A Multicenter Study of rhFGF 18 in Patients With Knee Osteoarthritis Not Requiring Surgery

• ClinicalTrials.gov Identifier: NCT01033994
• Recruitment Status: Completed
• First Posted: December 17, 2009
• Last Update Posted: June 25, 2014
• Sponsor: Merck KGaA, Darmstadt, Germany
• Information provided by (Responsible Party): Merck KGaA, Darmstadt, Germany

Tracking Information

• First Submitted Date: December 16, 2009
• First Posted Date: December 17, 2009
• Last Update Posted Date: June 25, 2014
• Study Start Date: October 2008
• Actual Primary Completion Date: October 2010 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 16, 2009)

• Change in cartilage thickness in the medial femoro-tibial compartment of the target knee joint, assessed by MRI [ Time Frame: 6 and 12 months after first injection ]
• Nature, incidence and severity of local and systemic treatment-emergent adverse events (TEAEs) [ Time Frame: MAD Cohorts: 1 year + 1 month; SAD Cohorts: 4 Weeks ]
• Proportion of subjects experiencing AIRs defined as increase of pain by 30mm on a 100mm visual analogue scale (VAS) associated with a self-reported synovial fluid effusion within 3 days following i.a. injection [ Time Frame: MAD Cohorts: Week 1, 2, 3, 13 14 and 15 (injections weeks); SAD Cohorts: Week 1 ]
• Laboratory assessments, including blood chemistry, hematology, urinalysis, and ECG [ Time Frame: MAD Cohorts: Week 0, 4, 13, 17, 52; SAD Cohorts: Weeks 0 & 4 ]

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: December 16, 2009)

• Change in cartilage thickness in the medial femoro-tibial compartment of the target knee joint, assessed by MRI [ Time Frame: 52 Weeks ]
• Change in total cartilage volume and thickness in the other compartments of the target knee joint, assessed by MRI [ Time Frame: 52 Weeks ]
• Change over time of structural as well as compositional parameters of the knee joint (e.g. cartilage and bone), evaluated by MRI [ Time Frame: 52 Weeks ]
• Change in WOMAC (Western Ontario MacMaster Osteoarthritis Questionaire) total score in the target knee from 5-point Likert scales [ Time Frame: 52 Weeks ]
• Change in WOMAC Function and Pain index scores in the target knee [ Time Frame: 52 Weeks ]
• Change in osteoarthritis (OA) pain in the target knee on a 100mm visual analogue scale (VAS) [ Time Frame: 52 Weeks ]
• Change in JSW in the target knee by x-ray [ Time Frame: 52 Weeks ]
• Presence of anti-AS902330 antibodies [ Time Frame: 52 Weeks ]
• Blood levels of AS902330 [ Time Frame: 52 Weeks ]
• MRI at 3 months, score on WOMAC questionnaire at 3, 6 and 12 months. [ Time Frame: 6 days ]

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Multicenter Study of rhFGF 18 in Patients With Knee Osteoarthritis Not Requiring Surgery
• Official Title: A Randomized, Double Blind, Placebo-controlled, Multicenter, Single and Multiple Ascending Dose Study of AS902330 (rhFGF-18) Administered Intra-articularly in Patients With Primary Osteoarthritis of the Knee Who Are Not Expected to Require Knee Surgery Within One Year

Brief Summary

Osteoarthritis (OA) is one of the most common diseases affecting the joints, usually those that are weight bearing such as the knees. OA is considered to be a disease of the cartilage in the joints even though it involves the whole joint, including the bone and synovium (thin lining of the joints which produces synovial fluid). With time, more and more of the cartilage is destroyed by the disease with inflammation commonly occurring.

AS902330 is expected to increase the production and development of specific bone cells: chondrocytes and osteoblasts (cells that produce and maintain bone and cartilage). This is expected to lead to repair and generation of the cartilage, and a narrowing of the space width between the knee joints in a selected region of the knee cartilage. The purpose of this study is to see how safe treatment with AS902330 is, and to evaluate its effect on the knee cartilage. In addition, the study will also measure the effects of AS902330 in the blood, which reflect disease activity.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Knee Osteoarthritis

Intervention

Biological: AS902330

10, 30 or 100 µg intra-articular injection per subject in the Single Ascending Dose (SAD) cohorts and 10, 30 or 100 µg intra-articular injection per week for three weeks per subject in the Multiple Ascending Dose (MAD) cohorts.

