Down syndrome clinical trial: FAQs

Posted 8:50 PM, October 30, 2008, by wetmore

We frequently receive emails from parents interested in our research, clinical trial plans, and related issues. We wrote a series of FAQs to post here as a resource for parents, doctors, and educators. If you have additional questions that aren't addressed here, please contact us.

The INDD-X Team

There has been hope for cognitive treatments for Down syndrome individuals in the past, but in each case clinical trial results have been negative. Why should we be more hopeful now?

As you are perhaps aware, in the last few years, scientists and clinicians working to understand the underlying cause of reduced brain function in Down syndrome have made unprecedented progress in understanding why nerve cells in the brain are not born in appropriate numbers in individuals with Down syndrome as well as a likely cause of why brain circuits in this patient population have a reduced capacity to encode and process new information. Perhaps more exciting is the realization that these deficits, in particular those related to cognition, are not permanent but can be gently pushed back into a normal range of function. This is important as it shows for the first time that the fate of this patient population is not set and that there is indeed hope that with time safe treatments can be developed to improve the quality of life for individuals with Down syndrome and other neurodevelopmental disorders. As such it seems appropriate that members of the medical profession should now become involved to explore whether these treatment strategies have any validity in individuals with Down syndrome.

So should we have more hope now given that previous attempts have failed? There are no simple answers to this question. As with all challenges that face mankind, we often make three steps back for every step forward. In the case of Down syndrome progress has been very slow. However, during the last few years our insights into what is wrong suggest that we may have turned the corner. Our work and those of many other groups indicate that the excessive inhibition of neuronal circuits is the underlying cause of why learning and memory is impaired in Down syndrome. Unfortunately, previous clinical trials were not motivated by such a deep understanding, and thus subject to failure.

We are motivated to work with a wonderful team of scientists and physicians at Stanford and across the country to explore the feasibility and safety of new drugs that potentially can improve learning and memory in this patient population. However, we do not expect a miracle cure. Rather, we expect that our initial efforts will lead to some level of improvement and that careful research and testing over a period of years will ultimately lead to a set of drugs that can dramatically improve the quality of life for individuals with Down syndrome. Importantly, the challenges we face are not unique to Down syndrome and in fact have been faced by teams of researchers trying to solve the puzzles of cancer and AIDs. These difficult diseases provide an important lesson that some avenues of research will succeed while others fail. Nonetheless, we consider the prospects for our current research program to be excellent based on our growing understanding of underlying mechanisms of brain dysfunction in Down syndrome.

Do you or Stanford endorse any specific treatment regimen?

We firmly believe both as scientists and physicians that any treatment needs to be vetted through the FDA. We feel strongly that the FDA clinical trial procedure is critical to maintain the highest standards of safety and most objective, placebo-controlled tests of efficacy. As such, we do not currently endorse any therapy. This said, we look forward to working with the Down syndrome community and the medical profession to test and evaluate the benefits and safety of several potential treatment strategies, with the long view that they will meet FDA approval.

What is your relationship with the Changing Minds Foundation?

Although we are aware of Dr. Cody’s projects and thankful for her promised support of our research efforts, neither myself nor Stanford University have any official relationship with her or the Changing Minds Foundation. This said, we are of the opinion that the work she has done with physicians in Houston shows promise and should be evaluated through a placebo-controlled study. In this regard, we look forward to working with her to design and conduct clinical trials to determine if this treatment is safe and/or efficacious. Here, we will engage our experienced Scientific Advisory Board to help design these trials and conduct them in accordance with the FDA and Institutional Review Boards (oversight committees of a sort) at each clinical trial site.

What is the status of a clinical trial to test the safety and efficacy of a cognitive therapy for Down syndrome?

Clinical trials are in the planning stages, and specific details have not been finalized. However, I want to clearly emphasize that our trial(s) will be 100% consistent with ‘mainstream medicine’ regarding safety monitoring, cognitive tests for efficacy, and placebo controls. We have recruited a Scientific Advisory Board of experts in Down syndrome, cognitive testing, and clinical trials. Clinical trials will be designed and implemented in close collaboration with this panel of experts, the FDA, and Institutional Review Boards (oversight committees of a sort) at each trial site. More detailed information is not available at this time as we are still in the planning stage, but I can assure you and other parents that our efforts will adhere to the highest standards of safety and science.

What treatment drugs will be used in a clinical trial?

We believe pentylenetetrazol (PTZ) is the most promising drug explored to date due to effectiveness in an animal model, a long history of safe use in humans, and additional benefits for cheap manufacture and (relatively) speedy clinical trials. As with other details related to the clinical trial, this may change. We have used several drugs in the laboratory model that have been effective for memory improvements.

Are pentylenetetrazol (PTZ) and other GABA antagonists safe? Many websites discuss PTZ as a way to induce seizures in lab animals.

