Kathie Turner was on her way to a clinic for one last test to determine if she qualified for Clarity AD, a clinical trial for people with early-stage Alzheimer's disease, when her cellphone rang. A nurse from the clinic was calling to inform her that because of the pandemic she shouldn't come in for her brain scan.

It was March 12, 2020, and Turner, who is 55 and lives in West Frankfort, IL, was halfway to Washington University's Knight Alzheimer Disease Research Center (ADRC) in St. Louis. The imaging center the clinic uses is located within a nearby hospital that was treating COVID-19 patients. "That was the one time having this beautiful state-of-the-art imaging center in the middle of a giant hospital was a disadvantage," says Joy Snider, MD, PhD, director of the Knight ADRC clinical trials unit. In mid-March, as the number of cases in St. Louis rose, the center's researchers started shifting as many in-person visits as possible to telehealth sessions. On April 7, the center stopped all in-person visits for study participants except those necessary for safety, such as adverse reactions to a study drug.

The timing was especially bad for Turner. All screening tests for the trial had to occur within a 90-day period, and Turner still hadn't had the requisite PET scan for amyloid beta, the main molecular culprit in Alzheimer's disease. This made her what Dr. Snider called a "screen fail." In order to join the trial, Turner would have to do all the screening—including physical and neurologic exams, tests of memory and thinking, brain imaging, and blood tests—again.

Turner had hoped to join a trial testing whether infusions of an antibody (BAN2401, which was first produced by BioArctic and is now being jointly developed by Biogen and Eisai) that binds to amyloid beta can slow cognitive decline in people in the disease's early stages. Learning she couldn't continue was a real setback for Turner, who dealt with her diagnosis last January by committing to participating in research. "It deflated my fight," she says.

The pandemic disrupted not just screenings for prospective participants but also all trials underway. Some patients had to skip doses of investigational drugs when in-person visits were suspended. "The main danger of taking participants off these investigational drugs is that their disease might progress faster," says Dr. Snider. "The danger to the clinical trial is that the data may not be meaningful." But study sponsors have been understanding about missing doses and have adjusted their handling of data accordingly, Dr. Snider says.

Cognitive assessments couldn't be converted to telehealth because of study procedures, although follow-ups could be done over the phone, says Dr. Snider. Once local COVID-19 cases began to decrease in early June, the center reopened for study visits, with extensive modifications to protect patients and staff. "We never shut down 100 percent, but we did stop having in-person visits for a period of time," says Dr. Snider.

Examples of Disruptions

What happened at the Knight ADRC occurred at institutions across the country—and around the world. Among the projects affected was a trial of intranasal insulin to treat neurologic problems associated with HIV infection, which was suspended at the recruitment stage, says Justin C. McArthur, MBBS, MPH, FAAN, chair of the neurology department at Johns Hopkins University School of Medicine in Baltimore. "We didn't interrupt treatment because we hadn't started, but we haven't been able to recruit and enroll any new patients," says Dr. McArthur, who is leading the study.

At Stanford University, a privately funded trial of a deep brain stimulation system to treat epilepsy was halted, says Kevin Graber, MD, clinical professor of neurology and the trial's site director. "The pandemic stopped us from getting off the ground," he says. The same thing happened to David K. Simon, MD, PhD, professor of neurology at Harvard Medical School and director of the Parkinson's Disease & Movement Disorders Center at Beth Israel Deaconess Medical Center in Boston, who was poised to recruit patients for a study to test a potentially neuroprotective drug in people with Parkinson's disease. "Since this study requires in-person visits, we've had to wait until our institution allows them," Dr. Simon says.

An independently published report by Benjamin Carlisle, PhD, a research fellow at the Berlin Institute of Health in Germany, found that 1,630 clinical trials had been stopped or paused because of the pandemic. The number reflects trials that cited the pandemic as the reason for stopping; the actual number may be higher, says Dr. Carlisle, who updates the data in the report regularly. Of the trials interrupted, 7.9 percent were related to neurologic conditions.

