Intravenous immunoglobulin therapy for small fiber neuropathy: study protocol for a randomized controlled trial

Bianca T A de Greef, Margot Geerts, Janneke G J Hoeijmakers, Catharina G Faber, Ingemar S J Merkies, Bianca T A de Greef, Margot Geerts, Janneke G J Hoeijmakers, Catharina G Faber, Ingemar S J Merkies

Abstract

Background: Small fiber neuropathy is the most common cause of neuropathic pain in peripheral neuropathies, with a minimum prevalence of 53/100,000. Patients experience excruciating pain, and currently available anti-neuropathic and other pain drugs do not relieve the pain substantially. Several open-label studies have suggested an immunological basis in small fiber neuropathy and have reported efficacy of treatment with intravenous immunoglobulin. Therefore, immunological mechanisms conceivably may play a role in small fiber neuropathy. To date, no randomized controlled study with intravenous immunoglobulin in patients with small fiber neuropathy has been performed.

Methods/design: This study is a randomized, double-blind, placebo-controlled, clinical trial in patients with idiopathic small fiber neuropathy. The primary objective is to investigate the efficacy of intravenous immunoglobulin versus placebo on pain alleviation. A 1-point change in the PI-NRS compared to baseline is considered the minimum clinically important difference. In the IVIg-treated group, we assume a response rate of approximately 60 % based on the criteria composed by the IMMPACT group for measurement of pain. Based on this, a sample size of 60 patients is needed. Eligible patients fulfilling the inclusion/exclusion criteria will be randomized to receive either intravenous immunoglobulin or placebo (0.9 % saline). The treatment regimen will start with a loading dose of 2 g/kg body weight over 2-4 consecutive days, followed by a maintenance dose of 1 g/kg body weight over 1-2 consecutive days given three times at a 3-week interval. The primary endpoint is the comparison of the percentage of responder subjects between the two treatment groups from the first randomization during the 12 weeks of treatment. A responder is defined as ≥ 1-point Pain Intensity Numerical Rating Scale improvement on the mean weekly peak pain relative to baseline. The secondary outcomes are pain intensity, pain qualities, other small fiber neuropathy-related complaints, daily and social functioning, as well as quality of life. In addition, safety assessments will be performed for adverse events, vital signs, and laboratory values outside the normal range. Responders during the 12-week treatment period will be followed during a 3-month extension phase.

Discussion: This is the first randomized, double-blind, placebo-controlled clinical trial with intravenous immunoglobulin in patients with idiopathic small fiber neuropathy. Positive findings will result in a new treatment option for small fiber neuropathy and support an immunological role in this condition.

Trial registration: ClinicalTrials.gov, NCT02637700 . Registered on 16 December 2015.

Keywords: Immunology; Intravenous immunoglobulin; Painful neuropathy; Randomized controlled trial; Small fiber neuropathy.

Figures

Fig. 1
Fig. 1
Schematic diagram representing overall study design and study visits Legend: IVIg = intravenous immunoglobulin, red triangles represent the treatment visits. The first treatment visit is spread out over 2-4 consecutive days, treatment visit 2-4 will consist of 1-2 consecutive days

