27 Mar 2020

The coronavirus pandemic is upending not only life as we knew it, but Alzheimer’s clinical studies as well. In the United States, Europe, and Australia, most sites have put observational cohort studies on hold, and many have stopped dosing and in-person clinic visits for treatment and prevention trials. Details vary from site to site, with clinics in less-hit areas continuing to administer treatments and monitor safety for enrolled participants—for now. The situation may change as the pandemic progresses, with all trials eventually suspending in-person contact, researchers acknowledge.

COVID-19 has shut down dosing in clinical trials worldwide.

Nearly all observational studies are paused.

Researchers turn to telemedicine to keep participants engaged.

What then? Across the board, clinic leaders said they are staying in contact with their participants and carers through remote methods such as phone calls, video conferences, internet contacts, even postcards. Researchers can continue to collect some clinical and cognitive data through these means. Meanwhile, they are using the down time to analyze data and prepare manuscripts.

How badly will these stoppages affect the trials? If the disruption due to coronavirus proves short-lived, on the order of two months or so, most of the two dozen researchers Alzforum heard from for this story thought the consequences would be manageable. Trials allow for some skipped doses, and there are statistical methods of dealing with what’s called data “missingness” (yes, that’s a thing). Researchers spoke of the need to obtain protocol waivers, catch up on assessments afterward, and possibly extend studies.

If the crisis stretches on, however, the damage of missed interventions could reach deeper into datasets, muddying interpretation of results and possibly derailing shorter trials altogether. Researchers also worry that some of their elderly participants could die from coronavirus, or become discouraged by the upheaval and drop out of Alzheimer’s studies. Some said that with recruitment halted and new trials on hold, the field may lose steam.

“This is an unparalleled event, which will have a huge impact on research in the long term,” Philip Scheltens at VU University, Amsterdam, told Alzforum. Others agreed that progress will stall, and said data integrity could be compromised by the massive protocol deviations required. “There are more questions than answers right now,” William Klunk at the University of Pittsburgh wrote to Alzforum. Even so, researchers across the board said they will continue pushing forward with the current trials, no matter how bad the disruption becomes. “We can’t quit now,” David Knopman at the Mayo Clinic in Rochester, Minnesota, told Alzforum.

Where the Virus Rages, It Takes Trials Down With It

In general terms, for a clinical trial, the extent of the damage depends on where its sites are located. At some centers, researchers have halted recruitment and most in-person visits, but still allow enrolled participants to come into the clinic to receive infusions of study drug, or other interventions. At the moment, this is the case in Melbourne, Australia, in Amsterdam, and at the Cleveland Clinic Lou Ruvo Center for Brain Health in Ohio, for example. At other sites, interventions are on hold, but participants may still come in for safety checks, such as MRI scans for ARIA. This is the status at Washington University in St. Louis, the Oregon Health and Science University in Portland, and Rush University in Chicago, among others. In some of the hardest-hit areas at this point, such as New York City, Boston, and Barcelona, Spain, everything is shut down. “So far, participants and sponsors have been quite understanding and supportive of our decision,” Gad Marshall at Brigham and Women’s Hospital in Boston wrote to Alzforum.

Clinic personnel are often left with difficult decisions as they weigh the potential risks and benefits of missed treatments versus possible exposure to coronavirus. Doug Galasko at the University of California, San Diego, said the Alzheimer’s Disease Research Center there is evaluating each trial separately, and still allowing some in-person visits for interventions that are deemed critical. Clinicians screen patients for coronavirus symptoms, wear protective equipment, and maintain social distancing during the visit. “This describes the situation today, but it is fluid, and [orders] may become more restrictive,” Galasko wrote.

For large multicenter trials, variability from site to site poses a particular problem, introducing heterogeneity. For example, A4 study visits are completely shut down at many U.S. sites, but continue as normal in Japan. “We are working to figure out the best options for sites in order to prioritize participant safety and minimize the impact to overall data integrity,” Reisa Sperling at Brigham and Women’s Hospital wrote to Alzforum. “The situation continues to evolve rapidly.”

John Dwyer, who runs the Global Alzheimer’s Platform Foundation based in Washington, D.C., said his organization is working with its sites and drug sponsors to try to blunt the pandemic’s effect on trials while keeping everyone safe. “We’re figuring out how we can creatively and responsibly adjust study protocols to maintain the integrity of the studies and keep the momentum,” he told Alzforum. For example, some sponsors are looking into administering drugs via home visits. Other aspects of studies, such as cognitive tests, can be completed remotely.

Pharmaceutical companies are in the same boat, trying to balance participant and staff safety against the need to continue treatment. Rachelle Doody at Roche told Alzforum that both enrollment and dosing are continuing in the company’s trials of gantenerumab and semorinemab, as well as in API’s study of crenezumab in Colombia. “The COVID-19 situation is dynamic, and we are reviewing the status of our clinical trials globally on an ongoing basis,” Doody wrote to Alzforum.

