ARTICLE IN BRIEF
The lead study author of the A4 prevention trial for Alzheimer's discusses their thinking behind the trial design, what they anticipate will be challenges, and what they hope to achieve.
In the last few years it has become clear that the pathology of the disease begins a decade, maybe even two decades, before any signs of cognitive decline emerge. The question on the table is this: Can Alzheimer's disease (AD) be stopped before symptoms begin? Or can we even slow or push back its onset so people can live without cognitive challenges for a longer period of time?
Reisa A. Sperling, MD, a professor of neurology at Harvard Medical School and director of the Center for Alzheimer's Research and Treatment at the Brigham and Women's Hospital and Massachusetts General Hospital, has taken care of patients with dementia for decades.
About three years ago, Dr. Sperling thought it was time to start a prevention trial for older people without a known genetic history of AD. The DIAN (Dominantly Inherited Alzheimer Network) study was already in the pipeline to test whether treatment could push back the clock on the inevitable genetic hit in people with rare causative mutations known to trigger AD. That group represents less than two percent of those who develop Alzheimer's. What about the rest of those patients? Can we stop Alzheimer's before symptoms appear?
In the March 19 online edition of Science Translational Medicine, Dr. Sperling discusses A4, a new secondary prevention trial in older people with amyloid accumulation at high risk for Alzheimer's disease dementia. In a phone interview with Neurology Today, she discussed the thinking behind the trial design and outcomes. Excerpted remarks from the interview appear here.
WHAT IS THE A4 TRIAL?
A4 stands for Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease. We wanted to identify at-risk individuals with evidence of Alzheimer's changes in the brain and assign them to a randomized double-blind treatment protocol with an anti-amyloid agent or placebo and follow them over time to see if it makes a difference. We know that about 30 percent of people over 65 years of age have evidence of amyloid deposition in their brains. There are enough data to tell us that these people are at higher risk for developing clinical signs of Alzheimer's.
WHAT ARE YOUR HOPES FOR THE STUDY?
We think a secondary prevention trial in older people with amyloid accumulation should provide insights into whether anti-amyloid therapy could delay cognitive decline. But this is just the first step. In time, we will be able to test other therapies that come along. Maybe it will take a combination of drugs. But this study will tell us if our design is right and if we can get to the disease early enough to make a difference. The failures we have had testing amyloid-modifying therapies in patients with moderate dementia makes us think that we may need to begin much earlier if we want to alter the disease course. The motto for the A4 study is “Now is the time” because we think now is the time for this study based on the advances in science, now is the time for an individual to begin treatment before memory loss has begun, and now is time because Alzheimer's disease is a looming public health epidemic.
HOW DID YOU BEGIN THINKING ABOUT THE DESIGN OF THE STUDY?
About three years ago, the data started to emerge from amyloid imaging and cerebrospinal fluid studies that there were normal older individuals with amyloid in their brains who had abnormalities on functional MRI and positron emission tomography scans and atrophy in certain brain regions hit by Alzheimer's and even subtle changes on cognitive tests. We would use this information to create criteria that researchers could use to detect evidence of preclinical Alzheimer's disease.
I worked on these guidelines and I remember thinking that if we could actually measure preclinical AD, why couldn't we do a clinical trial to see if we could alter the trajectory of the disease.
My colleague, Paul Aisen, MD, director of the Alzheimer's Disease Cooperative Study (ADCS) and professor of neurosciences at the University of California, San Diego, and I decided that it was time to do such a study. The ADCS was up for its grant renewal and we decided to map out the study and see what happens.
The National Institute on Aging [NIA] funded the grant, contributing about $36 million to the A4 study. It was a substantial vote of confidence. A4 is a major collaborative effort between the NIA, Eli Lilly and Company, which is supplying the medicine for the trial and additional support, and the Alzheimer's Association that recently gave us $8 million to look at those people in the study who don't have amyloid build-up to learn about other factors that may contribute to cognitive decline.
WHY DID YOU CHOOSE SOLANEZUMAB, WHICH HAD NEGATIVE PHASE 3 RESULTS?
