Part 2 of a two-part story. Click here for Part 1.
The COVID-19 pandemic has touched every aspect of health, from neurologic disease broadly (see Part 1 of this story) to clinical research. At the 15th International Conference on Alzheimer's and Parkinson's Diseases, held virtually March 9–14, clinical investigators talked about how they tried to prevail despite interruptions and preserve their trials. Looking to the future, how they will handle people who had COVID-19, or develop it during a trial, remains unclear.
- Home nursing allowed dosing to continue in Roche's gantenerumab trials.
- Other trials used telemedicine to continue recruitment and interventions.
- How will researchers include people who had COVID in clinical trials?
"Many more questions were raised than answered," Ronald Petersen, Mayo Clinic, Rochester, Minnesota, told Alzforum. One thing is certain—the research community will feel the effects of trial delays for a long time. "The pandemic has delayed clinical research by three or four years," Tomislav Babic, Worldwide Clinical Trials, U.K., estimated.
At AD/PD, Alison Searle, who works in clinical operations at Roche, described what her company did to continue Phase 3 trials testing whether the plaque-binding antibody gantenerumab slows cognitive decline in early AD. Gantenerumab is injected under the skin and was designed to be given at home, either by the participant or a home nurse. Serendipitously, this allowed researchers to ramp up at-home visits once social distancing became necessary.
In March 2020, Roche expanded home nursing capacity to almost twice as many participants at twice the number of sites. Home visits were allowed earlier in the trial, at week 12 versus week 16, which opened up home administration for most participants. Local study investigators had discretion about whether and how to continue visits based on the impact of COVID-19 in their region. There were temporary interruptions in dosing and study visits at certain sites due to the local impact of the pandemic. In total, about half of the possible home visits were completed during the first COVID peak in April 2020. The other visits were either done in the clinic or delayed by lockdowns. On average, five times more monthly home visits were made in the COVID era than before.
As COVID-19 vaccines roll out, Roche will not track who has been vaccinated, Searles said. However, it will space out vaccination and gantenerumab dosing to ensure side effects can be attributed correctly.
For its part, Eisai/Biogen also implemented home administration—in this case infusions given by a nurse—and remote assessments during trials for the anti-amyloid antibody BAN2401 (Nov 2020 news). While this change has allowed the gantenerumab and BAN2401 trials to proceed through the pandemic, other trials may be unable to do the same. "Home nursing feasibility varies by country and is not a universal solution right now," Searles noted.
How have other researchers adapted? Roy Alcalay, Columbia University, New York, described how the PD Generation (PDGENE) trial of genetic testing in Parkinson's transitioned from in-person counseling and testing to remote visits via phone. The scientists made this change because of the pandemic, and were then pleasantly surprised to discover that losing the geographic constraint of clinic location opened their trial to more participants across the country and sped up recruitment.
Mark Espeland, Wake Forest School of Medicine, Winston-Salem, North Carolina, described how the World-Wide FINGERS study group navigated through the lockdowns (Röhr et al., 2021). This network of 13 lifestyle intervention trials involves 27 countries (Kivipelto et al., 2020). Espeland and colleagues discussed three, each at a different stage. Japan's J-MINT is recruiting, the U.S. POINTER study is recruiting and delivering interventions, and Germany's AgeWell.de is delivering interventions and follow-up. Each had to adapt differently to stay the course (see image below).
Going with the Flow. In three FINGERS trials, steps were delayed to accommodate lockdowns (grayed areas) and waves of COVID-19 cases (gray bars). [Courtesy of Röhr et al., 2021, Alzheimer's & Dementia.]
J-MINT halted recruitment from late February to late May 2020, restarting in person with social distancing, masking, and other familiar safety measures. Slowed recruitment has delayed the trial by more than six months.
Just as interventions were taking off in Germany, the first lockdown grounded the AgeWell.de study. Like their Japanese counterparts, the Germans instituted COVID safety measures to resume in-person meetings as quickly as possible. They also offered telephone visits for participants reluctant to meet in person. To gauge how debilitating social distancing and closures were, the researchers mailed participants a survey during the first lockdown. They will do so again to track the pandemic's impact over time.
During its March-to-July pause, the U.S. POINTER team tried to keep its participants hopeful and motivated with regular phone and video check-ins. Virtual intervention meetings continued after the trial resumed.
