Pharmacometric Analysis Linking Immunoglobulin Exposure to Clinical Efficacy Outcomes in Chronic Inflammatory Demyelinating Polyneuropathy
CPT: pharmacometrics & systems pharmacology. 2021
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.
Electrophysiological predictors of response to subcutaneous immunoglobulin therapy in chronic inflammatory demyelinating polyneuropathy
Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology. 2021;132(9):2184-2190
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.
Placebo Effect in Chronic Inflammatory Demyelinating Polyneuropathy: The PATH study and a systematic review
J Peripher Nerv Syst. 2020
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.
Electrophysiological testing in chronic inflammatory demyelinating polyneuropathy patients treated with subcutaneous immunoglobulin: The Polyneuropathy And Treatment with Hizentra (PATH) study
Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology. 2020
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.
Patient-reported outcomes with subcutaneous immunoglobulin in chronic inflammatory demyelinating polyneuropathy: the PATH Study
European journal of neurology. 2019
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.
Efficacy and safety of IVIG in CIDP: combined data of the PRIMA and PATH studies
Journal of the peripheral nervous system : JPNS. 2019
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.
Subcutaneous immunoglobulin for maintenance treatment in chronic inflammatory demyelinating polyneuropathy (PATH): a randomised, double-blind, placebo-controlled, phase 3 trial
The Lancet. Neurology. 2017;17((1):):35-46. 35
BACKGROUND Approximately two-thirds of patients with chronic inflammatory demyelinating polyneuropathy (CIDP) need long-term intravenous immunoglobulin. Subcutaneous immunoglobulin (SCIg) is an alternative option for immunoglobulin delivery, but has not previously been investigated in a large trial of CIDP. The PATH study compared relapse rates in patients given SCIg versus placebo. METHODS Between March 12, 2012, and Sept 20, 2016, we studied patients from 69 neuromuscular centres in North America, Europe, Israel, Australia, and Japan. Adults with definite or probable CIDP who responded to intravenous immunoglobulin treatment were eligible. We randomly allocated participants to 0.2 g/kg or 0.4 g/kg of a 20% SCIg solution (IgPro20) weekly versus placebo (2% human albumin solution) for maintenance treatment for 24 weeks. We did randomisation in a 1:1:1 ratio with an interactive voice and web response system with a block size of six, stratified by region (Japan or non-Japan). The primary outcome was the proportion of patients with a CIDP relapse or who were withdrawn for any other reason during 24 weeks of treatment. Patients, caregivers, and study personnel, including those assessing outcomes, were masked to treatment assignment. Analyses were done in the intention-to-treat and per-protocol sets. This trial is registered with ClinicalTrials.gov, number NCT01545076. FINDINGS In this randomised, double-blind, placebo-controlled trial, we randomly allocated 172 patients: 57 (33%) to the placebo group, 57 (33%) to the low-dose group, and 58 (34%) to the high-dose group. In the intention-to-treat set, 36 (63% [95% CI 50-74]) patients on placebo, 22 (39% [27-52]) on low-dose SCIg, and 19 (33% [22-46]) on high-dose SCIg had a relapse or were withdrawn from the study for other reasons (p=0.0007). Absolute risk reductions were 25% (95% CI 6-41) for low-dose versus placebo (p=0.007), 30% (12-46) for high-dose versus placebo (p=0.001), and 6% (-11 to 23) for high-dose versus low-dose (p=0.32). Causally related adverse events occurred in 47 (27%) patients (ten [18%] in the placebo group, 17 [30%] in the low-dose group, and 20 [34%] in the high-dose group). Six (3%) patients had 11 serious adverse events: one (2%) patient in the placebo group, three (5%) in the low-dose group, and two (3%) in the high-dose group; only one (an acute allergic skin reaction in the low-dose group) was assessed to be causally related. INTERPRETATION This study, which is to our knowledge, the largest trial of CIDP to date and the first to study two administrations of immunoglobulins and two doses, showed that both doses of SCIg IgPro20 were efficacious and well tolerated, suggesting that SCIg can be used as a maintenance treatment for CIDP. FUNDING CSL Behring.
Subcutaneous immunoglobulin for maintenance treatment in chronic inflammatory demyelinating polyneuropathy – A multicenter, randomized, double-blind, placebo-controlled trial: The PATH Study
Muscle & Nerve. 2017;56 Suppl 1:S1-S16
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.
