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Intravenous immunoglobulin for maintenance treatment of chronic inflammatory demyelinating polyneuropathy: a multicentre, open-label, 52-week phase III trial.

ABSTRACT: OBJECTIVE:Short-term efficacy of induction therapy with intravenous immunoglobulin (Ig) in patients with chronic inflammatory demyelinating polyneuropathy (CIDP) is well established. However, data of previous studies on maintenance therapy were limited up to 24-week treatment period. We aimed to investigate the efficacy and safety of longer-term intravenous Ig therapy for 52 weeks. METHODS:This study was an open-label phase 3 clinical trial conducted in 49 Japanese tertiary centres. 49 patients with CIDP who fulfilled diagnostic criteria were included. After an induction intravenous Ig therapy (0.4?g/kg/day for five consecutive days), maintenance dose intravenous Ig (1.0?g/kg) was given every 3 weeks for up to 52 weeks. The primary outcome measures were the responder rate at week 28 and relapse rate at week 52. The response and relapse were defined with the adjusted Inflammatory Neuropathy Cause and Treatment scale. RESULTS:At week 28, the responder rate was 77.6% (38/49 patients; 95% CI 63% to 88%), and the 38 responders continued the maintenance therapy. At week 52, 4 of the 38 (10.5%) had a relapse (95%?CI 3% to 25%). During 52 weeks, 34 (69.4%) of the 49 enrolled patients had a maintained improvement. Adverse events were reported in 94% of the patients; two patients (66-year-old and 76-year-old men with hypertension or diabetes) developed cerebral infarction (lacunar infarct with good recovery), and the other adverse effects were mild and resolved by the end of the study period. CONCLUSIONS:Maintenance treatment with 1.0 g/kg intravenous Ig every 3 weeks is an efficacious therapy for patients with CIDP, and approximately 70% of them had a sustained remission for 52 weeks. Thrombotic complications should be carefully monitored, particularly in elderly patients with vascular risk factors. TRIAL REGISTRATION NUMBER:ClinicalTrials.gov (NCT01824251).

SUBMITTER: Kuwabara S

PROVIDER: S-EPMC5629934 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Intravenous immunoglobulin for maintenance treatment of chronic inflammatory demyelinating polyneuropathy: a multicentre, open-label, 52-week phase III trial.

Kuwabara Satoshi S Mori Masahiro M Misawa Sonoko S Suzuki Miki M Nishiyama Kazutoshi K Mutoh Tatsuro T Doi Shizuki S Kokubun Norito N Kamijo Mikiko M Yoshikawa Hiroo H Abe Koji K Nishida Yoshihiko Y Okada Kazumasa K Sekiguchi Kenji K Sakamoto Ko K Kusunoki Susumu S Sobue Gen G Kaji Ryuji R

Journal of neurology, neurosurgery, and psychiatry 20170802 10

<h4>Objective</h4>Short-term efficacy of induction therapy with intravenous immunoglobulin (Ig) in patients with chronic inflammatory demyelinating polyneuropathy (CIDP) is well established. However, data of previous studies on maintenance therapy were limited up to 24-week treatment period. We aimed to investigate the efficacy and safety of longer-term intravenous Ig therapy for 52 weeks.<h4>Methods</h4>This study was an open-label phase 3 clinical trial conducted in 49 Japanese tertiary centre ...[more]

