. 2020 Sep;25(3):230-237.

doi: 10.1111/jns.12402. Epub 2020 Aug 5.

Placebo effect in chronic inflammatory demyelinating polyneuropathy: The PATH study and a systematic review

Richard A Lewis¹, David R Cornblath², Hans-Peter Hartung³, Gens Sobue⁴, John-Philip Lawo⁵, Orell Mielke⁵, Billie L Durn⁵, Vera Bril⁶, Ingemar S J Merkies^{7

8}, Paul Bassett⁹, Alexa Cleasby⁹, Ivo N van Schaik^{10

11}; PATH study group

Collaborators, Affiliations

Collaborators

PATH study group:
A Sabet, K George, L Roberts, R Carne, S Blum, R Henderson, P Van Damme, J Demeestere, S Larue, C D'Amour, P Kunc, M Valis, J Sussova, T Kalous, R Talab, M Bednar, T Toomsoo, I Rubanovits, K Gross-Paju, U Sorro, M Saarela, M Auranen, J Pouget, S Attarian, G Le Masson, A Wielanek, C Desnuelle, E Delmon, P Clavelou, D Aufauvre, J Schmidt, J Zschuentzsch, C Sommer, D Kramer, O Hoffmann, C Goerlitz, J Haas, M Chatzopoulos, R Yoon, R Gold, P Berlit, A Jaspert-Grehl, D Liebetanz, A Kutschenko, M Stangel, C Trebst, P Baum, F Bergh, J Klehmet, A Meisel, F Klostermann, J Oechtering, H Lehmann, M Schroeter, T Hagenacker, D Mueller, A Sperfeld, F Bethke, Israel V Drory, A Algom, D Yarnitsky, B Murinson, A Di Muzio, F Ciccocioppo, S Sorbi, S Mata, A Schenone, M Grandis, G Lauria, D Cazzato, G Antonini, S Morino, D Cocito, M Zibetti, T Yokota, T Ohkubo, T Kanda, M Kawai, K Kaida, H Onoue, S Kuwabara, M Mori, M Iijima, K Ohyama, M Baba, M Tomiyama, K Nishiyama, T Akutsu, K Yokoyama, K Kanai, I N van Schaik, F Eftimov, N C Notermans, N Visser, C Faber, J Hoeijmakers, K Rejdak, U Chyrchel-Paszkiewicz, C Casanovas Pons, M Antonia, J Gamez, M Salvado, C Marquez Infante, S Benitez, M Lunn, J Morrow, D Gosal, T Lavin, I Melamed, A Testori, S Ajroud-Driss, D Menichella, E Simpson, E Chi-Ho Lai, M Dimachkie, R J Barohn, S Beydoun, H Johl, D Lange, A Shtilbans, S Muley, S Ladha, M Freimer, J Kissel, N Latov, R Chin, E Ubogu, S Mumfrey, T Rao, P MacDonald, K Sharma, G Gonzalez, J Allen, D Walk, L Hobson-Webb, K Gable

Affiliations

¹ Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, California, USA.
² Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
³ Department of Neurology, UKD and Center for Neurology and Neuropsychiatry, LVR Klinikum, Heinrich Heine University, Düsseldorf, Germany.
⁴ Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
⁵ CSL Behring, Marburg, King of Prussia, Pennsylvania, USA.
⁶ Ellen and Martin Prosserman Centre for Neuromuscular Diseases, Division of Neurology, Department of Medicine, University Health Network, University of Toronto, Toronto, Ontario, Canada.
⁷ Department of Neurology, Maastricht University Medical Center, Maastricht, The Netherlands.
⁸ Curaçao Medical Center, Willemstad, Curaçao.
⁹ Meridian HealthComms Ltd, Manchester, UK.
¹⁰ Department of Neurology, Amsterdam University Medical Centres, Amsterdam, The Netherlands.
¹¹ The Netherlands and Spaarne Gasthuis, Haarlem, The Netherlands.

PMID: 32627277
PMCID: PMC7497019
DOI: 10.1111/jns.12402

Placebo effect in chronic inflammatory demyelinating polyneuropathy: The PATH study and a systematic review

Richard A Lewis et al. J Peripher Nerv Syst. 2020 Sep.

. 2020 Sep;25(3):230-237.

doi: 10.1111/jns.12402. Epub 2020 Aug 5.

Authors

Collaborators

PATH study group:
A Sabet, K George, L Roberts, R Carne, S Blum, R Henderson, P Van Damme, J Demeestere, S Larue, C D'Amour, P Kunc, M Valis, J Sussova, T Kalous, R Talab, M Bednar, T Toomsoo, I Rubanovits, K Gross-Paju, U Sorro, M Saarela, M Auranen, J Pouget, S Attarian, G Le Masson, A Wielanek, C Desnuelle, E Delmon, P Clavelou, D Aufauvre, J Schmidt, J Zschuentzsch, C Sommer, D Kramer, O Hoffmann, C Goerlitz, J Haas, M Chatzopoulos, R Yoon, R Gold, P Berlit, A Jaspert-Grehl, D Liebetanz, A Kutschenko, M Stangel, C Trebst, P Baum, F Bergh, J Klehmet, A Meisel, F Klostermann, J Oechtering, H Lehmann, M Schroeter, T Hagenacker, D Mueller, A Sperfeld, F Bethke, Israel V Drory, A Algom, D Yarnitsky, B Murinson, A Di Muzio, F Ciccocioppo, S Sorbi, S Mata, A Schenone, M Grandis, G Lauria, D Cazzato, G Antonini, S Morino, D Cocito, M Zibetti, T Yokota, T Ohkubo, T Kanda, M Kawai, K Kaida, H Onoue, S Kuwabara, M Mori, M Iijima, K Ohyama, M Baba, M Tomiyama, K Nishiyama, T Akutsu, K Yokoyama, K Kanai, I N van Schaik, F Eftimov, N C Notermans, N Visser, C Faber, J Hoeijmakers, K Rejdak, U Chyrchel-Paszkiewicz, C Casanovas Pons, M Antonia, J Gamez, M Salvado, C Marquez Infante, S Benitez, M Lunn, J Morrow, D Gosal, T Lavin, I Melamed, A Testori, S Ajroud-Driss, D Menichella, E Simpson, E Chi-Ho Lai, M Dimachkie, R J Barohn, S Beydoun, H Johl, D Lange, A Shtilbans, S Muley, S Ladha, M Freimer, J Kissel, N Latov, R Chin, E Ubogu, S Mumfrey, T Rao, P MacDonald, K Sharma, G Gonzalez, J Allen, D Walk, L Hobson-Webb, K Gable

