Abstract

Intravenous immunoglobulin treatment for chronic inflammatory demyelinating polyneuropathy usually starts with a 2.0 g/kg induction dose followed by 1.0 g/kg maintenance doses every 3 weeks. No dose-ranging studies with intravenous immunoglobulin maintenance therapy have been published. The Progress in Chronic Inflammatory Demyelinating polyneuropathy (ProCID) study was a prospective, double-blind, randomised, parallel-group, multicentre, phase III study investigating the efficacy and safety of 10% liquid intravenous immunoglobulin (panzyga®) in patients with active chronic inflammatory demyelinating polyneuropathy. Patients were randomised 1:2:1 to receive the standard intravenous immunoglobulin induction dose and then either 0.5, 1.0 or 2.0 g/kg maintenance doses every 3 weeks. The primary endpoint was the response rate in the 1.0 g/kg group, defined as an improvement ≥ 1 point in adjusted Inflammatory Neuropathy Cause and Treatment score at Week 6 versus baseline and maintained at Week 24. Secondary endpoints included dose response and safety. This trial was registered with EudraCT (Number 2015-005443-14) and clinicaltrials.gov (NCT02638207). Between August 2017 and September 2019, the study enrolled 142 patients. All 142 were included in the safety analyses. As no post infusion data were available for three patients, 139 were included in the efficacy analyses, of whom 121 were previously on corticosteroids. The response rate was 80% (55/69 patients) (95% confidence interval: 69-88%) in the 1.0 g/kg group, 65% (22/34; confidence interval: 48-79%) in the 0.5 g/kg group, and 92% (33/36; confidence interval 78-97%) in the 2.0 g/kg group. While the proportion of responders was higher with higher maintenance doses, logistic regression analysis showed that the effect on response rate was driven by a significant difference between the 0.5 and 2.0 g/kg groups, whereas the response rates in the 0.5 and 2.0 g/kg groups did not differ significantly from the 1.0 g/kg group. Fifty-six percent of all patients had an adjusted Inflammatory Neuropathy Cause and Treatment score improvement 3 weeks after the induction dose alone. Treatment-related adverse events were reported in 16 (45.7%), 32 (46.4%) and 20 (52.6%) patients in the 0.5, 1.0 and 2.0 g/kg dose groups, respectively. The most common adverse reaction was headache. There were no treatment-related deaths. Intravenous immunoglobulin 1.0 g/kg was efficacious and well tolerated as maintenance treatment for patients with chronic inflammatory demyelinating polyneuropathy. Further studies of different maintenance doses of intravenous immunoglobulin in chronic inflammatory demyelinating polyneuropathy are warranted.

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.

Abstract

Intravenous immunoglobulins (IVIg) are an efficacious treatment for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Biomarkers for disease activity are lacking, making the need for ongoing treatment difficult to assess, leading to potential overtreatment, and high health care costs. Our objective was to determine whether IVIg withdrawal is non-inferior to continuing IVIg treatment and to determine how often patients are overtreated. We performed a randomized, double-blind, IVIg-controlled non-inferiority trial in seven centers in the Netherlands. Adults with clinically stable CIDP using IVIg maintenance treatment for at least 6 months were included. Patients received either IVIg withdrawal (placebo) as investigational treatment or continuation of IVIg treatment (control). The primary outcome was the mean change in logit scores from baseline to 24-weeks follow-up on the patient-reported Inflammatory Rasch-Overall Disability Scale (iRODS). The non-inferiority margin was predefined as between-group difference in mean change scores of -0.65. Patients who deteriorated could reach a relapse endpoint according to predefined criteria. Patients with a relapse endpoint after IVIg withdrawal entered a restabilization phase. All patients from the withdrawal group who remained stable, were included in an open-label extension phase of 52 weeks. We included 60 patients of whom 29 were randomised to IVIg withdrawal and 31 to continuation of treatment. The mean age was 58 years (SD 14.7) and 67% was male. The between-group difference in mean change iRODS scores was -0.47 (95%CI -1.24 to 0.31), indicating that non-inferiority of IVIg withdrawal could not be established. In the IVIg withdrawal group, 41% remained stable for 24 weeks, compared to 58% in the IVIg continuation group (-17%; 95%CI -39 to 8). Of the IVIg withdrawal group, 28% remained stable at end of the extension phase. Of the patients in the restabilization phase, 94% restabilized within 12 weeks. In conclusion, it remains inconclusive whether IVIg withdrawal is non-inferior compared to continuing treatment, partly due to larger than expected confidence intervals leading to an underpowered study. Despite these limitations, a considerable proportion of patients could stop treatment and almost all patients who relapsed were restabilized quickly. Unexpectedly, a high proportion of IVIg treated patients experienced a relapse endpoint, emphasizing the need for more objective measures for disease activity in future trials, as the patient reported outcome measures might not have been able to identify true relapses reliably. Overall, this study suggests that withdrawal attempts are safe and should be performed regularly in clinically stable patients.

