Throughout most of the COVID-19 pandemic, the primary research focus has been on the respiratory and inflammatory symptoms present during the illness’s acute phase. However, increasing evidence is emerging that cognitive symptoms persist well beyond the acute phase and well after patients have cleared the virus. These cognitive symptoms, such as problems with memory, attention, and reasoning, lead us to a number of questions about the connection between COVID-19 and cognition. What causes cognitive symptoms in COVID-19 patients and patients recovering from COVID-19? Which patients are at greatest risk of cognitive symptoms? What is the best way to assess cognition in COVID-19 patients? How long will the cognitive changes last, and are they permanent? Here we will look at what we currently know and discuss how to conduct future research effectively, including suggesting cognitive assessments that may help answer important questions about cognitive decline and COVID-19.

Causes of Cognitive Symptoms in COVID-19 Patients

Based on animal models and human studies, there are good reasons to expect that a virus like COVID-19 could have harmful cognitive effects. Some of the risk factors for severe COVID-19, such as advanced age, hypertension, diabetes, obesity, and COPD, make people more susceptible to cognitive complications during and after inflammatory states. This increased risk, or cognitive frailty, means that individuals most likely to suffer from severe COVID-19 are also the most susceptible to cognitive decline based on inflammation from the disease.

Lung damage from COVID-19 can result in hypoxemia, a below-normal level of oxygen in the blood. Cognitive decline has been observed in patients with conditions like COPD and sleep apnea who also experience chronic hypoxemia. Vascular inflammation may also contribute to cognitive decline in COVID-19 patients. Severe COVID-19 is associated with hyperinflammatory states, which in turn increase the risk of delirium. The resulting delirium can cause both long-term and short-term cognitive deficits. It is also likely that the virus has a direct neurological effect resulting from the breakdown of the blood brain barrier, vasogenic edema, oxidative stress, and microglial activation.

Additionally, because of the transmissibility of the disease, COVID-19 patients have not been afforded some of the measures frequently taken with ICU patients to minimize the potential of cognitive decline, such as the presence of family members to talk to sedated patients.

Identifying Patients at Greatest Risk

Patients who suffered from moderate to severe cases appear to be at higher risk for cognitive symptoms along with “long haulers,” patients who have cleared the virus but continue to have chronic symptoms. Some comorbidities make cognitive decline following COVID-19 more likely. These include hypertension, diabetes, obesity, and COPD. Advanced age also increases the risk.

Some treatments used during the acute phase of the illness are associated with an increased risk of cognitive decline. This risk is particularly apparent for mechanical ventilation and prolonged sedation. Patients with lung scarring regardless of illness severity during the acute phase appear to be at higher risk, possibly due to chronic hypoxemia.

Although many of the studies focused on moderate to severe cases or cases of long haulers, one of the largest studies examining more than 84,000 patients in the UK found that even patients with mild cases that did not report breathing difficulty exhibited cognitive deficits. The study did, however, show that the magnitude of the cognitive deficits scaled with symptom severity.

Future Research in COVID-19 and Cognition

Because of this disease’s relative newness, we do not know whether the cognitive deficits associated with COVID-19 are long-term, although they clearly last beyond the acute phase of the disease. Longitudinal studies examining cognitive and psychiatric changes will be important in understanding the potential impact. Some of the studies showed that executive function is one of the areas affected, but a clear picture of which cognitive domains are impacted has not emerged. Additionally, most published research did not incorporate performance-based cognitive tasks that could improve our understanding of the impact on activities of daily living (ADLs). While there is an emerging consensus that COVID-19 can cause cognitive decline, additional work with refined research tools such as cognitive tests is needed.

VeraSci offers two tools that can provide a clearer picture of cognition in COVID-19 and patients that have recovered from COVID-19. The Brief Assessment of Cognition (BAC) assesses several different domains of cognition and is sensitive to cognitive impairment in a wide range of clinical conditions, including cancer, heart disease, Alzheimer’s disease, depression, and schizophrenia. The BAC can be administered remotely, an important consideration for assessing COVID-19 patients. The Virtual Reality Functional Capacity Assessment Tool (VRFCAT) simulates key instrumental activities of daily living (iADLs) and detects meaningful changes in patients’ lives. As we move towards the development of treatments to improve cognitive performance for COVID patients, iADLs have an important role to play in demonstrating that a given treatment provides clinically meaningful improvement.

As experts in cognition, we have the expertise you need to move your research forward, from cognitive assessments to rater training to trial design. Contact us to learn more.

