GAP President John Dwyer was quoted in AlzForum about the challenges and changes in Alzheimer’s clinical trials due to COVID-19.
As Alzheimer’s research comes to, scientists are taking stock of the damage. In the academic world, the main cost was time (see Part 1 of this story). For most clinical studies, the damage was more tangible, with at least a brief interruption in dosing, and a complete halt of recruitment. Larger trials are bouncing back, with clinical visits and enrollment poised to resume in most areas. For some trials, however, the shutdown proved fatal. As researchers are grappling with how to move forward, new publications and the Food and Drug Administration are guiding them on ways to modify protocols and adjust statistical analyses. To help keep elderly study volunteers safe, many interactions are moving from in-person to phone or video. Researchers said they will adapt and forge ahead.
- Some clinical trials weathered the COVID-19 storm while others were terminated.
- Guidelines are out for how to restart human studies and adjust statistical analyses.
- Some patients declined faster during the pandemic, and trial recruitment slowed.
Most clinical trials hit pause at the same time as laboratory research, though some continued dosing (Mar 2020 news). As with benchwork, the rate of opening varies around the world.
In Australia, in-person visits stopped only briefly. Restrictions have already been lifted, with studies allowed to recruit anew, said Chris Rowe at the University of Melbourne. Staff screen participants for coronavirus exposure before a visit, check their temperatures at the door, stay at a distance during the visit, and clean thoroughly afterward. Masks are not required. Even so, some participants are reluctant to leave home for clinic visits, and have asked to delay their assessments, Rowe noted.
In Sweden, researchers are once again collecting biofluids and scanning brains, and recruitment of new patients is expected to resume in a few weeks, said Oskar Hansson at Lund University. The BioFINDER2 study still has a backlog of about 200 MRI scans, because the nurses who run the scanners are needed to care for COVID-19 patients.
In the U.S., clinical studies are opening up much more slowly. No in-person visits are allowed yet at most Boston institutions. Gad Marshall at Brigham and Women’s Hospital plans to bring back trial participants in July, and start recruiting new patients in August. To reduce their need to travel, the researchers are considering delivering drug infusions at home for immunotherapy trials, and will continue to use computer-based remote assessments as much as possible. Reisa Sperling at BWH is starting a pilot study of smartphone cognitive testing. Some sites for the A4 prevention trial are starting to open, but Boston is being cautious, Sperling noted.
“As the participants for AD trials are in the highest risk group [for COVID-19], I am not optimistic that we can work with them soon,” wrote Li-Huei Tsai at the Massachusetts Institute of Technology, Cambridge.
Likewise, in hard-hit New York City, in-person assessments may not resume for several weeks. “The risk to older persons and other vulnerable populations is still being appreciated as a significant threat,” Mary Sano at Mount Sinai School of Medicine wrote to Alzforum. In Chicago, too, all in-person visits remain on hold, said David Bennett at Rush University.
Other U.S. areas fared better. At Washington University in St. Louis, in-person visits are on again for trials, but not for observational studies. “Most of our participants missed at least some doses of study medications, but all are resuming now,” wrote Joy Snider at the Knight Alzheimer’s Disease Research Center Clinical Trials Unit. Imaging schedules were the most disrupted, with some patients having to stop dosing because they could not complete required imaging, and some new participants failing screening procedures due to missed scans. They will be rescreened, delaying the recruitment timeline. Meanwhile, in rural Rochester, Minnesota, dosing has restarted for trials, and observational visits will follow in a few weeks, said David Knopman at the Mayo Clinic there.
In Japan, large studies like A4 had a hiatus of one to two months. Although participants are coming back now, some have been lost to the study because they became frail having to isolate at home, and can no longer participate, said Takeshi Iwatsubo at the University of Tokyo. For trials that are still enrolling, such as the Japanese Trial-Ready Cohort (J-TRC), the lifestyle study J-MINT and a trial of the BAN2401 anti-A? immunotherapy, recruitment of healthy elderly volunteers has slowed (Nov 2018 news). “Activities are slowly coming back, but with many delays and limitations,” Iwatsubo wrote.
Some parts of the world, such as South America, are still waiting for the peak of the outbreak. In Argentina, lockdown continues, with no observational study visits allowed, Ricardo Allegri at the Instituto de Investigaciones Neurológicas (FLENI) in Buenos Aires wrote to Alzforum. Dosing does continue for some trials, with blood draws and drug delivery done in patients’ homes, he added.