The Path Forward
How to bridge the data gaps created by lockdowns is a question that haunts statisticians who are currently searching for solutions. It also plagues internal review boards as they adjust protocols. "Missing dosing and data collection appointments means that primary endpoints are not measured at the planned intervals, causing dramatic protocol deviations," Roger Nitsch, Neurimmune, Switzerland, explained. The FDA is trying to support trialists and has issued guidance on this problem.
What about people who had COVID-19? "Will someone still be eligible for a study if they were sick or treated with an experimental drug?" Petersen asked. To avoid potentially muddied results from unknown long-term effects of the virus, researchers only include people free of the disease, for now, Babic said. "Trials may specifically enroll people who had COVID-19 to study effects on neurological diseases and dementia, but trials likely will not mix COVID and non-COVID people," he explained. Researchers are just beginning to study lingering COVID symptoms, termed “long-COVID” (see Part 1 of this story).
What if a participant contracts COVID-19 during a trial? "Should you make subgroups for them, or should they be excluded?" Petersen asked. "We have not stratified people if they catch the flu while in a trial, but we may treat COVID infection differently, especially based on its severity," he added. Babic agreed, saying that researchers should not automatically drop people who develop mild COVID-19. Dietmar Thal, KU Leuven, Belgium, suggested that trials note cases of COVID-19 and monitor but do not automatically exclude these participants. "If in a few years we know that having COVID is not a big problem regarding pathophysiology and treatment of AD, then those patients could still be included in the trial," he said. Nitsch proposed trying to match how many people contract COVID-19 in each arm of a study, though this may be tricky to control.
There is no one-size-fits-all solution. In exploratory trials, counting COVID-19 as an adverse event and excluding participants who develop it during the trial may be best, Babic explained. This may not be necessary for confirmatory studies.
There is at least one upside to the pandemic—the research community has learned to adapt and become more resilient. "Clinical trial planning can now incorporate changes made during the pandemic, such as home visits and drug administration, to be better prepared for the future," Babic said.—Chelsea Weidman Burke
- COVID-19 Worsens Neurological Problems, Delirium
- Coronavirus Takes Its Toll on Alzheimer’s Clinical Studies
- In the Wake of COVID-19: Trials Interrupted, Delayed, Cancelled
- Begone 2020: Despite COVID, Alzheimer’s Research Advanced
- BAN2401 Forges AHEAD into Phase 3, Preclinical AD
- Röhr S, Arai H, Mangialasche F, Matsumoto N, Peltonen M, Raman R, Riedel-Heller SG, Sakurai T, Snyder HM, Sugimoto T, Carrillo M, Kivipelto M, Espeland MA, World‐Wide FINGERS Study Group. Impact of the COVID-19 pandemic on statistical design and analysis plans for multidomain intervention clinical trials: Experience from World-Wide FINGERS. Alzheimers Dement (N Y). 2021;7(1):e12143. Epub 2021 Mar 11 PubMed.
- Kivipelto M, Mangialasche F, Snyder HM, Allegri R, Andrieu S, Arai H, Baker L, Belleville S, Brodaty H, Brucki SM, Calandri I, Caramelli P, Chen C, Chertkow H, Chew E, Choi SH, Chowdhary N, Crivelli L, Torre R, Du Y, Dua T, Espeland M, Feldman HH, Hartmanis M, Hartmann T, Heffernan M, Henry CJ, Hong CH, Håkansson K, Iwatsubo T, Jeong JH, Jimenez-Maggiora G, Koo EH, Launer LJ, Lehtisalo J, Lopera F, Martínez-Lage P, Martins R, Middleton L, Molinuevo JL, Montero-Odasso M, Moon SY, Morales-Pérez K, Nitrini R, Nygaard HB, Park YK, Peltonen M, Qiu C, Quiroz YT, Raman R, Rao N, Ravindranath V, Rosenberg A, Sakurai T, Salinas RM, Scheltens P, Sevlever G, Soininen H, Sosa AL, Suemoto CK, Tainta-Cuezva M, Velilla L, Wang Y, Whitmer R, Xu X, Bain LJ, Solomon A, Ngandu T, Carrillo MC. World-Wide FINGERS Network: A global approach to risk reduction and prevention of dementia. Alzheimers Dement. 2020 Jul;16(7):1078-1094. Epub 2020 Jul 5 PubMed.