Sprifermin (AS902330) in Cartilage Injury Repair (CIR)

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

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.

Study Overview

• Status: Terminated
• Conditions: Isolated Cartilage Injury of the Knee
• Intervention / Treatment: Drug: Sprifermin (AS902330) 10 mcg; Drug: Sprifermin (AS902330) 30 mcg; Drug: Sprifermin (AS902330) 100 mcg; Other: Placebo

• Study Type: Interventional
• Enrollment (Actual): 74
• Phase: Phase 2

Contacts and Locations

Study Locations

• Germany
  • Darmstadt, Germany
    • Please contact the Merck KGaA Communication Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Other: Placebo; Placebo matched to sprifermin (AS902330) will be administered as intra-articular injection once every week for 3 consecutive weeks.
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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Baseline, Month 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Baseline, Months 3 and 6
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.	Baseline, Months 3, 6 and 12
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.	Baseline, Months 3, 6 and 12
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.	Months 3 (M3), 6 (M6) and 12 (M12)
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.	Baseline, Month 12
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.	Month 12
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.	Baseline, Months 6 and 12
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.	Baseline, Months 3, 6 and 12
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.	Months 3, 6 and 12
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.	Baseline up to Month 12
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.	Baseline up to Month 12
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.	Week 1 (pre-dose), Week 2 (pre-dose), Week 4, Months 3 and 12

Collaborators and Investigators

• Sponsor: Merck KGaA, Darmstadt, Germany

Study record dates

Study Major Dates

• Study Start: March 1, 2010
• Primary Completion (Actual): April 1, 2013
• Study Completion (Actual): April 1, 2013

Study Registration Dates

• First Submitted: February 9, 2010
• First Submitted That Met QC Criteria: February 9, 2010
• First Posted (Estimate): February 10, 2010

Study Record Updates

• Last Update Posted (Estimate): March 23, 2016
• Last Update Submitted That Met QC Criteria: February 22, 2016
• Last Verified: February 1, 2016

More Information

Terms related to this study

• Keywords: Knee cartilage injury; fibroblast growth factor 18; FGF18
• Additional Relevant MeSH Terms: Wounds and Injuries
• Other Study ID Numbers: EMR700692_003

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No