Trials and Tribulations: Neurology Research During COVID-19 – Medscape

With some pivotal trials on hold, the COVID-19 pandemic is slowing the pace of research in Alzheimer's disease (AD), stroke, and multiple sclerosis (MS).

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.

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 theAlzheimer'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 Alzheimers 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 tominimize risk to participants, site staff and study integrity, we have implemented an optional study hiatus for both the double-blind andopen-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 theability of participants to remain in the studydespitedisruptions from the COVID-19 pandemic," said Sperling, who is professor of neurology at Harvard Medical School and director of the Center forAlzheimer Research andTreatment at Brigham and Women'sHospital andMassachusetts GeneralHospital 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, Barcelonaeta Brain Research Center, and the way we work," Jos Lus 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.

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 waysto move as much as possible toward telemedicine and digital interactions during this time."

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 theMellen Center for Multiple Sclerosis Treatment and Researchat 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.

"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 traineesare 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 asflexible as possible to protect our participants and minimize the impact to our overall study integrity," she said.

Molinuevo Guix, of the Barcelonaeta 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.

Follow Damian McNamara on Twitter: @MedReporter. For more Medscape Neurology news, join us on Facebook and Twitter.

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Trials and Tribulations: Neurology Research During COVID-19 - Medscape

Into the Lungs and Beyond – Harvard Medical School

This article is part of Harvard Medical Schoolscontinuing coverageof medicine, biomedical research, medical education and policy related to the SARS-CoV-2 pandemic and the disease COVID-19.

What makes SARS-CoV-2, the virus behind COVID-19, such a threat?

A new study in Cell led by researchers at Harvard Medical School, Boston Children's Hospital and MIT pinpoints the likely cell types the virus infects.

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The study also unexpectedly showed that one of the bodys main defenses against viral infections may actually help the virus infect those very cells.

The study, published as a peer-reviewed pre-proof, will help focus efforts to understand what SARS-CoV-2 does in the body, why some people are more susceptible, and how best to search for treatments, the researchers say.

Multiple research models

When news broke about a new coronavirus in China, Jose Ordovas-Montanes, assistant professor of pediatrics at HMS and Boston Childrens, and colleague Alex Shalek at MIT had already been studying different cell types from throughout the human respiratory system and intestine. They also had gathered data from primates and mice.

In February, they began diving into these data.

We started to look at cells from tissues such as the lining of the nasal cavity, the lungs and gut, based on reported symptoms and where the virus has been detected, said Ordovas-Montanes, who is co-senior author of the new study along with Shalek. We wanted to provide the best information possible across our entire spectrum of research models.

COVID-19-susceptible cells

Recent research had found that SARS-CoV-2, like the closely related SARS-CoV that caused the SARS pandemic, uses a receptor called ACE2 to gain entry into human cells, aided by an enzyme called TMPRSS2.

That led Ordovas-Montanes, Shalek and colleagues to ask a simple question: Which cells in respiratory and intestinal tissue express both ACE2 and TMPRSS2?

To get the answer, the team turned to single-cell RNA sequencing. This identifies which of roughly 20,000 genes are on in individual cells.

They found that only a tiny percentage of human respiratory and intestinal cellsoften well below 10 percentmake both ACE2 and TMPRSS2.

Those cells fall into three types: goblet cells in the nose that secrete mucus; lung cells known as type II pneumocytes that help maintain the alveoli (the sacs where oxygen is taken in); and one type of so-called enterocytes that line the small intestine and are involved in nutrient absorption.

Sampling from non-human primates showed a similar pattern of susceptible cells.

Many existing respiratory cell lines may not contain the full mix of cell types, and may miss the types that are relevant, said Ordovas-Montanes. Once you understand which cells are infected, you can start to ask, How do these cells work? Is there anything within these cells that is critical for the viruss life cycle?

"With more refined cellular models, we can perform better screens to find what existing drugs target that biology, providing a stepping stone to go into mice or non-human primates.

Interferon: Helpful or harmful?

But it was the studys second finding that most intrigued the scientists.

They discovered that the ACE2 gene, which encodes the receptor SARS-CoV-2 uses to enter human cells, is stimulated by interferonone of the bodys main defenses when it detects a virus.

Interferon actually turned on the ACE2 gene at higher levels, potentially giving the virus new portals to get in.

ACE2 is also critical in protecting people during various types of lung injury, said Ordovas-Montanes. When ACE2 comes up, thats usually a productive response. But since the virus uses ACE2 as a target, we speculate that it might be exploiting that normal protective response.

Interferons, in fact, are being tested as a treatment for COVID-19. Whether they would help or do more harm than good is not yet clear.

It might be that in some patients, because of the timing or the dose, interferon can contain the virus, while in others, interferon promotes more infection, said Ordovas-Montanes. We want to better understand where the balance lies, and how we can maintain a productive antiviral response without producing more target cells for the virus to infect.

ACE inhibitors and cytokine storms

The findings may also raise new lines of inquiry around ACE inhibitors. These drugs are commonly used to treat hypertension, which has been linked to more severe COVID-19 disease. Are ACE inhibitors affecting peoples risk?

ACE and ACE2 work in the same pathway, but they actually have different biochemical properties, Ordovas-Montanes said. Its complex biology, but it will be important to understand the impact of ACE inhibitors on peoples physiological response to the virus.

Its also too soon to try to relate the study findings to the cytokine storm, a runaway inflammatory response that has been reported in very sick COVID-19 patients.

Cytokines are a family of chemicals that rally the bodys immune responses to fight infections. Interferon is part of the family.

It might be that were seeing a cytokine storm because of a failure of interferon to restrict the virus to begin with, so the lungs start calling for more help," he said. "Thats exactly what were trying to understand right now.

Future directions

In addition, the team wants to explore what SARS-CoV-2 is doing in the cells it targets and to study tissue samples from children and adults to understand why COVID-19 is typically less severe in younger people.

Carly Ziegler, Samuel Allon and Sarah Nyquist of MIT and Harvard and Ian Mbano of the Africa Health Research Institute were co-first authors on the paper. The study was done in collaboration with the Human Cell Atlas Lung Biological Network.

This has been an incredible community effort not just within Boston, but also with collaborators around the world who have shared their unpublished data to try and make potentially relevant information available as rapidly as possible, said Shalek. Its inspiring to see how much can be accomplished when everyone comes together to tackle a problem.

This work was supported in part by the National Institutes of Health (U24AI118672, AI201700104, R56AI139053, R01GM081871, T32GM007753, AI078908, HL111113, HL117945, R37AI052353, R01AI136041, R01HL136209, U19AI095219, U19HL129902, UM1AI126623, U19AI051731, R01HL095791, R33AI116184, U19AI117945, UM1AI126617), Bill and Melinda Gates Foundation, MIT Stem Cell Initiative through Foundation MIT, Aeras Foundation, Damon Runyon Cancer Research Foundation (DRG-2274-16), Richard and Susan Smith Family Foundation, UMass Center for Clinical and Translational Science Project Pilot Program, Office of the Assistant Secretary of Defense for Health Affairs (W81XWH-15-1-0317), P.B. Fondation pour la Recherche Medicale (DEQ20180339158) and Agence Nationale pour la Recherche (ANR-19-CE14-0027).

Adapted from a post in Discoveries, the Boston Children's clinical and research innovation portal.

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Into the Lungs and Beyond - Harvard Medical School