PMID: 28768822

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Project description:BACKGROUND:The long-acting injectable antipsychotic aripiprazole once-monthly 400 mg (AOM 400) was recently approved for maintenance treatment of bipolar I disorder (BP-I). The purpose of this study was to evaluate the safety, tolerability, and efficacy of AOM 400 as long-term maintenance treatment for BP-I. METHODS:This open-label multicenter study evaluated the effectiveness of AOM 400 as maintenance treatment for BP-I by assessing safety and tolerability (primary objective) and efficacy (secondary objective). The study enrolled AOM 400-naive ("de novo") patients as well as AOM 400-experienced ("rollover") patients with BP-I from a lead-in randomized, placebo-controlled clinical trial that demonstrated the efficacy of AOM 400 in the maintenance treatment of BP-I (Calabrese et al. in J Clin Psychiatry 78:324-331, 2017). Safety variables included frequency and severity of treatment-emergent adverse events (TEAEs) and TEAEs resulting in study discontinuation. Efficacy was assessed by the proportion of patients maintaining stability throughout the maintenance phase, as well as mean changes from baseline in Young Mania Rating Scale (YMRS), Montgomery-Asberg Depression Rating Scale, and Clinical Global Impressions for Bipolar Disorder-Severity of Illness Scale (CGI-BP-S) total scores. Patient acceptability and tolerability of treatment was assessed using the Patient Satisfaction with Medication Questionnaire-Modified. RESULTS:Of 464 patients entering the maintenance phase, 379 (82%) were de novo and 85 (18%) were rollover. TEAEs were more common in de novo than rollover patients. The overall discontinuation rate due to TEAEs was 10.3% (48/464). Improvements in YMRS and CGI-BP-S total scores were maintained during the study, and the vast majority of both de novo (87.0%) and rollover (97.6%) patients maintained stability through their last visit. Overall, the need for rescue medication during the maintenance phase was minimal (<?10% of patients). Patient satisfaction levels were high, with both de novo and rollover patients rating the side effect burden of AOM 400 as greatly improved relative to previous medications. CONCLUSION:AOM 400 was safe, effective, and well tolerated by both de novo and AOM 400-experienced patients with BP-I for long-term maintenance treatment. Trial registration ClinicalTrials.gov, NCT01710709.

Project description:BackgroundChronic inflammatory demyelinating polyneuropathy (CIDP) is a rare, progressive autoimmune disease causing peripheral nervous system dysfunction. Guidelines recommend immunoglobulin (IG) therapy as an immunomodulatory agent in CIDP. Drawbacks and unmet needs with intravenous immunoglobulin (IVIG) include adverse effects and wear-off effects, along with the burden of administration based on site of care. Subcutaneous administration of Hizentra, a subcutaneous immunoglobulin (SCIG) reduces patient burden by allowing self-administration outside the hospital setting and has fewer adverse events (AEs).ObjectiveWe aimed to compare the expected cost of treatment and the budget impact of Hizentra compared with IVIG for maintenance treatment of CIDP in the United States.MethodsA decision tree model was developed to estimate the expected budget impact of maintenance treatment with Hizentra for US stakeholders. The model adopts primarily a US integrated delivery network perspective and, secondarily, a commercial perspective over a 1-year time horizon. Pharmacy costs were based on a payment mix of average sales price (73%), wholesale acquisition cost (2%), and average wholesale price (25%). Costs in the model reflect 2022 US dollars. In accordance with the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) guidelines and recommendations for budget impact modeling, no discounting was performed. The PATH clinical study of Hizentra maintenance in CIDP was used to determine clinical inputs for relapse rates at initial assessment (24 weeks) and at 52 weeks for Hizentra. The ICE clinical study of Gamunex maintenance in CIDP was the basis of relapse rates for Gamunex (and other IVIGs). Literature-based estimates were obtained for infusion costs by site of care, costs of IVIG infusion-related complications, and significant IVIG AE rates. Hizentra AE rates from the US Hizentra prescribing information were assessed but were not included in the model as the AEs in CIDP were mild, easily treated, and self-limited. Sensitivity analyses and scenario analyses were conducted to evaluate variations from the base case.ResultsThe model showed that a Hizentra starting dose of 0.2 g/kg is expected to result in annual cost savings of US$32,447 per patient compared with IVIG. For a hypothetical 25-million-member plan, the budget impact of a 10% market share shift from IVIG to Hizentra is expected to result in savings of US$2,296,235.ConclusionThis analysis projects that Hizentra is likely associated with favorable economic benefit compared with IVIG in managing CIDP.