Affiliations

¹ Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, California, USA.
² Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
³ Department of Neurology, UKD and Center for Neurology and Neuropsychiatry, LVR Klinikum, Heinrich Heine University, Düsseldorf, Germany.
⁴ Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
⁵ CSL Behring, Marburg, King of Prussia, Pennsylvania, USA.
⁶ Ellen and Martin Prosserman Centre for Neuromuscular Diseases, Division of Neurology, Department of Medicine, University Health Network, University of Toronto, Toronto, Ontario, Canada.
⁷ Department of Neurology, Maastricht University Medical Center, Maastricht, The Netherlands.
⁸ Curaçao Medical Center, Willemstad, Curaçao.
⁹ Meridian HealthComms Ltd, Manchester, UK.
¹⁰ Department of Neurology, Amsterdam University Medical Centres, Amsterdam, The Netherlands.
¹¹ The Netherlands and Spaarne Gasthuis, Haarlem, The Netherlands.

PMID: 32627277
PMCID: PMC7497019
DOI: 10.1111/jns.12402

Abstract

The Polyneuropathy And Treatment with Hizentra (PATH) study required subjects with chronic inflammatory demyelinating polyneuropathy (CIDP) to show dependency on immunoglobulin G (IgG) and then be restabilized on IgG before being randomized to placebo or one of two doses of subcutaneous immunoglobulin (SCIG). Nineteen of the 51 subjects (37%) randomized to placebo did not relapse over the next 24 weeks. This article explores the reasons for this effect. A post-hoc analysis of the PATH placebo group was undertaken. A literature search identified other placebo-controlled CIDP trials for review and comparison. In PATH, subjects randomized to placebo who did not relapse were significantly older, had more severe disease, and took longer to deteriorate in the IgG dependency period compared with those who relapsed. Published trials in CIDP, whose primary endpoint was stability or deterioration, had a mean non-deterioration (placebo effect) of 43%, while trials with a primary endpoint of improvement had a placebo response of only 11%. Placebo is an important variable in the design of CIDP trials. Trials designed to show clinical improvement will have a significantly lower effect of this phenomenon than those designed to show stability or deterioration.

Keywords: CIDP; immunoglobulin; non-relapse; placebo; relapse.

PubMed Disclaimer

Figures

**FIGURE 1**
Time to show deterioration in the immunoglobulin G (IgG) dependency test period stratified by relapse status in the subcutaneous immunoglobulin (SCIG)‐treatment period for placebo group subjects (n = 51; non‐relapsers = 19; relapsers = 32). Each line represents an individual placebo group subject from the subcutaneous immunoglobulin (SCIG) randomized phase, where line colour refers to a subjects' relapse status during this phase (blue solid line, relapsed; red dashed line, did not relapse). Line height indicates time (in weeks) for that individual to show dependency (ie, deterioration) during the IgG dependency test period. *95% Wilson score CI. CI, unadjusted confidence interval

**FIGURE 2**
Forest plots from the meta‐analysis showing improvement in placebo subjects in the improvement endpoint studies (n = 9) and non‐deterioration in placebo subjects in the stability vs deterioration endpoint studies (n = 5). CI, confidence interval; ES, effect size

See this image and copyright information in PMC

References

1. Colloca L, Barsky AJ. Placebo and Nocebo effects. N Engl J Med. 2020;382(6):554‐561. - PubMed
1. Oaklander AL, Lunn MP, Hughes RA, van Schaik IN, et al. Treatments for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP): an overview of systematic reviews. Cochrane Database Syst Rev. 2017;(1):CD010369. - PMC - PubMed
1. Van den Bergh PY, Hadden RD, Bouche P, et al. European Federation of Neurological Societies/Peripheral Nerve Society guideline on management of chronic inflammatory demyelinating polyradiculoneuropathy: report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society—first revision. Eur J Neurol. 2010;17(3):356‐363. - PubMed
1. van Schaik IN, Bril V, van Geloven N, et al. Subcutaneous immunoglobulin for maintenance treatment in chronic inflammatory demyelinating polyneuropathy (PATH): a randomised, double‐blind, placebo‐controlled phase 3 trial. Lancet Neurol. 2018;17(1):35‐46. - PubMed
1. van Schaik IN, van Geloven N, Bril V, Hartung HP, et al. Subcutaneous immunoglobulin for maintenance treatment in chronic inflammatory demyelinating polyneuropathy (The PATH Study): study protocol for a randomized controlled trial. Trials. 2016;17(1):345. - PMC - PubMed

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Placebo effect in chronic inflammatory demyelinating polyneuropathy: The PATH study and a systematic review

Collaborators

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Placebo effect in chronic inflammatory demyelinating polyneuropathy: The PATH study and a systematic review

Authors

Collaborators

Affiliations

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References

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