- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01919164
A Study to Investigate the Safety and Effectiveness of Different Doses of Sprifermin in Participants With Osteoarthritis of the Knee (FORWARD)
June 18, 2020 updated by: EMD Serono Research & Development Institute, Inc.
A Multicenter, Randomized, Double-blind, Placebo Controlled, Parallel-group Trial to Investigate the Efficacy and Safety of Different Intra Articular (i.a.) Dosages of Sprifermin in Subjects With Primary Osteoarthritis of the Knee
This was a multicenter, randomized, double-blind, placebo-controlled, parallel-group Phase 2 trial of Sprifermin administered intra-articularly in participants with primary osteoarthritis of the knee and Kellgren-Lawrence Grade 2 or 3.
The trial was intended to investigate the efficacy and safety of different intra articular dosages of Sprifermin in these individuals.
Study Overview
Status
Completed
Conditions
Intervention / Treatment
Detailed Description
Participants were equally randomized to either one of 4 treatment arms or a placebo arm.
The trial consists of a Screening period lasting up to 42 days, a two-year double-blind placebo-controlled (DBPC) treatment phase, which begins at randomization (Week 0) and ends at Year 2, and a 3-year extended follow-up phase.
Study Type
Interventional
Enrollment (Actual)
549
Phase
- Phase 2
Contacts and Locations
This section provides the contact details for those conducting the study, and information on where this study is being conducted.
Study Locations
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Buenos Aires, Argentina
- Research Site
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Brno, Czechia
- Research Site
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Pardubice, Czechia
- Research Site
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Prague, Czechia
- Research Site
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Aalborg, Denmark
- Research Site
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Ballerup, Denmark
- Research Site
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Vejle, Denmark
- Research Site
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Tallinn, Estonia
- Research Site
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Hong Kong, Hong Kong
- Research Site
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Lodz, Poland
- Research Site
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Bucharest, Romania
- Research Site
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Colorado
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Lakewood, Colorado, United States
- Research Site
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Maryland
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Baltimore, Maryland, United States, 21201
- Research Site
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Participation Criteria
Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.
Eligibility Criteria
Ages Eligible for Study
38 years to 83 years (Adult, Older Adult)
Accepts Healthy Volunteers
No
Genders Eligible for Study
All
Description
Inclusion Criteria:
- Age from 40 to 85 years; of either sex
- Primary femorotibial osteoarthritis according to American College of Rheumatology (ACR) clinical and radiographic criteria , and meeting protocol-specified X-ray criteria in the target knee at screening
- Pain score in the target knee and/or the need for regular symptomatic treatment of knee pain with paracetamol (acetaminophen), systemic non-steroidal anti-inflammatory drugs (NSAIDs) including cyclooxygenase (COX)-2 selective inhibitors (coxibs), or tramadol on most days in the previous month (that is, more than half of the days in the previous month)
- A history of pain due to Osteoarthritis in the target knee for at least 6 months
- A protocol-specified pain score for the target knee in response to Question 1 of the WOMAC pain index ("how much pain have you had [in the target knee, over the past 48 hours] when walking on a flat surface?") after washout of at least 5 half-lives of analgesic medication(s): acetaminophen, topical or oral NSAIDS, coxibs, opioids, and/or tramadol
- Women of childbearing potential must use a form of contraception with a failure rate of less than 1 percent per year throughout the trial
Exclusion Criteria:
- Malalignment of greater than 5 degrees in the femorotibial axis of the target knee
- Clinical signs of inflammation (redness) in the target knee
- Intra-articular administration of corticosteroids or hyaluronic acid into either knee within 6 months before Screening
- Planned knee surgery (affecting either the target or the contralateral knee) within the next two years
- Concomitant conditions or treatments deemed to be incompatible with trial participation
- Any contraindication to MRI according to MRI guidelines, including the inability to undergo a knee MRI exam because of inability to fit in the scanner or knee coil
- Pregnancy or breastfeeding
- Participation in another clinical trial within the 30 days (or 5 half-lives of the investigated compound, whichever is longer) before screening
- Legal incapacity or limited legal capacity
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Quadruple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
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Placebo Comparator: Placebo
Participants received Placebo matched to Sprifermin as intra-articular injection once every week for 3 consecutive weeks for 4 cycles, that is at week 0, 1, 2 in Cycle 1; at week 26, 27, 28 in Cycle 2; at week 52, 53, 54 in Cycle 3 and at week 78, 79, 80 in Cycle 4 at interval of 6 months.
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Participants received Placebo matched to sprifermin as intra-articular injection.
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Experimental: Sprifermin (AS902330) 30 mcg/placebo - 2 Cycles
Participants received Sprifermin 30 mcg as intra-articular injection once every week for 3 consecutive weeks for 2 alternative cycles, that is at week 0, 1, 2 in Cycle 1 and at week 52, 53, 54 in Cycle 3; and received placebo matched to Sprifermin once every week for 3 consecutive weeks for 2 alternative cycles, that is at week 26, 27, 28 in Cycle 2 and at week 78, 79, 80 in Cycle 4 at interval of 6 months.
