TY - JOUR
T1 - Oral fingolimod for chronic inflammatory demyelinating polyradiculoneuropathy (FORCIDP Trial)
T2 - a double-blind, multicentre, randomised controlled trial
AU - FORCIDP Trial Investigators
AU - Hughes, Richard
AU - Dalakas, Marinos C.
AU - Merkies, Ingemar
AU - Latov, Norman
AU - Léger, Jean Marc
AU - Nobile-Orazio, Eduardo
AU - Sobue, Gen
AU - Genge, Angela
AU - Cornblath, David
AU - Merschhemke, Martin
AU - Ervin, Carolyn Marie
AU - Agoropoulou, Catherine
AU - Hartung, Hans Peter
AU - Day, Timothy
AU - Spies, Judith
AU - Roberts, Leslie
AU - Van Damme, Philip
AU - Van den Bergh, Peter YK
AU - Maertens de Noordhout, Alain
AU - Dionne, Annie
AU - Larue, Sandrine
AU - Massie, Rami
AU - Melanson, Michel
AU - Camu, William
AU - De Seze, Jérôme
AU - Le Masson, Gwendal
AU - Pouget, Jean
AU - Schmidt, Jens
AU - Kimiskidis, Vasilios K.
AU - Chapman, Joab
AU - Drory, Vivian E.
AU - Fazio, Raffaella
AU - Gallia, Francesca
AU - Kusunoki, Susumu
AU - Mori, Masahiro
AU - Iijima, Masahiro
AU - Okamoto, Tomoko
AU - Baba, Masayuki
AU - Faber, Catharina G.
AU - van Schaik, Ivo N.
AU - Fryze, Waldemar
AU - Motta, Ewa
AU - Selmaj, Krzysztof
AU - Casasnovas, Carlos
AU - Sola, Antonio Guerrero
AU - Illa, Isabel
AU - Holt, James
AU - Miller, James AL
AU - Lunn, Michael P.
AU - Brannagan, Thomas H.
N1 - Funding Information: We thank the study patients for their participation. We also acknowledge the consultation and support provided during the initial stages of this programme by Philip von Rosenstiel (Biogen, Boston, MA, USA), Lixin Zhang Auberson, and Dieter Haering (Novartis Pharma, Basel, Switzerland), as well as the editorial assistance provided by Sivaram Vedantam and Uma Kundu (Novartis Healthcare, Hyderabad, India), for which no separate payment was made. Institutions wishing to analyse data from the study can apply online. Funding Information: RH has received compensation for consultancy from CSL Behring, LFB, and Novartis. MCD reports personal fees from Therapth Laboratory, Baxalta, Octapharma, Hoffman La Roche, and Therapeutic Advances in Neurology ; grants and personal fees from Novartis and Dysimmune Diseases Foundation; and grants from Genzyme, Merck Serono, Genesis, and CSL. IM reports grants from Talecris Talents Program, GBS CIDP Foundation International, Princess Beatrix Foundation, and the European Union 7th Framework Program; and other support from being a steering committee member for various studies for LFB, CSL Behring, Novartis, Grifols, and Octapharma; he serves on the editorial board of the Journal of Peripheral Nervous System and is a member of the Inflammatory Neuropathy Consortium and the Peripheral Nerve Society. NL reports personal fees from Novartis, during the conduct of the study; outside the submitted work he has received grants and personal fees from Shire, consulting fees from Pfizer, stock ownership in Therapath, and book royalties from the American Academy of Neurology. J-ML has received grants for clinical trials from LFB, honoraria for lectures from CSL Behring and LFB, and honoraria for scientific board membership from CSL Behring, LFB, Pharnext, and Terumo BCT. EN-O reports personal fees and grants from Novartis, during the conduct of the study; outside the submitted work, he reports personal fees from Baxter Italy, CSL Italy, Kedrion Biopharma Italy, LFB France, and UCB UK. GS reports personal fees from Novartis, during the conduct of the study; outside of the submitted work, GS has served on scientific advisory boards for Kanae Science Foundation for the Promotion of Medical Science and the Takeda Foundation; he serves on a steering committee for CSL Behring, and has received funding for travel and speaker honoraria from Mitsubishi Tanabe Pharma, Shionogi, Bristol Myers Squibb, Sumitomo Dainippon Pharma, Novartis Pharma, Bayer, Yakuhin, Pfizer Japan, Boehringer Ingelheim Japan, Kissei Pharmaceutical, Janssen Pharmaceutical, Teijin Pharma, FP Pharmaceutical Corporation, Nihon Pharmaceutical, Japan Blood Products Organization, Kowa Pharmaceutical, Ono Pharmaceutical, and Eisai; he has also received grants from the Ministry of Health, Labour and Welfare of Japan, the Japanese Ministry of Education, Culture, Sports, Science and Technology, and the Japan Society for the Promotion of Science. DC reports personal fees from Novartis, during the conduct of the study; outside of the submitted work, he has received compensation for consultancy from Acetylon Pharmaceuticals, Alnylam Pharmaceuticals, Annexon Biosciences, Akros Pharma, Biotest Pharmaceuticals, Boehringer Ingelheim, Cigna Health Management, CSL Behring, DP Clinical, Grifols, Karos Pharmaceuticals, Neurocrine Biosciences, Novartis, Octapharma, Pharnext, Sun Pharmaceuticals, and