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A Randomized, Double-Blind, Placebo-Controlled Trial of the Corticosteroid-Sparing Effects of Immunoglobulin in Myasthenia Gravis
Bril V, Szczudlik A, Vaitkus A, Rozsa C, Kostera-Pruszczyk A, Hon P, Bednarik J, Tyblova M, Köhler W, Toomsoo T, et al
Neurology. 2022
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Editor's Choice
Abstract
BACKGROUND AND OBJECTIVES Myasthenia gravis (MG) is an autoimmune disease characterized by dysfunction at the neuromuscular junction. Treatment frequently includes corticosteroids (CS) and intravenous immunoglobulin (IVIG). This study was conducted to determine if immune globulin (human), 10% caprylate/chromatography purified (IGIV-C) could facilitate CS dose reduction in CS-dependent MG patients. METHODS In this randomized, double-blind, placebo-controlled trial, CS-dependent MG patients (MGFA class II-Iva; AChR+) received a loading dose of 2 g/kg IGIV-C over 2 days (maximum 80 g/day) or placebo at week 0 (baseline). Maintenance doses (1 g/kg IGIV-C or placebo) were administered every three weeks through week 36. Tapering of CS was initiated at week 9 and continued through week 36 unless the patient worsened (QMG score ≥ 4 points from baseline). CS doses were increased (based on current CS dose) in patients who worsened. Patients were withdrawn if worsening failed to improve within 6 weeks or if a second CS increase was required. The primary efficacy endpoint (at week 39) was a ≥ 50% reduction in CS dose. Secondary and safety endpoints were assessed throughout the study and follow-up (weeks 42 and 45). The study results and full protocol are available at: ://clinicaltrials.gov/ct2/show/NCT02473965. RESULTS The primary endpoint (≥ 50% reduction in CS dose) showed no significant difference between the IGIV-C treatment (60.0% of patients) and placebo (63.3%). There were no significant differences for secondary endpoints. Safety data indicated that IGIV-C was well-tolerated. DISCUSSION In this study, IGIV-C was not more effective than placebo in reducing daily CS dose. These results suggest that effects of IGIV-C and CS are not synergistic and may be mechanistically different. TRIAL REGISTRATION INFORMATION The trial was registered on clinicaltrialsregister.eu (EudraCT #: 2013-005099-17) and clinicaltrials.gov (identifier NCT02473965). CLASSIFICATION OF EVIDENCE This study provides Class II evidence that IVIG infusions in adult patients with MG do not increase the percentage of patients achieving a ≥ 50% reduction in corticosteroid dose compared to placebo.
PICO Summary
Population
Corticosteroids-dependent myasthenia gravis patients (n= 60).
Intervention
Immune globulin injection, 10% caprylate/chromatography purified IGIV-C (n= 30).
Comparison
Placebo (n= 30).
Outcome
The primary endpoint (≥ 50% reduction in corticosteroids dose) showed no significant difference between the IGIV-C treatment (60.0% of patients) and placebo (63.3%). There were no significant differences for secondary endpoints. Safety data indicated that IGIV-C was well-tolerated.
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Analysis of Relapse by Inflammatory Rasch-built Overall Disability Scale Status in the PATH Study of Subcutaneous Immunoglobulin in Chronic Inflammatory Demyelinating Polyneuropathy
Merkies ISJ, van Schaik IN, Bril V, Hartung HP, Lewis RA, Sobue G, Lawo JP, Mielke O, Cornblath DR
Journal of the peripheral nervous system : JPNS. 2022
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Abstract
BACKGROUND AND AIMS Clinical trials in chronic inflammatory demyelinating polyneuropathy (CIDP) often assess efficacy using the ordinal Inflammatory Neuropathy Cause and Treatment (INCAT) disability score. Here, data from the PATH study was reanalyzed using change in Inflammatory Rasch-built Overall Disability Scale (I-RODS) to define CIDP relapse instead of INCAT. METHODS The PATH study comprised an intravenous immunoglobulin (IVIG) dependency period and an IVIG (IgPro10 [Privigen®]) restabilization period; subjects were then randomized to weekly maintenance subcutaneous immunoglobulin (SCIG; IgPro20 [Hizentra®]) 0.2 g/kg or 0.4 g/kg or placebo for 24 weeks. CIDP relapse was defined as ≥1-point deterioration in adjusted INCAT, with a primary endpoint of relapse or withdrawal rates. This retrospective exploratory analysis redefined relapse using I-RODS via three different cut-off methods: an individual variability method, fixed cut-off of ≥8-point deterioration on I-RODS centile score or ≥4-point deterioration on I-RODS raw score. RESULTS Relapse or withdrawal rates were 47% for placebo, 34% for 0.2 g/kg IgPro20 and 19% for 0.4 g/kg IgPro20 using the raw score; 40%, 28% and 15%, respectively using the centile score, and 49%, 40% and 27%, respectively using the individual variability method. INTERPRETATION IgPro20 was shown to be efficacious as a maintenance therapy for CIDP when relapse was defined using I-RODS. A stable response pattern was shown for I-RODS across various applied cut-offs, indicating that any could be used in future clinical trials.
