From Baseline to 2 Years as Assessed by Questionnaire | -0.30 scores on a scale | Standard Deviation 1.031 |
Secondary
Change in SF-36 General Health Assessment Questionnaire (Overall Score) From Baseline to 2 Years
Overall assessment of general health as determined by scoring use an SF-36 Questionnaire (Range 0-100 with higher scores better - indicating less disability)
Time frame: 2 Years
Population: Patients with completed SF-36 questionnaire at 104 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| TissueGene-C | Change in SF-36 General Health Assessment Questionnaire (Overall Score) From Baseline to 2 Years | 7.6 scores on a scale |
| Placebo Control | Change in SF-36 General Health Assessment Questionnaire (Overall Score) From Baseline to 2 Years | 6.7 scores on a scale |
Secondary
Comparative Evaluation of Knee Magnetic Resonance Images (MRIs) From Baseline to 1 Year
Comparison of pre-procedure 3T MRI scans to those obtained at months 12 following dose administration by an independent radiographic reviewer. Evaluations will be scored using Whole Organ Magnetic Resonance imaging Score (WORMS) Cartilage Morphology Subscore (Range 0-6, with higher scores being worse)
Time frame: 1 Year
Population: Patients with available baseline and 1-year MRIs
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| TissueGene-C | Comparative Evaluation of Knee Magnetic Resonance Images (MRIs) From Baseline to 1 Year | 0.03 scores on a scale |
| Placebo Control | Comparative Evaluation of Knee Magnetic Resonance Images (MRIs) From Baseline to 1 Year | -0.49 scores on a scale |
Secondary
Number of Participants With Adverse Events Due to Clinically Significant Changes in Hematology and Urinalysis Tests
The number of participants with changes in clinical hematology, chemistry, and urinalysis test results through 2 years that were considered Adverse Events
Time frame: 2 Years
Population: All patients
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TissueGene-C | Number of Participants With Adverse Events Due to Clinically Significant Changes in Hematology and Urinalysis Tests | 17 participants |
| Placebo Control | Number of Participants With Adverse Events Due to Clinically Significant Changes in Hematology and Urinalysis Tests | 5 participants |
Secondary
Number of Participants With Change in Pain Severity Measured by Incidence and Dose of Analgesia
The number of participants that had a change in pain severity as measured by the incidence and dose of analgesic medications
Time frame: 2 Years
Population: Patients taking at least one analgesia medication
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TissueGene-C | Number of Participants With Change in Pain Severity Measured by Incidence and Dose of Analgesia | 37 participants |
| Placebo Control | Number of Participants With Change in Pain Severity Measured by Incidence and Dose of Analgesia | 20 participants |
Secondary
The Incidence and Severity of Adverse Events in Treated Patients
The incidence and severity of adverse events assessed through 104 weeks (2 years) after dose administration
Time frame: 2 Years
Population: All patients receiving treatment with either active or placebo
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| TissueGene-C | The Incidence and Severity of Adverse Events in Treated Patients | Moderate | 41 participants |
| TissueGene-C | The Incidence and Severity of Adverse Events in Treated Patients | Severe | 8 participants |
| TissueGene-C | The Incidence and Severity of Adverse Events in Treated Patients | Mild | 12 participants |
| Placebo Control | The Incidence and Severity of Adverse Events in Treated Patients | Moderate | 18 participants |
| Placebo Control | The Incidence and Severity of Adverse Events in Treated Patients | Mild | 7 participants |
| Placebo Control | The Incidence and Severity of Adverse Events in Treated Patients | Severe | 4 participants |
Secondary
The Incidence of Total Knee Arthroplasty
Quantification of the incidence of total knee arthroplasty of the treated knee subsequent to treatment with TissueGene-C
Time frame: 2 Years
Population: All patients that participated in the study
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TissueGene-C | The Incidence of Total Knee Arthroplasty | 1 participants |
| Placebo Control | The Incidence of Total Knee Arthroplasty | 1 participants |
Secondary
The Number of Patients Experiencing Injection Site Reactions Related to Treatment
The number of patients with observations of the administration site deemed related to treatment with either active or placebo, including arthralgia, swelling, irritation, pain, stiffness or abnormalities
Time frame: 2 Years
Population: All participants receiving placebo or active treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TissueGene-C | The Number of Patients Experiencing Injection Site Reactions Related to Treatment | 35 participants |
| Placebo Control | The Number of Patients Experiencing Injection Site Reactions Related to Treatment | 5 participants |