Recruiting for Phase 1 AD trials with biomarker and cognitive testing

Lev Gertsik and Lydia Morris are investigators at Parexel’s Los Angeles Early Phase Clinical Unit (EPCU), one of four sites where we recruit patients for Phase I clinical trials. Working under the leadership of Anita Mardian, they share an enthusiasm for scientific inquiry, a knack for problem-solving, and a driving belief in the dignity and value of the volunteers and patients they work with daily. 

In early 2023, they launched an investigator-initiated clinical trial, sponsored by Parexel, that uses blood testing to identify healthy older adults in the early stages of beta-amyloid (Aβ) and tau protein accumulation who have previously participated in a Phase I clinical trial. Aβ and tau are biomarkers of Alzheimer’s disease (AD) that accumulate in the brain long before AD and its associated cognitive decline can be diagnosed. Parexel’s trial uses a blood test similar to one that was recently reported to achieve 91% accuracy in detecting AD pathology. ¹

Here, Lev and Lydia discuss what motivated them to design this novel study and why they believe the approach could reinvigorate an AD clinical research infrastructure struggling to recruit enough patients for testing desperately needed new therapies.

Addressing the unmet need for early screening

Alzheimer’s disease (AD) was the fifth leading cause of death among U.S. adults 65 and older in 2021.² It’s an epidemic that will affect all of us, if not directly, then indirectly, as caregivers and members of society. As investigators and human beings, we are intellectually and emotionally invested in finding a disease-modifying treatment for AD. Hundreds of promising agents are in the development pipeline. However, recruiting even small cohorts of patients for Phase I studies is a bottleneck, choking the flow of critical data to study sponsors. 

There are many reasons for this. Early-stage AD trials often present a high burden for patients and their families, including extended inpatient stays and invasive procedures, such as lumbar punctures. Unlike later-stage trials, Phase I safety and tolerability trials do not offer any potential therapeutic benefit. Participating in an early phase study may require patients to turn down or postpone access to available treatments. Finally, if AD is diagnosed late in the disease process, a patient may be too medically or physically frail to participate.

Our psychology and psychiatry team started tackling some of these challenges almost a decade ago, with support from our patient recruitment team, by establishing a Memory Clinic within our Los Angeles Early Phase Clinical Unit (EPCU). By offering free comprehensive cognitive evaluations to community members with concerns about their mental functioning, we addressed an unmet need in our community—the need for access to early screening and identification of Mild Cognitive Impairment (MCI) and AD. Underdiagnosis and late diagnosis of AD had significantly slowed clinical trial recruitment in our community. 

We created the Memory Clinic to facilitate early AD detection, build strong relationships with local physicians, patients, and families, and disseminate no-obligation information about clinical trial participation to interested parties. We achieved these goals and improved recruitment to our Phase I trials of MCI and AD.³ However, recruiting patients for the highest-burden MCI and AD protocols remained a challenge.

Narrowing the gap between academic advances and patient care

Establishing the Memory Clinic was a critical first step, but it didn’t change the high burden and low benefit of Phase I study participation for AD patients and their families. We continued searching for solutions and concluded we needed to introduce new technologies and approaches. As we monitored academic advances in AD research, we realized we could help bridge the gap between cutting-edge research and patient care. At the Memory Clinic, we can detect declines in cognition. However, blood biomarkers precede cognitive changes and can reveal presymptomatic AD.

We knew we could leverage novel FDA-approved biomarker tests to catch AD earlier and allow people to potentially improve their prognosis by participating in a clinical trial. So, we wrote a protocol to identify and follow healthy research participants who may be at risk of developing AD based on Aβ and tau blood biomarker data or cognitive testing results. The only burdens for those participants are a blood draw and cognitive testing by a trained rater.

In AD, Aβ plaque and tau proteins inside neurons become tangled clumps, blocking the brain's communication channels. Our goal is to find a treatment that could prevent or clear these toxic proteins from the brain.

