Observational Data as External Control Arm to Study the Effectiveness of New Therapies for Guillain-Barré Syndrome

Background and ObjectivesDespite treatment with IV immunoglobulins (IVIg) and plasma exchange, many patients with Guillain-Barré syndrome (GBS) have poor outcome or considerable residual complaints. Randomized controlled trials (RCTs) are challenging for many reasons while increasingly available real-world data (RWD) might provide new opportunities to study treatment effectiveness and accelerate research progress. This study assessed the potential to construct a control group from observational data to compare effectiveness of new treatments for GBS with the current standard treatment. MethodsAs a proof of concept, we emulated the Second IVIg Dose (SID)-GBS RCT by using data from the prospective observational International GBS Outcome Study (IGOS). Patients treated with SID in the RCT (intervention) were compared with IGOS patients treated with a single course of IVIg (controls), selected based on the SID-GBS eligibility criteria. Included were patients aged 12 years and older from Europe/America with a poor prognosis and treated with IVIg 2 g/kg in 2–5 days started <2 weeks from onset of weakness. A propensity score was calculated based on known prognostic baseline factors, including age, preceding diarrhea, limb weakness, and the GBS Disability Scale (GBS-DS). Each patient treated with SID was matched with up to 3 IGOS controls using nearest neighbor matching on their propensity score. The primary outcome was the GBS-DS at week 4, analyzed with ordinal logistic regression. ResultsAfter applying the eligibility criteria, 187 of 1907 IGOS patients (10%) were available for matching. Before matching, substantial baseline imbalances existed for age, preceding diarrhea, and GBS-DS. Ninety-six percent (47/49) of patients treated with SID were matched to 61% (114/187) IGOS controls, which resulted in an adequate balance in all included baseline variables. The odds ratio for improvement on the GBS-DS at week 4 was 0.8 (95% CI 0.4–1.6) (>1 SID favorable). DiscussionThis study demonstrated the feasibility of a design to emulate a RCT in GBS by selecting external controls from RWD. Almost all patients treated with SID in the RCT could be matched to RWD controls with adequate balance. As in the RCT, SID was not associated with better outcome. This design offers promising opportunities for comparative studies of new treatments in GBS and other rare neurologic diseases.

Authors

Institutions

Publication Details

Journal
Neurology Open Access
Published
2026-08-21
DOI
https://doi.org/10.1212/wn9.0000000000000155
Primary Topic
Peripheral Neuropathies and Disorders
Type
article
Field-Weighted Citation Impact
0.00

Funders

Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

Observational Data as External Control Arm to Study the Effectiveness of New Therapies for Guillain-Barré Syndrome

R.D.M. Hadden, H. J. Gilhuis, Satoshi Kuwabara, KIERA BRENNAN et al.
Neurology Open Access
Peripheral Neuropathies and Disorders
article

Observational Data as External Control Arm to Study the Effectiveness of New Therapies for Guillain-Barré Syndrome

R.D.M. Hadden, H. J. Gilhuis, Satoshi Kuwabara, KIERA BRENNAN, Linda W.G. Luijten, T.H. Brannagan, Hester F. Lingsma, Eduardo Nobile‐Orazio, S.W. Reddel, Amy Davidson, G. Cavaletti, Hans‐Peter Hartung, Christa Walgaard, Thomas Harbo, J. Fehmi, Bart C. Jacobs, Shahram Attarian, R. Bhavaraju-Sanka, S. Chen, Christine Verboon, J.M. Addington, Eveline J.A. Wiegers, M. Htut, B. Islam, R. C. M. Thomma, E. Dardiotis, A. Y. Doets, C. Casasnovas, G. Gutiérrez-Gutiérrez, J. K. L. Holt, J. Roodbol, Z. Islam, L. Martín-Aguilar, B. van den Berg, V. Granit, N. Shahrizaila, M. van Woerkom, F. A. Barroso, J. M. Goldstein, G. Galassi, S. E. Leonhard, S. Arends, K. Bateman, Q. D. Mohammad, G. Antonini, P. Ripellino, J. Bürmann, L. Querol, L. Benedetti, A. Humm, C. Cutellè, Kenneth C. Gorson, A. Grapperon, Y.A.M. Grimbergen, U.A. Badrising, I.R. Bella, R.A.C. Hughes, M.P.J. Garssen, T. Fujioka, M.M. Dimachkie, M. Busby, P.Y.K van den Bergh, J.M. Gilchrist, C. Castellano, S. Butterworth, E. Baroncelli, P.N. Gengadharan, N.A. Goyal, J.S. Cosgrove, David R. Cornblath, S. Kusunoki, S. Ajroud-Driss, K.G. Claeys, T.E. Feasby, F. Eftimov, C. Balducci, F. Pelouto, T. García-Sobrino, M.E. Conti, S.T. Hsieh, Y. Péréon, Y. Wang, H.J. Willison, A. Echaniz-Laguna, J.G.J. Hoeijmakers, T.E. Bertorini, E.A. Fulgenzi, T. Hundsberger, M.C. Dalakas, Laura Christine De Koning, C. Briani, H.C. Lehmann, C.J. Gijsbers, Pieter A. Van Doorn, R. Fazio, C.C. Chao, L. Gutmann, C. Fokke, R.C. Reisin, M. Bellucci
article en

