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

Knee Osteoarthritis Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01033994
• Other study ID #: 28980
• Status: Completed
• Phase: Phase 1
• First received: December 16, 2009
• Last updated: June 24, 2014
• Start date: October 2008
• Est. completion date: December 2010

Study information

• Verified date: June 2014
• Source: Merck KGaA
• Contact: n/a
• Is FDA regulated: No
• Health authority: Bulgaria: Bulgarian Drug AgencyCanada: Health CanadaCroatia: Ministry of Health and Social CareGermany: Federal Institute for Drugs and Medical DevicesPoland: Office for Registration of Medicinal Products, Medical Devices and Biocidal ProductsSerbia and Montenegro: Agency for Drugs and Medicinal DevicesSouth Africa: Medicines Control CouncilSweden: Regional Ethical Review BoardUnited States: Food and Drug AdministrationFinland: Finnish Medicines Agency
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 192
• Est. completion date: December 2010
• Est. primary completion date: October 2010
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 40 Years and older

Eligibility

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

Study Design

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

Related Conditions & MeSH terms

• Knee Osteoarthritis
• Osteoarthritis
• Osteoarthritis, Knee

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.

Locations

Country	Name	City	State
Bulgaria	UMHAT "Sv. Ivan Rilski", Clinical Research Unit for Phase I	Sofia
Canada	SKDS Research, Inc.	Newmarket
Canada	Kells Medical Research Group	Pointe Claire
Canada	Centre de rhumatologie St-Louis	Quebec
Canada	Groupe de Recherche en Maldies Osseuses de Quebec	Quebec
Canada	London Road Diagnostic Clinic	Sarnia
Canada	Albion Finch Medical Centre	Toronto
Croatia	Clinical hospital Split	Split
Croatia	Clinical Hospital "Sestre Milosrdnice"	Zagreb
Croatia	Polyclinic for internal medicine, gynecology, radiology, physical medicine and rehabilitation	Zagreb
Finland	Kuopio University Hospital, Department of Ortopaedics	Kuopio
Finland	Oulu University Hospital, Surgical and Intensive Care Division	Oulu
Finland	Turku University Central Hospital, Orthopedic Research Unit	Turku
Germany	PAREXEL International GmbH	Berlin
Poland	NZOZ Centrum Medyczne Artur Racewicz	Bialystok
Poland	Krakowskie Centrum Medyczne NZOZ	Cracow
Poland	REUMED Sp. z o.o.,	Lublin
Poland	Niepubliczny Zaklad Opieki Zdrowotnej Nasz Lekarz	Torun
Poland	Centrum Leczenia Chorob Cywilizacyjnych	Warsaw
Poland	Centrum Medyczne OSTEOMED Sp. z o.o.	Warsaw
Serbia	Clinical Hospital Center Bezanijska Kosa	Beograd
Serbia	Institute of Rheumatology Resavska 69	Beograd
Serbia	• Name: Institute of diagnostic, prevention and rechabilitation of cardiovascular and rheumatoid diseases	Niska Banja
South Africa	FARMOVS-PAREXEL (Pty) Ltd, University of the Free State	Bloemfontein
South Africa	PAREXEL -George	George
South Africa	PAREXEL-Port Elizabeth, Mercantile Hospital	Port Elizabeth
Sweden	Ortopediska mottagningen	Hässleholm
Sweden	Kirurg- och ortopedkliniken Kungälvs sjukhus, 442 83 Kungälv	Kungälv

Sponsors (1)

Lead Sponsor	Collaborator
Merck KGaA

Countries where clinical trial is conducted

Bulgaria,  Canada,  Croatia,  Finland,  Germany,  Poland,  Serbia,  South Africa,  Sweden, 

References & Publications (2)

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. 20 — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in cartilage thickness in the medial femoro-tibial compartment of the target knee joint, assessed by MRI		6 and 12 months after first injection	No
Primary	Nature, incidence and severity of local and systemic treatment-emergent adverse events (TEAEs)		MAD Cohorts: 1 year + 1 month; SAD Cohorts: 4 Weeks	Yes
Primary	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		MAD Cohorts: Week 1, 2, 3, 13 14 and 15 (injections weeks); SAD Cohorts: Week 1	No
Primary	Laboratory assessments, including blood chemistry, hematology, urinalysis, and ECG		MAD Cohorts: Week 0, 4, 13, 17, 52; SAD Cohorts: Weeks 0 & 4	Yes
Secondary	Change in cartilage thickness in the medial femoro-tibial compartment of the target knee joint, assessed by MRI		52 Weeks	Yes
Secondary	Change in total cartilage volume and thickness in the other compartments of the target knee joint, assessed by MRI		52 Weeks	Yes
Secondary	Change over time of structural as well as compositional parameters of the knee joint (e.g. cartilage and bone), evaluated by MRI		52 Weeks	Yes
Secondary	Change in WOMAC (Western Ontario MacMaster Osteoarthritis Questionaire) total score in the target knee from 5-point Likert scales		52 Weeks	Yes
Secondary	Change in WOMAC Function and Pain index scores in the target knee		52 Weeks	Yes
Secondary	Change in osteoarthritis (OA) pain in the target knee on a 100mm visual analogue scale (VAS)		52 Weeks	Yes
Secondary	Change in JSW in the target knee by x-ray		52 Weeks	Yes
Secondary	Presence of anti-AS902330 antibodies		52 Weeks	Yes
Secondary	Blood levels of AS902330		52 Weeks	Yes
Secondary	MRI at 3 months, score on WOMAC questionnaire at 3, 6 and 12 months.		6 days	Yes