References

Durham, NC—January 19, 2021—VeraSci—a global clinical research company offering eClinical software, translation services, and expertise in endpoints and assessments—is pleased to announce a new partnership with ActiGraph, a leading provider of medical-grade wearable activity and sleep monitoring devices.

VeraSci’s Innovation Lab will be incorporating ActiGraph’s CentrePoint Insight Watch into an NIH-funded study examining the relationship between real-time measurements of gait and actigraphy collected by industry-grade wearables and established cognitive and functional endpoints that are sensitive to decline early in the Alzheimer’s disease continuum.

Preliminary data have indicated a correlation between remotely captured gait and actigraphy measures and established cognition and function measures. These data suggest that wearables can provide meaningful information regarding cognitive health and may ultimately contribute to continuous assessment of cognition and function in clinical trials.

“Wearables present an incredible opportunity to gather data in ways that haven’t been feasible before. We can gather information directly while patients are engaged in their daily lives” says VeraSci CEO Dr. Rich Keefe, “Our partnership with ActiGraph advances our commitment to pairing scientific knowledge with cutting-edge technology to improve the tools and measurements available in clinical trials.”

“This partnership between ActiGraph and VeraSci provides an exciting opportunity to better understand the relationship between real-world physical behavior, function, and cognition,” said Matt Biggs, ActiGraph’s Head of Business Operations. “We believe that these types of collaborations will help to jumpstart the creation of novel digital endpoints for global health communities.”

Research reported in this release was supported by the National Institute on Aging of the National Institutes of Health Small Business Innovation Research (SBIR) program under Award Number R44AG058345. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

About VeraSci

VeraSci is a clinical research company offering eClinical software, translation services, and expertise in endpoints and assessments. VeraSci brings scientific expertise, strategic innovation, and unwavering commitment to each project, helping clients worldwide develop novel therapies. Learn more at www.verasci.com.

About ActiGraph

ActiGraph is a leading provider of medical-grade physical activity and sleep monitoring solutions for the global scientific community. ActiGraph’s FDA-cleared wearable actigraphy monitors and robust analytics platform have been widely used to quantify human movement in academic and population health research for nearly two decades. In recent years, the company’s monitoring solutions have been steadily adopted by pharmaceutical and life sciences organizations seeking to capture real-world objective outcomes related to physical activity, mobility, and sleep behavior for patients enrolled in clinical trials. For more information, visit www.actigraphcorp.com.

 

Durham, NC—December 18, 2020—VeraSci—a global clinical research company offering eClinical software, translation services, and expertise in endpoints and assessments—is concluding a successful year marked by extensive hiring and expanded service offerings. This growth has allowed the company to successfully take on an increasing number of large, global clinical trials. VeraSci has hired 49 new employees in 2020 and added capabilities in remote clinical trials, placebo response mitigation, and wearable devices.

2020 has been a challenging year for companies that provide products and services for clinical trials as COVID-19 delayed or canceled many studies. VeraSci credits its continued success to having quickly adapted to implement remote assessment methods and revise standard methods to allow the safe collection of data. These new innovative solutions prevented delays and cancellations and allowed studies to proceed without missing data.

According to VeraSci CEO Dr. Rich Keefe, “We were able to present our clients with solutions that enabled critical research to continue. Through our expertise and adaptability, we have met the unique challenges that COVID-19 presented for our industry.”

VeraSci expects growth to continue into 2021 having recently been awarded several large phase 3 clinical trials. They are actively recruiting for several open positions to support this growth. Additionally, VeraSci has plans to launch new technology products in the first half of 2021.

“We are proud of our accomplishments this year and believe they position us well for future success,” says VeraSci President Caren Gadigian, “Growing our talent pool and expanding our capabilities allows us to take on larger projects with an extended global reach while maintaining the level of quality and service our clients expect.”

About VeraSci

VeraSci is a clinical research company offering eClinical software, translation services, and expertise in endpoints and assessments. VeraSci brings scientific expertise, strategic innovation, and unwavering commitment to each project, helping clients worldwide develop novel therapies.

Neuropsychopharmacology recently published “Placebo Response Mitigation with a Participant-Focused Psychoeducational Procedure: A Randomized, Single-Blind, All Placebo Study in Major Depressive and Psychotic Disorders”. Dr. Bill Horan, Vice President Clinical Science at VeraSci, and VeraSci CEO Dr. Rich Keefe co-authored the publication.

Development programs for CNS disorders face discouragingly low success rates. Placebo response has a potentially devastating impact on CNS trials and has contributed substantially to the late-stage failure of promising treatments. According to the paper, “no empirically-validated participant focused strategies to mitigate the phenomenon have been available.”

