However, researchers remain determined to forge ahead — with many redesigning their studies, at least in part to optimize the safety of their participants and research staff.
Keeping people engaged while protocols are on hold; expanding normal safety considerations; and re-enlisting statisticians to keep their findings as significant as possible are just some of study survival strategies underway.
Alzheimer's Disease Research on Hold
The pandemic is having a significant impact on Alzheimer's research, and medical research in general, says Heather Snyder, PhD, vice president, Medical & Scientific Relations at the Alzheimer's Association.
"Many clinical trials worldwide are pausing, changing, or halting the testing of the drug or the intervention," she told Medscape Medical News. "How the teams have adapted depends on the study," she added. "As you can imagine, things are changing on a daily basis."
The US Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) trial, for example, is on hold until at least May 31. The Alzheimer's Association is helping to implement and fund the study along with Wake Forest University Medical Center.
"We're not randomizing participants at this point in time and the intervention — which is based on a team meeting, and there is a social aspect to that — has been paused," Snyder said.
Another pivotal study underway is the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s study (the A4 Study). Investigators are evaluating if an anti-amyloid antibody, solanezumab (Eli Lilly and Co), can slow memory loss among people with amyloid on imaging but no symptoms of cognitive decline at baseline.
"The A4 Study is definitely continuing. However, in an effort to minimize risk to participants, site staff and study integrity, we have implemented an optional study hiatus for both the double-blind and open-label extension phases," lead investigator Reisa Anne Sperling, MD, told Medscape Medical News.
"We wanted to prioritize the safety of our participants as well as the ability of participants to remain in the study…despite disruptions from the COVID-19 pandemic," said Sperling, who is professor of neurology at Harvard Medical School and director of the Center for Alzheimer Research and Treatment at Brigham and Women's Hospital and Massachusetts General Hospital in Boston.
The ultimate goal is for A4 participants to receive the full number of planned infusions and assessments, even if it takes longer, she added.
Many AD researchers outside the United States face similar challenges. "As you probably are well aware, Spain is now in a complete lockdown. This has affected research centers like ours, Barcelonaβeta Brain Research Center, and the way we work," José Luís Molinuevo Guix, MD, PhD, told Medscape Medical News.
All participants in observational studies like the ALFA+ study and EPAD initiatives, as well as those in trials including PENSA and AB1601, "are not allowed, by law, to come in, hence from a safety perspective we are on good grounds," added Molinuevo Guix, who directs the Alzheimer's disease and other cognitive disorders unit at the Hospital Clinic de Barcelona.
The investigators are creating protocols for communicating with participants during the pandemic and for restarting visits safely after the lockdown has ended.
Stroke Studies Amended or Suspended
A similar situation is occurring in stroke trials. Stroke is "obviously an acute disease, as well as a disease that requires secondary prevention," Mitchell Elkind, MD, president-elect of the American Heart Association, told Medscape Medical News.
"One could argue that patients with stroke are going to be in the hospital anyway — why not enroll them in a study? They're not incurring any additional risk," he said. "But the staff have to come in to see them, and we're really trying to avoid exposure."
One ongoing trial, the AtRial Cardiopathy and Antithrombotic Drugs In Prevention After Cryptogenic Stroke (ARCADIA), stopped randomly assigning new participants to secondary prevention with apixaban or aspirin because of COVID-19. However, Elkind and colleagues plan to provide medication to the 440 people already in the trial.
"Wherever possible, the study coordinators are shipping the drug to people and doing follow-up visits by phone or video," said Elkind, chief of the Division of Neurology Clinical Outcomes Research and Population Sciences at Columbia University in New York City.
Protecting patients, staff, and ultimately society is a "major driving force in stopping the randomizations," he stressed.
ARCADIA is part of the StrokeNet prevention trials network, run by the NIH's National Institute of Neurologic Disorders and Stroke (NINDS). Additional pivotal trials include the Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST) and the Multi-arm Optimization of Stroke Thrombolysis (MOST) studies, he said.
Joseph Broderick, MD, director of the national NIH StrokeNet, agreed that safety comes first. "It was the decision of the StrokeNet leadership and the principal investigators of the trials that we needed to hold recruitment of new patients while we worked on adapting processes of enrollment to ensure the safety of both patients and researchers interacting with study patients," he told Medscape Medical News.
Potential risks vary based on the study intervention and the need for in-person interactions. Trials that include stimulation devices or physical therapy, for example, might be most affected, added Broderick, professor and director of the UC Gardner Neuroscience Institute at the University of Cincinnati in Ohio.
Nevertheless, "there are potential ways…to move as much as possible toward telemedicine and digital interactions during this time."
Multiple Challenges in Multiple Sclerosis
At the national level, the COVID-19 pandemic has had an "unprecedented impact on almost all the clinical trials funded by NINDS," said Clinton Wright, MD, director of the Division of Clinical Research at NINDS. "Investigators have had to adapt quickly."
Supplementing existing grants with money to conduct research on COVID-19 and pursuing research opportunities from different institutes are "some of the creative approaches [that] have come from the NIH [National Institutes of Health] itself," Wright said. "Other creative approaches have come from investigators trying to keep their studies and trials going during the pandemic."
