PMID- 31593273
OWN - NLM
STAT- MEDLINE
DCOM- 20191023
LR  - 20200408
IS  - 1538-3598 (Electronic)
IS  - 0098-7484 (Print)
IS  - 0098-7484 (Linking)
VI  - 322
IP  - 14
DP  - 2019 Oct 8
TI  - Effect of Intra-Articular Sprifermin vs Placebo on Femorotibial Joint Cartilage 
      Thickness in Patients With Osteoarthritis: The FORWARD Randomized Clinical Trial.
PG  - 1360-1370
LID - 10.1001/jama.2019.14735 [doi]
AB  - IMPORTANCE: Sprifermin is under investigation as a disease-modifying 
      osteoarthritis drug. OBJECTIVE: To evaluate the effects of sprifermin on changes 
      in total femorotibial joint cartilage thickness in the more symptomatic knee of 
      patients with osteoarthritis. DESIGN, SETTING, AND PARTICIPANTS: FORWARD (FGF-18 
      Osteoarthritis Randomized Trial with Administration of Repeated Doses) was a 
      5-year, dose-finding, multicenter randomized clinical trial conducted at 10 
      sites. Eligible participants were aged 40 to 85 years with symptomatic, 
      radiographic knee osteoarthritis and Kellgren-Lawrence grade 2 or 3. Enrollment 
      began in July 2013 and ended in May 2014; the last participant visit occurred on 
      May 8, 2017. The primary outcome at 2 years and a follow-up analysis at 3 years 
      are reported. INTERVENTIONS: Participants were randomized to 1 of 5 groups: 
      intra-articular injections of 100 mug of sprifermin administered every 6 months 
      (n = 110) or every 12 months (n = 110), 30 mug of sprifermin every 6 months 
      (n = 111) or every 12 months (n = 110), or placebo every 6 months (n = 108). Each 
      treatment consisted of weekly injections over 3 weeks. MAIN OUTCOMES AND 
      MEASURES: The primary end point was change in total femorotibial joint cartilage 
      thickness measured by quantitative magnetic resonance imaging at 2 years. The 
      secondary end points (of 15 total) included 2-year change from baseline in total 
      Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores. 
      The minimal clinically important difference (MCID) is unknown for the primary 
      outcome; for total WOMAC score in patients with hip and knee osteoarthritis, the 
      absolute MCID is 7 U (95% CI, 4 to 10 U) and the percentage MCID is 14% (95% CI, 
      9% to 18%). RESULTS: Among 549 participants (median age, 65.0 years; 379 female 
      [69.0%]), 474 (86.3%) completed 2-year follow-up. Compared with placebo, the 
      changes from baseline to 2 years in total femorotibial joint cartilage thickness 
      were 0.05 mm (95% CI, 0.03 to 0.07 mm) for 100 mug of sprifermin administered 
      every 6 months; 0.04 mm (95% CI, 0.02 to 0.06 mm) for 100 mug of sprifermin every 
      12 months; 0.02 mm (95% CI, -0.01 to 0.04 mm) for 30 mug of sprifermin every 6 
      months; and 0.01 mm (95% CI, -0.01 to 0.03 mm) for 30 mug of sprifermin every 12 
      months. Compared with placebo, there were no statistically significant 
      differences in mean absolute change from baseline in total WOMAC scores for 100 
      mug of sprifermin administered every 6 months or every 12 months, or for 30 mug of 
      sprifermin every 6 months or every 12 months. The most frequently reported 
      treatment-emergent adverse event was arthralgia (placebo: n = 46 [43.0%]; 100 mug 
      of sprifermin administered every 6 months: n = 45 [41.3%]; 100 mug of sprifermin 
      every 12 months: n = 50 [45.0%]; 30 mug of sprifermin every 6 months: n = 40 
      [36.0%]; and 30 mug of sprifermin every 12 months: n = 48 [44.0%]). CONCLUSIONS 
      AND RELEVANCE: Among participants with symptomatic radiographic knee 
      osteoarthritis, the intra-articular administration of 100 mug of sprifermin every 
      6 or 12 months vs placebo resulted in an improvement in total femorotibial joint 
      cartilage thickness after 2 years that was statistically significant, but of 
      uncertain clinical importance; there was no significant difference for 30 mug of 
      sprifermin every 6 or 12 months vs placebo. Durability of response also was 
      uncertain. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01919164.
FAU - Hochberg, Marc C
AU  - Hochberg MC
AD  - School of Medicine, University of Maryland, Baltimore.
FAU - Guermazi, Ali
AU  - Guermazi A
AD  - School of Medicine, Boston University, Boston, Massachusetts.
