You May be the Key to Finding a Cure for Alzheimer’s Disease

by Women's Brain Health Initiative:Volunteers Urgently Needed for Alzheimer’s Disease Clinical Trials.The prevalence of dementia is expanding rapidly. According to Alzheimer’s Disease International (ADI), someone in the world develops dementia every three seconds. In 2015, there were an estimated 46.8 million individuals worldwide living with dementia and this figure is believed to be close to 50 million people in 2017. The ADI reports that this number will almost double every 20 years, reaching 75 million in 2030 and 131.5 million in 2050.There is currently no cure for dementia or treatment to stop its progression or reverse the symptoms. To date, five drugs have been approved for the treatment of Alzheimer’s disease – the most common type of dementia. Many of these medications are aimed at slowing the rate at which symptoms worsen. The benefit from these drugs is generally modest, and many patients and their families may not even notice any benefit at all. Indeed, drug development for Alzheimer’s disease has proven to be very difficult. No new drugs have been approved for Alzheimer’s disease since 2003.With so many individuals facing this devastating disease globally, and very limited treatment options available, the need to identify new drugs for Alzheimer’s disease is urgent. Fortunately, a variety of clinical trials are underway around the world assessing ways to prevent, delay the onset, slow the progression, or cure the disease, and to impact symptoms more substantially than the currently-approved medications.What is a Clinical Trial?Clinical trials are a critical stage in the research process in which the effects of a health-related intervention (including drugs and non-drug treatments) are evaluated. During clinical trials, the medical strategy, treatment, or device is tested on humans to determine its safety and efficacy. According to ADI, the entire drug development process takes an average of 13 years.Before clinical trials commence, preclinical testing is conducted in a laboratory using tissue cultures and animals to see whether a given treatment has the potential to treat the disease or illness. If an approach seems promising, clinical trials begin and proceed through three phases:

• Phase 1: tests safety and tolerability of the intervention in both healthy volunteers and in volunteers with the condition under study (for safety purposes, clinical trials start with small groups of patients).
• Phase 2: assesses safety, tolerability, and optimal dose, and begins to assess efficacy in the target population.
• Phase 3: confirms safety, further examines side effects, and compares new treatments with other available treatment options (using larger groups of patients).

If a drug proves successful in phase 3, health regulatory authorities review the results and decide whether to approve the drug. Even after a drug is approved and is being used as a treatment, it often continues to be studied in Phase 4 trials to examine whether any uncommon side effects surface as the drug is administered in greater numbers of people.Sometimes, when a drug is being “repurposed”(meaning that its safety has already been established in association with a different disease), the drug development process can be shortened – in some instances skipping phase 1 trials and in rare instances skipping phase 2 trials.Clinical Trials Depend on VolunteersUnlike the preclinical phases of research, clinical trials rely entirely on volunteer participation. As Dr. Knebl and Dr. Patki emphasize, “medical research would grind to a halt without volunteer subjects.”Vast Numbers of Volunteers are RequiredAt the world’s first G8 Summit on Dementia in December 2013, ministers from each of the participating countries agreed to set a goal to identify a cure or disease-modifying therapy for dementia by 2025. In order to reach this target, a great amount of research – proceeding at a quick pace – is necessary. In turn, vast numbers of volunteers will be needed for clinical trials.In a recent article entitled “Alzheimer’s disease drug development pipeline: 2017,” published in Alzheimer’s & Dementia, Dr. Jeffrey Cummings and his colleagues reported that a total of 54,073 participants are required to take part in the 139 clinical trials that are already in the pipeline. These figures are based on the number of studies that are currently in various phases of testing, as registered on clinicaltrials.gov (a U.S. government website that includes nearly all U.S. clinical trials, as well as most international studies).While the clinicaltrials.gov database is fairly comprehensive, it is not exhaustive, and this study only examined active trials of drugs and did not include non-drug or biomarker studies, which also require participants. Consequently, the actual number of trials underway and participants needed is even higher than these researchers stated. A 2016 article published on the BrightFocus Foundation website indicates that “more than 400 clinical trials are currently looking at new treatments for Alzheimer’s disease and many of them are actively recruiting.”Making matters even more difficult, typically only between 10% and 50% of interested volunteers are eligible to participate in clinical trials. Using the conservative rule of thumb of ten people screened for each enrolled participant, researchers will need to recruit upward of 540,000 potential volunteers to find the number of participants noted by Dr. Jeffrey Cummings and his team.The Challenges of Finding Enough VolunteersNot surprisingly, then, recruiting volunteers will be a massive undertaking. Volunteer recruitment is frequently described as the slowest and most expensive part of clinical trials. In fact, recruitment periods are often longer than the treatment component of the study. Pharmaceutical Research and Manufacturers of America (PhRMA), in its 2013 report on Alzheimer’s drug development, noted that recruiting and retaining clinical trial participants is “currently the greatest obstacle to developing new Alzheimer’s treatments.”A 2013 Research!America poll found that the majority of Americans (72%) indicate that they would likely participate in clinical trials if recommended by their doctor. However, many researchers struggle to find sufficient numbers of individuals to partake in their clinical trials. There are a variety of explanations to account for this gap between interest in participation and actual enrollment. According to the ADI, some of the major factors impeding sufficient enrollment in dementia trials include the following:

