Background Three small trials have suggested effects of intravenous immunoglobulins (IVIG) on biomarkers and symptoms of mild-to-moderate Alzheimer’s disease (AD). We explored the safety, the effective dose, and the infusion interval for Octagam®10% in this patients’ group. Methods The study was a 24-week multicentre, double-blind, placebo-controlled phase II trial with 8 treatment arms at 7 sites in the USA and 5 sites in Germany. Participants aged 50–85 years were randomised (using a computer-generated randomisation sequence) to either 4 weekly infusions (n=22) (0.2 g/0.5 g/0.8 g/kg body weight), 2 weekly infusions (0.1g/0.25 g/0.4 g/kg) (n=21) or to placebo (n=7, 4-weekly, n=8, 2 weekly). The primary endpoint was the mean area under the curve (AUC) of plasma Aβ1–40 after the last infusion for one infusion interval. We considered the AUC of plasma Aβ1–40 being more representative of the potential effect of IVIG than a single time point measurement. Secondary outcomes included changes in (a) the concentrations of Aβ1–40, Aβ1–42, anti-Aβ autoantibodies in CSF/plasma and tau/ptau181 in CSF, (b) cognitive and functional scales, and (c) brain imaging (MRI/FDG-PET). Patients’ safety was assessed by recording of adverse events, clinical examinations, MRI investigations, electrocardiography and laboratory tests. The infusions were performed by site personnel who were otherwise not involved in any other assessments; therefore, the patients, caregivers, and investigators were blinded to the treatment allocations. The study medication was blinded by using intransparent overpouches and infusion lines. The trial is registered at ClinicalTrials.gov (NCT00812565) and controlled-trials.com (ISRCTN64846759). Findings Fifty-six patients were randomized. AUC of plasma Aβ1–40, was not significantly different from the placebo for five of the six IVIG arms (median with range: −18.00 [−1347.0; 1068.5] for 0.2 g/kg; 364.25 [−5834.5; 1953.5] for 0.5 g/kg and −351.75 [−1084.0; 936.5] for 0.8 g/kg every 4 weeks compared to −116.25 [−1379.0; 5266.0] for the placebo; −13.75 [−1729.0; 307.0] for 0.1 g/kg, −32.50 [−1102.5; 451.5] for 0.25 g/kg and 47.00 [−341.0; 72.5] for 0.4 g/kg compared to 159.50 [51.5; 303.0] for the placebo; p=0.02 for comparison of the latter two groups). Adverse events were reported in 59.5% and 64.3% of the patients in the IVIG and placebo groups, respectively. No unexpected serious adverse events occurred. Interpretation IVIG had a very acceptable safety profile in the patients. The trial did not confirm results from previous studies. Longer trials with greater power are required to assess potential cognitive and functional effects of IVIG in AD.

Objective: To evaluate the tolerability and safety of Octagam® 5% and 10% across all indications, ages, and treatment regimens, using data from four non-interventional post-authorization safety studies (PASS); this analysis was performed following changes in the preparation of raw material used to manufacture Octagam. Methods: All four studies included in- and out-patients prescribed Octagam for treatment of their medical condition. Physicians used case report forms to document baseline demographics, Octagam treatment details, and data on the efficacy of Octagam, and recorded all adverse drug reactions (ADRs) and other safety data. Results: Altogether 21,780 infusions of Octagam in 2,397 patients were included in our analysis. The most frequent indication for Octagam was secondary immunodeficiencies (SID; n = 1,368, 11,348 infusions), followed by primary immunodeficiencies (PID; n = 363; 3,923 infusions). During the individual patient observation, 83% of SID and 67% of PID patients were free of any infection. In up to 85% of all investigator assessments, Octagam was rated to have a favorable effect. In autoimmune diseases, investigators assessed Octagam as being beneficial in 70% (immune thrombocytopenia) up to 100% (Guillain-Barré syndrome), depending on the indication. The majority of patients (92%) tolerated Octagam treatment without any ADR. The overall incidence of reported ADRs was 1.0% for all infusions. The majority of ADRs were considered non-serious (93%) and mild or moderate (87%) in severity. No unexpected ADR signal was detected. Conclusions: This analysis demonstrates that the changes in the preparation of raw material used to manufacture Octagam did not affect the safety profile of Octagam® 5% and 10%.

SummaryObjectivesTo assess the efficacy and safety of intravenous immunoglobulin (IVIG) 10% (Panzyga®), a novel human normal IVIG 10%, in patients with chronic immune thrombocytopenia (ITP).BackgroundFirst‐line treatment options in ITP include IVIGs.MethodsIn this prospective, open‐label, non‐controlled, multicentre, phase III study, patients received a daily dose of IVIG 10% (1 g kg−1 body weight) for two consecutive days. The primary end point was clinical response rate; secondary end points included alternate response definitions, time to response, response duration, platelet counts, regression of bleeding and safety.ResultsForty patients were enrolled (57·5% male, mean age 36·7 years); the full analysis set comprised 36 patients. A clinical response was seen for 29 of 36 patients (80·6%). Median time to response and response duration was 2 days and 14 days, respectively. IVIG 10% was well tolerated at a maximum infusion rate of 8 mg (kg min)−1 in all but one patient; adverse events were mainly mild to moderate in severity, and the most frequent was headache (42·5%).ConclusionIVIG 10% is well tolerated even at a high infusion speed and induces a rapid platelet count increase, thus decreasing the bleeding rate and the severity of bleeding events.Trial registry: http://ClinicalTrials.gov record: NCT01349790.

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Objectives: To provide detailed data on the tolerability and safety of octagam® 10%, a ready-touse intravenous immunoglobulin, in a subgroup of patients with immune thrombocytopenia (ITP) involved in an integrated analysis of post-authorisation safety surveillance (PASS) studies. Methods: A subgroup analysis was conducted using data collected from two noninterventional studies that included patients with ITP treated with octagam® 10%. Patients were observed and monitored for possible adverse drug reactions (ADRs) during or after administration of octagam® 10%, with a particular focus on thromboembolic events (TEEs). ADRs were analysed at the case and event level.Results: In this analysis of 112 patients receiving octagam® 10% (mean dose 0.4 g/kg/infusion), there were five cases with at least one adverse drug reaction (ADR) associated with 626 infusions of octagam® 10% (case incidence of 0.8% per infusion). ADRs were of mild or moderate severity. There were a total of 10 events, most commonly back pain (n = 3) and headache (n = 2). Nausea, dizziness and a sensation of heaviness were also reported. The remaining two events involved drug exposure during pregnancy. There were no TEEs or other serious ADRs. Discussion: In this subgroup analysis of patients who received octagam® 10% (manufactured using an amended process) in two PASS studies, the overall ADR rate was low, with ADRs occurring in only 0.8% of all infusions. No TEEs or other serious ADRs were reported. Conclusions: Routine clinical use of octagam® 10% was safe and well tolerated, with no unexpected safety issues, in patients with ITP. The two studies from which data were taken are registered with the International Standard Randomised Controlled Trial Number Registry, numbers ISRCTN58800347 and ISRCTN02245668.