Intravenous immunoglobulin for treatment of mild-to-moderate Alzheimer's disease: a phase 2, randomised, double-blind, placebo-controlled, dose-finding trial

Abstract

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.

Development of a core outcome set for disease modification trials in mild to moderate dementia: a systematic review, patient and public consultation and consensus recommendations

“…ADLs were measured in 55 trials, using 12 measures. 27,28,33,37,41,45,46,49,51,52,54,55,57,59,61,63,64,66,68,77,78,81,[85][86][87][88][89][90]92,97,104,[106][107][108][110][111][112]114,115,118,119,[121][122][123][124][125]128,134,135,137,138,[142][143][144][145] Biological markers were measured in 51 trials using a variety of nine biological t...…”

Perspective on future role of biological markers in clinical therapy trials of Alzheimer's disease: A long-range point of view beyond 2020

“…The distinctive features of CSF, together with the low incidence of complications after lumbar puncture [62] have supported the introduction of lumbar puncture and analyses of CSF biomarkers into routine clinical practice in some centers [63,64]. CSF biomarkers are also increasingly used in clinical drug trials, both for enrichment of the target population at inclusion and to evaluate the biochemical effects of treatment [65][66][67].…”

A phase 3 trial of IV immunoglobulin for Alzheimer disease

“…8 Prior human studies involved small numbers of participants but showed good safety and tolerability, though were underpowered to detect efficacy. [9][10][11][12][13][14] We report the results of a phase 3 trial testing the safety and efficacy of 2 doses of IVIg in mild to moderate AD dementia.…”