Syntimmune; he has served as a member of data safety monitoring boards for Pfizer, Ionis Pharmaceuticals, Axovant Sciences, and Ampio Pharmaceuticals; and is on the board of directors of GBS-CIDP Foundation International, the Foundation for Peripheral Neuropathy, and The Peripheral Nerve Society; furthermore, The Johns Hopkins University has licensed technology (The Total Neuropathy Score) to the following companies for which DC receives a royalty: Acetylon Pharmaceuticals, AstraZeneca Pharmaceuticals, Calithera Biosciences, Genentech, Neurocrine Biosciences, Merrimack Pharmaceuticals, Seattle Genetics, Shire Development. MM is an employee of Novartis Pharma and reports personal fees from Novartis during the conduct of the study. CME works for Novartis, and was the trial statistician for this study. CA is an employee of Novartis Pharma and reports personal fees from Novartis during the conduct of the study. H-PH reports personal compensation for serving on steering committees from CSL Behring, Novartis, and Octapharma and speaker honoraria from CSL Behring and Novartis; outside of the submitted work he has received personal compensation for serving on steering committees and speaker honoraria from Biogen, GeNeuro, Genzyme, Merck Serono, Novartis, Receptos Celgene, Roche, and Teva. AG has nothing to disclose. Publisher Copyright: © 2018 Elsevier Ltd
PY - 2018/8
Y1 - 2018/8
N2 - Background: Fingolimod is approved for the treatment of relapsing-remitting multiple sclerosis and was effective in experimental autoimmune neuritis in rats, a possible model for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). We aimed to evaluate the efficacy of fingolimod in delaying disability progression in patients with CIDP who withdrew from currently effective treatments (intravenous immunoglobulin [IVIg] or corticosteroids). Methods: This double-blind, multicentre, randomised, placebo-controlled, parallel-group, event-driven study was done at 48 neurology centres in Australia, Canada, Israel, Japan, the USA, and nine countries in Europe. Participants with CIDP who were receiving IVIg or corticosteroids were randomly assigned (1:1) to once-daily oral fingolimod 0·5 mg or placebo. Owing to the event-driven design, treatment duration was flexible and could be up to 4·5 years. Randomisation was done with an automated interactive voice response-web response system and was stratified by Inflammatory Neuropathy Cause and Treatment (INCAT) disability scale scores. Previous IVIg treatment was discontinued after one final course ending the day before the first dose of fingolimod or placebo was given, whereas corticosteroids were tapered off over 8 weeks after randomisation. The primary endpoint was time to first confirmed worsening (≥1 point increase on the adjusted INCAT disability scale score versus baseline) and was assessed in the full analysis set, which consisted of all patients who underwent randomisation and had at least one efficacy assessment for the primary analysis. The survival distribution functions of time to first worsening were estimated within each treatment group according to the Kaplan-Meier survival distribution function and compared with a stratified log-rank test. The trial is registered with ClinicalTrials.gov, number NCT01625182. Findings: Of 106 participants randomly assigned between Jan 24, 2013, and March 10, 2016, 54 received fingolimod (41 who had been receiving IVIg and 13 who had been receiving corticosteroids) and 52 received placebo (41 who had been receiving IVIg and 11 who had been receiving corticosteroids). The trial ended for futility as recommended by an independent data monitoring committee after an interim analysis when 44 confirmed worsening events had occurred. At the end of the study, the survival estimate of the proportion of participants free from confirmed worsening was not significantly different between the fingolimod group (42%, 95% CI 23–60) and the placebo group (43%, 28–59; p=0·91). Adverse events occurred in 41 (76%) participants receiving fingolimod and 44 (85%) on placebo, and serious adverse events occurred in nine (17%) and four (8%) patients, respectively. The most common adverse events with fingolimod were headache (12 [22%] patients), hypertension (ten [19%]), and extremity pain (seven [13%]). Adverse events leading to study discontinuation occurred in seven (13%) participants on fingolimod and none on placebo. Interpretation: Fingolimod 0·5 mg once-daily was not better than placebo for the treatment of CIDP. Future trial designs should take account of the possibility that if IVIg is stopped abruptly, some patients might relapse soon afterwards whereas others might remain in remission. Funding: Novartis Pharma.
