Isolated Cartilage Injury of the Knee Clinical Trial
Official title:
A Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group Phase II Trial to Investigate the Efficacy and Safety of Weekly Intra-articular (i.a.) Injections of 10, 30, and 100 µg of AS902330 for Three Consecutive Weeks in Patients With Acute Cartilage Injury of the Knee
Many people all over the world suffer from cartilage injuries in the knee. Symptoms include
pain, joint swelling, and loss of function. Without repair, cartilage injury may ultimately
lead to osteoarthritis (OA). Natural healing is poor, and to date treatment is available
only for deep cartilage defects involving also the underlying bone. A promising candidate
for drug treatment of cartilage injury is AS902330, a recombinant form of the human
fibroblast growth factor (FGF) 18.
So far, the drug has been used in subjects with different stages of knee OA in two ongoing
studies without emerging safety issues following single and multiple intra-articular
injections of ascending doses. However, OA represents late-stage cartilage injury, where
repair might be difficult due to diffuse damage, reduced responsiveness of the cartilage,
and/or the involvement of other joint structures.
This clinical trial is meant to provide the proof of concept and to identify an efficacious
dose of AS902330 for the treatment of adult subjects with acute cartilage injuries of the
knee. The first subject for this trial was treated on the 19th of April 2010.
| Status | Terminated |
| Enrollment | 74 |
| Est. completion date | April 2013 |
| Est. primary completion date | April 2013 |
| Accepts healthy volunteers | No |
| Gender | Both |
| Age group | 18 Years to 45 Years |
| Eligibility |
Inclusion Criteria: - Acute cartilage lesion of ICRS grade 2 to 4 at the femoral condyle of the knee (= target knee) - Age: 18 to 45 years - Sex: male or female. Women of childbearing potential (that is, all female subjects after puberty unless they are post-menopausal for at least 2 years or surgically sterile) must have negative serum and urine pregnancy tests at screening and Visit 1, respectively, and must use a highly effective method of contraception. - History of pain and effusion of the target knee post-injury - Injury within 4 to 12 weeks prior to 1st treatment with investigational medicinal product (IMP) - Written informed consent prior to any trial-related activity Exclusion Criteria: - Personal medical history of osteoarthritis OA in either knee - Any previous surgery on the target knee - History of swelling of the target knee along with pain on weight-bearing, or arthroscopy for diagnostic purposes during the 12 months preceding injury - Corticosteroid (intra-articular) injection into the target knee during the preceding 12 months - Any other intra-articular injection into the target knee during the preceding 3 months - Any concurrent injury (for example, arthrolith, anterior cruciate ligament rupture, meniscus tear) of the target knee requiring surgical intervention - OA or any pre-existing cartilage damage in the target knee, as revealed by MRI - Legal incapacity or limited legal capacity - Subjects who are imprisoned or institutionalized by regulatory or court order - Pregnancy or lactation - Participation in another clinical trial within the past 30 days - Any condition or findings in the medical history or in the pre-trial assessments that in the opinion of the Investigator constitutes a risk or contraindication for participation in the trial or that could interfere with the trial objectives, conduct or evaluation - Known hypersensitivity to the trial treatment or diluents - Significant renal or hepatic impairment, as indicated by: Aspartate aminotransferase (AST), alanine aminotransferase (ALT), or alkaline phosphatase (AP) greater than (>) 3 times the upper limit of normal (ULN); total bilirubin >1.5 times ULN (except in case of Gilbert's syndrome); creatinine >1.5 times ULN; hemoglobin less than (<5.5) millimole per liter (mmol/L), white blood cell count (WBC) <2.5 x 109 per liter, or platelets <75 x 109 per liter) - Any suspicion of intra-articular infection - Any known active infections that may compromise the immune system such as human immunodeficiency virus (HIV), Hepatitis B or C infection - History of sarcoma and/or of other active malignancy within five years, except adequately treated basal cell or squamous cell carcinoma of the skin - Open growth plate, as revealed by MRI - Diagnostic arthroscopy after injury and within 4 weeks prior to treatment start |
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment
| Country | Name | City | State |
|---|---|---|---|
| Germany | Please contact the Merck KGaA Communication Center | Darmstadt |
| Lead Sponsor | Collaborator |
|---|---|
| Merck KGaA |
Germany,
| Type | Measure | Description | Time frame | Safety issue |
|---|---|---|---|---|
| Primary | Percent Change from Baseline in Cartilage Defect Volume at Month 12 | Percent change in cartilage defect volume at Month 12 based on central magnetic resonance imaging (MRI) will be calculated as: (volume at Month 12 minus volume at baseline)*100/volume at baseline. | Baseline, Month 12 | No |
| Secondary | Percent Change from Baseline in Cartilage Defect Volume and Cartilage Defect Thickness in the target knee at Months 3 and 6 | Percent change in cartilage defect volume and cartilage defect thickness at Months 3 and 6 based on central MRI will be calculated as: ([volume or thickness at Months 3 and 6 minus volume or thickness at baseline, respectively]*100)/volume or thickness at baseline. | Baseline, Months 3 and 6 | No |