Safety of a 4-factor prothrombin complex concentrate versus plasma for vitamin K antagonist reversal: an integrated analysis of two phase IIIb clinical trials
Academic Emergency Medicine : Official Journal of the Society for Academic Emergency Medicine. 2016;23((4):):466-75
OBJECTIVES Clinicians often need to rapidly reverse vitamin K antagonists in the setting of major hemorrhage or urgent need for surgery. Little is known about the safety profile of the traditional reversal agent, plasma, or the newly approved agent, four-factor prothrombin complex concentrate (4F-PCC), in a randomized setting. This is an integrated analysis of safety data from two clinical trials that evaluated 4F-PCC versus plasma for the treatment of patients requiring rapid vitamin K antagonist reversal for acute major bleeding or prior to an urgent surgical/invasive procedure. METHODS This descriptive analysis comprised adverse event data from two phase IIIb, randomized, controlled trials. The bleeding and surgical studies were performed across 36 and 33 sites, respectively, in nine countries, with the integrated analysis comprising 388 patients (4F-PCC: n=191; plasma: n=197) aged ≥18 years, who required vitamin K antagonist reversal due to major bleeding or prior to an urgent surgical/invasive procedure. Patients received either 4F-PCC, containing non-activated factors II, VII, IX, X and proteins C and S (Beriplex(R) /Kcentra(R) , CSL Behring), or plasma, both dosed according to baseline international normalized ratio and body weight. Patients were also to receive vitamin K1. Adverse events and serious adverse events were assessed up to Day 10 and 45, respectively. RESULTS The proportion of patients with adverse events (4F-PCC: 115/191 [60.2%]; plasma: 124/197 [62.9%]) and serious adverse events (4F-PCC: 54/191 [28.3%]; plasma: 49/197 [24.9%]) was similar between groups. The proportion of patients with thromboembolic events was also similar between groups (4F-PCC: 14/191 [7.3%]; plasma: 14/197 [7.1%]). There were 13 (6.8%) deaths in the 4F-PCC group and 13 (6.6%) in the plasma group. Fluid overload events occurred in more patients in the plasma group than the 4F-PCC group (25 [12.7%] and 9 [4.7%], respectively). CONCLUSIONS These safety data represent the largest controlled assessment of a 4F-PCC to date. For patients requiring urgent vitamin K antagonist reversal, 4F-PCC had a similar safety profile to plasma (adverse events, serious adverse events, thromboembolic events and deaths), but was associated with fewer fluid overload events. This article is protected by copyright. All rights reserved.
Increased risk of volume overload with plasma compared with four-factor prothrombin complex concentrate for urgent vitamin K antagonist reversal
BACKGROUND Plasma is commonly used for vitamin K antagonist (VKA) reversal, but observational studies suggest that it is associated with transfusion-related adverse reactions (e.g., volume overload). However, this issue has not previously been addressed in a randomized controlled trial (RCT). STUDY DESIGN AND METHODS Factors associated with volume overload were examined using data from two Phase IIIb RCTs comparing plasma with four-factor prothrombin complex concentrate (4F-PCC, Beriplex/Kcentra, CSL Behring) for urgent VKA reversal. VKA-treated patients with major bleeding (NCT00708435) or requiring an urgent surgical or invasive procedure (NCT00803101) were randomly assigned (1:1) to receive either plasma or 4F-PCC, concomitant with vitamin K. Adverse events (AEs) and serious AEs were prospectively captured up to Day 10 and 45, respectively. Volume overload predictors were evaluated on a univariate and multivariate basis. RESULTS A total of 388 patients (4F-PCC, n=191; plasma, n=197) were enrolled. Volume overload occurred in 34 (9%) patients (4F-PCC, n=9; plasma, n=25). In univariate analyses, use of plasma (vs. 4F-PCC), use of nonstudy plasma and/or platelets, race, history of congestive heart failure (CHF), and history of renal disease were associated with volume overload. In multivariate analyses, use of plasma (vs. 4F-PCC), history of CHF, and history of renal disease were independent volume overload predictors. In an additional analysis restricted to volume overload events recorded up to Day 7, only use of plasma (vs. 4F-PCC) was an independent volume overload predictor. CONCLUSIONS After adjusting for other potential risk factors, plasma use was independently associated with a greater risk of volume overload than 4F-PCC in patients requiring urgent VKA reversal.Copyright © 2015 AABB.