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A Study to Investigate the Safety and Effectiveness of Different Doses of Sprifermin in Participants With Osteoarthritis of the Knee (FORWARD)

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ClinicalTrials.gov Identifier: NCT01919164
Recruitment Status : Completed
First Posted : August 8, 2013
Results First Posted : July 13, 2020
Last Update Posted : July 13, 2020
Sponsor:
Collaborator:
Nordic Bioscience A/S
Information provided by (Responsible Party):
EMD Serono ( EMD Serono Research & Development Institute, Inc. )

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.

Condition or disease Intervention/treatment Phase
Osteoarthritis, Knee Drug: Sprifermin Drug: Placebo Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 549 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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
Actual Study Start Date : July 29, 2013
Actual Primary Completion Date : May 5, 2016
Actual Study Completion Date : May 7, 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Osteoarthritis

Arm Intervention/treatment
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.
Drug: Placebo
Participants received Placebo matched to sprifermin as intra-articular injection.

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.
Drug: Sprifermin
Participants received Sprifermin as intra-articular injection.
Other Name: Recombinant Human Fibroblast Growth Factor-18 (rhFGF-18)

Drug: Placebo
Participants received Placebo matched to sprifermin as intra-articular injection.

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.
Drug: Sprifermin
Participants received Sprifermin as intra-articular injection.
Other Name: Recombinant Human Fibroblast Growth Factor-18 (rhFGF-18)

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.
Drug: Sprifermin
Participants received Sprifermin as intra-articular injection.
Other Name: Recombinant Human Fibroblast Growth Factor-18 (rhFGF-18)

Drug: Placebo
Participants received Placebo matched to sprifermin as intra-articular injection.

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.
Drug: Sprifermin
Participants received Sprifermin as intra-articular injection.
Other Name: Recombinant Human Fibroblast Growth Factor-18 (rhFGF-18)




Primary Outcome Measures :
  1. 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) ]
    The change in cartilage thickness at 2 years was calculated based on quantitative magnetic resonance imaging (qMRI).


Secondary Outcome Measures :
  1. 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 ]
    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.

  2. 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 ]
    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.

  3. 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 ]
    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.

  4. 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 ]
    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).

  5. 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 ]
    The change in cartilage thickness was calculated based on quantitative magnetic resonance imaging (qMRI).

  6. 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 ]
    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.

  7. 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) ]
    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.

  8. 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) ]


Information from the National Library of Medicine

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Ages Eligible for Study:   40 Years to 85 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01919164


Locations
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United States, Colorado
Research site
Lakewood, Colorado, United States
United States, Maryland
Research site
Baltimore, Maryland, United States, 21201
Argentina
Research site
Buenos Aires, Argentina
Czechia
Research site
Brno, Czechia
Research site
Pardubice, Czechia
Research site
Prague, Czechia
Denmark
Research site
Aalborg, Denmark
Research site
Ballerup, Denmark
Research site
Vejle, Denmark
Estonia
Research site
Tallinn, Estonia
Hong Kong
Research Site
Hong Kong, Hong Kong
Poland
Research site
Lodz, Poland
Romania
Research site
Bucharest, Romania
Sponsors and Collaborators
EMD Serono Research & Development Institute, Inc.
Nordic Bioscience A/S
Investigators
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Study Director: Medical Responsible, MD Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany
  Study Documents (Full-Text)

Documents provided by EMD Serono ( EMD Serono Research & Development Institute, Inc. ):
Study Protocol  [PDF] March 5, 2013
Statistical Analysis Plan  [PDF] August 11, 2016

Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: EMD Serono Research & Development Institute, Inc.
ClinicalTrials.gov Identifier: NCT01919164    
Other Study ID Numbers: EMR700692_006
2011-003059-20 ( EudraCT Number )
First Posted: August 8, 2013    Key Record Dates
Results First Posted: July 13, 2020
Last Update Posted: July 13, 2020
Last Verified: June 2020
Keywords provided by EMD Serono ( EMD Serono Research & Development Institute, Inc. ):
Osteoarthritis of knee
Recombinant Human Fibroblast Growth Factor-18 (rhFGF-18)
Sprifermin
Placebo
Additional relevant MeSH terms:
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Osteoarthritis
Osteoarthritis, Knee
Arthritis
Joint Diseases
Musculoskeletal Diseases
Rheumatic Diseases
Mitogens
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action