It took us a year to figure out the investigational treatment to use in the clinical trial. A committee of nine researchers looked at all of the published (and unpublished) phase 2 and phase 3 data on anti-amyloid agents. We thought Lilly's antibody, solanezumab, looked the safest and it seemed to show a cognitive signal in a subgroup of patients with mild AD. Even though the results of a phase 3 study on solanezumab were not positive, that signal suggests that it may have a chance at slowing the progression of the disease if we gave it 10 years earlier.
IS SOLANEZUMAB THE ONLY DRUG BEING STUDIED?
Our thinking was that solanezumab would be the first drug we studied in preclinical AD but certainly not the last. Anti-amyloid antibodies are thought to clear amyloid-beta from the brain. But the beta-secretase inhibitors that are now being tested reduce the production of amyloid. An agent that goes after the production of amyloid-beta should be given as early as possible, and I hope this might be the drug we test in the “A5” trial. Ultimately, it will probably be a combination approach that will slow or prevent the disease altogether.
WHAT ABOUT THE ETHICS OF TREATING PEOPLE WHO MIGHT NEVER GET SICK?
We frequently treat individuals with risk factors who may or may not progress to manifest symptoms, such as chemotherapy for Stage 1 cancer, lowering cholesterol, and anticoagulation medications. These medications all have some risk of adverse events. There are already data suggesting that amyloid-positive individuals as a group are at significantly increased risk of progression to symptomatic AD, but we do not know the risk yet at an individual level.
Our A4 consent form clearly states that some individuals may not progress to AD dementia in their lifetime. We will of course work to minimize any risks to participants. We carefully considered the risk-benefit ratio for A4, which is part of the reason we chose solanezumab. It has a very good safety profile.
The A4 population is clinically normal, fully able to make the decision about participation for themselves based on all of the available information. Most important, they know that we do not yet have all of the answers. This seems the most ethical way to proceed.
WHO DO YOU HOPE WILL JOIN THE STUDY?
Since this is the first prevention trial in clinically normal older people, we hope that we get a diverse group of people interested in helping us find a successful treatment for Alzheimer's. We are looking to enroll over a thousand people at 60 centers throughout the US and Canada, and we just added Australia. That means we probably need to screen about 5,000 people (and reach out to twice that many).
Those who are enrolled in the study will be 65 to 85 years old and at entry into the study they will be cognitively normal (based on history and a series of neurocognitive tests) and have evidence of amyloid accumulation in their brains on screening PET scans.
Throughout the study, they will be closely followed with repeat brain scans and neurocognitive testing. Each person will be randomly assigned to receive solanezumab (an IV infusion once a month) or a placebo dose delivered in the same way. There will be a three-month evaluation period and 168 weeks of treatment. We just screened our first study subject in early March and several others are ready to be tested.
WHAT ARE YOUR SELECTION CRITERIA?
To make sure that people enrolled in the study are on the same cognitive playing field, those who score higher than one standard deviation above the age- and education-normative values, or one standard deviation below, will not be eligible. We are also requiring that one in five people screened for the study are from an under-represented minority so that we can get much needed answers about the role of ethnicity in risk for Alzheimer's disease. It will be tough to recruit enough minorities for screening in some parts of the country, but we have to try. We need to know why African-Americans and Latinos are at higher risk for AD. We don't have the data to speak to that.
People who are eligible for the study must have a Clinical Dementia Rating (CDR) total score of zero, with no evidence of dementia or problems in daily functioning. Everyone who is eligible will have a PET scan to measure amyloid deposition. If there is evidence of accumulation, people can continue screening for the study.
WHAT ARE THE CRITERIA FOR EXCLUDING PEOPLE?
There is a whole list of medical conditions that will lead to a person's exclusion from the study. A list can be found on clinicaltrials.gov. The study investigators will obviously assess depression and a person's risk for suicide. Any history of depression or bipolar disease in the past two years will keep a person out of the study. Also, people with a history within the past five years of chronic alcohol or drug abuse or dependence will be excluded from the study.
WHY DID YOU DECIDE TO TELL STUDY PARTICIPANTS ABOUT THEIR PET FINDINGS?
We thought a lot about disclosing the PET scan results and decided it was best to do that. The participants need to know. They are making a very big commitment to be part of the study. As I look around other fields in medicine — heart disease, cancer — this is what we do. We identify people with lab tests or imaging. We have the ability to try that in Alzheimer's. We had ethicists weigh in on this. We needed to know what to tell them about the studies on amyloid deposition and the risk for AD.