On the other hand, Eli Lilly is halting enrollment and postponing new trials while continuing dosing in ongoing trials, and other pharmaceutical companies are shifting their overall priorities away from some current indications and toward COVID-19 (Mar 23 Endpoint News; March 26 Endpoint News).

The disruption may be most devastating to short trials. Li-Huei Tsai at Massachusetts Institute of Technology, Cambridge, is running a six-month trial of visual and auditory stimulation meant to synchronize gamma waves in the brain. Participants administer the intervention themselves at home, but need to come into the clinic every three months for testing. “Now none of those can be carried out. We are trying to change the protocol to [testing] every six months. I hope we can salvage the trial,” Tsai wrote to Alzforum. For other ongoing trials that were planned to last only a few weeks, she has had to simply stop the studies.

Despite the challenges now, most researchers believe a majority of ongoing trials can be preserved, provided the stoppage remains relatively brief. Statisticians will have to work out how to account for protocol deviations and analyze discrepant data, noted Mary Sano at Mount Sinai School of Medicine in New York. Dwyer praised recent guidance from the Food and Drug Administration and the National Institutes of Health. Both agencies have expressed an openness to granting protocol waivers and extensions. “They realize these are extraordinary times, and they’re encouraging flexibility and thoughtfulness to maintain participant and team safety,” Dwyer said.

James Leverenz at the Cleveland Clinic in Ohio said this is true of other study sponsors, too. “Our sponsors, including the NIH, to date have been supportive and understand the impact on our research productivity,” he wrote to Alzforum.

Richard Hodes, who leads the National Institute on Aging, said the NIA wants to hear from researchers about what impact the pandemic is having on their studies, and what is needed to maintain the work. “We want to understand what it will take to sustain the infrastructure during this pause, and what it will take to gear back up. We’re committed to doing that,” Hodes told Alzforum (see Mar 27 blog post for additional resources).

Observational Cohorts Try to Weather the Storm

The picture is more uniform for observational studies. Because clinic visits are not critical for participants’ health, this type of human AD research has been halted nearly everywhere, with but a few exceptions. Ricardo Allegri at the FLENI Neurological Research Institute in Buenos Aires, Argentina, who leads the DIAN study there, said that for now, his group is continuing to follow up with current participants, though they delayed enrolling new families. In Australia, visits are currently ongoing for AIBL participants; however, Chris Rowe at the University of Melbourne noted that imaging has been postponed, and visits are likely to be suspended altogether soon. In Sweden, the BioFINDER2 study is still allowing participants younger than 70 to come to the clinic for visits; this is based on guidance from the government. “These recommendations can change at any time,” noted Oskar Hansson at Lund University.

Researchers elsewhere, including across the United States, the Netherlands, and in Spain reported a complete stoppage of in-person visits. On March 24, The New York Times reported that 5,400 of Spain’s current documented 40,000 cases are among health care workers.

Enrollment of new participants into AD studies has halted everywhere. “We will from next week stop all new recruitments to the BioFINDER2 study, but we have already recruited 1,100 new subjects in the last 2.5 years, so it is not a catastrophe for the study,” Hansson wrote to Alzforum.

Most researchers believe the harm to long-term observational studies can be overcome. “Observational studies have much less frequent visits [than trials] and this situation is less likely to influence them,” Marshall wrote to Alzforum. David Bennett at Rush University in Chicago leads several large cohort studies, such as the Religious Orders Study and Rush Memory and Aging Project. He said, “Our studies will continue, but it will be a bit of work to get everything running like a machine again.” Hansson noted that if the pandemic lasts until July, BioFINDER2 will have a backlog of 150 lumbar punctures, 150 MRI scans, and 250 PET scans. “We might reduce the MRI protocol so each participant can be scanned in 20 minutes instead of 60 to more easily catch up,” Hansson wrote to Alzforum.

Michael Weiner at the University of California San Francisco, who runs ADNI, said the disruptions would harm that study’s data and budget. Other aspects of Alzheimer’s cohort studies are threatened as well. Bennett noted that his staff has had to halt autopsies of deceased participants until more protective gear arrives, to guard against coronavirus transmission.

New Reality for Scientists, Clinicians, Patients

Beyond affecting research studies, the coronavirus pandemic has transformed the work lives of researchers and clinicians themselves. Forced to stay at home, scientists are using the time to analyze data and write up results. “The research community is very resilient,” noted José Luis Molinuevo at Barcelonaβeta Brain Research Center in Spain. “I’m running my research team with virtual meetings every week. They are working from home, analyzing data we’ve collected over the last years, and getting new ideas.” Researchers are conferring with colleagues by video, and recording talks for upcoming conferences such as AAT-AD/PD, which will be fully virtual. Many wonder if the move toward remote interactions heralds a permanent change. “The world will never be the same after this,” Scheltens said.

