Subcutaneous immunoglobulin for maintenance treatment in chronic inflammatory demyelinating polyneuropathy (PATH): a randomised, double-blind, placebo-controlled, phase 3 trial

on behalf of the, PATH study group, PATH study group

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Abstract

Background Approximately two-thirds of patients with chronic inflammatory demyelinating polyneuropathy (CIDP) need long-term intravenous immunoglobulin. Subcutaneous immunoglobulin (SCIg) is an alternative option for immunoglobulin delivery, but has not previously been investigated in a large trial of CIDP. The PATH study compared relapse rates in patients given SCIg versus placebo. Methods Between March 12, 2012, and Sept 20, 2016, we studied patients from 69 neuromuscular centres in North America, Europe, Israel, Australia, and Japan. Adults with definite or probable CIDP who responded to intravenous immunoglobulin treatment were eligible. We randomly allocated participants to 0·2 g/kg or 0·4 g/kg of a 20% SCIg solution (IgPro20) weekly versus placebo (2% human albumin solution) for maintenance treatment for 24 weeks. We did randomisation in a 1:1:1 ratio with an interactive voice and web response system with a block size of six, stratified by region (Japan or non-Japan). The primary outcome was the proportion of patients with a CIDP relapse or who were withdrawn for any other reason during 24 weeks of treatment. Patients, caregivers, and study personnel, including those assessing outcomes, were masked to treatment assignment. Analyses were done in the intention-to-treat and per-protocol sets. This trial is registered with ClinicalTrials.gov, number NCT01545076. Findings In this randomised, double-blind, placebo-controlled trial, we randomly allocated 172 patients: 57 (33%) to the placebo group, 57 (33%) to the low-dose group, and 58 (34%) to the high-dose group. In the intention-to-treat set, 36 (63% [95% CI 50–74]) patients on placebo, 22 (39% [27–52]) on low-dose SCIg, and 19 (33% [22–46]) on high-dose SCIg had a relapse or were withdrawn from the study for other reasons (p=0·0007). Absolute risk reductions were 25% (95% CI 6–41) for low-dose versus placebo (p=0·007), 30% (12–46) for high-dose versus placebo (p=0·001), and 6% (−11 to 23) for high-dose versus low-dose (p=0·32). Causally related adverse events occurred in 47 (27%) patients (ten [18%] in the placebo group, 17 [30%] in the low-dose group, and 20 [34%] in the high-dose group). Six (3%) patients had 11 serious adverse events: one (2%) patient in the placebo group, three (5%) in the low-dose group, and two (3%) in the high-dose group; only one (an acute allergic skin reaction in the low-dose group) was assessed to be causally related. Interpretation This study, which is to our knowledge, the largest trial of CIDP to date and the first to study two administrations of immunoglobulins and two doses, showed that both doses of SCIg IgPro20 were efficacious and well tolerated, suggesting that SCIg can be used as a maintenance treatment for CIDP. Funding CSL Behring.

Original languageEnglish (US)
Pages (from-to)35-46
Number of pages12
JournalThe Lancet Neurology
Volume17
Issue number1
DOIs
StatePublished - Jan 2018