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Participants received Placebo matched to sprifermin as intra-articular injection.
Participants received Sprifermin as intra-articular injection.
Other Names:
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Experimental: Sprifermin (AS902330) 30 mcg- 4 Cycles
Participants received Sprifermin 30 micrograms (mcg) as intra-articular injection once every week for 3 consecutive weeks for 4 cycles, that is at week 0, 1, 2 in Cycle 1; at week 26, 27, 28 in Cycle 2; at week 52, 53, 54 in Cycle 3 and at week 78, 79, 80 in Cycle 4 at interval of 6 months.
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Participants received Sprifermin as intra-articular injection.
Other Names:
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Experimental: Sprifermin (AS902330) 100 mcg/Placebo (2 cycles)
Participants received Sprifermin 100 mcg as intra-articular injection once every week for 3 consecutive weeks for 2 alternative cycles, that is at week 0, 1, 2 in Cycle 1 and at week 52, 53, 54 in Cycle 3; and received placebo matched to Sprifermin once every week for 3 consecutive weeks for 2 alternative cycles, that is at week 26, 27, 28 in Cycle 2 and at week 78, 79, 80 in Cycle 4 at interval of 6 months.
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Participants received Placebo matched to sprifermin as intra-articular injection.
Participants received Sprifermin as intra-articular injection.
Other Names:
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Placebo Comparator: Sprifermin (AS902330) 100 mcg- 4 Cycles
Participants received Sprifermin 100 mcg as intra-articular injection once every week for 3 consecutive weeks for 4 cycles, that is at week 0, 1, 2 in Cycle 1; at week 26, 27, 28 in Cycle 2; at week 52, 53, 54 in Cycle 3 and at week 78, 79, 80 in Cycle 4 at interval of 6 months.
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Participants received Sprifermin as intra-articular injection.
Other Names:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
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Change From Baseline in Cartilage Thickness in the Total Femorotibial Joint as Evaluated by Quantitative Magnetic Resonance Imaging (qMRI) at Year 2
Time Frame: Baseline, Year 2 (Week 104)
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The change in cartilage thickness at 2 years was calculated based on quantitative magnetic resonance imaging (qMRI).
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Baseline, Year 2 (Week 104)
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
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Changes From Baseline in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain Subscale, Stiffness Subscale, Physical Function Subscale and Total Score at Week 52, Week 78 and Week 104
Time Frame: Baseline, Week 52, Week 78 and Week 104
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WOMAC pain subscale consists of 5 questions (Likert Scale) relating to pain.
Sum of items of pain subscale ranges from 0-11.
Higher scores=worse pain.
Stiffness subscale consists of 2 questions relating articular function.
Sum of items of stiffness subscale ranges from 0-8.
Higher scores=worse function.
Physical function subscale consists of 17 question relating to physical activities.
Sum of items of physical function subscale ranges from 0-68.
Higher scores= worse functional limitations.
Each sub-scale is directly transformed into a 0-100 scale, where higher score indicates worse condition.
WOMAC total score(24questions) is sum of total subscales which was directly transformed into score range from 0-100.
Higher scores=worse condition.
Negative value in change is indicative of improvement.
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Baseline, Week 52, Week 78 and Week 104
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Change From Baseline in the 20-meter Walk Test at Week 12, 26, 38, 52, 64, 78, 90 and 104
Time Frame: Baseline, Week 12, 26, 38, 52, 64, 78, 90 and 104
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The 20-meter walk test is an objective test of physical function which consists of measuring the time needed for the participant to walk 20 meters at a normal pace.
A stopwatch was used for time measurement.
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Baseline, Week 12, 26, 38, 52, 64, 78, 90 and 104
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Change From Baseline in the Patient's Global Assessment (PGA) at Week 12, 26, 38, 52, 64, 78, 90 and 104
Time Frame: Baseline, Week 12, 26, 38, 52, 64, 78, 90 and 104
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The Patient Global Assessment is based on participant's answer to the question "Considering all the ways your osteoarthritis of the knee has affected you during the last 48 Hours, select the number that best describes the impact of your knee osteoarthritis on your daily life", and can take on values between 0-10 (0=None, 10=Extreme), for summaries the values are rescaled to 0-100 by multiplication with 10.
Higher scores indicated worsening of condition.
A negative value in change in Patient's Global Assessment is indicative of an improvement.
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Baseline, Week 12, 26, 38, 52, 64, 78, 90 and 104
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Change From Baseline in Minimal Joint Space Width (mJSW) in the Medial and Lateral Compartments as Evaluated by X-ray at Week 52 and 104
Time Frame: Baseline, Week 52 and 104
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Change in joint space narrowing was visualized with the "fixed flexion" knee radiograph.
Determination of joint space narrowing by X-ray is considered to be a semi-quantitative method for assessment of progression of knee Osteoarthritis (OA).