Abstract

BACKGROUND The purpose of this study was to assess the five-year treatment effects of a short course of intravenous immunoglobulin (IVIG) in subjects with mild cognitive impairment (MCI) due to Alzheimer disease (AD). METHODS Fifty subjects 50 to 84 years of age with MCI due to AD were administered 0.4 g/kg 10% IVIG or 0.9% saline every two weeks x five doses in a randomized double-blinded design as part of a two-year study. Twenty-seven subjects completed an additional three-year extension study. MRI brain imaging, cognitive testing, and conversion to dementia were assessed annually. Participants were stratified into early MCI (E-MCI) and late MCI (L-MCI). The primary endpoint was brain atrophy measured as annualized percent change in ventricular volume (APCV) annually for five years. ANOVA was used to compare annualized percent change in ventricular volume from baseline between the groups adjusting for MCI status (E-MCI, L-MCI). RESULTS Differences in brain atrophy between the groups, which were statistically significant after one year, were no longer significant after five years. IVIG-treated L-MCI subjects did demonstrate a delay in conversion to dementia of 21.4 weeks. CONCLUSION An eight-week course of IVIG totaling 2 g/kg in MCI is safe but is not sufficient to sustain an initial reduction in brain atrophy or a temporary delay in conversion to dementia at five years. Other dosing strategies of IVIG in the early stages of AD should be investigated to assess more sustainable disease-modifying effects. Trial registration ClinicalTrials.gov NCT01300728. Registered 23 February 2011.

Abstract

OBJECTIVE This is the first double-blind, randomized, controlled trial evaluating the efficacy and safety of intravenous immunoglobulin (IVIg) versus placebo in patients with idiopathic small fiber neuropathy (I-SFN). METHODS Between July 2016 and November 2018, 60 Dutch patients with skin-biopsy proven idiopathic SFN randomly received a starting dose of IVIg (2 g/kg body weight) or matching placebo (0.9% saline). Subsequently, 3 additional infusions of IVIg (1 g/kg) or placebo were administered at 3-weekly intervals. The primary outcome was a 1-point change in Pain Intensity Numerical Rating Scale (PI-NRS) at 12 weeks compared to baseline. RESULTS Thirty patients received IVIg, and 30 received placebo. In both groups, 29 patients completed the trial. In 40% of patients receiving IVIg, the mean average pain was decreased with at least 1 point, compared to 30% of the patients receiving placebo (p-value 0.588, OR 1.56, 95%CI 0.53-4.53). No significant differences were found on any of the other pre-specified outcomes including general wellbeing, autonomic symptoms, and overall functioning and disability. CONCLUSIONS This RCT showed that IVIg treatment had no significant effect on pain in patients with painful idiopathic SFN.

Abstract

Iron deficiency anemia (IDA) is common among children with cerebral palsy (CP), and studies on the efficacy of lactoferrin (Lf) in the treatment of IDA are limited. This study aimed to compare the efficacy of Lf with that of iron hydroxide polymaltose complex (IPC) in the treatment of IDA in children with CP. This randomized controlled study, conducted at Alexandria University Children's Hospital, enrolled 70 children aged 1-10 years with CP and IDA; 35 children randomly received IPC, whereas the other 35 received Lf. Four children withdrew from the study; thus, only 66 children were analyzed (32 in the IPC group and 34 in the Lf group). At baseline, the hemoglobin level and other blood parameters were similar between the two intervention groups. After four weeks of treatment, both the IPC and Lf groups showed significant improvements in hemoglobin (Hb), serum ferritin (SF), serum iron, total iron-binding capacity, mean corpuscular volume, and mean corpuscular hemoglobin from baseline. Upon comparing the two treatment groups, adjusted mean Hb and SF changes in the Lf group were significantly higher than that of the IPC group (p =0.001and p= 0.033, respectively), and constipation was less likely to occur in the Lf group than the IPC group (p = 0.049 ).Conclusion: Lactoferrin is effective and superior to IPC as an oral iron replacement therapy in children with CP and IDA, as it has fewer side effects. What is Known: • Lactoferrin (LF) is a natural glycoprotein capable of treating iron deficiency anemia (IDA). • Studies on the efficacy of Lf in the treatment of IDA in children with cerebral palsy (CP) are limited. What is New? • This trial compared the efficacy of Lf and iron hydroxide polymaltose complex (IPC) as treatments of IDA in children with CP. • Lf is effective and even better than IPC as a treatment of IDA in children with CP, as it has fewer side effects.

