Back to resultsSprifermin (AS902330) in Cartilage Injury Repair (CIR)
Primary Purpose
Isolated Cartilage Injury of the Knee
Status
Terminated
Phase
Phase 2
Locations
Germany
Study Type
Interventional
Intervention
Sprifermin (AS902330) 10 mcg
Sprifermin (AS902330) 30 mcg
Sprifermin (AS902330) 100 mcg
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Isolated Cartilage Injury of the Knee focused on measuring Knee cartilage injury, fibroblast growth factor 18, FGF18
Eligibility Criteria
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 (ALP) 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 * 10^9 per liter, or platelets <75 *10^9 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
Sites / Locations
- Please contact the Merck KGaA Communication Center
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm Type
Experimental
Experimental
Experimental
Placebo Comparator
Arm Label
Sprifermin (AS902330) 10 mcg
Sprifermin (AS902330) 30 mcg
Sprifermin (AS902330) 100 mcg
Placebo
Arm Description
Outcomes
Primary Outcome Measures
Percent Change From Baseline in Cartilage Defect Volume at Month 12
Percent change in cartilage defect volume was calculated based on central magnetic resonance imaging (MRI): (volume at Month 12 minus volume at baseline)*100/volume at baseline.
Secondary Outcome Measures
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 was calculated as: ([volume or thickness at Months 3 and 6 minus volume or thickness at baseline, respectively]*100)/volume or thickness at baseline.
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 was calculated as volume at Months 3, 6 and 12 minus volume at baseline, respectively.
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 was calculated as thickness at Months 3, 6 and 12 minus thickness at baseline, respectively.
Number of Participants With Response to Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) Sub-scales
MOCART scoring system (comprising 9 variables) was used to describe the morphology & signal intensity of the repair tissue following MRI -degree of defect repair [DDR] score 0 (subchondral bone exposed) to 20 (complete repair); integration to the border zone [IBZ] score 0 (> 50% of length of repair tissue) to 15 (complete integration to border zone);surface of repair tissue [SRT] score 0 (>50% surface repair tissue/total degradation) to 10(surface intact);structure of repair tissue [StRT] score 0(inhomogenous/cleft formation) to 5 (homogenous);signal intensity [T2] Mapping Sequence [T2MS] and Hi-Res Sagittal Pharmacodynamic Sequence [Hi-Res SPS] score 0 (marked hyper intense for T2MS and hypo intense for Hi-Res SPS) to 15 (iso intense); subchondral lamina,subchondral bone score 0 (not impact) to 5 (intact);adhesions & effusion score 0 (yes) and 5 (no). Higher values represent more favorable outcome of repair.
Change From Baseline in Boston Leeds Osteoarthritis Knee Score (BLOKS) Sub-scale (Bone Marrow Lesion [BML] Size, Osteophyte Size, Meniscal Extrusion Score [MES], and Meniscal Tear Score [MTS]) Scores 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. Change from baseline in summary scores for BML size, osteophyte size, MES, and MTS were reported. Summary scores for BML size range from 0 to 27, for osteophyte size range from 0 to 36, for MES range from 0 to 12, and for MTS range from 0 to 32, with lower scores corresponding to favorable outcomes.
Number of Participants With Shift From Baseline in BLOKS Sub-Scales (Cartilage 1, Synovitis, Effusion) Scores 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. Total number of participants with shift from baseline in various BLOKS sub-scales (cartilage 1 [patella medial, patella lateral, femur medial trochlea, femur lateral trochlea, medial weight bearing femur, lateral weight bearing femur, tibia medial, tibia lateral], synovitis, and effusion) scores at Month 12 were reported.
Number of Participants 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 grades range from 1 to 4 where higher grades indicate more severity of injury. Number of participants with change value of -3, -2, -1, 0, 1, and 2 from baseline in ICRS grade at Months 6 and 12 were reported. Lower change value indicates less severity of injury.
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 (FDL), function in sports and recreation activities (FSRA), and quality of life (QoL). Sub-scale scores range from 0-100, with 0 representing extreme knee problems and 100 no knee problems. The IKDC consists of 19 items to summarize symptoms such as 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 0-100 where high score represents high levels of function.
Number of Participants With Global Evaluation of Treatment Benefit
Participants were asked to evaluate and rate the treatment benefit as poor, fair, good, very good or excellent.
Number of Participants 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.
