Matt Hoffman, Senior Editor for NeurologyLive, has covered medical news for MJH Life Sciences, NeurologyLive’s parent company, since 2017. He hosts the NeurologyLive Mind Moments podcast, as well as Second Opinion on Medical World News. Follow him on Twitter @byMattHoffman or email him at email@example.com
Although treatment needs to be assessed in a larger trial, it also showed improvements in 2 measurements of functional ability.
Sharon J. Sha, MD, MS
Treatment with young fresh frozen plasma (yFFP), from donors aged 18 to 30 years, has been shown to be safe, well tolerated, and feasible for Alzheimer disease symptom amelioration in a randomized clinical trial.
With a primary end point being safety and tolerability, the use of yFFP showed no related serious adverse events (AEs) in any of the 18 patients. One patient discontinued participation because of urticaria and another because of an unrelated stroke. No statistically significant difference between the plasma group, of which 94.4% (n = 17) experienced an AE, and the placebo group, of which 100.0% (n = 9) experienced an AE. All of these reported AEs were mild to moderate in severity.1
The most common AEs in the plasma group included hypertension (n = 3; 16.7%), dizziness (n = 2; 11.1%), sinus bradycardia (n = 3; 16.7%), headache (n = 3; 16.7%), and sinus tachycardia (n = 3; 16.7%).
“The importance of this study is that young plasma is safe and tolerable to give to patients with Alzheimer disease,” lead author Sharon J. Sha, MD, MS, told NeurologyLive. “There are hopeful findings and trends in the exploratory parameters such as functional ability and functional brain connectivity from this very small study that could be confirmed with a larger study.”
The clinical associate professor of neurology and neurological sciences at Stanford University and her colleagues acknowledged the limitations of the study, in that it had a small sample size, short duration, and experienced a design change. Although, Sha noted that the results warrant further exploration in larger, double-blinded trials.
“There are currently no disease-modifying drugs for Alzheimer disease, and with almost 6 million Americans with Alzheimer disease, there is a huge need to find a medicine that can help,” Sha said. “This work was based off the findings that older mice given young plasma—either mouse young plasma or human young plasma—can improve cognition and increase synaptic plasticity.”
The trial randomized 9 patients under a double-blind crossover protocol to receive 4 once-weekly infusions of either 1 unit (~250 mL) of yFFP from male donors, or 250 mL saline, followed by a 6-week washout period and a crossover to 4 once-weekly infusions of an alternate treatment. After an open-label adjustment, 9 patients received 4 weekly yFFP infusions only, and their subjective measurements were unmasked.
The mean visit adherence was 86% (interquartile range, 87% to 100%) and adherence, when accounting for a reduction in the total visit requirement due to early patient discontinuation, was 96% (interquartile range, 89% to 100%).
Sha and colleagues also assessed several exploratory end points of efficacy, as 7 (77.8%) patients in open-label plasma cohort and 9 patients in the crossover cohort had posttreatment assessments. Of these assessments, posttreatment improvements were seen In the Functional Activities Questionnaire, of−4.56 points (95% CI, −6.11 to −3.01; P = .001), and the Alzheimer’s Disease Cooperative Study Activities of Daily Living Inventory in mild cognitive impairment, of 3.17 points (95% CI, 0.70 to 5.65; P = .03).
“The surprise was that there were improvements in 2 of 3 measures of functional ability,” Sha said. “However, these were exploratory measures, the analysis was not corrected for multiple comparisons, and the total number of patients in the analyses were very small. As such, this should be repeated with a larger sample that is designed for this statistical analysis.”
“We were also surprised by the large number of APOE4 mutation carriers in our patients. Consequently, this may not be generalizable to all patients with Alzheimer disease,” she added. In total, 87.5% (n = 7) of patients in the crossover group and 77.8% (n = 7) of patients in the plasma only group were APOE4 carriers. In patients with late-onset, nonfamilial Alzheimer, it is estimated that 37% carry APOE4, compared to about 14% of the general popilation.2
Notably, in an accompanying editorial,3 David S. Knopman, MD, acknowledged that the confirmation of yFFP infusions for Alzheimer symptoms was “a major goal for early-phase therapeutic development. Many promising therapies founder on the later appearance of safety concerns, whether a common and mild one that would make the widespread practical use of the therapy onerous or an uncommon one that is life-threatening.”
Although, Knopman did write that while most early phase trials focus on safety, an attempt to observe some level of treatment benefit tends to be a secondary goal. “Unfortunately, the current trial failed to observe any efficacy signal, leaving the investigators with neither a justification to continue nor cease development of FFP as a treatment for [Alzheimer disease] dementia. Frustratingly, the only definitive way to address the question of the efficacy of therapies for disorders in the AD spectrum is to conduct a large, long, randomized clinical trial,” he wrote.
As a struggle of small trials, Knopman suggested 3 way to work within the limits of the association between effect size, sample size, and statistical significance—all of which, he recognized, are challenging to incorporate into an early-phase trial, especially with a limited budget:
“They need to identify the active agents in their therapy and how they interact with the [Alzheimer] brain,” Knopman wrote. “They need to prove that they have a reasonable dose before moving on to a larger and longer trial. They also need to establish criteria for their next trial that will give them a reasonable indication as to whether to pursue this avenue of therapeutics or give it up.”
1. Sha SJ, Deutsch GK, Tian L, et al. Safety, tolerability, and feasibility of young plasma infusion in the plasma for Alzheimer symptom amelioration study: a randomized clinical trial. JAMA Neurol. epub October 29, 2018. doi: 10.1001/jamaneurol.2018.3288.
2. Kassam Z. APOE4 gene variant linked to Alzheimer’s. Drug Target Review website. drugtargetreview.com/news/32082/apoe4-gene-variant-alzheimers. Published June 4, 2018. Accessed October 31, 2018.
3. Knopman DS. Early-phase randomized clinical trials—expectations vs. hard reality. JAMA Neurol. epub October 29, 2018. doi: 10.1001/jamaneurol.2018.3301.