Abstract

INTRODUCTION This systematic review provides supporting evidence for the accompanying clinical practice guideline on the treatment of central disorders of hypersomnolence in adults and children. The review focuses on prescription medications with U.S. Food & Drug Administration approval and nonpharmacologic interventions studied for the treatment of symptoms caused by central disorders of hypersomnolence. METHODS The American Academy of Sleep Medicine commissioned a task force of experts in sleep medicine to perform a systematic review. Randomized controlled trials and observational studies addressing pharmacological and nonpharmacological interventions for central disorders of hypersomnolence were identified. Statistical analyses were performed to determine the clinical significance of all outcomes. Finally, the Grading of Recommendations Assessment, Development and Evaluation (GRADE) process was used to assess the evidence for the purpose of making specific treatment recommendations. RESULTS The literature search identified 678 studies; 144 met the inclusion criteria and 108 provided data suitable for statistical analyses. Evidence for the following interventions is presented: armodafinil, clarithromycin, clomipramine, dextroamphetamine, flumazenil, intravenous immune globulin (IVIG), light therapy, lithium, l-carnitine, liraglutide, methylphenidate, methylprednisolone, modafinil, naps, pitolisant, selegiline, sodium oxybate, solriamfetol, and triazolam. The task force provided a detailed summary of the evidence along with the quality of evidence, the balance of benefits and harms, patient values and preferences, and resource use considerations. CITATION Maski K, Trotti LM, Kotagal S, et al. Treatment of central disorders of hypersomnolence: an American Academy of Sleep Medicine systematic review, meta-analysis, and GRADE assessment. J Clin Sleep Med. 2021;17(9):1895-1945.

Abstract

BACKGROUND Treatment with one standard dose (2 g/kg) of intravenous immunoglobulin is insufficient in a proportion of patients with severe Guillain-Barré syndrome. Worldwide, around 25% of patients severely affected with the syndrome are given a second intravenous immunoglobulin dose (SID), although it has not been proven effective. We aimed to investigate whether a SID is effective in patients with Guillain-Barré syndrome with a predicted poor outcome. METHODS In this randomised, double-blind, placebo-controlled trial (SID-GBS), we included patients (≥12 years) with Guillain-Barré syndrome admitted to one of 59 participating hospitals in the Netherlands. Patients were included on the first day of standard intravenous immunoglobulin treatment (2 g/kg over 5 days). Only patients with a poor prognosis (score of ≥6) according to the modified Erasmus Guillain-Barré syndrome Outcome Score were randomly assigned, via block randomisation stratified by centre, to SID (2 g/kg over 5 days) or to placebo, 7-9 days after inclusion. Patients, outcome adjudicators, monitors, and the steering committee were masked to treatment allocation. The primary outcome measure was the Guillain-Barré syndrome disability score 4 weeks after inclusion. All patients in whom allocated trial medication was started were included in the modified intention-to-treat analysis. This study is registered with the Netherlands Trial Register, NTR 2224/NL2107. FINDINGS Between Feb 16, 2010, and June 5, 2018, 327 of 339 patients assessed for eligibility were included. 112 had a poor prognosis. Of those, 93 patients with a poor prognosis were included in the modified intention-to-treat analysis: 49 (53%) received SID and 44 (47%) received placebo. The adjusted common odds ratio for improvement on the Guillain-Barré syndrome disability score at 4 weeks was 1·4 (95% CI 0·6-3·3; p=0·45). Patients given SID had more serious adverse events (35% vs 16% in the first 30 days), including thromboembolic events, than those in the placebo group. Four patients died in the intervention group (13-24 weeks after randomisation). INTERPRETATION Our study does not provide evidence that patients with Guillain-Barré syndrome with a poor prognosis benefit from a second intravenous immunoglobulin course; moreover, it entails a risk of serious adverse events. Therefore, a second intravenous immunoglobulin course should not be considered for treatment of Guillain-Barre syndrome because of a poor prognosis. The results indicate the need for treatment trials with other immune modulators in patients severely affected by Guillain-Barré syndrome. FUNDING Prinses Beatrix Spierfonds and Sanquin Plasma Products.

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.

Abstract

BACKGROUND Pressure ulcer is one of the common complications occurring in spinal cord injury (SCI) patients. Platelet-rich plasma (PRP) has been found useful in the treatment of pressure ulcers in few studies. The purpose of this study was to evaluate the role of PRP in pressure ulcer healing in comparison to hydrogel dressing in SCI patients. METHODS In this randomized interventional study, 52 patients of SCI having pressure ulcers of grade III/IV were randomized into two groups of 26 each. In group A patients, hydrogel dressing was done while freshly prepared PRP was used in patients of group B. Pressure ulcers were evaluated at baseline and after three weeks and six weeks in terms of ulcer surface area, volume, Pressure Ulcer Scale for Healing (PUSH) score, histopathology, and ulcer healing parameters. Data were collected and quantitative variables were compared using unpaired t-test or Mann-Whitney test between the two groups and qualitative variables were compared using the chi-square test or Fisher's exact test. A p-value of <0.05 was considered statistically significant. RESULTS Baseline characteristics were comparable in both groups. There was a significant improvement in ulcers in terms of surface area, volume, and PUSH score in both the groups but it was comparable (p-value >0.05). There was a significant improvement in the PRP group as compared to the other group in terms of epithelization, granulation, and neovascularization at three and six-week follow-up. CONCLUSIONS This study suggests that PRP is a possible and better alternative to conventional dressing methods for the treatment of pressure ulcers.