The paper presented results from a study evaluating the efficacy of the Placebo-Control Reminder Script (PCRS), a brief script read to participants immediately before administering study assessments. The study demonstrated that participants who received the PCRS reported significantly smaller reductions in depression than those who did not (all participants were receiving placebo).

“This is an important step forward in the development of new drugs for devastating CNS disorders including depression, schizophrenia, and chronic pain,” says Dr. Horan, “A scientifically-backed instrument that reduces placebo response will allow effective treatments to show a positive signal, a necessary step in bringing new treatments to market.”

About VeraSci

VeraSci is a clinical research company offering eClinical software, translation services, and expertise in endpoints and assessments. VeraSci brings scientific expertise, strategic innovation, and unwavering commitment to each project, helping clients worldwide develop novel therapies.

This blog series shares what’s happening day-to-day in our Innovation Lab. VeraSci created the Innovation Lab to pair scientific knowledge with cutting-edge technology to improve the tools and measurements available for clinical trials. We originally presented these results at the Clinical Trials on Alzheimer’s Disease (CTAD) Digital Event. Click here to download the poster.

Measurements from validated wearable technologies have the potential to revolutionize clinical trials by facilitating site-less clinical trial designs. However, for this to become a reality, endpoints collected using wearables must undergo the same clinical and technological validation processes required by currently accepted tools. VeraSci’s Innovation Lab has been conducting an NIH-funded study examining the relationship between real-time measurements of gait and actigraphy collected by industry-grade wearables and established cognitive and functional endpoints that are sensitive to decline early in the Alzheimer’s disease continuum.

The preliminary data presented at CTAD and summarized below suggest correlations between remotely captured actigraphy and gait measures and established assessments of cognition and function, suggesting wearables can provide meaningful information regarding cognitive health and may ultimately contribute to continuous assessment of cognition and function in clinical trials.

About the Study

The study has enrolled 38 older adults (55+), including 26 healthy controls and 12 age-matched individuals with subjective cognitive decline. Participants attended two in-person study visits separated by one week of passive data collection using two wearable devices. At the first visit, participants completed well-established motor, cognitive, and functional assessments, including the Computerized Finger Tapping Test (CTAP), Timed 25-Foot Walk Test (T25-FW), Timed “Up and Go” (TUG), VeraSci’s Brief Assessment of Cognition (BAC), and the Virtual Reality Functional Capacity Assessment Tool (VRFCAT). At the second visit, participants repeated a portion of the in-office walking assessments.

The two wearable devices used by participants were the Empatica E2 wristband and the Moticon Science Insoles. The Empatica E2 wristband provided continuous measurement of motor activity (i.e., actigraphy), galvanic skin response, skin temperature, and sleep. The Moticon Science Insoles passively collect gait and movement data. The insoles characterize the subject’s gait across a gait cycle and within a specific phase of a gait cycle (see figure below).

phases of the gait cycle

Results

Participants with subjective cognitive decline performed significantly worse than the healthy controls on the BAC and the VRFCAT, indicating objective impairments in the subject cognitive decline sample.

Cognitive scores by group
VRFCAT scores by group

Participants with subjective cognitive decline performed worse on a portion of motor functioning assessments administered at the first visit. They were significantly slower than the healthy control group at completing the TUG. On the CTAP, individuals with subjective cognitive decline produced significantly fewer button presses with their non-dominant hand and using both hands, but the difference for the dominant hand was not significant.

For the Empatica E2 device, compliance rates during the at-home portion of the study were significantly lower for individuals with subjective cognitive decline than the healthy control group. Correlational analyses across the combined sample indicated several associations between E2 endpoints and cognition (see table below). There was a strong positive correlation between cognition/function and daily activity/movement. The average waking activity level was positively correlated with BAC verbal fluency, verbal list learning, symbol coding, and VRFCAT completion time.

The Moticon Science Insoles revealed that participants with subjective cognitive decline exhibit different gait parameters than healthy control subjects. Correlational analyses across the combined sample revealed associations of gait measures with functional capacity and cognitive endpoints (see table below). These results suggest that lower gait efficiency is associated with reduced functional capacity.

correlation between empatica and cognitive measures

Conclusions

These preliminary findings highlight the challenges of integrating wearable technologies into clinical trials for participants with even mild cognitive defects.

Despite compliance issues, preliminary data indicate moderate correlations between remotely captured actigraphy and gait measures and established assessments of cognition and function, suggesting wearables can provide meaningful information regarding cognitive health and may ultimately contribute to continuous assessment of cognition and function in clinical trials.