• lack of awareness of opportunities;
• low physician awareness;
• the study partner requirement;
• trial design;
• cultural and linguistic challenges; and
• coexisting conditions.

Lack of awareness of opportunities is one of the biggest challenges to dementia trial recruitment. Many individuals affected by dementia do not know that they can participate in clinical trials or where to find information on studies in their areas. Even those who do learn about research opportunities may not fully understand the clinical trial process.Most individuals with concerns about their memory or cognitive function will first visit their primary care physicians, who are often thought of as a trusted source of health-related information. Primary care physicians are therefore in a strong position to inform patients about research they might want to participate in. However, like individuals living with dementia and their families, low physician awareness of clinical trials is a significant barrier to trial enrollment.The ADI reports that a survey across five European countries found that only 19% of physicians, on average, were aware of a single clinical trial recruiting in their areas. Only 22% of respondents in the 2013 Research!America poll indicated that their doctors or other health care professionals had ever spoken to them about medical research. Similarly, a poll conducted by Imperial Clinical Research Services found that physicians were even less likely to bring up the topic of medical research with their patients (88% of respondents indicated that their primary care physician had never mentioned a study). Reasons for this include concerns about risks for their patients and long distance to a research site.For many individuals living with dementia, the lack of a study partner is another hurdle to participation. A study partner is often mandatory in most dementia studies as they assist in the consent process, transport participants to and from trial sites, help the Alzheimer’s patient comply with all research requirements (such as taking medication in the right dosage at the right time(s)), and provide feedback to the researchers on trial outcomes (such as assessing any improvements in cognitive performance, memory, and daily functioning).Consequently, some individuals may be excluded from enrollment because they do not have access to a study partner or the study partner may not have the time or resources to provide the support needed for trial participation. Participating is often challenging, if not impossible, for those caregivers who work full-time and are not available to attend numerous lengthy appointments during the typical 9-to-5 clinic hours. Caregivers may also feel burnt-out from providing the usual everyday support and therefore perceive research participation as too significant of an undertaking.the lack of a study partner is another hurdle to participation. A study partner is often mandatory in most dementia studies as they assist in the consent process, transport participants to and from trial sites, help the Alzheimer’s patient comply with all research requirements (such as taking medication in the right dosage at the right time(s)), and provide feedback to the researchers on trial outcomes (such as assessing any improvements in cognitive performance, memory, and daily functioning).Additionally, clinical trials are designed with specific inclusion criteria for enrollment, which limits the number of volunteers who qualify for participation by trial design. Many Alzheimer’s and dementia studies require volunteers to undergo diagnostic tests such as lumbar punctures or magnetic resonance imaging (MRI) scans, which may be viewed as intrusive or time consuming. Cultural and linguistic challenges can also hinder participation as individuals from diverse communities may be skeptical or suspicious of research and institutional settings, or the volunteers may not speak the same language as the clinicians.Many clinical trials test interventions for a specific disease, thereby limiting the number of potential participants to those without coexisting conditions. Further, individuals taking medications for dementia symptoms or other health conditions may involuntarily exclude themselves from trial participation.Prevention trials must also overcome the unique challenge of some individuals not wanting to undergo testing to see whether they are at risk of developing Alzheimer’s disease (which is a key part of determining eligibility to participate in this type of research). In spite of this, though, more and more individuals are interested in understanding their dementia risk when they realize that they might be able to mitigate that risk through participating in a clinical trial.Who Can Participate in Clinical Trials?People with varying stages of Alzheimer’s disease and those at risk of developing Alzheimer’s disease are needed for clinical trials. If you think that you may be experiencing early symptoms of cognitive impairment, research is an option to consider. Cognitively healthy individuals are also needed for Phase 1 trials.The Need for Greater Diversity Among VolunteersFor study findings to be applicable beyond the laboratory environment, participants must be representative of the general population of individuals with or at risk of developing Alzheimer’s disease. Unfortunately, however, this is usually not the case. According to a 2014 article entitled “Facilitating Alzheimer’s Disease Research Recruitment” by Dr. Joshua D. Grill and Dr. James E. Galvin, Alzheimer’s disease trial participants “tend to be younger, more educated, and more often Caucasian than is typical for the general AD population.”Researchers struggle to find volunteers from diverse racial and ethnic backgrounds. For instance, a 2007 review found that more than 90% of participants in the U.S. National Institutes of Health Alzheimer’s studies and 97% of participants in industry-funded Alzheimer’s studies were non-Latino Caucasians. Yet, in 2006, 19% of adults aged 65 or older in the U.S. were non-Caucasian. Even more concerning, many of the racial and ethnic groups that are underrepresented in clinical trials are actually at higher risk of developing dementia.Likewise, study participants have historically been unrepresentative of the Alzheimer’s population when it comes to education level. While there has been an overrepresentation of highly-educated participants in Alzheimer’s clinical trials, epidemiological studies show that less-educated individuals (those with less than 12 years of schooling) are at higher risk for developing Alzheimer’s disease.Reasons People VolunteerPeople volunteer to participate in Alzheimer’s research for multiple reasons, both personal and altruistic. Two of the most common reasons are (i) that the individual with or at risk of developing Alzheimer’s disease hopes to benefit personally from a new treatment and (ii) that the individual wants to help find treatments or a cure for future generations.What to Expect if You VolunteerClinical trials typically proceed as follows:

