title: Randomized Placebo-Controlled and Controlled Non-Inferiority Phase III Trials Comparing Trafermin, a Recombinant Human Fibroblast Growth Factor 2, and Enamel Matrix Derivative in Periodontal Regeneration in Intrabony Defects.
abstract: We investigated the efficacy, safety, and clinical significance of trafermin, a recombinant human fibroblast growth factor (rhFGF)-2, for periodontal regeneration in intrabony defects in Phase III trials. Study A, a multicenter, randomized, double-blind, placebo-controlled study, was conducted at 24 centers. Patients with periodontitis with 4-mm and 3-mm or deeper probing pocket depth and intrabony defects, respectively, were included. A total of 328 patients were randomly assigned (2:1) to receive 0.3% rhFGF-2 or placebo, and 323 patients received the assigned investigational drug during flap surgery. One of the co-primary endpoints, the percentage of bone fill at 36 weeks after drug administration, was significantly greater in the rhFGF-2 group at 37.131% (95% confidence interval [CI], 32.7502 to 41.5123; n = 208) than it was in the placebo group at 21.579% (95% CI, 16.3571 to 26.8011; n = 100; p < 0.001). The other endpoint, the clinical attachment level regained at 36 weeks, was not significantly different between groups. Study B, a multicenter, randomized, blinded (patients and evaluators of radiographs), and active-controlled study was conducted at 15 centers to clarify the clinical significance of rhFGF-2. Patients with 6-mm and 4-mm or deeper probing pocket depth and intrabony defects, respectively, were included. A total of 274 patients were randomly assigned (5:5:2) to receive rhFGF-2, enamel matrix derivative (EMD), or flap surgery alone. A total of 267 patients received the assigned treatment during flap surgery. The primary endpoint, the linear alveolar bone growth at 36 weeks, was 1.927 mm (95% CI, 1.6615 to 2.1920; n = 108) in the rhFGF-2 group and 1.359 mm (95% CI, 1.0683 to 1.6495; n = 109) in the EMD group, showing non-inferiority (a prespecified margin of 0.3 mm) and superiority of rhFGF-2 to EMD. Safety problems were not identified in either study. Therefore, trafermin is an effective and safe treatment for periodontal regeneration in intrabony defect, and its efficacy was superior in rhFGF-2 compared to EMD treatments.
authors.affiliation: Osaka University Graduate School of Dentistry, Suita, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kitamura
authors.affiliation: Kaken Pharmaceutical Co., Ltd, Tokyo, Japan.
authors.forename: Motoki
authors.initials: M
authors.lastname: Akamatsu
authors.affiliation: Graduate School of Dental Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Masamitsu
authors.initials: M
authors.lastname: Kawanami
authors.affiliation: School of Dentistry, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Furuichi
authors.affiliation: Graduate School of Oral Medicine, Matsumoto Dental University, Shiojiri, Japan.
authors.forename: Takeo
authors.initials: T
authors.lastname: Fujii
authors.affiliation: School of Dentistry, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Japan.
authors.forename: Mari
authors.initials: M
authors.lastname: Mori
authors.affiliation: Dental Training Center, Kensei-kai Medical Incorporated Association, Numazu, Japan.
authors.forename: Kazushi
authors.initials: K
authors.lastname: Kunimatsu
authors.affiliation: Graduate School of Dentistry, Tohoku University, Sendai, Japan.
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Shimauchi
authors.affiliation: School of Dentistry at Matsudo, Nihon University, Matsudo, Japan.
authors.forename: Yorimasa
authors.initials: Y
authors.lastname: Ogata
authors.affiliation: School of Dentistry, Showa University, Tokyo, Japan.
authors.forename: Matsuo
authors.initials: M
authors.lastname: Yamamoto
authors.affiliation: School of Medicine, Keio University, Tokyo, Japan.
authors.forename: Taneaki
authors.initials: T
authors.lastname: Nakagawa
authors.affiliation: School of Dentistry, Nihon University, Tokyo, Japan.
authors.forename: Shuichi
authors.initials: S
authors.lastname: Sato
authors.affiliation: School of Dentistry, Nihon University, Tokyo, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Ito
authors.affiliation: Machida Municipal Hospital, Tokyo, Japan.
authors.forename: Takefumi
authors.initials: T
authors.lastname: Ogasawara
authors.affiliation: Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Izumi
authors.affiliation: School of Dental Medicine, Tsurumi University, Yokohama, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Gomi
authors.affiliation: Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan.
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Yamazaki
authors.affiliation: Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan.
authors.forename: Hiromasa
authors.initials: H
authors.lastname: Yoshie
authors.affiliation: Dental Hospital, Aichi-Gakuin University, Nagoya, Japan.
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Fukuda
authors.affiliation: School of Dentistry, Aichi-Gakuin University, Nagoya, Japan.
authors.forename: Toshihide
authors.initials: T
authors.lastname: Noguchi
authors.affiliation: Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
authors.forename: Shogo
authors.initials: S
authors.lastname: Takashiba
authors.affiliation: Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Hidemi
authors.initials: H
authors.lastname: Kurihara
authors.affiliation: Institute of Health Biosciences, Graduate School, University of Tokushima, Tokushima, Japan.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Nagata
authors.affiliation: Department of Periodontology, Kyushu University, Fukuoka, Japan.
authors.forename: Takafumi
authors.initials: T
authors.lastname: Hamachi
authors.affiliation: Medical Corporation Fukuwa-kai Beppu Dental Clinic, Fukuoka, Japan.
authors.forename: Katsumasa
authors.initials: K
authors.lastname: Maeda
authors.affiliation: Medical Corporation Fukuwa-kai Beppu Dental Clinic, Fukuoka, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Yokota
authors.affiliation: Fukuoka Dental College, Fukuoka, Japan.
authors.forename: Ryuji
authors.initials: R
authors.lastname: Sakagami
authors.affiliation: Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Hara
authors.affiliation: Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Noguchi
authors.affiliation: Graduate School of Dentistry, Tohoku University, Sendai, Japan.
authors.forename: Toshi
authors.initials: T
authors.lastname: Furuuchi
authors.affiliation: Graduate School of Dentistry, Tohoku University, Sendai, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Sasano
authors.affiliation: Nakayamadera Imai Clinic, Takarazuka, Japan.
authors.forename: Enyu
authors.initials: E
authors.lastname: Imai
authors.affiliation: Rinku General Medical Center, Osaka, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Ohmae
authors.affiliation: Kaken Pharmaceutical Co., Ltd, Tokyo, Japan.
authors.forename: Hayuru
authors.initials: H
authors.lastname: Koizumi
authors.affiliation: Kaken Pharmaceutical Co., Ltd, Tokyo, Japan.
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Watanuki
authors.affiliation: Osaka University Graduate School of Dentistry, Suita, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Murakami
mesh_terms: D000328:Adult; D000368:Aged; D003743:Dental Enamel / Q000502:physiology*; D004311:Double-Blind Method; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000008:administration & dosage*; D005346:Fibroblast Growth Factors / Q000008:administration & dosage*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000008:administration & dosage*; D010518:Periodontitis / Q000188:drug therapy* / Q000378:metabolism; D011994:Recombinant Proteins / Q000008:administration & dosage; D012038:Regeneration / Q000187:drug effects*
chemical_list: D010446:Peptide Fragments; D011994:Recombinant Proteins; D016222:Fibroblast Growth Factor 2; C114444:trafermin; D005346:Fibroblast Growth Factors
keywords: CELL/TISSUE SIGNALING; CLINICAL TRIALS; CYTOKINES; DENTAL BIOLOGY; ENDOCRINE PATHWAYS