Number of Participants With Acute Inflammatory Reactions
Acute inflammatory reaction (AIR) 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.
Number of Participants With Binding Antibodies (BAbs) and Neutralizing Antibodies (NAbs) to Fibroblast Growth Factor 18 (FGF18)
Number of participants with BAbs and NAbs to FGF18 at Week 1 (pre-dose), Week 2 (pre-dose), Week 4, Months 3 and 12 were reported.
Full Information
NCT ID
NCT01066871
First Posted
February 9, 2010
Last Updated
February 22, 2016
Sponsor
Merck KGaA, Darmstadt, Germany
1. Study Identification
Unique Protocol Identification Number
NCT01066871
Brief Title
Sprifermin (AS902330) in Cartilage Injury Repair (CIR)
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
Study Type
Interventional
2. Study Status
Record Verification Date
February 2016
Overall Recruitment Status
Terminated
Why Stopped
The study was discontinued due to low recruitment.
Study Start Date
March 2010 (undefined)
Primary Completion Date
April 2013 (Actual)
Study Completion Date
April 2013 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Merck KGaA, Darmstadt, Germany
4. Oversight
Data Monitoring Committee
No
5. Study Description
Brief Summary
Several 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 sprifermin (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 sprifermin (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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Isolated Cartilage Injury of the Knee
Keywords
Knee cartilage injury, fibroblast growth factor 18, FGF18
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
74 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Sprifermin (AS902330) 10 mcg
Arm Type
Experimental
Arm Title
Sprifermin (AS902330) 30 mcg
Arm Type
Experimental
Arm Title
Sprifermin (AS902330) 100 mcg
Arm Type
Experimental
Arm Title
Placebo
Arm Type
Placebo Comparator
Intervention Type
Drug
Intervention Name(s)
Sprifermin (AS902330) 10 mcg
Intervention Description
Sprifermin (AS902330) will be administered at a dose of 10 microgram (mcg) as intra-articular injection once every week for 3 consecutive weeks.
Intervention Type
Drug
Intervention Name(s)
Sprifermin (AS902330) 30 mcg
Intervention Description
Sprifermin (AS902330) will be administered at a dose of 30 mcg as intra-articular injection once every week for 3 consecutive weeks.
Intervention Type
Drug
Intervention Name(s)
Sprifermin (AS902330) 100 mcg
Intervention Description
Sprifermin (AS902330) will be administered at a dose of 100 mcg as intra-articular injection once every week for 3 consecutive weeks.
Intervention Type
Other
Intervention Name(s)
Placebo
Intervention Description
Placebo matched to sprifermin (AS902330) will be administered as intra-articular injection once every week for 3 consecutive weeks.
Primary Outcome Measure Information:
Title
Percent Change From Baseline in Cartilage Defect Volume at Month 12
Description
Percent change in cartilage defect volume was calculated based on central magnetic resonance imaging (MRI): (volume at Month 12 minus volume at baseline)*100/volume at baseline.
Time Frame
Baseline, Month 12
Secondary Outcome Measure Information:
Title
Percent Change From Baseline in Cartilage Defect Volume and Cartilage Defect Thickness in the Target Knee at Months 3 and 6
Description
Percent change in cartilage defect volume and cartilage defect thickness at Months 3 and 6 based on central MRI was calculated as: ([volume or thickness at Months 3 and 6 minus volume or thickness at baseline, respectively]*100)/volume or thickness at baseline.
Time Frame
Baseline, Months 3 and 6
Title
Change From Baseline in Cartilage Defect Volume in the Target Knee at Months 3, 6 and 12
Description
The change in cartilage defect volume at Months 3, 6 and 12 based on central MRI was calculated as volume at Months 3, 6 and 12 minus volume at baseline, respectively.
Time Frame
Baseline, Months 3, 6 and 12
Title
Change From Baseline in Cartilage Defect Thickness in the Target Knee at Months 3, 6 and 12
Description
The change in cartilage defect thickness at Months 3, 6 and 12 based on central MRI was calculated as thickness at Months 3, 6 and 12 minus thickness at baseline, respectively.
