Repurposing clinical trial data to understand potential effects of functional unblinding on efficacy of Alzheimer's drug - Gantenerumab

Alzheimer’s disease (AD) is the most common cause of dementia, estimated to affect about 6 million Americans currently. It is characterized clinically by impairment in memory, language and visuospatial function (ability to see, understand, and interact with the space around us and the objects within it) to the point that a person is no longer able to care for themselves independently.

In Alzheimer’s patients who donate their brains, the microscopic changes show tiny abnormal protein clusters called amyloid between cells and called tau inside cells.

Recently, the Food and Drug Administration (FDA) approved two antibody drugs, aducanumab and lecanemab, that target amyloid protein and help treat Alzheimer's disease. The clinical benefit of these antibodies in Alzheimer's disease is small and the side effect profile is concerning as about 1 of 4 patients who are treated may develop brain swelling or brain bleeding. These side effects are serious enough that in the clinical trials when they occurred the medication was paused. This raises the possibility that patients and their study partners, who were not supposed to know if they were on active treatment or placebo in this blinded study, likely learned that they were on active treatment when they had this common side effect. This is called "functional unblinding" and has the potential for exaggerating the apparent clinical effect of the drug since patients who knew they were on active treatment may have been prone to the placebo effect (when people feel better after taking a treatment that doesn't actually have any active ingredients, simply because they believe it will work).

Gantenerumab is another anti-amyloid antibody that has been tested in several trials but that has not been shown to provide any clear clinical benefit. Here we will use data from one of the Gantenerumab studies, called Scarlet Road, to try and assess the impact of functional unblinding and the placebo effect on the main outcome measure, the Clinical Dementia Rating Sum of Boxes (CDR-SB) Score. The CDR-SB is measure of day-to-day living activities and some cognitive measures like tests of memory. We will determine if patients who had brain swelling or brain bleeding performed better than expected compared to similar patients who did not have brain swelling or brain bleeding. If this is true it would suggest that the CDR-SB outcome measure, used in many of the antibody trials, may be prone to functional unblinding and the placebo effect and that the results reported in anti-amyloid antibody trials suggesting some clinical benefit may be incorrect. This would have an important impact on how doctors assess the true clinical benefit, or lack thereof, of this type of medication.