1. There may be an initial phone screening to determine whether the interested volunteer satisfies certain criteria.
2. Interested volunteers and their study partners may visit the study site to meet with the study physician and staff members to learn more about the trial, including the purpose of the study, the study requirements, and the potential risks and benefits of participation. Volunteers are provided with ample time for discussion and questions.
3. Those who decide to proceed sign an informed consent form. Signing this document signifies that both the study participant and the study partner understand the risks associated with the study and, notwithstanding these risks, voluntarily agree to participate in the study. While participants and study partners are free to withdraw from the study at any time, the majority of individuals who enroll in an Alzheimer’s trial are retained through trial completion. Across disease severities, these retention rates do not substantively vary (mild cognitive impairment Alzheimer’s trials had an average retention rate of 71.6%, mild-to-moderate Alzheimer’s trials 77.77%, and moderate-to-severe and severe Alzheimer’s trials 75.4%).
4. Next, a comprehensive screening process is initiated to further determine whether the individual is eligible to participate. This may include reviewing medical history and medications, performing cognitive testing, and undergoing blood work, physical examinations, electrocardiogram (ECG), and/or MRI and positron emission tomography (PET) scans.
5. The participant and study partner will visit the study site for follow-up visits that again may involve cognitive testing, blood work, physical examinations, ECGs, MRIs and/or other scans of the brain. The procedures and number of follow-up visits vary by study.Participants who meet the eligibility criteria return to the research site for a baseline visit, at which point they are randomly assigned to a study group (i.e. active study drug or placebo). Many studies are conducted as a “double-blind” trial, which means that both the participants and the researchers do not know who has been assigned to each study group. This helps to avoid participant and investigator bias that would invalidate study results.

Length of Clinical TrialsClinical trials typically vary in length from three months to five years. The duration of the trial largely depends upon the time that it takes to recruit sufficient volunteers. Dr. Jeffrey Cummings and his colleagues reported that, on average, the duration of a trial (including recruitment and treatment period) was the shortest for phase 1 trials (at 755 days). Phase 2 trials took an average of 1,140 days to complete, while phase 3 trials averaged 1,677 days.How to Volunteer for a StudyHopefully, going forward, primary care physicians will be more likely to provide their Alzheimer’s patients (or those at risk) with information about clinical trials. Doctor referrals have great potential to increase the number of volunteers.If your doctor does not mention clinical trial opportunities to you, be proactive and ask about them. Your inquiry may prompt your doctor to learn more and get back to you with information. Even better, ask your doctor to refer you to a clinical trial site where you will be able to receive information first hand.There are also a variety of online tools that may be helpful in identifying a clinical trial of interest. Clinicaltrials.gov is one of the most comprehensive among this group of online resources.Two websites that provide Canadian-specific information are:

• The Consortium of Canadian Centres for Clinical Cognitive Research, which provides online information about current cognitive-specific studies (http://c5r.ca/current-studies/); and
• The Government of Canada, which has an online form that you can complete to search for clinical trials (https://health-products.canada.ca/ctdb-bdec/index-eng.jsp).