In some cases, researchers have mailed medications to study volunteers or deposited them in a lockbox at the clinic so patients can drive by and pick them up, says Serena Spudich, MD, MA, endowed professor of neurology at Yale School of Medicine in New Haven, CT, who is conducting a study on drugs to treat HIV-related neurologic problems. In other trials, nurses have made house calls to administer injections or infusions at home.

Now that some clinics have resumed in-person visits, patients are noticing changes. All personnel are wearing masks, fewer people are in the clinic at one time, and rigorous cleaning procedures have been implemented. At the Knight ADRC and at Beth Israel, study participants and staff members are screened for COVID-19 symptoms.

These protective measures come with challenges of their own. "Some of our cognitive testing is difficult when participants are wearing a mask. We have trouble understanding each other. It's particularly tough for people who are hard of hearing," says Dr. Snider. These inconveniences should be temporary, but the long-term consequences of the pandemic on neurologic research may affect recruitment and funding. On the plus side, the use of telemedicine—which is more convenient for patients because they don't have to travel—has increased for clinical trials.

In the best of situations, trial participants often worry about the safety and effectiveness of the drugs or whether they'll be given a placebo instead of the medication. During the pandemic, study subjects also worry about their exposure to the coronavirus. "A lot of patients feel uneasy about coming into a hospital for a study visit," says Dr. Simon. "That may dissuade some patients from volunteering."

The National Institutes of Health (NIH) is supporting a lot of COVID-19 research, which means there may be less money for non-COVID neurologic research, says Dr. Simon. "It's not clear to me yet if there's going to be additional funding for non-COVID-19 research or if there's going to be some shunting away from non-COVID-19 research," he says. Neurology's share of funding, therefore, could shrink. Given the economic downturn, overall funding could shrink. "In recent years, NIH funding really hasn't risen that much," says Dr. Graber. "It might stay stable, but when the national economy takes a big hit, often NIH funding takes a hit too."

Just as most neurologists transitioned to telehealth during the pandemic, researchers eventually did too. "Our clinical practice switched over within two to four weeks, first by telephone and then via videoconference call," says Dr. Snider. "On the clinical trials side it took longer, but we were able to resume some study visits using home health nurses and are now doing some assessments remotely via telephone or Zoom."

Beth Israel's Institutional Review Board, an independent committee that oversees clinical trials with human participants, "has encouraged telehealth research when feasible," says Dr. Simon. "It's variable across the studies, but some have adjusted to allow at least some of the visits or assessments to be done by telehealth." Stanford has adopted a similar policy, says Sharon J. Sha, MD, MS, clinical associate professor of neurology and medical director of the Stanford Neuroscience Clinical Trials Group. Whether and how telemedicine is incorporated depends on the trial, she adds. "For example, some of my Alzheimer's trials began allowing remote cognitive assessments and neurologic examinations."

Using telehealth for clinical trials is challenging, and data from video or phone assessments are harder to validate, says Dr. Snider. "Some sponsors are concerned about the data being reliable and meaningful." Once incorporated, though, telehealth could save money for sponsors and travel time for participants, she adds. It also may provide better information since people would be tested in a familiar environment rather than in an artificial setting in the clinic, Dr. Snider says.

When the Knight ADRC reopened in early July, Kathie Turner began the screening process for Clarity AD a second time, with cognitive testing, an electrocardiogram, and a physical exam. By early August, she had completed her PET scan, the test that had been canceled in March. To her neurologist's surprise, the scan did not show amyloid beta plaques in her brain. The finding not only disqualified her for the trial, it cast doubt on her original diagnosis.

"I remain certain that she has very mild dementia," says Turner's neurologist, Justin M. Long, MD, PhD, a Washington University assistant professor of neurology. "But I am less certain that Alzheimer's disease is the underlying cause." He and Dr. Snider are investigating whether other tests, such as cerebrospinal fluid analysis, might be helpful in determining whether Turner would be eligible for Clarity or other studies in the future.