References

    1. Peters MJ, Bakkers M, Merkies IS, Hoeijmakers JG, van Raak EP, Faber CG. Incidence and prevalence of small-fiber neuropathy: a survey in the Netherlands. Neurology. 2013;81(15):1356–60. doi: 10.1212/WNL.0b013e3182a8236e.
    1. Gorson KC, Ropper AH. Idiopathic distal small fiber neuropathy. Acta Neurol Scand. 1995;92(5):376–82. doi: 10.1111/j.1600-0404.1995.tb00150.x.
    1. Hoeijmakers JG, Faber CG, Lauria G, Merkies IS, Waxman SG. Small-fibre neuropathies-advances in diagnosis, pathophysiology and management. Nat Rev Neurol. 2012;8(7):369–79. doi: 10.1038/nrneurol.2012.97.
    1. Lauria G, Merkies IS, Faber CG. Small fibre neuropathy. Curr Opin Neurol. 2012;25(5):542–9. doi: 10.1097/WCO.0b013e32835804c5.
    1. Bakkers M, Faber CG, Hoeijmakers JG, Lauria G, Merkies IS. Small fibers, large impact: quality of life in small-fiber neuropathy. Muscle Nerve. 2014;49(3):329–36. doi: 10.1002/mus.23910.
    1. Devigili G, Tugnoli V, Penza P, Camozzi F, Lombardi R, Melli G, et al. The diagnostic criteria for small fibre neuropathy: from symptoms to neuropathology. Brain. 2008;131(Pt 7):1912–25. doi: 10.1093/brain/awn093.
    1. Bednarik J, Vlckova-Moravcova E, Bursova S, Belobradkova J, Dusek L, Sommer C. Etiology of small-fiber neuropathy. J Peripher Nerv Syst. 2009;14(3):177–83. doi: 10.1111/j.1529-8027.2009.00229.x.
    1. Hoitsma E, Marziniak M, Faber CG, Reulen JP, Sommer C, De Baets M, et al. Small fibre neuropathy in sarcoidosis. Lancet. 2002;359(9323):2085–6. doi: 10.1016/S0140-6736(02)08912-2.
    1. Bakkers M, Merkies IS, Lauria G, Devigili G, Penza P, Lombardi R, et al. Intraepidermal nerve fiber density and its application in sarcoidosis. Neurology. 2009;73(14):1142–8. doi: 10.1212/WNL.0b013e3181bacf05.
    1. Goransson LG, Herigstad A, Tjensvoll AB, Harboe E, Mellgren SI, Omdal R. Peripheral neuropathy in primary sjogren syndrome: a population-based study. Arch Neurol. 2006;63(11):1612–5. doi: 10.1001/archneur.63.11.1612.
    1. Goransson LG, Brun JG, Harboe E, Mellgren SI, Omdal R. Intraepidermal nerve fiber densities in chronic inflammatory autoimmune diseases. Arch Neurol. 2006;63(10):1410–3. doi: 10.1001/archneur.63.10.1410.
    1. Chamberlain JL, Pittock SJ, Oprescu AM, Dege C, Apiwattanakul M, Kryzer TJ, et al. Peripherin-IgG association with neurologic and endocrine autoimmunity. J Autoimmun. 2010;34(4):469–77. doi: 10.1016/j.jaut.2009.12.004.
    1. Ferrari S, Morbin M, Nobile-Orazio E, Musso A, Tomelleri G, Bertolasi L, et al. Antisulfatide polyneuropathy: antibody-mediated complement attack on peripheral myelin. Acta Neuropathol. 1998;96(6):569–74. doi: 10.1007/s004010050937.
    1. Dabby R, Weimer LH, Hays AP, Olarte M, Latov N. Antisulfatide antibodies in neuropathy: clinical and electrophysiologic correlates. Neurology. 2000;54(7):1448–52. doi: 10.1212/WNL.54.7.1448.
    1. Zafrir B, Zimmerman M, Fellig Y, Naparstek Y, Reichman N, Flatau E. Small fiber neuropathy due to isolated vasculitis of the peripheral nervous system. Isr Med Assoc J. 2004;6(3):183–4.
    1. Kelkar P, McDermott WR, Parry GJ. Sensory-predominant, painful, idiopathic neuropathy: inflammatory changes in sural nerves. Muscle Nerve. 2002;26(3):413–6. doi: 10.1002/mus.10202.
    1. Uceyler N, Kafke W, Riediger N, He L, Necula G, Toyka KV, et al. Elevated proinflammatory cytokine expression in affected skin in small fiber neuropathy. Neurology. 2010;74(22):1806–13. doi: 10.1212/WNL.0b013e3181e0f7b3.
    1. Hughes RA, Donofrio P, Bril V, Dalakas MC, Deng C, Hanna K, et al. Intravenous immune globulin (10 % caprylate-chromatography purified) for the treatment of chronic inflammatory demyelinating polyradiculoneuropathy (ICE study): a randomised placebo-controlled trial. Lancet Neurol. 2008;7(2):136–44. doi: 10.1016/S1474-4422(07)70329-0.
    1. European Federation of Neurological S. Peripheral Nerve S, van Schaik IN, Bouche P, Illa I, Leger JM, et al. European Federation of Neurological Societies/Peripheral Nerve Society guideline on management of multifocal motor neuropathy. Eur J Neurol. 2006;13(8):802–8. doi: 10.1111/j.1468-1331.2006.01466.x.
    1. Parambil JG, Tavee JO, Zhou L, Pearson KS, Culver DA. Efficacy of intravenous immunoglobulin for small fiber neuropathy associated with sarcoidosis. Respir Med. 2011;105(1):101–5. doi: 10.1016/j.rmed.2010.09.015.
    1. Wakasugi D, Kato T, Gono T, Ito E, Nodera H, Kawaguchi Y, et al. Extreme efficacy of intravenous immunoglobulin therapy for severe burning pain in a patient with small fiber neuropathy associated with primary Sjogren's syndrome. Mod Rheumatol. 2009;19(4):437–40. doi: 10.3109/s10165-009-0180-2.
    1. Dabby R, Gilad R, Sadeh M, Lampl Y, Watemberg N. Acute steroid responsive small-fiber sensory neuropathy: a new entity? J Peripher Nerv Syst. 2006;11(1):47–52. doi: 10.1111/j.1085-9489.2006.00062.x.
