Home Visits Improve Willingness To Participate In Alzheimer's Clinical Trials

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Alzheimer's clinical trials that include home visits could result in shorter recruitment periods and increased patient retention rates, and may save considerable time and expense.

Clinical trials are essential to testing the safety and benefit of promising new treatments for Alzheimer's and other diseases. Slow recruitment and loss of participants during the trial slows the progress of developing new treatments. It also increases the costs of research.

Clinical trials for Alzheimer's face special challenges. They recruit not just the person with the disease but also at least one other person close to them, commonly called a caregiver, who has to accompany them on study visits. The patients often have functional and behavioral problems that make it difficult to get them ready for a study visit. The caregivers often have their own health problems and job demands that present challenges to study participation. In some cases, caregivers face the added burden of making a decision regarding treatment that may expose their loved one to risk.

"Other than lack of sufficient funding, recruiting and retaining clinical study volunteers is now the single greatest impediment to developing better treatment and prevention strategies for Alzheimer's," said William Thies, PhD, vice president for Medical and Scientific Relations at the Alzheimer's Association. The Alzheimer's Association recently implemented a Clinical Studies Initiative to elevate awareness and support of Alzheimer's clinical research among physicians and the public.

With the expected rapid escalation in the number of people with Alzheimer's in the near future, and the accompanying financial, societal and personal catastrophes, scientists in government, academia and industry are working to improve drug discovery and the clinical trials that are used to test drug therapies. This includes improving the earliest stage of drug discovery on the "front end" so that development is more efficient and the compounds are more likely to be effective, plus understanding better and improving the recruitment and retention of participants into Alzheimer's clinical studies.

Jason Karlawish, PhD, associate professor of medicine and associate director of the PENN Memory Center, and his colleagues at the University of Pennsylvania recently completed a study addressing the challenges of recruiting and retaining study participants for Alzheimer's clinical trials. They tested whether redesigned clinical trials might improve caregivers' willingness to participate in Alzheimer's trials by analyzing the value of four possible alterations in the study.

The researchers interviewed 108 caregivers of community dwelling persons with Alzheimer's who were followed at the PENN Memory Center. The caregivers were asked questions about their willingness to participate in hypothetical studies which differed according to four variables: location of study visits, method of transportation to study visits, chance of receiving a drug or placebo, and level of risk of the study drug. Participants were asked to rank their willingness to participate in each varying study on a seven-point scale.

The scientists found that 17 percent of participants were willing to participate in a high risk Alzheimer's disease redesigned clinical trial with no amenities. When home visits were added, the willingness to participate increased to 27 percent. Low risk, home visits, and a higher chance of the active treatment increased the willingness to participate to 60 percent. The additional willingness generated by reducing travel inconvenience offset negative study features, such as taking a high-risk drug. Home visits also made caregivers of sicker patients more willing to participate in studies.

"Altering studies to include home visits could result in shorter recruitment periods and increased patient retention rates," Karlawish said. "The amount of time we save through these alterations could offset the added costs of the home visits, and, in fact, we may save considerable time and expense if the participants don't have to come in to the clinic so often."

Over the past three decades, a problem has emerged in new drug discovery and development in which an increasing investment in research by industry and government is not proportionally reflected in successful new therapies. As such, a potential crisis is emerging, especially for diseases such as Alzheimer's, which is projected to reach epidemic proportions in the near future.

The United States Food and Drug Administration (FDA) and National Institutes of Health (NIH) have made requests that academia and industry address the emerging crisis across multiple diseases by exploring strategies to improve efficiency and innovation in the drug discovery and development process.

D.M. Watterson, Ph.D., Co-Director of the Center for Drug Discovery and Chemical Biology, John G. Searle Endowed Chair in Molecular Biology and Biochemistry, and Professor of Molecular Pharmacology and Biological Chemistry in the Feinberg School of Medicine at Northwestern University in Chicago, and colleagues from the Center for Drug Discovery and Chemical Biology (CDDCB) in Chicago, IL, met with their colleagues in industry and at government agencies to identify how they could respond to the need for a more effective process. Together, they developed "smart chemistry" integrated with "smart biology" approaches to drug discovery that have a potential for making the process more efficient, facilitate innovation, and identify novel compounds that might alter disease progression.

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The "smart chemistry" approach uses the information found in chemical and pharmacological databases to identify common strengths of molecules, defined by their physical properties, that turn out to be good drugs. The chemists mine these databases and propose testable hypotheses about what common themes among the physical properties of small molecules with different structures make them more drug-like. The identification of common themes aids in the design of new molecules.