We wrote a protocol to identify and follow healthy research participants who may be at risk of developing AD based on beta-amyloid (Aβ) and tau blood biomarker data or cognitive testing results.

Building on our longstanding relationships with hundreds of active, healthy EPCU volunteers, we contacted those aged 60 and over who had participated in a study within the last five years. While AD patients and their families are typically inexperienced with and overwhelmed by clinical research, our experienced participants are comfortable with high-burden early-phase studies. They trust our study team, know the trials are safe, and understand the scientific value and aims of Phase I research. Parexel research has shown that healthy elderly with higher cognitive functioning are more likely to participate in clinical studies.⁴ 

Participation rates have been high among those we’ve invited, and the database is growing. About 20% of participants enrolled in the protocol to date have biomarkers and cognitive results consistent with MCI due to AD, and nearly 50% have pTau181 levels suggestive of sub-clinical or clinical AD.⁵ We will publish these data when the study is complete. Elevated Aβ and tau levels or poor cognitive testing results do not guarantee a participant will develop AD, but they appear to be risk factors for conversion.⁶

Our database of ”biomarker positive” participants can be recruited into early-phase trials instead of AD patients, and they may one day enroll in later-stage efficacy trials if they qualify. For sponsors running Phase I trials in AD, this database of participants could dramatically accelerate Phase I timelines. It gives sponsors data critical to advancing to later phase trials in a fraction of the time it would take to recruit that same cohort of MCI and AD patients.

Delivering scientific and clinical expertise via personal relationships

Recruiting AD patients for clinical trials is often a heartbreaking task: many patients do not meet the strict inclusion and exclusion criteria, or their illness is too advanced at diagnosis to benefit from treatment. In our work with Memory Clinic patients, we have met wonderful and courageous people, some with advanced AD and facing a terrifying prognosis. Many have agreed to participate in early-stage studies, even knowing they stand little chance of benefiting but wanting to help others in the future.

One older woman—we’ll call her Evelyn—remains impossible to forget. Her physician referred her to us because she was experiencing changes in thinking and behavior. After evaluating her, we found she had cognitive and cerebrospinal fluid hallmarks of early-stage AD. She was eager to participate in a Phase I trial and willing to give her time and biological samples for the greater good. Unfortunately, her veins could not withstand the treatment infusions, and she was unable to continue. She was devastated, and so were we. We have maintained regular contact with Evelyn by phone because we had a personal relationship with her. She inspires us to redouble our commitment to advancing AD research.

Healthy volunteers in Phase I trials are usually motivated by monetary compensation. However, this is not the case with patient volunteers, especially older ones. They are much more motivated by the opportunity to advance treatment for AD, both for their sake and for their children and grandchildren.

When we demonstrate our commitment to the well-being of patients and families, whether or not they participate in one of our clinical trials, we build relationships. We help facilitate family meetings and provide referrals, such as local support groups, at the time of the diagnosis. Our work with these families continues beyond the initial diagnosis, as we invite patients back for follow-up evaluations and offer ongoing advice and recommendations. Many of these families are waiting for the right clinical trial and welcome a call from us to check in about how they are doing or let them know about a new study they may be eligible for. We’ve built warmth and trust with these families because they know we are invested in their health and advancing new AD therapies. 

A successful clinical trial requires more than cutting-edge blood biomarker tests and clinical expertise. To bring scientific advances and technical expertise to the patients who need them, you must build relationships with the people in your community and understand their individual stories.

Acknowledgments: The authors would like to thank Svetlana Semanova for her scientific guidance, Stephanie Law for her compassionate, relationship-building work with “Evelyn” and others, Claudia Aguilar and Warren Youssefian for their recruitment work, and their coworkers past and present at the Los Angeles EPCU who have shaped and supported these projects.

A successful clinical trial requires more than cutting-edge blood biomarker tests and clinical expertise. To bring scientific advances and technical expertise to the patients who need them, you must build relationships with the people in your community and understand their individual stories.

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