Back to resultsA Study to Investigate the Safety and Effectiveness of Different Doses of Sprifermin in Participants With Osteoarthritis of the Knee (FORWARD)
Primary Purpose
Osteoarthritis, Knee
Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Sprifermin
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Osteoarthritis, Knee focused on measuring Osteoarthritis of knee, Recombinant Human Fibroblast Growth Factor-18 (rhFGF-18), Sprifermin, Placebo
Eligibility Criteria
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
Sites / Locations
- Research site
- Research site
- Research site
- Research site
- Research site
- Research site
- Research site
- Research site
- Research site
- Research site
- Research Site
- Research site
- Research site
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm 5
Arm Type
Placebo Comparator
Experimental
Experimental
Experimental
Placebo Comparator
Arm Label
Placebo
Sprifermin (AS902330) 30 mcg/placebo - 2 Cycles
Sprifermin (AS902330) 30 mcg- 4 Cycles
Sprifermin (AS902330) 100 mcg/Placebo (2 cycles)
Sprifermin (AS902330) 100 mcg- 4 Cycles
Arm Description
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.
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.
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.
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.
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.
Outcomes
Primary Outcome Measures
Change From Baseline in Cartilage Thickness in the Total Femorotibial Joint as Evaluated by Quantitative Magnetic Resonance Imaging (qMRI) at Year 2
The change in cartilage thickness at 2 years was calculated based on quantitative magnetic resonance imaging (qMRI).
Secondary Outcome Measures
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
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.
Change From Baseline in the 20-meter Walk Test at Week 12, 26, 38, 52, 64, 78, 90 and 104
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.
Change From Baseline in the Patient's Global Assessment (PGA) at Week 12, 26, 38, 52, 64, 78, 90 and 104
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.
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
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).
Change From Baseline in Cartilage Thickness in the Medial and Lateral Compartments as Well as in the Total Femorotibial Joint
The change in cartilage thickness was calculated based on quantitative magnetic resonance imaging (qMRI).
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
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.
Synovial Fluid Levels of Sprifermin/FGF-18
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.
Serum Levels of Sprifermin/FGF-18
Full Information
NCT ID
NCT01919164
First Posted
August 7, 2013
Last Updated
June 18, 2020
Sponsor
EMD Serono Research & Development Institute, Inc.
Collaborators
Nordic Bioscience A/S
1. Study Identification
Unique Protocol Identification Number
NCT01919164
Brief Title
A Study to Investigate the Safety and Effectiveness of Different Doses of Sprifermin in Participants With Osteoarthritis of the Knee
Acronym
FORWARD
Official Title
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
Study Type
Interventional
2. Study Status
Record Verification Date
June 2020
Overall Recruitment Status
Completed
Study Start Date
July 29, 2013 (Actual)
Primary Completion Date
May 5, 2016 (Actual)
Study Completion Date
May 7, 2019 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
EMD Serono Research & Development Institute, Inc.
Collaborators
Nordic Bioscience A/S
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
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.
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Osteoarthritis, Knee
Keywords
Osteoarthritis of knee, Recombinant Human Fibroblast Growth Factor-18 (rhFGF-18), Sprifermin, Placebo
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
549 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
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.
Arm Title
Sprifermin (AS902330) 30 mcg/placebo - 2 Cycles
Arm Type
Experimental
Arm Description
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.
Arm Title
Sprifermin (AS902330) 30 mcg- 4 Cycles
Arm Type
Experimental
Arm Description
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.
Arm Title
Sprifermin (AS902330) 100 mcg/Placebo (2 cycles)
Arm Type
Experimental
Arm Description
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.
Arm Title
Sprifermin (AS902330) 100 mcg- 4 Cycles
Arm Type
Placebo Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Sprifermin
Other Intervention Name(s)
Recombinant Human Fibroblast Growth Factor-18 (rhFGF-18)
Intervention Description
Participants received Sprifermin as intra-articular injection.
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Participants received Placebo matched to sprifermin as intra-articular injection.
Primary Outcome Measure Information:
Title
Change From Baseline in Cartilage Thickness in the Total Femorotibial Joint as Evaluated by Quantitative Magnetic Resonance Imaging (qMRI) at Year 2
Description
The change in cartilage thickness at 2 years was calculated based on quantitative magnetic resonance imaging (qMRI).
Time Frame
Baseline, Year 2 (Week 104)
Secondary Outcome Measure Information:
Title
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
Description
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.
Time Frame
Baseline, Week 52, Week 78 and Week 104
Title
Change From Baseline in the 20-meter Walk Test at Week 12, 26, 38, 52, 64, 78, 90 and 104
Description
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.
Time Frame
Baseline, Week 12, 26, 38, 52, 64, 78, 90 and 104
Title
Change From Baseline in the Patient's Global Assessment (PGA) at Week 12, 26, 38, 52, 64, 78, 90 and 104
Description
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.
Time Frame
Baseline, Week 12, 26, 38, 52, 64, 78, 90 and 104
Title
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
Description
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).
Time Frame
Baseline, Week 52 and 104
Title
Change From Baseline in Cartilage Thickness in the Medial and Lateral Compartments as Well as in the Total Femorotibial Joint
Description
The change in cartilage thickness was calculated based on quantitative magnetic resonance imaging (qMRI).
Time Frame
Medial and Lateral: Baseline, Week 26, 52, 78 and 104; Total: Baseline, Week 26, 52 and 78
Title
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
Description
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.
Time Frame
Baseline, Week 26, 52, 78 and 104
Title
Synovial Fluid Levels of Sprifermin/FGF-18
Description
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.
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)
Title
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)
10. Eligibility
Sex
All
Minimum Age & Unit of Time
40 Years
Maximum Age & Unit of Time
85 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Medical Responsible, MD
Organizational Affiliation
Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany
Official's Role
Study Director
Facility Information:
Facility Name
Research site
City
Lakewood
State/Province
Colorado
Country
United States
Facility Name
Research site
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21201
Country
United States
Facility Name
Research site
City
Buenos Aires
Country
Argentina
Facility Name
Research site
City
Brno
Country
Czechia
Facility Name
Research site
City
Pardubice
Country
Czechia
Facility Name
Research site
City
Prague
Country
Czechia
Facility Name
Research site
City
Aalborg
Country
Denmark
Facility Name
Research site
City
Ballerup
Country
Denmark
Facility Name
Research site
City
Vejle
Country
Denmark
Facility Name
Research site
City
Tallinn
Country
Estonia
Facility Name
Research Site
City
Hong Kong
Country
Hong Kong
Facility Name
Research site
City
Lodz
Country
Poland
Facility Name
Research site
City
Bucharest
Country
Romania
12. IPD Sharing Statement
Citations:
PubMed Identifier
33962962
Citation
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.
Results Reference
derived
PubMed Identifier
33752164
Citation
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.
Results Reference
derived
PubMed Identifier
32098758
Citation
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.
Results Reference
derived
PubMed Identifier
31593273
Citation
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.
Results Reference
derived
Links:
URL
https://clinicaltrials.emdgroup.com/en/trial-details/?id=EMR700692_006
Description
Trial Awareness and Transparency website Scope
URL
https://medical.emdserono.com/en_US/home.html
Description
US Medical Information website, Medical Resources
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A Study to Investigate the Safety and Effectiveness of Different Doses of Sprifermin in Participants With Osteoarthritis of the Knee
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