"The 'smart chemistry' approach to discovery allows a better fit between biology and chemistry at both the virtual molecule design phase and in the assembly line phase of synthetic production and testing," Watterson said. "This makes possible a more rapid and less costly response to biomedical needs as well as the generation of new molecules that are candidate compounds for development into new drugs."

According to Watterson, the emphasis is on synthesizing compounds that have a higher probability to be stable, non-toxic, and cause fewer adverse effects. Minozac, a compound designed and synthesized in the Wattersonlaboratory, is an example of a novel compound developed using the integration of "smart chemistry" with "smart biology." Minozac limits excessive production of brain proinflammatory cytokines, which are small proteins that can cause tissue injury, and improves neurologic outcomes in animal models of diseases such as Alzheimer's, traumatic brain injury (TBI) and epilepsy. Minozac has been licensed to industry for clinical development.

Collaborative studies with Linda Van Eldik, PhD, co-director of CDDCB and a Professor of Cell and Molecular Biology at the Feinberg School of Medicine, are exploring animal models of Alzheimer's and other brain disorders that have brain inflammation as a key contributor to disease progression. The ultimate goal is to develop a series of novel molecules which would be effective against a variety of disorders where brain inflammation and proinflammatory cytokine overproduction are involved.

As clinical trials move forward with promising new treatments for Alzheimer's, stakeholder perspectives can inform decisions about what risks are acceptable for what kinds of treatment benefits. Pharmaceutical companies, clinicians and the FDA need to understand patients' and family members' willingness to accept risky treatments for Alzheimer's. This information will provide important guidance on what drugs are appropriate for Alzheimer's treatment.

"Several of the potential treatments being tested may present more than minimal risks to patients," Karlawish said. "For example, researchers had to stop one of the early studies of the anti-amyloid vaccination because subjects developed encephalitis, a dangerous inflammation of the brain."

Karlawish and colleagues studied the willingness of persons with Alzheimer's to take risk to treat their disease. The study involved interviews with 34 community dwelling persons with very mild to moderate Alzheimer's who were followed at the PENN Memory Center and theircaregivers. Patients were asked whether they would want to take medications which would delay the progression of Alzheimer's by one year, under varying levels of risk. The risks discussed were similar to those for drugs currently being researched for the treatment of the disease, and ranged from a 30 percent chance of pain to a 10 percent chance of death. Caregivers were asked similar questions on behalf of their relative.

The researchers found that patients with more insight into the symptoms, diagnosis, and prognosis of their cognitive impairment were generally more risk tolerant. Risk-takers were also more likely to be judged competent to make a treatment decision and more capable of thinking through risks, benefits and purpose of an Alzheimer's medicine.

"From the patient perspective, the willingness to take a risky Alzheimer's treatment is more driven by their awareness of their illness and their capacity to understand, appreciate, and reason through a treatment's purpose, benefits and risks to themselves, and not so much on the severity of their Alzheimer's disease," Karlawish said.

While the tremendous burden of Alzheimer's on people with the disease, families and society is acknowledged, there is little quantitative evidence of the level of risk individuals are willing to accept for treatment benefits. At the Alzheimer's Association Prevention Conference, Reed Johnson, PhD, Senior Fellow and Principal Economist at RTI Health Solutions, and colleagues reported results from a study on how much risk American older adults are willing to take in exchange for a disease modifying treatment for Alzheimer's.

For the study, a nationally representative panel of 2,146 U.S. adults 60 years of age and older (avg. 70 years) completed an Internet-based questionnaire. Respondents chose between pairs of hypothetical treatment alternatives, including different, 7-year, Alzheimer's-progression profiles and first year risk of death/permanent severe disability due to stroke or encephalopathy. The maximum acceptable risk (MAR) respondents were willing to accept in exchange for treatment benefits was calculated for various clinical benefit levels. Results were stratified based on respondent characteristics and familiarity with Alzheimer's.

The scientists found that respondents were willing to accept a 46.8 percent increase in the chance of death or disability in exchange for the benefit of preventing Alzheimer's disease progression beyond the mild state. Individual characteristics that had statistically higher MARs were younger versus older respondents, more educated versus less educated, and respondents familiar with Alzheimer's versus less familiar.

"We found that older Americans are so concerned about the serious consequences of Alzheimer's that they are willing to trade a higher risk of other disabling illness or death in order to have access to a treatment that could delay the progressive and lethal consequences of Alzheimer's," Johnson said. "This survey is the first to our knowledge that is able to quantify this fear of Alzheimer's in a manner that could be useful to health authorities as they plan for the increase in Alzheimer's brought on by the aging of our population."

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