Learn more about VeraSci’s experience in Alzheimer’s clinical trials.

Dr. Luca Pani is the former Director General of the Italian Medicines Agency and a former member of the Board of Directors of the Committee for Human Medicines (CHMP) and of the Scientific Advice Working Party (SAWP) for the European Medicines Agency (EMA) in London. Luca is a recognized expert in basic and clinical pharmacology and regulatory science with particular emphasis on health technology assessments linked with novel negotiation strategies for the reimbursement of precision medicines. He is a Professor of Pharmacology and Clinical Pharmacology, University of Modena and Reggio Emilia in Italy and a Professor of Clinical Psychiatry, University of Miami.

It is important for anyone developing therapeutics that could be used to treat pediatric populations to take into account both FDA and EU regulations. EU Regulations seek to improve children’s health by: increasing high-quality, ethical research of medicines for children; increasing the availability of authorized medicines for children; and increasing information about medicines without conducting unnecessary studies on children or delaying medicines’ authorization for adult populations.

 

When are Pediatric Investigation Plans (PIPs) Required?

Pediatric development is mandatory in the EU for new products unless a waiver is granted. Waivers can be either product-specific or class-specific and only apply to specific conditions and dosage forms. Deferrals can be granted that allow studies in children to be completed after applying for marketing authorization in adults. For existing products, a Pediatric Investigation Plan (PIP) is mandatory when seeking a new indication, route, or dosage form if the product is protected by a patent or a Supplementary Protection Certificate (SPC). Off-patent products already authorized in the EU that do not have a valid SPC do not require PIPs. They are also not required for new medicinal products in certain groups, including traditional herbal products, homeopathic products, generic products, hybrid products, and biosimilar products. There are three types of waivers:

  • Total waivers apply to all pediatric subsets of specific conditions.
  • Partial waivers apply to some pediatric subsets or some indications but still require a PIP.
  • Some classes of products for a condition or all products for a condition may have a class-waiver.

The legal grounds for obtaining a waiver are (1) a product is not safe or effective in pediatric populations, (2) the disease or condition occurs only in adult populations, or (3) there is no significant therapeutic benefit in pediatric populations. The EMA may grant a deferral to avoid delaying marketing authorization in adults and may allow one or more studies in the PIP to be completed after the marketing authorization application (MAA). Deferrals are granted at the study or measure level. In some cases, regulators may require that sponsors initiate pediatric trials prior to marketing authorization, but may grant marketing authorization for adult populations prior to the completion of the pediatric trials. All types of deferrals must establish completion dates. Incentives are available for all correctly completed PIPs, and additional incentives are available for voluntary development through the Pediatric-Use Marketing Authorization (PUMA) program. “Correctly completed” means that the studies performed comply with the PIP agreed to in the compliance statement of the marketing authorization (MA), the results of studies are in the Summary of Product Characteristics (SmPC) and the patient’s leaflet, and the product is authorized in all member states (except for PUMA candidates). Non-orphan products can receive a 6-month extension on patent protection. Orphan products can receive two additional years of market exclusivity. Products submitted under PUMA can receive eight years of data protection, two additional years of market protection, and a partial EMA fee exemption for a year. Incentives are provided even when the PIP results are negative, but not when the results are inconclusive or when a waiver is granted.

What Does a PIP Cover?

PIPs are designed to collect data on efficacy, safety, and age-appropriate formulation. The PIP will outline studies needed and may include nonclinical studies in juvenile animals (i.e., toxicology, pharmacodynamics, pharmacokinetics, carcinogenicity, genotoxicity), safety, and proof-of-concept studies, dose-finding studies, and efficacy studies. PIPs will also provide timelines for each study. For new products, PIPs should be developed by the end of phase 1 clinical trials in adults. Amendments to the PIP may be made throughout phase 2 and phase 3. Data from adult studies cannot provide a full picture of the safety of a product in a pediatric population. Animal studies and clinical trials in pediatric populations are needed to determine the impact of a therapeutic on organ development, growth, maturation of function, neurobehavioral development, and realization of potentials. It is essential to ensure that pharmacovigilance mechanisms are adapted to meet the specific challenges of collecting safety data in a pediatric population, including data on possible long-term effects. Sponsors may be required to set up a risk management system or conduct specific post-marketing studies in instances where there is a particular cause for concern. Sponsors should start thinking about pediatric development early. Getting an agreement on a PIP with EMA typically takes 8-12 months and needs to be done before studies in children begin. 

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