Sprifermin (AS902330) in Cartilage Injury Repair (CIR)

Phase 2

Terminated

Conditions: Isolated Cartilage Injury of the Knee

Interventions: Drug: Sprifermin (AS902330) 10 mcg
Drug: Sprifermin (AS902330) 100 mcg
Drug: Sprifermin (AS902330) 30 mcg
Other: Placebo

Registration Number: NCT01066871

Lead Sponsor: Merck KGaA, Darmstadt, Germany

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.

Detailed Description: Not available

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 74

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Sprifermin (AS902330) 10 mcg	Sprifermin (AS902330) 10 mcg	-
Sprifermin (AS902330) 100 mcg	Sprifermin (AS902330) 100 mcg	-
Sprifermin (AS902330) 30 mcg	Sprifermin (AS902330) 30 mcg	-
Placebo	Placebo	-

Primary Outcome Measures

Name	Time	Method
Percent Change From Baseline in Cartilage Defect Volume at Month 12	Baseline, 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

Name	Time	Method
Percent Change From Baseline in Cartilage Defect Volume and Cartilage Defect Thickness in the Target Knee at Months 3 and 6	Baseline, 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	Baseline, 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	Baseline, 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	Months 3 (M3), 6 (M6) and 12 (M12)	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	Baseline, 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	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	Baseline, 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	Baseline, 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	Months 3, 6 and 12	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)	Baseline up to Month 12	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	Baseline up to Month 12	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)	Week 1 (pre-dose), Week 2 (pre-dose), Week 4, Months 3 and 12	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.