Abstract

Background and ObjectivesDespite treatment with IV immunoglobulins (IVIg) and plasma exchange, many patients with Guillain-Barré syndrome (GBS) have poor outcome or considerable residual complaints. Randomized controlled trials (RCTs) are challenging for many reasons while increasingly available real-world data (RWD) might provide new opportunities to study treatment effectiveness and accelerate research progress. This study assessed the potential to construct a control group from observational data to compare effectiveness of new treatments for GBS with the current standard treatment. MethodsAs a proof of concept, we emulated the Second IVIg Dose (SID)-GBS RCT by using data from the prospective observational International GBS Outcome Study (IGOS). Patients treated with SID in the RCT (intervention) were compared with IGOS patients treated with a single course of IVIg (controls), selected based on the SID-GBS eligibility criteria. Included were patients aged 12 years and older from Europe/America with a poor prognosis and treated with IVIg 2 g/kg in 2–5 days started <2 weeks from onset of weakness. A propensity score was calculated based on known prognostic baseline factors, including age, preceding diarrhea, limb weakness, and the GBS Disability Scale (GBS-DS). Each patient treated with SID was matched with up to 3 IGOS controls using nearest neighbor matching on their propensity score. The primary outcome was the GBS-DS at week 4, analyzed with ordinal logistic regression. ResultsAfter applying the eligibility criteria, 187 of 1907 IGOS patients (10%) were available for matching. Before matching, substantial baseline imbalances existed for age, preceding diarrhea, and GBS-DS. Ninety-six percent (47/49) of patients treated with SID were matched to 61% (114/187) IGOS controls, which resulted in an adequate balance in all included baseline variables. The odds ratio for improvement on the GBS-DS at week 4 was 0.8 (95% CI 0.4–1.6) (>1 SID favorable). DiscussionThis study demonstrated the feasibility of a design to emulate a RCT in GBS by selecting external controls from RWD. Almost all patients treated with SID in the RCT could be matched to RWD controls with adequate balance. As in the RCT, SID was not associated with better outcome. This design offers promising opportunities for comparative studies of new treatments in GBS and other rare neurologic diseases.

Neurology Open AccessVol. 2(3)
Tufts University (US), The University of Sydney (AU), Humanitas University (IT), Johns Hopkins University (US), Chiba University (JP), Johns Hopkins Medicine (US), Erasmus MC (NL), Aarhus University Hospital (DK), Albert Schweitzer Ziekenhuis (NL), Institut de Neurosciences de la Timone (FR), IJsselland Ziekenhuis (NL), Institute of Neuroimmunology of the Slovak Academy of Sciences (SK), Elisabeth-TweeSteden Ziekenhuis (NL), Hôpital de la Timone (FR), Heinrich Heine University Düsseldorf (DE), Palacký University Olomouc (CZ), University of Glasgow (GB)
Prinses Beatrix Spierfonds
Openalex Percentile: Top 10%
Peripheral Neuropathies and Disorders
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.