X-rays of both the target knee and the contralateral knee were performed.
X-rays were read centrally.
X-ray images were used to measure mJSW in the medial femorotibial and lateral femorotibial compartments and to determine the participant's baseline Kellgren-Lawrence grades (KLG).
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Baseline, Week 52 and 104
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Change From Baseline in Cartilage Thickness in the Medial and Lateral Compartments as Well as in the Total Femorotibial Joint
Time Frame: Medial and Lateral: Baseline, Week 26, 52, 78 and 104; Total: Baseline, Week 26, 52 and 78
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The change in cartilage thickness was calculated based on quantitative magnetic resonance imaging (qMRI).
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Medial and Lateral: Baseline, Week 26, 52, 78 and 104; Total: Baseline, Week 26, 52 and 78
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Change From Baseline in Cartilage-Volume in the Medial and Lateral Compartments as Well as in the Total Femorotibial Joint at Week 26, 52, 78 and 104
Time Frame: Baseline, Week 26, 52, 78 and 104
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The change in cartilage volume in the medial and lateral compartments as well as in the total femorotibial joint at Week 26, 52, 78 and 104 was calculated based on qMRI.
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Baseline, Week 26, 52, 78 and 104
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Synovial Fluid Levels of Sprifermin/FGF-18
Time Frame: Pre-dose at Week 0, 2 hours post-dose at Week 1 and 2 of Cycle 1, 2, 3 and 4 (each cycle is of 28 days)
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Levels of sprifermin/FGF-18 in synovial fluid were measured to provide a first estimate of the residence time of sprifermin in the synovial fluid.
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Pre-dose at Week 0, 2 hours post-dose at Week 1 and 2 of Cycle 1, 2, 3 and 4 (each cycle is of 28 days)
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Serum Levels of Sprifermin/FGF-18
Time Frame: Pre-dose at Week 0, 2 hours post-dose at Week 1 and 2 of Cycle 1, 2, 3 and 4 (each cycle is of 28 days)
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Pre-dose at Week 0, 2 hours post-dose at Week 1 and 2 of Cycle 1, 2, 3 and 4 (each cycle is of 28 days)
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Collaborators and Investigators
This is where you will find people and organizations involved with this study.
Collaborators
Investigators
- Study Director: Medical Responsible, MD, Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany
Publications and helpful links
The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.
General Publications
- Eckstein F, Hochberg MC, Guehring H, Moreau F, Ona V, Bihlet AR, Byrjalsen I, Andersen JR, Daelken B, Guenther O, Ladel C, Michaelis M, Conaghan PG. Long-term structural and symptomatic effects of intra-articular sprifermin in patients with knee osteoarthritis: 5-year results from the FORWARD study. Ann Rheum Dis. 2021 Aug;80(8):1062-1069. doi: 10.1136/annrheumdis-2020-219181. Epub 2021 May 7.
- Guehring H, Moreau F, Daelken B, Ladel C, Guenther O, Bihlet AR, Wirth W, Eckstein F, Hochberg M, Conaghan PG. The effects of sprifermin on symptoms and structure in a subgroup at risk of progression in the FORWARD knee osteoarthritis trial. Semin Arthritis Rheum. 2021 Apr;51(2):450-456. doi: 10.1016/j.semarthrit.2021.03.005. Epub 2021 Mar 11.
- Eckstein F, Kraines JL, Aydemir A, Wirth W, Maschek S, Hochberg MC. Intra-articular sprifermin reduces cartilage loss in addition to increasing cartilage gain independent of location in the femorotibial joint: post-hoc analysis of a randomised, placebo-controlled phase II clinical trial. Ann Rheum Dis. 2020 Apr;79(4):525-528. doi: 10.1136/annrheumdis-2019-216453. Epub 2020 Feb 25.
- Hochberg MC, Guermazi A, Guehring H, Aydemir A, Wax S, Fleuranceau-Morel P, Reinstrup Bihlet A, Byrjalsen I, Ragnar Andersen J, Eckstein F. Effect of Intra-Articular Sprifermin vs Placebo on Femorotibial Joint Cartilage Thickness in Patients With Osteoarthritis: The FORWARD Randomized Clinical Trial. JAMA. 2019 Oct 8;322(14):1360-1370. doi: 10.1001/jama.2019.14735.
Study record dates
These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.
Study Major Dates
Study Start (Actual)
July 29, 2013
Primary Completion (Actual)
May 5, 2016
Study Completion (Actual)
May 7, 2019
Study Registration Dates
First Submitted
August 7, 2013
First Submitted That Met QC Criteria
August 7, 2013
First Posted (Estimate)
August 8, 2013
Study Record Updates
Last Update Posted (Actual)
July 13, 2020
Last Update Submitted That Met QC Criteria
June 18, 2020
Last Verified
June 1, 2020
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
Other Study ID Numbers
- EMR700692_006
- 2011-003059-20 (EudraCT Number)
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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