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Pharmacometric Analysis Linking Immunoglobulin Exposure to Clinical Efficacy Outcomes in Chronic Inflammatory Demyelinating Polyneuropathy
Tortorici MA, Yuraszeck T, Cornblath D, Bril V, Hartung HP, Sobue G, Lewis RA, Merkies ISJ, Lawo JP, Praus M, et al
CPT: pharmacometrics & systems pharmacology. 2021
Abstract
The two main objectives of this analysis were to (i) characterise the relationship between immunoglobulin (Ig) exposure and chronic inflammatory demyelinating polyneuropathy (CIDP) disease severity using data from 171 patients with CIDP who received either subcutaneous Ig (IgPro20; Hizentra®) or placebo (PATH study), and to (ii) simulate and compare exposure coverage with various dosing approaches considering weekly dosing to be the reference dose. IgG PK parameters including those from a previous population PK model were used to predict individual IgG profile and exposure metrics. Treatment-related changes in inflammatory neuropathy cause and treatment (INCAT) scores were best described by an E(max) model as a function of ΔIgG (total serum IgG at INCAT score assessment minus baseline IgG levels before intravenous Ig restabilisation). Simulations indicate that flexible dosing from daily to biweekly (every other week) provide an exposure coverage equivalent to that of a weekly Ig dose.
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Electrophysiological predictors of response to subcutaneous immunoglobulin therapy in chronic inflammatory demyelinating polyneuropathy
Alcantara M, Hartung HP, Lawo JP, Durn BL, Mielke O, Bril V
Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology. 2021;132(9):2184-2190
Abstract
OBJECTIVE To assess axonal function prior to subcutaneous immunoglobulin (SCIG) therapy or placebo in relation to relapse in chronic inflammatory demyelinating polyneuropathy (CIDP) to determine whether axonal damage can predict therapy response. METHODS Relapse rates in patients from the Polyneuropathy and Treatment with Hizentra (PATH) study, where patients were treated with placebo or SCIG (IgPro20), were analyzed by baseline (post-intravenous immunoglobulin stabilization) axonal damage (≤1 mV peroneal compound muscle action potential) status. RESULTS In patients with non-axonal damage, relapses were significantly higher with placebo (73.0%) than IgPro20 (0.2 g/kg: 39.1%, 0.4 g/kg: 19.2%). In patients with axonal damage, IgPro20 had no effect on relapse (placebo: 25.0%, IgPro20: 0.2 g/kg: 30.0%, 0.4 g/kg: 19.4%). Patients with axonal damage relapsed significantly less on placebo versus non-axonal damage, but they also demonstrated higher baseline disability. CONCLUSION Axonal damage may correspond to relapse upon treatment withdrawal; patients with axonal damage relapse less, possibly reflecting poor response to immunoglobulin therapy, while non-axonal damage patients may experience more relapse, perhaps indicating better treatment response. SIGNIFICANCE In CIDP patients with axonal loss, immunoglobulin therapy may not be as effective. Assessing axonal damage could help guide therapy, with immunoglobulins ideally used before substantial axonal damage arises.