| Secondary | Change from Baseline in Cartilage Defect Volume in the target knee at Months 3, 6 and 12 | The change in cartilage defect volume at Months 3, 6 and 12 based on central MRI will be calculated as volume at Months 3, 6 and 12 minus volume at baseline, respectively. | Baseline, Months 3, 6 and 12 | No |
| Secondary | Change from Baseline in Cartilage Defect Thickness in the target knee at Months 3, 6 and 12 | The change in cartilage defect thickness at Months 3, 6 and 12 based on central MRI will be calculated as thickness at Months 3, 6 and 12 minus thickness at baseline, respectively. | Baseline, Months 3, 6 and 12 | No |
| Secondary | Number of Subjects with Response to Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) Sub-scales at Months 3, 6 and 12 | The MOCART scoring system comprises 9 variables used to describe the morphology and signal intensity of the repair tissue following MRI (degree of defect repair, integration to the border zone, surface of repair tissue, structure of repair tissue, signal intensity [T2 Mapping Sequence and Hi-Res Sagittal Pharmacodynamic Sequence], subchondral lamina, subchondral bone, adhesions, and effusion). Number of subjects with response to various MOCART sub-scales will be reported. | Months 3, 6 and 12 | No |
| Secondary | Change from Baseline in Boston Leeds Osteoarthritis Knee Score (BLOKS) Sub-scale (Bone Marrow Lesion [BML] Size and Osteophyte Size) Score at Month 12 | The BLOKS scoring system assesses intra-articular regions within the knee according to the following features: BML size, cartilage 1, osteophyte size, synovitis, effusion, meniscal extrusion, and meniscal tear. Summary scores for BML size range from 0 to 27, with lower scores corresponding to favorable outcomes. Summary scores for osteophyte size range from 0 to 36, with lower scores corresponding to favorable outcomes. | Baseline, Month 12 | No |
| Secondary | Number of Subjects with Change from Baseline BLOKS Sub-Scale (Cartilage 1 Score, Synovitis Score, Effusion Score, Meniscal Extrusion Score, Meniscal Tear Score) at Month 12 | The BLOKS scoring system assesses intra-articular regions within the knee according to the following features: BML size, cartilage 1, osteophyte size, synovitis, effusion, meniscal extrusion, and meniscal tear. Number of subjects with change from baseline in various BLOKS sub-scales (cartilage 1 [patella medial], synovitis, effusion, meniscal extrusion, meniscal tear) scores at Month 12 will be reported. | Baseline, Month 12 | No |
| Secondary | Number of Subjects with Change from Baseline in International Cartilage Repair Society (ICRS) grade at Months 6 and 12 | The ICRS grading is used to score the amount of cartilage repair and damage. The total score ranges from 1 to 4 where higher score indicates more severity of injury. Number of subjects with change from baseline in ICRS grade at Months 6 and 12 will be reported. | Baseline, Months 6 and 12 | No |
| Secondary | Change from Baseline in Knee Injury and Osteoarthritis Outcome Score (KOOS) Sub-scale scores and International Knee Documentation Committee (IKDC) score at Months 3, 6 and 12 | The KOOS is a knee-specific self-administered questionnaire that assesses symptoms and problems associated with knee injury and osteoarthritis. It consists of 42 items grouped into 5 sub-scales: symptoms, pain, function in daily living, function in sports and recreation activities, and quality of life. Sub-scale scores range from 0 to 100, with 0 representing extreme knee problems and 100 representing no knee problems. The IKDC is composed of 19 items used to summarize symptoms including highest level of activity without significant pain, frequency and severity of pain scales, stiffness and swelling, highest levels of activity without significant swelling or giving way, knee lock or catch, highest level of activity that can be performed on a regular basis, effect of knee on ability to perform set tasks, knee function prior to injury, and current knee function. The IKDC scores range from 0 to 100 where a high score represents high levels of function and low levels of symptoms. | Baseline, Months 3, 6 and 12 | No |
| Secondary | Number of Subjects with Global Evaluation of Treatment Benefit | Subjects will be asked to evaluate and rate the treatment benefit as poor, fair, good, very good or excellent. | Months 3, 6 and 12 | No |
| Secondary | Number of Subjects with Treatment Emergent Adverse Events (TEAEs), Local TEAEs, Systemic TEAEs, TEAEs Leading to Discontinuation and Serious Adverse Events (SAEs) | An adverse event (AE) is defined as any untoward medical occurrence in a subject or clinical investigation subject administered a pharmaceutical product, which does not necessarily have a causal relationship with this treatment. An SAE is an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect. TEAEs are those AEs that either started or worsened in severity on or after the date of first dose of study drug and on or before Month 12. Local TEAEs are those only related to the target knee. Systemic TEAEs are those that are related to other parts of the body. | Baseline up to Month 12 | Yes |
| Secondary | Number of Subjects with Acute Inflammatory Reactions | Acute inflammatory reaction is defined as an increase of pain by 30 millimeter (mm) on a 100 mm visual analog scale (VAS) associated with a subject-reported synovial fluid effusion within 3 days following intra-articular injection. | Baseline up to Month 12 | Yes |
| Secondary | Number of Subjects with Binding Antibodies (BAbs) and Neutralizing Antibodies (NAbs) to Fibroblast Growth Factor 18 (FGF18) | Number of subjects with BAbs and NAbs to FGF18 at Week 1 (pre-dose), Week 2 (pre-dose), Week 4, Months 3 and 12 will be reported. | Week 1 (pre-dose), Week 2 (pre-dose), Week 4, Months 3 and 12 | No |