Project description:Background and purposeHigh peak serum immunoglobulin G (IgG) levels may not be needed for maintenance intravenous immunoglobulin (IVIg) treatment in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and such high levels may cause side effects. More frequent lower dosing may lead to more stable IgG levels and higher trough levels, which might improve efficacy. The aim of this trial is to investigate whether high frequent low dosage IVIg treatment is more effective than low frequent high dosage IVIg treatment.MethodsIn this randomized placebo-controlled crossover trial, we included patients with CIDP proven to be IVIg-dependent and receiving an individually established stable dose and interval of IVIg maintenance treatment. In the control arm, patients received their individual IVIg dose and interval followed by a placebo infusion at half the interval. In the intervention arm, patients received half their individual dose at half the interval. After a wash-out phase patients crossed over. The primary outcome measure was handgrip strength (assessed using a Martin Vigorimeter). Secondary outcome indicators were health-related quality of life (36-item Short-Form Health Survey), disability (Inflammatory Rasch-built Overall Disability Scale), fatigue (Rasch-built Fatigue Severity Scale) and side effects.ResultsTwenty-five patients were included and were treated at baseline with individually adjusted dosages of IVIg ranging from 20 to 80 g and intervals ranging from 14 to 35 days. Three participants did not complete the trial; the main analysis was therefore based on the 22 patients completing both treatment periods. There was no significant difference in handgrip strength change from baseline between the two treatment regimens (coefficient -2.71, 95% CI -5.4, 0.01). Furthermore, there were no significant differences in any of the secondary outcomes or side effects.ConclusionsMore frequent lower dosing does not further improve the efficacy of IVIg in stable IVIg-dependent CIDP and does not result in fewer side effects.

Project description:BackgroundSubcutaneous administration of Ig (SCIg) has gained popularity as an alternative route of administration but has never been rigorously examined in chronic inflammatory demyelinating polyneuropathy (CIDP).Methods/designThe primary objective of the PATH study (Polyneuropathy and Treatment with Hizentra) is to determine the efficacy of two different doses of SCIg IgPro20 (0.2 g/kg bw or 0.4 g/kg bw) in a 24-week maintenance treatment of CIDP in comparison to placebo. The primary efficacy endpoint will be the proportion of patients who show CIDP relapse (1-point deterioration on the adjusted Inflammatory Neuropathy Cause and Treatment (INCAT) disability score) or are withdrawn within 24 weeks after randomization for any reason. IVIg-dependent adult patients with definite or probable CIDP according to the European Federation of Neurological Societies/Peripheral Nerve Society who fulfil the inclusion and exclusion criteria will be eligible. Based on sample-size calculation and relapse assumptions in the three arms, a sample size of 58 is needed per arm (overall sample size will be 350, of which 174 will be randomized). All eligible patients will progress through three study periods: an IgG dependency period (≤12 weeks) to select those who are Ig dependent; an IVIg restabilization period (10 or 13 weeks), which will be performed using the 10 % IgPro10 product; and an SC treatment period (24 weeks, followed by a 1-week completion visit after last follow-up). Patients showing IVIg restabilization will be randomized to demonstrate the efficacy of SCIg IgPro20 maintenance treatment over placebo. After completing the study, subjects are eligible to enter a long-term, open-label, extension study of 1 year or return to their previous treatment. In case of CIDP relapse during the 24-week SC treatment period, IgPro10 rescue medication will be offered. Safety, tolerability, and patients' preference of Ig administration route will be examined.DiscussionThe PATH trial, which started in March 2012, is expected to finish at the end of 2016. The results will increase knowledge about the efficacy, safety, and tolerability of SCIg in maintenance management of CIDP patients.Trial registrationClinicalTrials.gov, NCT01545076 . Registered on 1 March 2012.

Dataset Information

Intravenous immunoglobulin for maintenance treatment of chronic inflammatory demyelinating polyneuropathy: a multicentre, open-label, 52-week phase III trial.

Publications

Intravenous immunoglobulin for maintenance treatment of chronic inflammatory demyelinating polyneuropathy: a multicentre, open-label, 52-week phase III trial.

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