Bibliographical note

Funding Information:
INvS chairs a steering committee for CSL Behring and received departmental honoraria for serving on scientific advisory boards for CSL Behring and Baxter. He received departmental research support from the Netherlands Organization for Scientific Research and Prinses Beatrix Spierfonds. All lecturing and consulting fees for INvS were donated to Stichting Klinische Neurologie, a local foundation that supports research in the field of neurological disorders. He serves on the editorial board of the Cochrane Neuromuscular Disease Group, is a member of the organising committee of the Inflammatory Neuropathy Consortium, a standing committee of the Peripheral Nerve Society, and is a member of the scientific board of the Kreuth III meeting on the optimal use of plasma-derived medicinal products, especially coagulation factors and normal immunoglobulins organised under the auspices of the European Directorate for the Quality of Medicines and HealthCare. VB is a consultant to CSL Behring, Grifols, Union Chimique Belge, Bionevia, and ArgenX. She serves on international scientific advisory boards for the Myasthenia Gravis Foundation of America and Guillain-Barré Syndrome/Chronic Inflammatory Demyelinating Polyneuropathy (CIDP/GBS) Foundation International, and has received research support from CSL Behring, Grifols, Bionevia, Union Chimique Belge, and ArgenX. NvG received departmental honoraria for serving on a scientific advisory board for CSL Behring. H-PH received fees for consulting or serving on steering committees or advertisement boards from Baxter, Bayer Healthcare, Biogen, CSL Behring, Geneuro, Kedrion, Laboratoire francais du Fractionnement et des Biotechnologies, MedImmune, Merck, Novartis, Octapharma, Receptos Celgene, Roche, Sanofi Genzyme, and Teva, with approval by the Rector of Heinrich-Heine-University Düsseldorf. RAL is chair of the Inflammatory Neuropathy Consortium, a standing committee of the Peripheral Nerve Society. He is on the Board of Directors of the Peripheral Nerve Society, is a Medical Advisory Board member of the CIDP/GBS Foundation International, of the Myasthenia Gravis Foundation of America, and of the Myasthenia Gravis Foundation of California, and is a paid consultant for CSL Behring, Novartis, Pharnext, Axelacare, Biotest, and Nufactor. GS served on the scientific advisory boards for the Kanae Science Foundation for the Promotion of Medical Science and Takeda Foundation. He serves on a steering committee for CSL Behring. He received funding for travel and speaker honoraria from Mitsubishi Tanabe Pharma, Shionogi, Bristol-Myers Squibb, Sumitomo Dainippon Pharma, Novartis, Bayer Yakuhin, Pfizer Japan, Boehringer Ingelheim Japan, Kissei Pharmaceutical, Janssen, Teijin Pharma, FP Pharmaceutical, Nihon Pharmaceutical, the Japan Blood Products Organization, Kowa Pharmaceutical, Ono Pharmaceutical, and Eisai. He also received grants from the Ministry of Health, Labour and Welfare Japan, Japanese Ministry of Education, Culture, Sports, Science and Technology, and Japan Society for the Promotion of Science. J-PL is a CSL employee and biostatistician for this study. MP is a CSL employee and biostatistician for this study. OM is a CSL employee and programme director for this study. BLD is a CSL employee and clinical scientist for this study. DRC is a consultant for Acetylon, Alcobra Pharma, Alnylam Pharmaceuticals, Annexon Biosciences, Akros Pharma, Biotest Pharmaceuticals, Boehringer Ingelheim, Cigna Health Management, CSL Behring, DP Clinical, GlaxoSmithKline, Grifols, Karos Pharmaceuticals, Neurocrine Biosciences, Novartis, Octapharma, Pharnext, Sun Pharmaceuticals, and Syntimmune. He is on the data and safety monitoring board for Pfizer, Johnson & Johnson, Ionis Pharmaceuticals, GlaxoSmithKline, and Axovant Sciences. He has licensed technology for the Total Neuropathy Score for Acetylon, AstraZeneca, Calithera Biosciences, Genentech, Neurocrine Biosciences, Merrimack Pharmaceuticals, Seattle Genetics, and Shire Development Inc. He is on the Board of Directors for the CIDP/GBS Foundation International, Foundation for Peripheral Neuropathy, and Peripheral Nerve Society. ISJM received funding for research from the Talecris Talents programme, CIDP/GBS Foundation International, Prinses Beatrix Spierfonds, and European Union 7th Framework Programme (grant number 602273). Furthermore, a research foundation at the University of Maastricht received honoraria on behalf of him for participation in steering committees of the Talecris ICE Study, Laboratoire francais du Fractionnement et des Biotechnologies, CSL Behring, Novartis, Grifols, and Octapharma. He serves on the editorial board of the Journal of the Peripheral Nervous System , is a member of the Inflammatory Neuropathy Consortium, and is a member of the Peripheral Nerve Society.

Funding Information:
This study is funded by CSL Behring. We thank Amgad Shebl and Wilson Hu, CSL Behring safety physicians, for their work and review on ensuring the accuracy of safety data presented in this study.

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