AD  - Boston Imaging Core Lab LLC, Boston, Massachusetts.
FAU - Guehring, Hans
AU  - Guehring H
AD  - Merck KGaA, Darmstadt, Germany.
FAU - Aydemir, Aida
AU  - Aydemir A
AD  - EMD Serono Research and Development Institute Inc, Billerica, Massachusetts.
FAU - Wax, Stephen
AU  - Wax S
AD  - EMD Serono Research and Development Institute Inc, Billerica, Massachusetts.
FAU - Fleuranceau-Morel, Patricia
AU  - Fleuranceau-Morel P
AD  - EMD Serono Research and Development Institute Inc, Billerica, Massachusetts.
FAU - Reinstrup Bihlet, Asger
AU  - Reinstrup Bihlet A
AD  - Nordic Bioscience, Herlev, Denmark.
FAU - Byrjalsen, Inger
AU  - Byrjalsen I
AD  - Nordic Bioscience, Herlev, Denmark.
FAU - Ragnar Andersen, Jeppe
AU  - Ragnar Andersen J
AD  - Nordic Bioscience, Herlev, Denmark.
FAU - Eckstein, Felix
AU  - Eckstein F
AD  - Institute of Anatomy, Department of Imaging and Functional Musculoskeletal 
      Research, Paracelsus Medical University Salzburg and Nuremberg, Salzburg, 
      Austria.
AD  - Chondrometrics GmbH, Ainring, Germany.
LA  - eng
SI  - ClinicalTrials.gov/NCT01919164
PT  - Clinical Trial, Phase II
PT  - Comparative Study
PT  - Journal Article
PT  - Multicenter Study
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - JAMA
JT  - JAMA
JID - 7501160
RN  - 0 (fibroblast growth factor 18)
RN  - 62031-54-3 (Fibroblast Growth Factors)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Cartilage, Articular/*drug effects/pathology
MH  - Dose-Response Relationship, Drug
MH  - Double-Blind Method
MH  - Drug Administration Schedule
MH  - Female
MH  - Fibroblast Growth Factors/*administration & dosage/adverse effects
MH  - Follow-Up Studies
MH  - Humans
MH  - Injections, Intra-Articular
MH  - Knee Joint
MH  - Magnetic Resonance Imaging
MH  - Male
MH  - Middle Aged
MH  - Osteoarthritis, Knee/diagnostic imaging/*drug therapy/pathology
PMC - PMC6784851
COIS- Conflict of Interest Disclosures: Dr Hochberg reported being the president of 
      Rheumcon Inc; and receiving consulting fees from Bioiberica SA, Bristol-Myers 
      Squibb, Eli Lilly, EMD Serono, Galapagos, IBSA Biotechniq SA, Novartis Pharma AG, 
      Pfizer, Plexxikon, Samumed LLC, Theralogix LLC, and TissueGene Inc. Dr Guermazi 
      reported being the president of Boston Imaging Core Lab LLC; and receiving 
      consulting fees from OrthoTrophix, GE Healthcare, EMD Serono, Merck Serono, 
      AstraZeneca, Sanofi, TissueGene, Galapagos, Roche, and Pfizer. Dr Guehring is an 
      employee of Merck KGaA. Ms Aydemir and Drs Wax and Fleuranceau-Morel are 
      employees of EMD Serono (a business of Merck KGaA). Dr Wax also reported 
      receiving consulting fees from Merck Serono; and holding a patent with EMD 
      Serono. Drs Reinstrup Bihlet, Byrjalsen, and Ragnar Andersen are employees and 
      shareholders in Nordic Bioscience. Dr Eckstein is an employee and shareholder of 
      Chondrometrics GmbH; and reported receiving grants and consulting fees from Merck 
      KGaA, Kolon TissueGene, Samumed LLC, AbbVie, Bioclinica, TissueGene, Servier 
      Roche, Medtronic, Ampio, Orthotrophix, Medivir, FNIH, and Galapagos.
EDAT- 2019/10/09 06:00
MHDA- 2019/10/24 06:00
PMCR- 2020/04/08
CRDT- 2019/10/09 06:00
PHST- 2019/10/09 06:00 [entrez]
PHST- 2019/10/09 06:00 [pubmed]
PHST- 2019/10/24 06:00 [medline]
PHST- 2020/04/08 00:00 [pmc-release]
AID - 2752470 [pii]
AID - joi190107 [pii]
AID - 10.1001/jama.2019.14735 [doi]
PST - ppublish
SO  - JAMA. 2019 Oct 8;322(14):1360-1370. doi: 10.1001/jama.2019.14735.