Large multisite trials face a particular challenge due to different conditions in different places. ADNI stopped visits across the board, and sites are only now beginning to open up, said its director, Michael Weiner at the University of California, San Francisco. Similarly, nearly all academic sites and medical centers in the Global Alzheimer’s Platform Foundation shut down at the height of the pandemic. John Dwyer, who runs GAP from Washington, D.C., said that about 80 percent of these sites are now active again and planning to start new trials. Private clinical trial sites in the GAP network opened earlier, starting new trials in May. Even during the height of the pandemic, most GAP sites maintained dosing, except for trials that were halted by the sponsor. “A great deal of ingenuity and collaboration with sponsors made this possible,” Dwyer said. “One site repurposed an ambulance and dosed subjects there.”
Roche reported temporary interruptions in dosing at some site locations for its gantenerumab, semorinemab, and crenezumab programs. The company will extend the double-blind portion of its Phase 3 GRADUATE 1 and 2 studies of gantenerumab between three to six months to make up time lost. It will also extend the Phase 2 LAURIET study of semorinemab for up to six months. No changes are planned for the Phase 2 TAURIEL study of semorinemab, or the crenezumab Colombian secondary prevention study. For the latter, the dosing interruption lasted for two months and is not expected to affect the outcome, Elizabeth Walmsley at Roche wrote to Alzforum.
Other global trials were delayed but are getting back on track. Paul Aisen at the University of Southern California, San Diego, said that the AHEAD 3-45 trial, which will test BAN2401 in primary and secondary prevention paradigms, will begin screening participants at most sites in July.
However, some studies have been lost altogether. The EPAD longitudinal cohort study has been terminated, with no more funding available to resume visits. A trial of intranasal insulin lost power due to dosing disruptions and has been scrapped. Other studies, such as a trial of the antibiotic rifaximin and a fecal transplant study, have been suspended.
Researchers Confer About How to Limit Disruption
Scientists are learning how to cope with coronavirus, altering procedures to keep trials viable. One concern is safety. For example, how to collect and handle biofluids, given that they could be contaminated with coronavirus? In the June 19 Journal of Alzheimer’s Disease, researchers led by Suzanne Schindler at WashU tackle this question. Together with biofluid experts around the world, Schindler came up with safety guidelines for biofluid collection that echo those being used in research labs: masks and personal protective equipment, prescreening of patients, physical distance, hand washing.
Those protocols appear adequate, as laboratories collecting biofluids have not reported any increase in infections among technicians, Schindler said. Schindler herself recently did lumbar punctures using these procedures, and said it went smoothly. “I felt more comfortable doing the clinic than I did going to the grocery store later that day,” she told Alzforum. “I think it can be done safely with minimal risk to patients and staff.”
For the most part, handling of the fluids themselves can follow normal procedures. “We already treat these specimens as if they are infectious,” Schindler said, noting that she often performs LPs on people infected with HIV or hepatitis C. One new caution for samples potentially infected with coronavirus is to avoid procedures such as vortexing that could produce aerosols. In small studies to date, coronavirus has been detected in the blood of up to 15 percent of infected people (Huang et al., 2020; Chen et al., 2020; Wang et al., 2020). It is very rare in cerebrospinal fluid, but has been found in at least one patient (Helms et al., 2020; Schaller et al., 2020; Huang et al., 2020).
Today, the Alzheimer’s Association is hosting a webinar to offer guidance for restarting clinical studies. The presenters are Greg Jicha at the University of Kentucky College of Medicine, Lexington, José Luis Molinuevo at Barcelonab Brain Research Center, and Vijayalakshmi Ravindranath at the Indian Institute of Science in Bangalore.
The association has been facilitating online meetings with leaders of many of the major dementia trials to discuss problems and brainstorm solutions. A particular focus is minimizing the harm protocol deviations do to data integrity. “There are big questions about how to deal with missing data, what are considerations for the trial statistics, and what adjustments need to be made,” Maria Carrillo of the Alzheimer’s Association wrote to Alzforum.
A new guidance from the FDA may be helpful. The agency suggests statistical methods to deal with missing data and adjust analyses. Likewise, a recent JAMA paper outlines approaches for maintaining trial integrity, such as excluding the period of time when the trial was disrupted, stratifying data that were collected differently, and using confidence intervals rather than p values (Fleming et al., 2020).
Dwyer noted that the long-term effects of research study stoppages and delays are not yet clear. In particular, studies may run out of funding due to the hiatus. “We hope that supplemental grants will be forthcoming so that research that was stopped can be resumed, but precious time has been lost in all studies,” he wrote.