Without going into too much detail, let me make a few comments about GABA receptor antagonists and drugs like PTZ. The first is that at the moment PTZ is a first principle drug and it will be up to the FDA to decide whether it is a viable drug for treating kids or adults with Down syndrome. In many respects, it is like nearly every drug on the market. There are doses at which it can be safely used and other doses that can cause mild to severe side effects. High doses of PTZ and related drugs can increase the risk of seizures, but at low doses, similar to those used in our work, there is a long history of safe use. Studies over the last 50 years have shown that it can be safely given to humans for years. Irrespective of this information is the issue of whether PTZ or related drugs can be used safely in kids with Down syndrome. This issue remains to be resolved. As I mentioned above and on our web site, we have created a Scientific Advisory Board who will work with us to determine whether PTZ or another drug are most appropriate for cognitive therapy in Down syndrome. What is clear is that reduced learning and memory are likely caused by over-inhibition of brain circuits in individuals with Down syndrome. Thus, any first order treatment ought to try to address this issue. Importantly, the GABA receptor system is the best studied in all of neuroscience and has been the intense focus of companies such as Roche, Pfizer, and Merck. As a consequence, doctors have many ways to monitor and treat over-excited circuits.

When will a trial begin? Where will it take place?

Our clinical trial strategy has three steps. The first will be to use the support from our fundraising to complete preclinical testing of drugs that show promise in our animal models. This will take approximately 6-9 months. We will then take the best of these drugs and meet with the FDA for approval to use them in a clinical setting. In parallel, we will work with several clinics across the county and with psychologists to identify appropriate testing measures to assess both safety and efficacy of these drugs. Finally, we hope to begin our placebo controlled phase I/II trial within 9 months to one year. It is expected that this phase of the project will be done 2-3 years from today. Once complete, it will still be necessary to engage a pharmaceutical company to complete a larger Phase III trial. Clearly, ours is just the first step, yet we feel it is an important one to encourage others to take up this cause and seek yet better drugs and treatment strategies.

Can I help an individual sign up for the trial? What are the eligibility constraints?

We are not yet recruiting patients for a trial, but we suggest you monitor our website for updates. If you would like to receive updates by email as well, contact me.

Why do you need funds from parents, families, and community organizations? Why not pharmaceutical companies or government agencies?

Over the last eight years the funds allocated by the US government to the National Institutes of Health to sponsor research have fallen dramatically. As such, many excellent laboratories across the country are being forced to close their doors and many scientists to seek other professions. Particularly hard hit are many of the laboratories studying Down syndrome as funds for ongoing studies, including my own, dry up.

Private foundations have played a critical role in partially compensating for reduced government funding. When times get tough and NIH resources scarce, families and scientists find a way to work together. Frequently, private foundations are funded by families of individuals affected by a particular disease. This has been true for foundations that support research in Parkinsons, multiple sclerosis, Down syndrome, and more. Unfortunately, further progress on Down syndrome research requires help with research funds from those who care most, e.g. parents and friends of individuals with Down syndrome. In this regard, we are most grateful for the support of the Down Syndrome Research and Treatment Foundation, who have helped finance part of our work. However, their resources are also limited and are insufficient at this time to support early phase clinical trials. This is one reason we have begun efforts to solicit support from the Down syndrome community at large. Any funds we raise through these efforts will fund preclinical research on Down syndrome and clinical trial costs. As with all donations to Stanford, these funds are managed by the university and applied to research costs with the same high standards as funds from government grants.

We would prefer to have funding from deep pocketbooks in the pharmaceutical or biotechnology industries to support a clinical trial, but these companies will not invest at such an early stage. We have endeavored for over two years to engage such companies but to no avail. The problem is that the risk is high for them and the return is low so that unless we can show in an early phase clinical trial that this strategy can work, they will not become engaged to finish the task of creating and testing new drugs. By running one or two early phase clinical trials on the best and safest drugs that we can find, we will reduce this barrier and gain industry partnerships. We hope our efforts will lay the foundation for subsequent trials funded by private companies.

How can I help?

Awareness of our research and clinical trials program is increasing, and we need your help to spread the word further to parents, doctors, and educators. To continue our research into the mechanisms of cognitive dysfunction in Down syndrome and to make a clinical trial a reality, we require financial assistance from private donors. For more information, and to download a related brochure, visit our website.

For more information on how you can support our research, please contact Deborah Stinchfield, (650.234.0663) at the Office of Medical Development, Stanford University School of Medicine.

For those making a gift via check, please make your check payable to Stanford University. In the memo line and in an accompanying note, indicate your gift is to support the Garner Down Syndrome Fund (DHAYQ).

Mail your gift to:

Deborah Stinchfield
Stanford Office of Medical Development
2700 Sand Hill Road
Menlo Park, CA 94025

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