Background:
Previous phase 2 trials indicated benefit from B-lymphocyte depletion in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
Objective:
To evaluate the effect of the monoclonal anti-CD20 antibody rituximab versus placebo in patients with ME/CFS.
Design:
Randomized, placebo-controlled, double-blind, multicenter trial. (ClinicalTrials.gov: NCT02229942)
Setting:
4 university hospitals and 1 general hospital in Norway.
Patients:
151 patients aged 18 to 65 years who had ME/CFS according to Canadian consensus criteria and had had the disease for 2 to 15 years.
Intervention:
Treatment induction with 2 infusions of rituximab, 500 mg/m2 of body surface area, 2 weeks apart, followed by 4 maintenance infusions with a fixed dose of 500 mg at 3, 6, 9, and 12 months (n = 77), or placebo (n = 74).
Measurements:
Primary outcomes were overall response rate (fatigue score ≥4.5 for ≥8 consecutive weeks) and repeated measurements of fatigue score over 24 months. Secondary outcomes included repeated measurements of self-reported function over 24 months, components of the Short Form-36 Health Survey and Fatigue Severity Scale over 24 months, and changes from baseline to 18 months in these measures and physical activity level. Between-group differences in outcome measures over time were assessed by general linear models for repeated measures.
Results:
Overall response rates were 35.1% in the placebo group and 26.0% in the rituximab group (difference, 9.2 percentage points [95% CI, −5.5 to 23.3 percentage points]; P = 0.22). The treatment groups did not differ in fatigue score over 24 months (difference in average score, 0.02 [CI, −0.27 to 0.31]; P = 0.80) or any of the secondary end points. Twenty patients (26.0%) in the rituximab group and 14 (18.9%) in the placebo group had serious adverse events.
Limitation:
Self-reported primary outcome measures and possible recall bias.
Conclusion:
B-cell depletion using several infusions of rituximab over 12 months was not associated with clinical improvement in patients with ME/CFS.
Primary Funding Source:
The Norwegian Research Council, Norwegian Regional Health Trusts, Kavli Trust, MEandYou Foundation, and Norwegian ME Association.
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Author, Article, and Disclosure Information
Haukeland University Hospital, Bergen, Norway (Ø.F., I.G.R., K.S., J.A., I.K., O.B., K.R., K.A.)
Oslo University Hospital, Oslo, Norway (K.L., I.H., S.S.M.)
Notodden Hospital, Notodden, Norway (H.T., A.E.L.)
St. Olavs Hospital, Trondheim, Norway (P.C.B., M.E.G., Ø.K., K.A.B., A.H.S.)
University Hospital of Northern Norway, Tromsø, Norway (C.S., L.M.B., A.E.G.)
Haukeland University Hospital and University of Bergen, Bergen, Norway (O.D., O.M.)
Note: All authors had authority over the preparation of the manuscript and the decision to submit it for publication. The manuscript is an accurate account of the study, and no important aspects of the trial have been omitted.
Acknowledgment: The authors thank the safety monitoring board for the trial (Professor Ola D. Saugstad and Associate Professor Unn M. Fagerli) and the following personnel at the trial centers for technical and scientific assistance: Helle Øvrebø, RN, OCN; Anne L. Falch, RN, OCN; and Tor H. Wiestad, MSc, at Haukeland University Hospital; Bente Bråthen Berg, RN; Semhar Abraham; and Liv Sæter Sjue, RN, at Oslo University Hospital; Thomas Fufa Baisa, MD, at Notodden Hospital; Hilde A. Abrahamsen, RN; Siv B. Rogstad, RN; and Vegard Strøm, RN, at St. Olavs Hospital; and Tom Sollid, CLS, at University Hospital of Northern Norway.
Financial Support: The RituxME trial received funding from the Norwegian Research Council, the Norwegian Regional Health Trusts, the MEandYou Foundation, the Norwegian ME Association, and the legacy of Torstein Hereid. The research group for ME/CFS at Haukeland University Hospital receives funding from the Kavli Trust.
Disclosures: Dr. Fluge reports grants for the study from the Norwegian Research Council, Norwegian Regional Health Trusts, Kavli Trust, MEandYou Foundation, and Norwegian ME Association during the conduct of the study. In addition, Haukeland University Hospital has patents and patent applications on the issue of B-cell depletion therapy for chronic fatigue syndrome (ME/CFS). Dr. Fluge is mentioned as an inventor in these applications. Dr. Rekeland reports grants from Norwegian Regional Health Trusts during the conduct of the study. Dr. Lien reports grants from Norwegian Regional Health Trusts during the conduct of the study. Dr. Schäfer reports grants from Norwegian Regional Health Trusts during the conduct of the study. Ms. Sørland reports grants from Norwegian Regional Health Trusts and nonfinancial support from NorCRIN (Norwegian Clinical Research Infrastructure Network) during the conduct of the study. Dr. Ktoridou-Valen reports grants from Norwegian Regional Health Trusts during the conduct of the study. Dr. Herder reports grants from Norwegian Regional Health Trusts during the conduct of the study. Dr. Baranowska reports grants from Norwegian Regional Health Trusts during the conduct of the study. Dr. Bohnen reports grants from Norwegian Regional Health Trusts during the conduct of the study. Ms. Martinsen reports grants from Norwegian Regional Health Trusts during the conduct of the study. Ms. Lonar reports grants from Norwegian Regional Health Trusts during the conduct of the study. Ms. Solvang reports grants from Norwegian Regional Health Trusts during the conduct of the study. Mr. Gya reports grants from Norwegian Regional Health Trusts during the conduct of the study. Ms. Risa reports grants from the Kavli Trust during the conduct of the study. Ms. Alme reports grants from the Kavli Trust during the conduct of the study. Dr. Mella reports grants for the study from the Norwegian Research Council, Norwegian Regional Health Trusts, Kavli Trust, MEandYou Foundation, and Norwegian ME Association during the conduct of the study. In addition, Haukeland University Hospital has patents and patent applications on the issue of B-cell depletion therapy for chronic fatigue syndrome (ME/CFS). Dr. Mella is mentioned as an inventor in these applications. Authors not named here have disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M18-1451.
Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that her spouse has stock options/holdings with Targeted Diagnostics and Therapeutics. Darren B. Taichman, MD, PhD, Executive Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Catharine B. Stack, PhD, MS, Deputy Editor, Statistics, reports that she has stock holdings in Pfizer, Johnson & Johnson, and Colgate-Palmolive. Christina C. Wee, MD, MPH, Deputy Editor, reports employment with Beth Israel Deaconess Medical Center. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Yu-Xiao Yang, MD, MSCE, Deputy Editor, reports that he has no financial relationships or interest to disclose.
Reproducible Research Statement:Study protocol: See Supplement 1. Statistical code: Example analysis codes are in the Methods section of the Appendix. Data set: Available to approved individuals through written agreements with the author and research sponsor.
Corresponding Author: Øystein Fluge, MD, PhD, Department of Oncology and Medical Physics, Haukeland University Hospital, Jonas Lies vei 65, N-5021 Bergen, Norway; e-mail, oystein.
Current Author Addresses: Drs. Fluge, Rekeland, and Ktoridou-Valen; Ms. Sørland; Ms. Risa; Ms. Alme; and Profs. Dahl and Mella: Department of Oncology and Medical Physics, Haukeland University Hospital, Jonas Lies vei 51, N-5021 Bergen, Norway.
Dr. Lien and Ms. Martinsen: CFS/ME Center, Division of Medicine, Aker Hospital, Oslo University Hospital, PO Box 4959 Nydalen, N-0424 Oslo, Norway.
Dr. Thürmer and Ms. Lonar: Telemark Hospital, Department of Medicine, Notodden Hospital, Henrik Wergelands gt. 9, N-3675 Notodden, Norway.
Prof. Borchgrevink; Drs. Gotaas, Kvammen, and Baranowska; and Ms. Solvang: Department of Pain and Complex Disorders, St. Olavs Hospital, PO Box 3250 Sluppen, N-7006 Trondheim, Norway.
Drs. Schäfer and Bohnen and Mr. Gya: Division of Rehabilitation Services, University Hospital of Northern Norway, PO Box 1, N-9038 Tromsø, Norway.
Dr. Aßmus: Department of Research and Development, Haukeland University Hospital, Jonas Lies vei 51, N-5021 Bergen, Norway.
Dr. Herder: Section for Climate Therapy, Oslo University Hospital, Rikshospitalet, PO Box 4950 Nydalen, N-0424 Oslo, Norway.
Dr. Bruland: Department of Medical Genetics and Molecular Medicine, Haukeland University Hospital, Jonas Lies vei 51, N-5021 Bergen, Norway.
Author Contributions: Conception and design: Ø. Fluge, O. Mella.
Analysis and interpretation of the data: Ø. Fluge, I.G. Rekeland, K. Sørland, J. Aßmus, O. Mella.
Drafting of the article: Ø. Fluge, I.G. Rekeland, K. Sørland, J. Aßmus, O. Mella.
Critical revision of the article for important intellectual content: Ø. Fluge, I.G. Rekeland, K. Sørland, J. Aßmus, K. Alme, O. Dahl, O. Mella.
Final approval of the article: Ø. Fluge, I.G. Rekeland, K. Lien, H. Thürmer, P.C. Borchgrevink, C. Schäfer, K. Sørland, J. Aßmus, I. Ktoridou-Valen, I. Herder, M.E. Gotaas, Ø. Kvammen, K.A. Baranowska, L.M.L.J. Bohnen, S.S. Martinsen, A.E. Lonar, A.H. Solvang, A.E.S. Gya, O. Bruland, K. Risa, K. Alme, O. Dahl, O. Mella.
Provision of study materials or patients: Ø. Fluge, I.G. Rekeland, K. Lien, H. Thürmer, P.C. Borchgrevink, C. Schäfer, K. Sørland, I. Ktoridou-Valen, I. Herder, M.E. Gotaas, Ø. Kvammen, K.A. Baranowska, L.M.L.J. Bohnen, S.S. Martinsen, A.E. Lonar, A.H. Solvang, A.E.S. Gya, O. Mella.
Statistical expertise: J. Aßmus.
Obtaining of funding: Ø. Fluge, O. Mella.
Administrative, technical, or logistic support: K. Sørland, S.S. Martinsen, A.E. Lonar, A.H. Solvang, A.E.S. Gya, O. Bruland, K. Risa, K. Alme, O. Dahl, O. Mella.
Collection and assembly of data: Ø. Fluge, I.G. Rekeland, K. Lien, H. Thürmer, C. Schäfer, K. Sørland, I. Herder, M.E. Gotaas, Ø. Kvammen, K.A. Baranowska, L.M.L.J. Bohnen, S.S. Martinsen, A.E. Lonar, A.H. Solvang, A.E.S. Gya, O. Mella.
This article was published at Annals.org on 2 April 2019.
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