Time Frame
Baseline, Months 3, 6 and 12
Title
Number of Participants With Response to Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) Sub-scales
Description
MOCART scoring system (comprising 9 variables) was used to describe the morphology & signal intensity of the repair tissue following MRI -degree of defect repair [DDR] score 0 (subchondral bone exposed) to 20 (complete repair); integration to the border zone [IBZ] score 0 (> 50% of length of repair tissue) to 15 (complete integration to border zone);surface of repair tissue [SRT] score 0 (>50% surface repair tissue/total degradation) to 10(surface intact);structure of repair tissue [StRT] score 0(inhomogenous/cleft formation) to 5 (homogenous);signal intensity [T2] Mapping Sequence [T2MS] and Hi-Res Sagittal Pharmacodynamic Sequence [Hi-Res SPS] score 0 (marked hyper intense for T2MS and hypo intense for Hi-Res SPS) to 15 (iso intense); subchondral lamina,subchondral bone score 0 (not impact) to 5 (intact);adhesions & effusion score 0 (yes) and 5 (no). Higher values represent more favorable outcome of repair.
Time Frame
Months 3 (M3), 6 (M6) and 12 (M12)
Title
Change From Baseline in Boston Leeds Osteoarthritis Knee Score (BLOKS) Sub-scale (Bone Marrow Lesion [BML] Size, Osteophyte Size, Meniscal Extrusion Score [MES], and Meniscal Tear Score [MTS]) Scores at Month 12
Description
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. Change from baseline in summary scores for BML size, osteophyte size, MES, and MTS were reported. Summary scores for BML size range from 0 to 27, for osteophyte size range from 0 to 36, for MES range from 0 to 12, and for MTS range from 0 to 32, with lower scores corresponding to favorable outcomes.
Time Frame
Baseline, Month 12
Title
Number of Participants With Shift From Baseline in BLOKS Sub-Scales (Cartilage 1, Synovitis, Effusion) Scores at Month 12
Description
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. Total number of participants with shift from baseline in various BLOKS sub-scales (cartilage 1 [patella medial, patella lateral, femur medial trochlea, femur lateral trochlea, medial weight bearing femur, lateral weight bearing femur, tibia medial, tibia lateral], synovitis, and effusion) scores at Month 12 were reported.
Time Frame
Month 12
Title
Number of Participants With Change From Baseline in International Cartilage Repair Society (ICRS) Grade at Months 6 and 12
Description
The ICRS grading is used to score the amount of cartilage repair and damage. The grades range from 1 to 4 where higher grades indicate more severity of injury. Number of participants with change value of -3, -2, -1, 0, 1, and 2 from baseline in ICRS grade at Months 6 and 12 were reported. Lower change value indicates less severity of injury.
Time Frame
Baseline, Months 6 and 12
Title
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
Description
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 (FDL), function in sports and recreation activities (FSRA), and quality of life (QoL). Sub-scale scores range from 0-100, with 0 representing extreme knee problems and 100 no knee problems. The IKDC consists of 19 items to summarize symptoms such as 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 0-100 where high score represents high levels of function.
Time Frame
Baseline, Months 3, 6 and 12
Title
Number of Participants With Global Evaluation of Treatment Benefit
Description
Participants were asked to evaluate and rate the treatment benefit as poor, fair, good, very good or excellent.
Time Frame
Months 3, 6 and 12
Title
Number of Participants With Treatment Emergent Adverse Events (TEAEs), Local TEAEs, Systemic TEAEs, TEAEs Leading to Discontinuation and Serious Adverse Events (SAEs)
Description
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.
Time Frame
Baseline up to Month 12
Title
Number of Participants With Acute Inflammatory Reactions
Description
Acute inflammatory reaction (AIR) 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.
Time Frame
Baseline up to Month 12
Title
Number of Participants With Binding Antibodies (BAbs) and Neutralizing Antibodies (NAbs) to Fibroblast Growth Factor 18 (FGF18)
Description
Number of participants with BAbs and NAbs to FGF18 at Week 1 (pre-dose), Week 2 (pre-dose), Week 4, Months 3 and 12 were reported.
Time Frame
Week 1 (pre-dose), Week 2 (pre-dose), Week 4, Months 3 and 12
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
45 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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 (ALP) 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 * 10^9 per liter, or platelets <75 *10^9 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Medical Responsible
Organizational Affiliation
Merck KGaA, Darmstadt, Germany
Official's Role
Study Director
Facility Information:
Facility Name
Please contact the Merck KGaA Communication Center
City
Darmstadt
Country
Germany
12. IPD Sharing Statement
Learn more about this trial
Sprifermin (AS902330) in Cartilage Injury Repair (CIR)
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