The situation is more dire for researchers with clinical expertise, particularly in hard-hit areas. Molinuevo noted that doctors in his group have been deployed to help treat coronavirus patients, and laboratories are lending materials to hospitals. In New York, even non-clinicians from research groups volunteer in hospitals, where they help screen employees for possible coronavirus symptoms, or remind janitors to wear masks and gloves. “There’s a lot of operational work that needs to be done. The rules are changing so fast. Every day there’s a new set of screening questions,” Sano told Alzforum.

Areas that are further behind in the epidemic try to learn from the experience of New York, Italy, and Spain. For example, in Ottawa, Canada, health care workers are gowning up even for routine patient care, as presymptomatic spread of this highly transmissible new virus is becoming clear. This means that clinician-researchers like Michael Schlossmacher of the Ottawa Hospital Research Institute oversee the work of their research groups from home some days of the week, and on other days they don protective gear to see patients. Schlossmacher's outpatient neurology clinic over the course of the past two weeks shifted more than 90 percent of its scheduled visits to secure video assessment or, where appropriate, phone calls. So far, both patients and practitioners feel this works well under the curcumstances, Schlossmacher wrote to Alzforum.

In many regions, neurodegeneration clinicians have not yet been tapped to help with general care, but that is likely coming, researchers said. In Chicago, Bennett’s clinic has been converted into a pediatric coronavirus screening site, and the hospital is in “surge mode,” with emergency rooms transformed into triage spaces in anticipation of a coming deluge of patients. “Right now it’s eerily quiet, but we expect things to pick up in the next week or so,” Bennett noted.

At the same time as clinicians are in demand, some researchers fear losing other research personnel because of a lack of work for them. Henne Holstege at Vrije University in Amsterdam recently hired a new employee to visit centenarians in their homes but, with all visits shut down, may be unable to renew this contract. Allegri noted that because of travel restrictions, he has been unable to train a new neurologist hired to evaluate DIAN participants. In addition to personnel problems, research clinics themselves are under financial pressure due to lost revenue. “I hope the new federally approved emergency funding will address the plight of hospitals and clinical trial sites,” Dwyer said.

The changes are especially hard on patients, who are now housebound. Because most participants in Alzheimer’s trials are over 65 and many have other health conditions, they are at high risk for complications and death from coronavirus. Even if they survive, Molinuevo fears that the trauma of going through a pandemic and potentially losing loved ones could precipitate trial dropouts.

Holstege is particularly concerned for her centenarians. “I am afraid to lose our whole cohort. We wrote all centenarians in the study a personal postcard to encourage them to keep strong and stay safe.”

Sano echoed the importance of staying in touch with participants, finding out what support they need, and reassuring them about future plans. It is helpful when trial leaders convey clear information about what protocol changes to expect, Sano said. “That helps our [clinic] staff give complete information to participants. If we don’t know what’s happening, that’s a hard message to share with patients.”

Many researchers worry about the effects of prolonged isolation on older participants. Jeffrey Kaye at the Oregon Health & Science University in Portland, a pioneer in home-based technology monitoring, tracks participant health and activity with a weekly questionnaire. He said that since the outbreak began, participants are more likely to report that they are lonely or depressed. Holstege agrees this is a huge problem. “In the long run, the loneliness that this viral outbreak inflicts on all elderly may turn out to be deadly, too,” she wrote.

To combat this, and to continue to gather data where possible, nearly all programs have turned to telemedicine. Researchers check in with participants via phone, video, or the internet. For the most part, participants are happy for the contact, researchers report. “A lot of these people are in lockdown, so they don’t mind if you call and keep them on the phone for an hour,” Bennett said.

Some researchers believe telemedicine may be the wave of the future for Alzheimer’s research. “The reliance on virtual meetings and remote assessments may well carry over once the pandemic ends,” predicted John Morris at Washington University in St. Louis. Galasko suggested that there could be a positive effect from this crisis if it helps researchers refine methods for remote assessment. Allegri’s group is also using this time to accelerate work on online cognitive assessments.

Kaye noted that the Centers for Medicare & Medicaid Services currently do not reimburse for telemedicine contacts. Allegri wrote that lack of telemedicine reimbursement from health insurance is a problem in Argentina, too. Both hope this crisis may change that policy. “For our populations, this option for assessment and care makes sense on so many levels,” Kaye wrote to Alzforum. However, he does not think it will ever fully replace in-person contact. “Technology is wonderful and helps us keep going in many ways, but ultimately human touch is still fundamental for us all.”

Overall, researchers vowed to find ways to deal with the challenges the pandemic poses. “We cannot let COVID-19 defeat our mission to find a successful treatment for Alzheimer’s disease,” Sperling said. Steven Salloway at Butler Hospital in Providence, Rhode Island, said his clinic is already preparing for life after the pandemic. “Staff are working hard to get new studies ready to launch and to be prepared to resume normal activities. … We are looking forward to the time when we can again move full-steam ahead in the fight against AD,” he wrote.

Dear readers around the globe: what’s this pandemic doing to your cohort studies and trials? Write to gabrielle@alzforum.org, and we will add your experience as a comment to this report.—Madolyn Bowman Rogers