Before they qualify, we rule out a history of depression and other medical conditions. They take a neurocognitive battery (along with the PET scan) that assesses their cognitive abilities. Once they move from the screening to the actual study then they meet with a study physician to go over the results. We will counsel them on their findings.
In another piece of the study, we are actually studying the effect of the disclosure process. We need to understand whether disclosure will impact neurocognitive test performance and any changes that they perceive on their memory. Of course, we need to explain that there is much we do not know yet, and that some people have amyloid accumulation and never develop AD. We think disclosure is important for people to make an informed decision about being in the study and seeing it through to the end. (A subset of people will also get imaging for tau but the test is so new that we are not revealing the results of these scans.)
Scientists at the University of Pennsylvania will be conducting a study on the effects of this disclosure process. Researchers will assess the impact of the consent process and of revealing the amyloid status to both amyloid-positive and amyloid-negative individuals.
WHAT WOULD DETERMINE THEIR READINESS TO RECEIVE INFO ABOUT AMYLOID STATUS?
We do a great deal to determine whether a person is a good fit for the study. We rule out depression and make sure that a physician does the counseling. We really want people to understand that there is an unknown risk of progression at the group level but not at the individual level. In other words, we don't know whether their amyloid levels means that they will develop mild cognitive impairment or AD. Of course, they also have to be clear that they may be taking a biologically active anti-amyloid agent even though they are cognitively normal.
TELL US ABOUT THE NATURAL HISTORY ARM OF THE STUDY?
The Alzheimer's Association is providing funding for a natural history arm of the study. About 500 people who had no evidence of amyloid deposition in their brains and were cognitively normal at entry into the study will be followed over the length of the trial. They will go through cognitive testing and blood collection but they will not receive any treatments (or placebo). This so-called “screen fail” design will enable us to determine non-amyloid factors in assessing those who go on to decline on cognitive tests. It would be nice to find funding to obtain other biomarkers and follow-up imaging.
WHAT ARE SOME OF THE UNUSUAL PIECES OF THE STUDY THAT YOU ARE EXCITED ABOUT?
Here is one that I think could be important for us and for future studies. Some of the cognitive testing in the study is performed on iPads that have the Cogstate card playing games that measure reaction time and visual recognition memory, and new tests we developed to study memory for names and faces. These measures have been shown to be powerful predictors of cognitive decline. We hope that this gets people excited about entering the study. We also have iPad tests that ask participants themselves about how they think their memory is functioning. And of course we will have repeat measures on several imaging studies that will help us in understanding how the clinical disease adds up to changes on these scans. We are also obtaining spinal taps to measure amyloid and tau levels in a subset of participants in the study, and another subset of people in the study will have a special new brain scan that measures tau pathology.
WHAT ARE YOU HOPING TO SEE BY THE END OF THE STUDY?
A4 is powered to detect a treatment effect of about 30 percent slowing in the rate of cognitive decline. That is our hope. Such an effect size would have an amazing impact on the clinical course. Imagine if we could delay dementia by just five years for individual patients?
WHAT ARE YOUR CONCERNS ABOUT THE STUDY?
There are many. We need to screen thousands of older people who are cognitively normal and then after they go through a scan to measure amyloid accumulation, we may tell them something that changes the way they perceive themselves. We will know after a year whether disclosure of this information is causing problems. Also, I worry that we may be underpowered to see an effect of 30 percent change in cognitive status after three years. We have an interim analysis built in and if people are not declining we may have to determine if our estimates are correct. Adding Australia means another 100 people in the study, which brings us to 1,100. If we need more people, we will just have to raise more money, as it is really important to get some clear answers from this study.
TUNE IN, LISTEN UP: What could the findings from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease trial (A4) — a new secondary prevention trial in older people with amyloid accumulation at high risk for Alzheimer's disease dementia — mean for Alzheimer's disease? Earlier detection and possibly earlier intervention, according to the lead author of the A4 trial. In this podcast interview, Reisa A. Sperling, MD, a professor of neurology at Harvard Medical School and director of the Center for Alzheimer's Research and Treatment at the Brigham and Women's Hospital and Massachusetts General Hospital, discusses the challenges the investigators foresee and the possible benefits: http://bit.ly/WzlC1O.