Regardless of her ultimate diagnosis, Turner hopes to continue participating in clinical trials. "I will keep doing everything I can to change the outcome of whatever it is I am fighting," she says.

Clinical Trials Seeking Volunteers

Clarity AD

• What: This phase 3 trial tests the effects of an antibody against amyloid beta on memory and thinking in patients with mild Alzheimer's disease. Patients will receive intravenous infusions of the drug or a placebo every two weeks and take memory and thinking tests at the start of the trial and after 18 months. At that point, patients who received the placebo may be able to switch to the study drug as part of an open-label extension.
• Where: 250 sites across the United States and the world. 
• When: Recruiting now
• Who: Contact individual study sites or Eisai medical information at 888-274-2378.
• Modifications for coronavirus: Patients participating at the Knight ADRC study site can receive infusions at home. Check-in is done by Zoom or phone whenever possible, but brain scans and cognitive assessments require in-person visits.

Alzheimer's Prevention Trial Webstudy

• What: An observational study that aims to identify people who might be at risk for Alzheimer's disease before they start showing symptoms, and to create a pool of subjects for other clinical trials. Healthy people between the ages of 50 and 85 may participate. Two thinking and memory tests every three months are required.
• When: Recruiting now
• Who: Email info@aptwebstudy.org for details.
• Modifications for coronavirus: Conducted online

COVID-19 and Neurology

• What: This study monitors the long-term neurologic effects of COVID-19 on people who have recovered from the virus.
• Where: New Haven, CT
• When: Fall 2020
• Who: Contact Dr. Serena Spudich at serena.spudich@yale.edu.
• Modifications for coronavirus: In development; some examinations may be conducted via telehealth.

Trial by Virus

While the pandemic has interrupted many clinical trials, it has sparked others. As they treat patients, neurologists are gathering data on the neurologic symptoms of COVID-19. And a department that shifted neurology visits from in-person to remote took the opportunity to study telehealth itself.

Before COVID-19 hit Connecticut hard, two researchers at Yale School of Medicine in New Haven-Serena Spudich, MD, MA, endowed professor of neurology, and Shelli Farhadian, MD, PhD, assistant professor of infectious diseases—had decided to track the coronavirus' effect on the brain. For their study, doctors are drawing blood and taking nasopharyngeal swabs from patients and asking about a variety of symptoms, including neurologic ones. At press time, about 300 people had enrolled.

Researchers often analyze case studies of unusual symptoms or review charts to see what doctors have documented, says Dr. Spudich. These accounts usually report the most pronounced or severe symptoms, such as trouble breathing or needing to use a ventilator. "They don't necessarily tell us whether the patient also had a headache," says Dr. Spudich, who is collecting more systematic information with Dr. Farhadian by asking every patient about the same set of neurologic symptoms.

The team also plans to study the long-term neurologic effects of the virus once patients recover. "Because so many people had neurologic symptoms while they were acutely ill, the question is, does that leave any kind of lasting impact?" says Dr. Spudich.

Another pandemic-related study was done at Children's Hospital of Philadelphia (CHOP), this one on the efficacy of telemedicine. From March 16 through April 24, CHOP neurologists conducted 2,589 telehealth appointments, by either phone or videoconferencing. They made notes about the quality and feasibility of each, including whether there were technical problems and whether an in-person follow-up was necessary.

Doctors flagged 5 percent of the visits as requiring an in-person follow-up—which suggests telemedicine sufficed an overwhelming majority of the time. "Before, researchers didn't have data about how many telemedicine visits in child neurology were adequate and didn't require immediate in-person follow-up," says Ingo Helbig, MD, a pediatric neurologist at CHOP. "We also didn't know whether it reached children of all ages and all diagnoses. Now we can say that telemedicine in child neurology works."