In clinical trials, "everything from electronic consent to in-home research drug delivery is being brought to bear."
"A few ongoing trials have been able to modify their protocols to obtain consent and carry out evaluations remotely by telephone or videoconferencing," Wright said. "This is especially critical for trials that involve medical management of specific risk factors or conditions, where suspension of the trial could itself have adverse consequences due to reduced engagement with research participants."
For participants already in MS studies, "each upcoming visit is assessed for whether it's critical or could be done virtually or just skipped. If a person needs a treatment that cannot be postponed or skipped, they come in," Jeffrey Cohen, MD, director of the Experimental Therapeutics Program at the Mellen Center for Multiple Sclerosis Treatment and Research at the Cleveland Clinic, Ohio, told Medscape Medical News.
New study enrollment is largely on hold and study visits for existing participants are limited, said Cohen, who is also president of the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).
Some of the major ongoing trials in MS are "looking at very fundamental questions in the field," Cohen said. The Determining the Effectiveness of earLy Intensive Versus Escalation Approaches for RRMS (DELIVER-MS) and Traditional Versus Early Aggressive Therapy for Multiple Sclerosis (TREAT-MS) trials, for example, evaluate whether treatment should be initiated with one of the less efficacious agents with escalation as needed, or whether treatment should begin with a high-efficacy agent.
Both trials are currently on hold because of the pandemic, as is the Best Available Therapy Versus Autologous Hematopoietic Stem Cell Transplant for Multiple Sclerosis (BEAT-MS) study.
"There has been a lot of interest in hematopoietic stem cell transplants and where they fit into our overall treatment strategy, and this is intended to provide a more definitive answer," Cohen said.
Making the Most of Down Time
"The pandemic has been challenging" in terms of ongoing MS research, said Benjamin M. Segal, MD, chair of the Department of Neurology and director of the Neuroscience Research Institute at The Ohio State University Wexner Medical Center, Columbus.
"With regard to the lab, our animal model experiments have been placed on hold. We have stopped collecting samples from clinical subjects for biomarker studies.
"However, my research team has been taking advantage of the time that has been freed up from bench work by analyzing data sets that had been placed aside, delving more deeply into the literature, and writing new grant proposals and articles," he added.
Two of Segal's trainees are writing review articles on the immunopathogenesis of MS and its treatment. Another postdoctoral candidate is writing a grant proposal to investigate how coinfection with a coronavirus modulates CNS pathology and the clinical course of an animal model of MS.
"I am asking my trainees to plan out experiments further in advance than they ever have before, so they are as prepared as possible to resume their research agendas once we are up and running again," Segal said.
Confronting current challenges while planning for a future less disrupted by the pandemic is a common theme that emerges.
"The duration of this [pandemic] will dictate how we analyze the data at the end [for the US POINTER study]. There is a large group of statisticians working on this," Snyder said.
Harvard Medical School's Sperling also remains undeterred.
"This is definitely a challenging time, as we must not allow the COVID-19 to interfere with our essential mission to find a successful treatment to prevent cognitive decline in AD. We do need, however, to be as flexible as possible to protect our participants and minimize the impact to our overall study integrity," she said.
Molinuevo Guix, of the Barcelonaβeta Brain Research Center, is also determined to continue his AD research.
"I am aware that after the crisis, there will be less [risk] but still a COVID-19 infection risk, so apart from trying to generate part of our visits virtually, we want to make sure we have all necessary safety measures in place. We remain very active to preserve the work we have done to keep up the fight against Alzheimer's and dementia," he said
Such forward thinking also applies to major stroke trials, said University of Cincinnati's Broderick.
"As soon as we shut down enrollment in stroke trials, we immediately began to make plans about how and when we can restart our stroke trials," he explained. "One of our trials can do every step of the trial process remotely without direct in-person interactions and will be able to restart soon."
An individualized approach is needed, Broderick added.
"For trials involving necessary in-person and hands-on assessments, we will need to consider how best to use protective equipment and expanded testing that will likely match the ongoing clinical care and requirements at a given institution.
"Even if a trial officially reopens enrollment, the decision to enroll locally will need to follow local institutional environment and guidelines. Thus, restart of trial enrollment will not likely be uniform, similar to how trials often start in the first place," Broderick added.
The NIH published uniform standards for researchers across its institutes to help guide them during the pandemic.
Future contingency plans also are underway at the NINDS.
"As the pandemic wanes and in-person research activities restart, it will be important to have in place safety measures that prevent a resurgence of the virus, such as proper personal protective equipment for staff and research participants, said Wright, the clinical research director at NINDS.
For clinical trials, NINDS is prepared to provide supplemental funds to trial investigators to help support additional activities undertaken as a result of the pandemic.
"This has been an instructive experience. The pandemic will end, and we will resume much of our old patterns of behavior," said Ohio State's Segal. "But some of the strategies that we have employed to get through this time will continue to influence the way we communicate information, plan experiments, and prioritize research activities in the future, to good effect."
Snyder, Sperling, Molinuevo Guix, Elkind, Broderick, Wright, Cohen, and Segal have disclosed no relevant disclosures.
Medscape Medical News © 2020
Cite this: Trials and Tribulations: Neurology Research During COVID-19 - Medscape - Apr 29, 2020.