    1. Goebel A. Immunoglobulin responsive chronic pain. J Clin Immunol. 2010;30(Suppl 1):S103–8. doi: 10.1007/s10875-010-9403-8.
    1. Souayah N, Chin RL, Brannagan TH, Latov N, Green PH, Kokoszka A, et al. Effect of intravenous immunoglobulin on cerebellar ataxia and neuropathic pain associated with celiac disease. Eur J Neurol. 2008;15(12):1300–3. doi: 10.1111/j.1468-1331.2008.02305.x.
    1. Jackson AL, Oates JA. A patient with adult erythermalgia: evidence suggesting an autoimmune etiology. Am J Med Sci. 2008;335(4):320–2. doi: 10.1097/MAJ.0b013e31812f65e7.
    1. Moody S, Pacheco S, Butler IJ, Koenig MK. Secondary erythromelalgia successfully treated with intravenous immunoglobulin. J Child Neurol. 2012;27(7):922–3. doi: 10.1177/0883073811427784.
    1. Nimmerjahn F, Ravetch JV. The antiinflammatory activity of IgG: the intravenous IgG paradox. J Exp Med. 2007;204(1):11–5. doi: 10.1084/jem.20061788.
    1. Berlot G, Rossini P, Turchet F. Biology of immunoglobulins. Transl Med. 2015;11:24–7.
    1. Finnerup NB, Attal N, Haroutounian S, McNicol E, Baron R, Dworkin RH, et al. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol. 2015;14(2):162–73. doi: 10.1016/S1474-4422(14)70251-0.
    1. Brouwer BA, de Greef BT, Hoeijmakers JG, Geerts M, van Kleef M, Merkies IS, et al. Neuropathic pain due to small fiber neuropathy in aging: current management and future prospects. Drugs Aging. 2015;32(8):611–21. doi: 10.1007/s40266-015-0283-8.
    1. Deng C, Hanna K, Bril V, Dalakas MC, Donofrio P, van Doorn PA, et al. Challenges of clinical trial design when there is lack of clinical equipoise: use of a response-conditional crossover design. J Neurol. 2012;259(2):348–52. doi: 10.1007/s00415-011-6200-0.
    1. McQuay H, Carroll D, Moore A. Variation in the placebo effect in randomised controlled trials of analgesics: all is as blind as it seems. Pain. 1996;64(2):331–5. doi: 10.1016/0304-3959(95)00116-6.
    1. Jensen MP, McFarland CA. Increasing the reliability and validity of pain intensity measurement in chronic pain patients. Pain. 1993;55(2):195–203. doi: 10.1016/0304-3959(93)90148-I.
    1. Galer BS, Jensen MP. Development and preliminary validation of a pain measure specific to neuropathic pain: the Neuropathic Pain Scale. Neurology. 1997;48(2):332–8. doi: 10.1212/WNL.48.2.332.
    1. Stewart JD, Low PA, Fealey RD. Distal small fiber neuropathy: results of tests of sweating and autonomic cardiovascular reflexes. Muscle Nerve. 1992;15(6):661–5. doi: 10.1002/mus.880150605.
    1. Merkies IS, Lauria G. 131st ENMC International Workshop: selection of outcome measures for peripheral neuropathy clinical trials 10–12 December 2004, Naarden, The Netherlands. Neuromuscul Disord. 2006;16(2):149–56. doi: 10.1016/j.nmd.2005.12.003.
    1. Farrar JT, Young JP, Jr, LaMoreaux L, Werth JL, Poole RM. Clinical importance of changes in chronic pain intensity measured on an 11-point numerical pain rating scale. Pain. 2001;94(2):149–58. doi: 10.1016/S0304-3959(01)00349-9.
    1. Dworkin RH, Turk DC, Wyrwich KW, Beaton D, Cleeland CS, Farrar JT, et al. Interpreting the clinical importance of treatment outcomes in chronic pain clinical trials: IMMPACT recommendations. J Pain. 2008;9(2):105–21. doi: 10.1016/j.jpain.2007.09.005.
    1. Farrar JT. What is clinically meaningful: outcome measures in pain clinical trials. Clin J Pain. 2000;16(2 Suppl):S106–12. doi: 10.1097/00002508-200006001-00018.
    1. Brouwer BA, Bakkers M, Hoeijmakers JG, Faber CG, Merkies IS. Improving assessment in small fiber neuropathy. J Peripher Nerv Syst. 2015;20(3):333–40. doi: 10.1111/jns.12128.
    1. Aaronson NK. Quality of life: what is it? How should it be measured? Oncology. 1988;2(5):69–76.
    1. Aaronson NK, Muller M, Cohen PD, Essink-Bot ML, Fekkes M, Sanderman R, et al. Translation, validation, and norming of the Dutch language version of the SF-36 Health Survey in community and chronic disease populations. J Clin Epidemiol. 1998;51(11):1055–68. doi: 10.1016/S0895-4356(98)00097-3.
    1. Sloan J, Symonds T, Vargas-Chanes D, Fridley B. Practical guidelines for assessing the clinical significance of health-related quality of life changes within clinical trials. The Innov Regulatory Sci. 2003;37(1):23–31. doi: 10.1177/009286150303700105.
    1. Themistocleous AC, Ramirez JD, Serra J, Bennett DL. The clinical approach to small fibre neuropathy and painful channelopathy. Pract Neurol. 2014;14:368–79. doi: 10.1136/practneurol-2013-000758.
    1. Durandy A, Kaveri SV, Kuijpers TW, Basta M, Miescher S, Ravetch JV, et al. Intravenous immunoglobulins--understanding properties and mechanisms. Clin Exp Immunol. 2009;158(Suppl 1):2–13. doi: 10.1111/j.1365-2249.2009.04022.x.

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