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Electrophysiological testing in chronic inflammatory demyelinating polyneuropathy patients treated with subcutaneous immunoglobulin: The Polyneuropathy And Treatment with Hizentra (PATH) study
Bril V, Hartung HP, Lawo JP, Durn BL, Mielke O
Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology. 2020
Abstract
OBJECTIVE To assess electrophysiology parameters that can reflect patients' clinical status and show changes in nerve function with treatment, in a study of subcutaneous immunoglobulin in chronic inflammatory demyelinating polyneuropathy. METHODS Nerve conduction studies (latency, conduction velocity, conduction block and compound muscle action potential [CMAP] on upper limb median, ulnar, and lower limb peroneal motor nerves) were conducted in the placebo-controlled PATH (Polyneuropathy And Treatment with Hizentra) study of two doses of maintenance subcutaneous immunoglobulin (SCIG) IgPro20 in CIDP. RESULTS Averaged proximal latency substantially increased with placebo (+1.1 ms) indicating electrophysiologic deterioration but remained stable with IgPro20 (0.2 g/kg bodyweight [bw]: +0.1 ms; 0.4 g/kg bw: -0.1 ms). Distal latencies were also more prolonged with placebo versus IgPro20. Averaged motor nerve conduction velocity substantially decreased with placebo (-1.6 m/s) versus increasing in both IgPro20 groups (+0.2 m/s and +1.0 m/s, respectively). Conduction block and CMAP amplitudes did not change substantially. CONCLUSION These findings support the effectiveness of maintenance IgPro20, as nerve function changed in the direction of increasing nerve dysfunction with placebo but remained stable with ongoing IgPro20 therapy. SIGNIFICANCE Electrophysiology testing can support assessment of clinical status in CIDP to determine treatment efficacy.
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Placebo Effect in Chronic Inflammatory Demyelinating Polyneuropathy: The PATH study and a systematic review
Lewis RA, Cornblath DR, Hartung HP, Sobue G, Lawo JP, Mielke O, Durn BL, Bril V, Merkies ISJ, Bassett P, et al
J Peripher Nerv Syst. 2020
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Abstract
Background and Aims The 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%. Interpretation 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. This article is protected by copyright. All rights reserved.
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Patient-reported outcomes with subcutaneous immunoglobulin in chronic inflammatory demyelinating polyneuropathy: the PATH Study
Hartung HP, Mallick R, Bril V, Lewis RA, Sobue G, Lawo JP, Mielke O, Durn BL, Cornblath DR, Merkies ISJ, et al
European journal of neurology. 2019
Abstract
BACKGROUND Chronic inflammatory demyelinating polyneuropathy (CIDP) causes weakness which adversely impacts function and quality of life (QOL). CIDP often requires long-term management with intravenous or subcutaneous immunoglobulin. The Polyneuropathy and Treatment with Hizentra((R)) (PATH) study showed subcutaneous immunoglobulin (SCIG) was efficacious in CIDP maintenance. Here, we assess patient-reported outcomes in patients on SCIG. METHODS Subjects stabilised on IVIG were randomly allocated to receive weekly 0.2 g/kg or 0.4 g/kg bodyweight of 20% SCIG (IgPro20) or placebo. Overall QOL/health status was assessed using the EuroQoL 5-Dimension Questionnaire (EQ-5D) health profile and visual analog scale (VAS), treatment satisfaction with the Treatment Satisfaction Questionnaire for Medicine (TSQM), and work-related impact with the Work Productivity and Activity Impairment Questionnaire for General Health (WPAI-GH). EQ-5D health profile was assessed in terms of the percentage of subjects maintained or improved at Week 25 of SCIG therapy on each of the EQ-5D domains versus baseline after IVIG stabilisation. TSQM and WPAI-GH were assessed by median score changes from baseline to Week 25. RESULTS 172 subjects were randomised to placebo (n=57), 0.2 g/kg IgPro20 (n=57) and 0.4 g/kg IgPro20 (n=58). Significantly higher proportions of IgPro20-treated subjects improved/maintained their health status on the EQ-5D usual activities dimension, and in additional dimensions (mobility and pain/discomfort) in sensitivity analyses. TSQM and WPAI-GH scores were more stable with IgPro20 treatment compared with placebo. CONCLUSIONS IgPro20 maintained, or improved, QOL in most subjects with CIDP, consistent with the PATH study findings that both IgPro20 doses were efficacious in maintaining CIDP. This article is protected by copyright. All rights reserved.