The National Institutes of Health have issued policy notices promising flexibility in application timelines and how funds are administered. “The National Institute on Aging is working with NIH and HHS to help ease the burden and provide guidance and policies to ensure research can continue as much as is safe during the pandemic and, later, can resume with minimal negative impact on data already collected,” NIA director Richard Hodes wrote to Alzforum.
Researchers Fear Drop in Recruitment
How will the stress of the pandemic affect Alzheimer’s research participants? Patients and their caregivers are particularly vulnerable to ill effects from changes in their routine and a lack of access to medical facilities (Mar 2020 news). Researchers are gathering data on this to find out what help patients need, and to assess how these stresses affect clinical and cognitive testing data. “Several studies have added components to examine the effect of the COVID-19 lockdown on cognition, mood, and other items of interest,” said William Klunk at the University of Pittsburgh.
Lisa Barnes at Rush University has developed a questionnaire to help with this task. To be administered to Alzheimer’s patients or caregivers, it can assess changes in their cognition, mood, or behavior, and whether those might be related to the stress of the pandemic. “We don’t know whether, or how, the virus may cause problems with cognition either directly or indirectly,” Barnes noted. The questionnaire will also measure racial, ethnic, or geographic disparities. Many studies show that underserved communities have worse outcomes after coronavirus infection. The questionnaire will be distributed to all Alzheimer’s Disease Research Centers for optional use with patients. “Once the data are available, they will open up possibilities for many other interesting research questions, including the potential impact of the virus or associated stress on biomarkers of Alzheimer’s disease,” Barnes wrote.
Those who work with patients already see signs of stress. Andrea Denny at WashU runs a support group for Alzheimer’s patients. Since the pandemic began, patients have requested that their monthly check-ins be doubled to biweekly. Support meetings are held online. Patients and caregivers report disrupted routines and more confusion. Many adult day centers are closed, increasing the burden on caregivers. Caregivers are finding it difficult to run errands such as going to the grocery store, since the AD patient may forget to physically distance or may resist wearing a mask. In other cases, AD patients in assisted living have had to move to memory care units because they were unable to follow safety protocols, and kept trying to leave their rooms or argued with staff. “Essentially, the pandemic pushed them to a higher level of care, with little chance of ever returning to the assisted-living floor,” Denny said. “This pandemic has certainly made a lonely and isolated situation much harder for many people.”
Despite this, most AD patients have continued to participate in clinical trials. “I have been incredibly impressed throughout this challenging time by the dedication of our clinical trial participants,” Snider said. Participants at WashU are eager to continue, and are willing to travel to the clinic or welcome study nurses into their homes. Staff have overcome technical challenges and kept their enthusiasm, she added. “Everyone has been creative and dedicated in figuring out how to adapt our procedures to be as safe as possible in the COVID era,” Snider said.
In some cases, participants have weathered the pandemic better than expected. Henne Holstege at Vrije University in Amsterdam studies a cohort of cognitively healthy centenarians who live in their homes. They all went into isolation when coronavirus hit the Netherlands, and most avoided infection. Of three participants who caught COVID-19, only one, who had other serious health issues, died. “I am extremely relieved that COVID-19 has not severely affected the centenarians in our population,” Holstege said. Nonetheless, her research has been delayed, as most of the participants are not yet comfortable having researchers enter their homes. “We’re taking it step by step,” Holstege said.
Many researchers worry that even as lockdowns end in most places, older people will continue to hesitate to leave home for study visits. They may weigh the risk/benefit ratio of participating differently than before, Klunk cautioned. This could blunt recruitment, already a challenge for Alzheimer’s trials. “Research participants will need to feel that their safety is being prioritized during visits, and many are nervous,” said Doug Galasko at the University of California, San Diego. Nancy Ip at the Hong Kong University of Science and Technology said she has already seen this effect in Hong Kong, where recruitment has dropped off since the pandemic began.
One solution is to lessen the need for in-person visits. Dwyer predicted that more studies will recruit, prescreen, and enroll participants via remote telephone and internet.
Researchers predict that the pandemic will lead to long-lasting changes in how trials are administered. Philip Scheltens at VU University, Amsterdam, said that half of the clinical check-ins at his institution will now be done remotely. “COVID-19 made changes that are here to stay,” Scheltens said.
Dwyer said these changes will help researchers deal with future outbreaks. “Researchers know more about how to operate safely during a COVID-dominated environment. And they will be better prepared to adapt to serving trial participants if there is a resurgence of COVID,” he wrote. Martin Ingelsson at Uppsala University, Sweden, agreed. “I think it will be possible to live with the disease, and [that will] allow us to resume more and more of our usual activities, including AD research.”—Madolyn Bowman Rogers
Originally posted by AlzForum on June 23, 2020.