Other Names:

• rhFGF 18
• Recombinant human fibroblast growth factor 18
• Sprifermin

Study Arms

• Experimental: AS902330
  Intervention: Biological: AS902330
• Placebo Comparator: Placebo
  Intervention: Biological: AS902330

Publications *

• Lohmander LS, Hellot S, Dreher D, Krantz EF, Kruger DS, Guermazi A, Eckstein F. Intraarticular sprifermin (recombinant human fibroblast growth factor 18) in knee osteoarthritis: a randomized, double-blind, placebo-controlled trial. Arthritis Rheumatol. 2014 Jul;66(7):1820-31. doi: 10.1002/art.38614.
• Onuora S. Osteoarthritis: Sprifermin shows cartilage-protective effects in knee OA. Nat Rev Rheumatol. 2014 Jun;10(6):322. doi: 10.1038/nrrheum.2014.68. Epub 2014 May 6.
• Roemer FW, Aydemir A, Lohmander S, Crema MD, Marra MD, Muurahainen N, Felson DT, Eckstein F, Guermazi A. Structural effects of sprifermin in knee osteoarthritis: a post-hoc analysis on cartilage and non-cartilaginous tissue alterations in a randomized controlled trial. BMC Musculoskelet Disord. 2016 Jul 9;17:267. doi: 10.1186/s12891-016-1128-2.
• Eckstein F, Wirth W, Guermazi A, Maschek S, Aydemir A. Brief report: intraarticular sprifermin not only increases cartilage thickness, but also reduces cartilage loss: location-independent post hoc analysis using magnetic resonance imaging. Arthritis Rheumatol. 2015 Nov;67(11):2916-22. doi: 10.1002/art.39265.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: December 16, 2009): 192
• Original Actual Enrollment: Same as current
• Actual Study Completion Date: December 2010
• Actual Primary Completion Date: October 2010 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Male or female >= 40 years of age; females must be postmenopausal or surgically sterile
2. Established diagnosis of primary femoro-tibial OA of the target knee by standard American College of Rheumatology Criteria for at least six months (clinical AND radiological criteria)
3. Radiological disease stage 2 or 3 (i.e., clear evidence of OA, but not most advanced disease) in the target knee according to the Kellgren-Lawrence grading of knee OA
4. No major knee surgery (e.g., partial or total knee replacement, interventional arthroscopy) in the target knee planned for at least 12 months after first injection of the study drug
5. Documented need for symptomatic PRN (as needed)-treatment for OA in the target knee with systemic non-steroidal anti-inflammatory drugs (NSAIDs) and/or other analgesics.
6. Total WOMAC score between 24 and 72 (out of 96, corresponding to mild, moderate, or severe, but not extreme OA symptoms) for the target knee while on oral symptomatic treatment at baseline
7. Full understanding of the requirements of the study and willingness to comply with all study visits and assessments
8. Patients must have read and understood the informed consent form, and must have signed it prior to any study-related procedure

Exclusion Criteria:

• any condition, including laboratory findings and findings in the medical history or in the pre-study assessments, that in the opinion of the Investigator constitutes a risk or contraindication for participation in the study or that could interfere with the study objectives, conduct or evaluation
• clinically significant abnormal hematology (hemoglobin, leucocytes, and platelets), or blood chemistry values (aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), bilirubin, and creatinine
• receipt of any investigational product or any experimental therapeutic procedure within the last 12 weeks preceding screening
• participation in FIH study 27575 or in a different cohort of this study
• i.a. treatment of the target knee with steroids or hyaluronic acid derivatives within the 3 months before baseline
• for MAD cohorts, any contra-indications to MRI according to MRI guidelines
• any condition that would interfere with efficacy or safety assessments in the target knee
• any drug or food supplement with potential disease-modifying effect (glucosamine, diacerin, chondroitin sulfate) unless given at a stable dose over at least 4 weeks prior to first injection
• use of electrotherapy or acupuncture for OA, unless there is a stable regimen for at least 4 weeks before baseline
• any known active infections, including suspicion of intra-articular infection and/or infections that may compromise the immune system such as HIV, Hepatitis B or Hepatitis 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
• signs and symptoms suggestive of transmissible spongiform encephalopathy
• secondary osteoarthritis: e.g., joint dysplasias, aseptic osteonecrosis, acromegaly, Paget's disease, Ehlers-Danlos syndrome, Gaucher's disease, Stickler's syndrome, joint infection, hemophilia, hemochromatosis, calcium pyrophosphate deposition disease, or neuropathic arthropathy whatever the cause

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 40 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Bulgaria, Canada, Croatia, Finland, Germany, Poland, Serbia, South Africa, Sweden

Administrative Information

• NCT Number: NCT01033994
• Other Study ID Numbers: 28980
• Has Data Monitoring Committee: Not Provided
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Merck KGaA, Darmstadt, Germany
• Study Sponsor: Merck KGaA, Darmstadt, Germany
• Collaborators: Not Provided

Investigators

• Study Director: Donatus Dreher, MD, PhD; Merck Serono S.A., Geneva

• PRS Account: Merck KGaA, Darmstadt, Germany
• Verification Date: June 2014