AB - Background: Fingolimod is approved for the treatment of relapsing-remitting multiple sclerosis and was effective in experimental autoimmune neuritis in rats, a possible model for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). We aimed to evaluate the efficacy of fingolimod in delaying disability progression in patients with CIDP who withdrew from currently effective treatments (intravenous immunoglobulin [IVIg] or corticosteroids). Methods: This double-blind, multicentre, randomised, placebo-controlled, parallel-group, event-driven study was done at 48 neurology centres in Australia, Canada, Israel, Japan, the USA, and nine countries in Europe. Participants with CIDP who were receiving IVIg or corticosteroids were randomly assigned (1:1) to once-daily oral fingolimod 0·5 mg or placebo. Owing to the event-driven design, treatment duration was flexible and could be up to 4·5 years. Randomisation was done with an automated interactive voice response-web response system and was stratified by Inflammatory Neuropathy Cause and Treatment (INCAT) disability scale scores. Previous IVIg treatment was discontinued after one final course ending the day before the first dose of fingolimod or placebo was given, whereas corticosteroids were tapered off over 8 weeks after randomisation. The primary endpoint was time to first confirmed worsening (≥1 point increase on the adjusted INCAT disability scale score versus baseline) and was assessed in the full analysis set, which consisted of all patients who underwent randomisation and had at least one efficacy assessment for the primary analysis. The survival distribution functions of time to first worsening were estimated within each treatment group according to the Kaplan-Meier survival distribution function and compared with a stratified log-rank test. The trial is registered with ClinicalTrials.gov, number NCT01625182. Findings: Of 106 participants randomly assigned between Jan 24, 2013, and March 10, 2016, 54 received fingolimod (41 who had been receiving IVIg and 13 who had been receiving corticosteroids) and 52 received placebo (41 who had been receiving IVIg and 11 who had been receiving corticosteroids). The trial ended for futility as recommended by an independent data monitoring committee after an interim analysis when 44 confirmed worsening events had occurred. At the end of the study, the survival estimate of the proportion of participants free from confirmed worsening was not significantly different between the fingolimod group (42%, 95% CI 23–60) and the placebo group (43%, 28–59; p=0·91). Adverse events occurred in 41 (76%) participants receiving fingolimod and 44 (85%) on placebo, and serious adverse events occurred in nine (17%) and four (8%) patients, respectively. The most common adverse events with fingolimod were headache (12 [22%] patients), hypertension (ten [19%]), and extremity pain (seven [13%]). Adverse events leading to study discontinuation occurred in seven (13%) participants on fingolimod and none on placebo. Interpretation: Fingolimod 0·5 mg once-daily was not better than placebo for the treatment of CIDP. Future trial designs should take account of the possibility that if IVIg is stopped abruptly, some patients might relapse soon afterwards whereas others might remain in remission. Funding: Novartis Pharma.
UR - http://www.scopus.com/inward/record.url?scp=85049474165&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/S1474-4422(18)30202-3
DO - https://doi.org/10.1016/S1474-4422(18)30202-3
M3 - Article
C2 - 30001923
SN - 1474-4422
VL - 17
SP - 689
EP - 698
JO - The Lancet Neurology
JF - The Lancet Neurology
IS - 8
ER -