Some examples of online resources that are dementia-specific and mainly geared towards U.S. residents include:

• The U.S. Alzheimer’s Association tool, TrialMatch® (http://www.alz.org/research/clinical_trials/find_clinical_trials_trialmatch.asp), which is a free, easy-to-use service where you submit information about yourself and the tool generates customized lists of studies that you may qualify for. The database is updated regularly and contains both drug and non-drug studies being conducted at sites across the U.S. and online;
• The Brain Health Registry (brainhealthregistry.org), led by researchers at University of California, San Francisco, streamlines the process for getting involved with clinical trials and helps researchers analyze the brain function of thousands of volunteers. After a simple sign-up process, volunteers provide a brief personal history and complete online brain tests (which feel like online games). A select number of volunteers will be asked if they would like to participate in clinical trials or perhaps undergo saliva or blood tests. Volunteers may choose to participate as little or as much as they like; and
• Alzheimer’s Prevention Registry (https://www.endalznow.org/), led by Banner Alzheimer's Institute, focuses specifically on connecting scientists with those who are interested in participating in prevention studies. Finding individuals to volunteer for prevention studies can be especially challenging since these individuals must be cognitively normal but at risk of developing Alzheimer’s disease. Because many of these individuals do not experience any symptoms, they most likely do not know that they are at risk (and therefore are not likely to seek out research opportunities unless prompted to do so).

If you are in the Toronto area, consider volunteering for a study at Toronto Memory Program, Canada’s largest clinical trial site for testing drugs to prevent and treat Alzheimer’s disease. Dr. Sharon Cohen, Neurologist and Medical Director at Toronto Memory Program, notes that “most individuals with or at risk for Alzheimer’s disease are completely unaware of clinical trial opportunities and are grateful to find a centre that offers the latest treatment approaches and options. At any given time, Toronto Memory Program is participating in 15 to 20 international trials and is actively recruiting participants for half of these trials.”Toronto Memory Program has been internationally recognized for its excellence in clinical research and for providing research opportunities to thousands of Canadians. For more information on trials at Toronto Memory Program, visit https://www.torontomemoryprogram.com/ or contact the Clinical Trial Educators at 416-386-9606. You may also wish to attend one of Dr. Cohen’s presentations about Alzheimer’s prevention and treatment. Details about upcoming dates and locations can be found in the “Events” section of the website.As Dr. Cohen observes, “Clinical trials are the hope for the future and volunteers are key. Researchers cannot achieve the urgently needed breakthroughs in Alzheimer’s disease without the assistance of volunteers willing to pioneer with them. The faster we complete recruitment for clinical trials, the sooner we will put an end to Alzheimer’s disease. It is not a matter of ‘if’ we will beat this disease but ‘when.’ As the number of individuals affected with Alzheimer’s disease rises, the call to action in clinical trials has never been greater.”Questions to Ask Before Enrolling in Clinical ResearchTo help you make an informed decision about participating in a clinical trial, consider asking the researchers the following questions:

• What is the purpose of this study and why is it important?
• What kinds of tests and examinations are involved? How long do they take and how often will they be performed? Where will they take place?
• Will I need to be hospitalized during the study? If so, how often and for how long?
• What else are participants required to do?
• Do I need to have a study partner? If yes, what is he or she required to do and how much time will it take?
• How long will the study take?
• How will my participation in the study impact my current care and treatment? During the study, who will be responsible for my care?
• How will you keep my doctor informed about my participation in the study?
• What other treatment choices are available and how do they compare with the study treatment?
• Will the study compare the experimental treatment with “standard” care or will there be a placebo group?
• What are the possible side effects from participation?
• What happens if my memory or health decline during the study?
• Are there any costs associated with the study? If yes, will my expenses be reimbursed?
• How will my privacy be protected?
• Will the study results be shared with me?
• If I withdraw from the study, will this affect my normal care?

Source: MIND OVER MATTER -V5