Part 2 of a three-part story.
Not to be confused with the TV series about chasing, preparing, and cooking wild food, researchers at the Alzheimer’s Association International Conference, held July 22-28 in Toronto, jokingly invoked this title phrase to express just how differently they will have to go about enrolling participants into future AD trials. Facetiousness aside, how will the Global Alzheimer’s Platform (GAP) and the European Prevention of Alzheimer’s Dementia (EPAD) find the people who may be on the trajectory toward Alzheimer’s dementia but do not know it, and prepare those people for intervention trials?
EPAD has built a registry as a tool to prescreen potential participants. It starts by gathering so-called parent cohorts maintained locally throughout Europe—population-based cohorts, aging studies, research cohorts enriched for family history, etc.—and exporting and harmonizing their de-identified data set into a virtual platform. On the register’s central search portal, a software program called PREPAD can query these federated data sets to find members of parent cohorts who are at different risk stages of Alzheimer’s dementia. This is being done with customized search algorithms that use the particular data points being collected in each contributing parent cohort. For some parent cohorts, the algorithm uses little more than age, a memory score, and family history, but for others it can incorporate more detailed data. For example, the UK Biobank comprises verbal recall scores, and of its 490,000 members, 17,000 are known to be more than one standard deviation below the norm and older than 55, said Luc Truyen of Janssen Research & Development, a company of Johnson & Johnson. Those people would be candidates for the EPAD longitudinal cohort.
When such candidates pop up, EPAD staff sends its encrypted IDs back to the owners of the respective parent cohorts. The local owner re-identifies the participants and invites them to join the EPAD longitudinal study for standardized clinical/cognitive and biomarker tracking of their Alzheimer’s risk. Once they have been followed in this study for one year, and their amyloid and tau biomarkers indicate they are at high risk of cognitive decline, they can join a PoC trial.
At AAIC, Lisa Vermunt of VU University Medical Center, Amsterdam, showed off the current status of this register. Vermunt works for Pieter Jelle Visser at VU Amsterdam and Maastricht, who co-leads this EPAD work package. As of this summer, the EPAD register contains 17,460 of its target number of 24,000 people age 50 and up drawn from parent cohorts in Spain, the United Kingdom, the Netherlands, Italy, and Sweden. Of the 17,460 people, 15,570 are cognitively normal, 940 have subjective cognitive impairment, and a few hundred have MCI or unknown status. The goal is to ramp up that number with additional cohorts in France, Switzerland, and other countries, Vermunt told Alzforum.
Will the parent cohort owner cooperate and pass its study subjects on to EPAD? And will these subjects come? Yes and yes, EPAD leader José Luis Molinuevo of Barcelonaβeta Brain Research Center in Barcelona, Spain, told Alzforum. The owners have signed an agreement, the first patients in Edinburgh and Barcelona have entered the EPAD longitudinal cohort study via a parent cohort (see May 2016 EPAD press release; July 2016 EPAD release), and eight more have joined in the last few weeks. One of the original parent cohorts is the Barcelona ALFA cohort of 3,000 people aged 45 and older who are cognitively normal but have a family history, and its nested ALFA+ cohort of more deeply phenotyped people (Molinuevo et al., 2016, Alzheimer’s & Dementia, in press).
Until now, EPAD’s goal was to create the register, the algorithms, and the longitudinal cohort infrastructure, and to show that the funnel system works, Molinuevo said. To do this, EPAD started with centers and parent cohorts related to its leaders. Now it is scaling up to include additional sites and to ramp up participant numbers. Geneva and Toulouse are being activated this month, Amsterdam and Stockholm in September, and sites in additional cities will follow this winter and next year. Ultimately, the cohort is to include 6,000 people with well-characterized preclinical dementia. Importantly, EPAD sites continually recruit new people into their local registers and parent cohorts. “We need a system to replenish local cohorts, so they can keep feeding people into the EPAD cohort and the trials,” Molinuevo told Alzforum.
For its part, GAP is exploring a range of recruitment processes. Like EPAD, it intends to tap multiple parent cohorts—“feeders” in GAP parlance. They include the Brain Health Registry at the University of California San Francisco, the Alzheimer’s Prevention Registry of the Banner Alzheimer’s Institute in Phoenix, the Healthy Brains registry of the Cleveland Clinic, and local ones such as the Alzheimer’s Prevention Registry at Butler Hospital in Providence, Rhode Island. The idea is to “white label” registries so they can combine a local and a GAP brand identity. This is necessary because registries have been found to recruit most strongly in their local catchment area.
Besides registries, GAP also welcomes data from large clinical studies such as IDEAS, which is conducting PET scans on 18,000 people in hopes of persuading the Centers for Medicare & Medicaid Services to reimburse clinical use of amyloid PET (Apr 2015 news). Also wanted are the many people who fail the elaborate screening procedure for large, early stage clinical trials such as A4 and the new programs. These include GENERATION, which evaluates two Novartis drugs, and EARLY, which tests a Janssen drug. “We want to put into the GAP registry all those people who have shown so much interest already. We want to engage them and find another trial that they do qualify for,” George Vradenburg, who leads the Global Alzheimer’s Platform (GAP), told Alzforum.
