The slight slowing of cognitive decline achieved by Leqembi and perhaps by Aduhelm has revived debate around how much change is needed to be “clinically meaningful.” Two recent papers—one a report from a working group convened by the Alzheimer’s Association, the other from scientists at Roche—and a webinar hosted by the advocacy group UsAgainstAlzheimer’s, dug into this topic.
Scientists from academia, pharmaceutical companies, and healthcare analysis firms reached no consensus on a threshold for meaningfulness, but broadly agreed that meaningfulness should be determined for each patient, rather than based on mean differences between placebo and treated groups, which can wash out individual effects. They also said the effects of disease-modifying treatments, which slow the rate of decline, have to be considered in the context of time, and stressed the need for outcome measures that better reflect what’s most important to the patient.
While AD clinical trials determine, statistically, if a treatment group declines more slowly than the placebo control group, they do not set out to determine the minimum difference that would be noticeable by a patient, caregiver, or physician. That’s a tougher nut to crack. Why is clinical meaningfulness so hard to discern? “Meaningfulness is a multifaceted concept that necessarily involves the individual opinion of physicians, patients, and caregivers,” Nicolas Villain at Sorbonne University in Paris told Alzforum. Todd Golde at the University of Florida, Gainesville, agreed. “I don’t think we have enough data to make firm conclusions. But for the first time we might be able to rigorously assess this in a prospective fashion,” Golde wrote (comments below).
Alzheimer’s researchers have tried before to quantify the least amount of cognitive change that is detectable and meaningful to patients. One oft-cited paper, written by Eli Lilly researchers led by Scott Andrews, found that a 1- to 2-point worsening on the CDR-SB for a given patient was the minimum change associated with a noticeable decrease in that person’s abilities (Andrews et al., 2019). Andrews, now at Takeda Pharmaceuticals in Indianapolis, said this finding has been misapplied to discount the small, yet statistically significant, benefits seen with anti-amyloid immunotherapy, such as the 0.45-point CDR-SB difference between treatment groups in the 18-month lecanemab Phase 3 trial (Dec 2022 conference news).
“It would be inappropriate to apply our analysis by saying you need a 1-point CDR-SB difference between groups. It sets up unrealistic expectations for these emerging therapies,” Andrews said in the webinar. Half a point on the CDR-SB is about the benefit provided by cholinesterase inhibitors that are approved for AD, but they do not alter the rate of decline.
In the December 8 Journal of Prevention of Alzheimer’s Disease, Roche researchers led by Claire Lansdall reached similar conclusions, reporting the minimal meaningful difference as 1.0 to 2.5 points on the CDR-SB. Like Andrews et al., they specified that this applies to within-patient change, not group differences. In addition, in both papers the minimum meaningful difference varied by disease stage, being smaller at earlier stages. This is likely because people who are less impaired are more aware of slight alterations in their abilities.
Meanwhile, in the February 7 Alzheimer’s & Dementia, researchers led by Ron Petersen at the Mayo Clinic in Rochester, Minnesota, reported the findings of the Alzheimer’s Association Clinical Meaningfulness Work Group. They concluded that for a disease-modifying therapy, an 18- or 24-month trial is too short to fully assess its potential benefits. This is because if the slowing of decline remains constant, the numeric benefit would be expected to accrue over time. For example, an average slowing of 0.5 points on the CDR-SB at 18 months would become 1 point by three years.
A majority of researchers contacted by Alzforum concurred with this assessment. “Disease-modifying therapies that improve the disease progression rate must be evaluated considering their potential long-term effects,” said Oskar Hansson at Lund University, Sweden, adding “Most of my patients and their loved ones tell me a 25 to 35 percent slowing of clinical progression is meaningful.” A third less progression would mean that a person who stayed on the drug for three years would be where they would have been at two years without treatment, buying them a year of extra time. Other commentators cautioned that whether the benefit grows remains to be seen, and asked whether unwanted effects such as greater ventricular volume would likewise be projected to grow (comments below).
Key Concerns. This draft model from the What Matters Most study shows the abilities patients and caregivers say they value most. [Courtesy of UsAgainstAlzheimer's AD PACE Initiative.]
In addition, scientists think current scales, such as the CDR-SB, poorly capture the types of change that matter most to patients. The Alzheimer’s Disease Patient and Caregiver Engagement “What Matters Most” study interviewed 60 people at different stages of AD, and their care partners, to learn what skills were most important to them (DiBenedetti et al., 2020). Researchers distilled those responses into a list of 42 cognitive or functional abilities, which fell into categories such as social life, thought processing, daily activities, and independence. Specific items in these categories included continuing to enjoy hobbies, remembering people’s names, managing money, and being able to live alone (see graphic; Hauber et al., 2023).
Next, researchers compared the items to those measured by common cognitive outcomes. Even the outcome measures that overlapped best with the list, such as the ADCS-ADL and CDR-SB, included only 12 of the 42 items. “We need to find a scale to capture more relevant signs [of decline],” Andrews noted in the webinar. “This list is a blueprint to help measurement scientists do that.”—Madolyn Bowman Rogers
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