Sprifermin (AS902330) in Cartilage Injury Repair (CIR)

This study has been terminated.
(The study was discontinued due to low recruitment.)
Sponsor:
Information provided by (Responsible Party):
Merck KGaA
ClinicalTrials.gov Identifier:
NCT01066871
First received: February 9, 2010
Last updated: February 22, 2016
Last verified: February 2016
  Purpose

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.


Condition Intervention Phase
Isolated Cartilage Injury of the Knee
Drug: Sprifermin (AS902330) 10 mcg
Drug: Sprifermin (AS902330) 30 mcg
Drug: Sprifermin (AS902330) 100 mcg
Other: Placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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

Further study details as provided by Merck KGaA:

Primary Outcome Measures:
  • Percent Change From Baseline in Cartilage Defect Volume at Month 12 [ Time Frame: Baseline, Month 12 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Baseline, Months 3 and 6 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Baseline, Months 3, 6 and 12 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Baseline, Months 3, 6 and 12 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Months 3 (M3), 6 (M6) and 12 (M12) ] [ Designated as safety issue: No ]
    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 [ Time Frame: Baseline, Month 12 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Month 12 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Baseline, Months 6 and 12 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Baseline, Months 3, 6 and 12 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Months 3, 6 and 12 ] [ Designated as safety issue: No ]
    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) [ Time Frame: Baseline up to Month 12 ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: Baseline up to Month 12 ] [ Designated as safety issue: Yes ]
    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) [ Time Frame: Week 1 (pre-dose), Week 2 (pre-dose), Week 4, Months 3 and 12 ] [ Designated as safety issue: No ]
    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.


Enrollment: 74
Study Start Date: March 2010
Study Completion Date: April 2013
Primary Completion Date: April 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Sprifermin (AS902330) 10 mcg Drug: Sprifermin (AS902330) 10 mcg
Sprifermin (AS902330) will be administered at a dose of 10 microgram (mcg) as intra-articular injection once every week for 3 consecutive weeks.
Experimental: Sprifermin (AS902330) 30 mcg Drug: Sprifermin (AS902330) 30 mcg
Sprifermin (AS902330) will be administered at a dose of 30 mcg as intra-articular injection once every week for 3 consecutive weeks.
Experimental: Sprifermin (AS902330) 100 mcg Drug: Sprifermin (AS902330) 100 mcg
Sprifermin (AS902330) will be administered at a dose of 100 mcg as intra-articular injection once every week for 3 consecutive weeks.
Placebo Comparator: Placebo Other: Placebo
Placebo matched to sprifermin (AS902330) will be administered as intra-articular injection once every week for 3 consecutive weeks.

  Eligibility

Ages Eligible for Study:   18 Years to 45 Years   (Adult)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01066871

Locations
Germany
Please contact the Merck KGaA Communication Center
Darmstadt, Germany
Sponsors and Collaborators
Merck KGaA
Investigators
Study Director: Medical Responsible Merck KGaA
  More Information

Responsible Party: Merck KGaA
ClinicalTrials.gov Identifier: NCT01066871     History of Changes
Other Study ID Numbers: EMR700692_003 
Study First Received: February 9, 2010
Results First Received: February 22, 2016
Last Updated: February 22, 2016
Health Authority: Bulgaria: Bulgarian Drug Agency, Ethics Committee for Multicenter Trials
Canada: Health Canada, Ethics Review Committee
Germany: Bundesinstitut für Arzneimittel und Medizinproduckte (BfArM), Federal Institute for Drugs and Medical Devices, Ethics Commission
Poland: Office for Registration of Medicinal Products, Medical Devices and Biocidal Products, Ethics Review Committee
Serbia: Agency for Drugs and Medicinal Devices, Ethics Review Committee
South Africa: Medicines Control Council, Ethics Committee of the University of the Free State
Slovenia: Agency for Medicinal Products - Ministry of Health
Hungary: National Institute of Pharmacy

Keywords provided by Merck KGaA:
Knee cartilage injury
fibroblast growth factor 18
FGF18

Additional relevant MeSH terms:
Wounds and Injuries

ClinicalTrials.gov processed this record on July 24, 2016