The idea is that from among a target number of 200,000 “feeders,” a quarter who are interested in clinical trials will consent to a GAP registry. This is to be a new virtual registry managed by staff at the GAP foundation. It will assign every member a Global Universal ID, capture a set of Web-based baseline data, genotype participants for ApoE, and attempt to collect cognitive follow-up data quarterly or biannually, depending on the test. An adaptive algorithm will be run periodically against this data to hone the algorithm’s ability to pick out those people who are most likely to have brain amyloid deposition. This serves to reduce the number of negative PET scans or lumbar punctures. This process will select a “trial-ready cohort” initially comprising 1,000 people with prodromal and 1,000 people with preclinical AD who are invited to be seen in person at GAP Net clinical sites. After biomarker testing, eligible people can move into trials; all others will revert to the GAP Registry and may be able to join a future trial.
The virtual registry and its public-facing website are currently being built, said Vradenburg, and the grant for the cohort is under review at the National Institute on Aging. GAP calls this cohort the Trial-Ready Cohort for Preclinical/Prodromal Alzheimer’s Disease, aka TRC-PAD; Reisa Sperling at Boston’s Brigham and Women’s Hospital, Paul Aisen at the University of Southern California, San Diego, and Jeffrey Cummings at the Cleveland Clinic Lou Ruvo Center for Brain Health in Las Vegas are its main drivers. “Despite the differences in details, everyone’s theory is recruit broadly, identify through risk algorithms those people who should get deeply phenotyped at higher cost, and move those who are suitable into trials,” Vradenburg said.
[Courtesy of GAP.]
Most online Alzheimer’s registries are but a few years old. They are beginning to deliver registrants to clinical trials, but have had little success thus far, said Jessica Langbaum of Banner. GAP calculates that in order to recruit the 4,500 people into trials who are being sought by current AD therapeutic studies, nearly 7 million would need to sign up for a registry. That’s because only 10 percent of registry members tend to get referred to sites, 4 percent of those get prescreened, a fifth of those drop out, and 80 percent of the remaining 22,500 people hit a snag during screening. Successful virtual registries invest extensive effort into building trust so their members will contact a study site and join a trial; successful local registries cultivate personal relationships to do so, said GAP’s president John Dwyer, an entrepreneur and business executive who joined GAP because his extended family has suffered from late-onset AD.
In one of several pilot studies to boost recruitment, GAP has invested $1 million in marketing for the Brain Health Registry. It broadcast public-service announcements with President Ronald Reagan’s son Ron and celebrities Paula Abdul, Leeza Gibbons, and Linda Gray, and it pursued various types of digital marketing and local media sponsorships. This netted 5,781 registrants, of whom nearly 1,000 have some data that hint they may be prodromal. Of those, 500 people agreed to be referred to three clinical trial sites, three have been enrolled, and more are in screening, Dwyer said. This experience suggests, though, that many people are reluctant to take cognitive tests online. Of those who do and later contact a site, some get disaffected because the site’s staff and institutional review board make them wait. “The sites can be a bottleneck. We have to engage fast, otherwise we lose people. When participants do this upfront work, their phone has to ring,” said Dwyer.
Beyond registries, GAP is experimenting with other “feeder” systems for recruiting people. Partnerships with health insurers could identify at-risk people based on their electronic health records, yielding referrals. Engaging minority communities could boost their participation rates. State governors could issue Medicaid directives, and the federal government could provide access to records by people insured via Medicare and the Veterans Affairs system.
In one such pilot, GAP engaged Jeffrey Burns at Kansas University Medical Center in Kansas City, well as Kansas City Mayor Sly James, and the CEO of its BlueCross/BlueShield insurance provider. Starting this September, GAP will target a marketing campaign to Kansas City BC/BS members, to city employees, and to large administrative services only (ASO) companies, whose employees are self-insured. The goal is to send interested people to Burns’ center or to their primary care providers for pre-screening and referral into the GAP registry, if appropriate. To help with processing the hoped-for spike in inquiries, GAP leaders may interpose a call center. How to bulk up capacity so sites are equipped to deal with successful outreach efforts has become a general concern as EPAD and GAP gear up.
To pre-screen large numbers of people quickly, GAP is currently using the AD8, a validated five-minute screening test (Galvin et al., 2007). They will also explore easy-to-use, inexpensive digital pen technology that captures subtle decrements in how people with preclinical AD draw; it could become a sensitive tool to log longitudinal change electronically while people see their primary care provider. For more on how site networks are forming, see Part 3 of this story.—Gabrielle Strobel
- $100M IDEAS: CMS Blesses Study to Evaluate Amyloid Scans in Clinical Practice
- Playing Where the Puck Is Going to Be: Trial Sites Skate Toward GAP Net, EPAD TDCs
- Galvin JE, Roe CM, Coats MA, Morris JC. Patient's rating of cognitive ability: using the AD8, a brief informant interview, as a self-rating tool to detect dementia. Arch Neurol. 2007 May;64(5):725-30. PubMed.
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