Clinical trial NCT01033994: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Knee Osteoarthritis
Keywords: Knee osteoarthritis
Fibroblast growth factor 18
Sprifermin
Lead sponsor: Merck KGaA, Darmstadt, Germany
Sponsor class: INDUSTRY
First posted: 2009-12-17
Enrollment: 192
Sex: ALL
Minimum age (years): 40
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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

Primary outcomes:
measure: Change in cartilage thickness in the medial femoro-tibial compartment of the target knee joint, assessed by MRI
timeFrame: 6 and 12 months after first injection
measure: Nature, incidence and severity of local and systemic treatment-emergent adverse events (TEAEs)
timeFrame: MAD Cohorts: 1 year + 1 month; SAD Cohorts: 4 Weeks
measure: 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
timeFrame: MAD Cohorts: Week 1, 2, 3, 13 14 and 15 (injections weeks); SAD Cohorts: Week 1
measure: Laboratory assessments, including blood chemistry, hematology, urinalysis, and ECG
timeFrame: MAD Cohorts: Week 0, 4, 13, 17, 52; SAD Cohorts: Weeks 0 & 4
Secondary outcomes:
measure: Change in cartilage thickness in the medial femoro-tibial compartment of the target knee joint, assessed by MRI
timeFrame: 52 Weeks
measure: Change in total cartilage volume and thickness in the other compartments of the target knee joint, assessed by MRI
timeFrame: 52 Weeks
measure: Change over time of structural as well as compositional parameters of the knee joint (e.g. cartilage and bone), evaluated by MRI
timeFrame: 52 Weeks
measure: Change in WOMAC (Western Ontario MacMaster Osteoarthritis Questionaire) total score in the target knee from 5-point Likert scales
timeFrame: 52 Weeks
measure: Change in WOMAC Function and Pain index scores in the target knee
timeFrame: 52 Weeks
measure: Change in osteoarthritis (OA) pain in the target knee on a 100mm visual analogue scale (VAS)
timeFrame: 52 Weeks
measure: Change in JSW in the target knee by x-ray
timeFrame: 52 Weeks
measure: Presence of anti-AS902330 antibodies
timeFrame: 52 Weeks
measure: Blood levels of AS902330
timeFrame: 52 Weeks
measure: MRI at 3 months, score on WOMAC questionnaire at 3, 6 and 12 months.
timeFrame: 6 days
Other outcomes:
Locations:
city: Sofia
country: Bulgaria
facility: UMHAT "Sv. Ivan Rilski", Clinical Research Unit for Phase I
city: Newmarket
country: Canada
facility: SKDS Research, Inc.
city: Pointe Claire
country: Canada
facility: Kells Medical Research Group
city: Quebec
country: Canada
facility: Centre de rhumatologie St-Louis
city: Quebec
country: Canada
facility: Groupe de Recherche en Maldies Osseuses de Quebec
city: Sarnia
country: Canada
facility: London Road Diagnostic Clinic
city: Toronto
country: Canada
facility: Albion Finch Medical Centre
city: Split
country: Croatia
facility: Clinical hospital Split
city: Zagreb
country: Croatia
facility: Clinical Hospital "Sestre Milosrdnice"
city: Zagreb
country: Croatia
facility: Polyclinic for internal medicine, gynecology, radiology, physical medicine and rehabilitation
city: Kuopio
country: Finland
facility: Kuopio University Hospital, Department of Ortopaedics
city: Oulu
country: Finland
facility: Oulu University Hospital, Surgical and Intensive Care Division
city: Turku
country: Finland
facility: Turku University Central Hospital, Orthopedic Research Unit
city: Berlin
country: Germany
facility: PAREXEL International GmbH
city: Bialystok
country: Poland
facility: NZOZ Centrum Medyczne Artur Racewicz
city: Cracow
country: Poland
facility: Krakowskie Centrum Medyczne NZOZ
city: Lublin
country: Poland
facility: REUMED Sp. z o.o.,
city: Torun
country: Poland
facility: Niepubliczny Zaklad Opieki Zdrowotnej Nasz Lekarz
city: Warsaw
country: Poland
facility: Centrum Leczenia Chorob Cywilizacyjnych
city: Warsaw
country: Poland
facility: Centrum Medyczne OSTEOMED Sp. z o.o.
city: Beograd
country: Serbia
facility: Clinical Hospital Center Bezanijska Kosa
city: Beograd
country: Serbia
facility: Institute of Rheumatology Resavska 69
city: Niska Banja
country: Serbia
facility: • Name: Institute of diagnostic, prevention and rechabilitation of cardiovascular and rheumatoid diseases
city: Bloemfontein
country: South Africa
facility: FARMOVS-PAREXEL (Pty) Ltd, University of the Free State
city: George
country: South Africa
facility: PAREXEL -George
city: Port Elizabeth
country: South Africa
facility: PAREXEL-Port Elizabeth, Mercantile Hospital
city: Hässleholm
country: Sweden
facility: Ortopediska mottagningen
city: Kungälv
country: Sweden
facility: Kirurg- och ortopedkliniken Kungälvs sjukhus, 442 83 Kungälv
Study officials:
affiliation: Merck Serono S.A., Geneva
name: Donatus Dreher, MD, PhD
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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. No abstract available.
citation: 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.
citation: 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.