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Efficacy and safety of IVIG in CIDP: combined data of the PRIMA and PATH studies
Merkies ISJ, van Schaik IN, Leger JM, Bril V, van Geloven N, Hartung HP, Lewis RA, Sobue G, Lawo JP, Durn BL, et al
Journal of the peripheral nervous system : JPNS. 2019
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Abstract
INTRODUCTION Intravenous immunoglobulin (IVIG) is a potential therapy for chronic inflammatory demyelinating polyneuropathy (CIDP). METHODS To investigate the efficacy and safety of the IVIG IgPro10 (Privigen(R)) for treatment of CIDP, results from PRIMA, a prospective, open-label, single-arm study of IVIG in Ig-naive or IVIG-pretreated subjects (NCT01184846, n=28) and PATH, a double-blind, randomized study including an open-label, single-arm IVIG phase in IVIG-pretreated subjects (NCT01545076 IVIG restabilization phase, n=207) were analyzed separately and together (n=235). Efficacy assessments included change in adjusted Inflammatory Neuropathy Cause and Treatment (INCAT) score, grip strength and Medical Research Council (MRC) sum score. Adverse drug reactions (ADRs) and ADRs/infusion were recorded. RESULTS Adjusted INCAT response rate was 60.7% in all PRIMA subjects at Week 25 (76.9% in IVIG-pre-treated subjects) and 72.9% in PATH. In the pooled cohort (n = 235), INCAT response rate was 71.9%, median time to INCAT improvement was 4.3 weeks. No clear demographic differences were noticed between early (responding before Week 7, n = 148) and late responders (n = 21). In the pooled cohort median change from baseline to last observation was -1.0 (IQR -2.0; 0.0) points for INCAT score; +8.0 (0.0; 20.0) kPa for maximum grip strength; +3.0 (1.0; 7.0) points for MRC sum score. In the pooled cohort, 271 adverse drug reactions (ADRs) were reported in 105 subjects (44.7%), a rate of 0.144 ADRs per infusion. CONCLUSIONS This analysis confirms the efficacy and safety of IgPro10, a recently FDA-approved IVIG for CIDP, in a population of mainly pre-treated subjects with CIDP. This article is protected by copyright. All rights reserved.
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Randomized, controlled crossover study of IVIg for demyelinating polyneuropathy and diabetes
Breiner A, Barnett Tapia C, Lovblom LE, Perkins BA, Katzberg HD, Bril V
Neurology(R) neuroimmunology & neuroinflammation. 2019;6(5)
Abstract
OBJECTIVE To determine whether IV immunoglobulin (IVIg) is more effective than placebo at reducing disability in patients with diabetes and demyelinating polyneuropathy features. METHODS This is a double-blinded, single-center, randomized, controlled crossover trial of IVIg treatment vs placebo. The primary outcome measure was the mean change in Overall Neuropathy Limitation Scale (ONLS) scores during the IVIg phasecompared with the placebo phase. Secondary outcomes include changes in the Rasch-built Overall Disability Scale, Medical Research Council sum scores, grip strength, electrophysiologic measurements, quality of life, and adverse effects. RESULTS Twenty-five subjects were recruited between March 2015 and April 2017. The mean change in ONLS scores was -0.2 points during the IVIg phase and 0.0 points during the placebo phase (p = 0.23). Secondary outcomes did not show significant differences between IVIg and placebo. CONCLUSIONS IVIg did not reduce disability, improve strength, or quality of life in patients with demyelinating polyneuropathy features and diabetes after 3 months of treatment in comparison with placebo. Therefore, careful consideration of the primary diagnosis is required before immunomodulatory therapy. CLASSIFICATION OF EVIDENCE This study provides Class I evidence that for patients with diabetes and demyelinating polyneuropathy features, IVIg did not significantly reduce disability.
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Subcutaneous immunoglobulin for maintenance treatment in chronic inflammatory demyelinating polyneuropathy – A multicenter, randomized, double-blind, placebo-controlled trial: The PATH Study
van Schaik IN, Bril V, van Geloven N, Hartung HP, Lewis RA, Sobue G, Lawo JP, Mielke O, Durn BL, Cornblath DR, et al
Muscle & Nerve. 2017;56 Suppl 1:S1-S16
Abstract
INTRODUCTION Patients with chronic inflammatory demyelinating polyneuropathy (CIDP) often require long-term intravenous immunoglobulin (IVIG) maintenance therapy. Subcutaneous immunoglobulin (SCIG) offers an alternative administration option with anticipated improvements in patient quality of life, convenience, and flexibility. OBJECTIVES To evaluate IgPro20 (SCIG) as a maintenance treatment in CIDP. METHODS A randomized, double-blind trial in CIDP patients (n=172) investigated 0.2 and 0.4 g/kg weekly doses of IgPro20 versus placebo. The primary outcome was percentage of patients with CIDP relapse/withdrawal during 24-weeks of treatment determined by Inflammatory Neuropathy Cause and Treatment score. Secondary endpoints included grip strength and patient satisfaction. RESULTS Both IgPro20 doses significantly reduced rate of CIDP relapse/withdrawal versus placebo. Grip strength remained stable with Hizentra(R), but deteriorated with placebo. Most subjects preferred SCIG over IVIG. Local reactions, reported in 33% of IgPro20-treated patients, were mild or moderate in intensity. CONCLUSION IgPro20 is efficacious and well-tolerated as maintenance treatment in CIDP. This article is protected by copyright. All rights reserved.