Clinical Trials

Food allergies affect one in every 13 American kids, yet when a child is diagnosed, modern medicine can’t do much to help. As parents of newly diagnosed kids quickly learn, the standard advice is to avoid allergy triggers completely, since that’s the only surefire way to prevent life-threatening episodes of anaphylactic shock. Many of the common allergy triggers – such as wheat, cow’s milk, soy, eggs and peanuts – are so ubiquitous that avoidance becomes a herculean task. Families have to be extra-cautious about everything from restaurant meals and school events to birthday parties and sleepovers at friends’ homes. In addition to the stress they cause for affected families, food allergies take a big medical toll. They’re responsible for 90,000 episodes of anaphylactic shock each year and 2,000 hospitalizations.

It’s hard enough if your child is allergic to just one food. But a growing number of children have severe allergies to multiple foods. Fortunately, a scientist at Stanford and Lucile Packard Children’s Hospital is working to help these kids. Building on a body of work – her own and others’ – demonstrating that it’s possible to safely desensitize children to a single food allergen, Kari Nadeau, MD, PhD, is now trying to find treatments that will address multiple food allergies simultaneously. Her quest is described in a new feature in this week’s New York Times Magazine:

Could patients be desensitized to more than one allergen at a time? No one had ever tried it, but more than a third of children with food allergies are allergic to more than one food. If it was safe to give patients x milligrams of one allergen, would it be safe to give them one-fifth of x milligrams of five different allergens, as long as the total dose remained the same? That would assume that allergens function in a linear, additive fashion — rather than a multiplicative one; it was also possible that they could interact with one another to produce a more severe reaction.

Nadeau experimented with blood samples of allergic patients and was encouraged to see that the allergens seemed not to interact with one another. She consulted with senior colleagues in the field to see if anyone would collaborate on a multiallergen study, but no one was interested. Scientifically the results would be harder to interpret than single-allergen trials. Moreover, each allergen would require getting separate F.D.A. approval, and it was difficult to get even one application approved. When she found herself home sick in bed with a virus for a few days in 2011, she decided she would “knock them all out” and wrote 13 Investigational New Drug Applications, each 90 or so pages long, and soon received F.D.A. approval for each one.

The entire story is a fascinating behind-the-scenes look at the science of immunology, and well worth reading. Those interested in learning more about Nadeau’s ongoing projects should check out her research group’s website.

Previously: Helping kids cope with allergies, New hope for people with severe milk allergies and Researchers find mechanism for destruction of key allergy-inducing complexes
Photo by Steve Fisch

An article in today’s New York Times highlights just-published work by Massachusetts General Hospital researchers and Stanford genomics expert Ron Davis, PhD, in which the scientists presented “stunning evidence that the mouse model has been totally misleading for at least three major killers – sepsis, burns and trauma.” As a result, according to the Times article, “years and billions of dollars have been wasted following false leads.”

The newspaper story is referring to a Proceedings of the National Academy of Sciences study that writer Gina Kolata says may help explain why every one of nearly 150 drugs tested at huge expense in patients with sepsis has failed.

This work goes back several years, with Davis and his associates finding patterns of gene activity that seemed to predict which sepsis victims will live and which will die. The researchers tried to publish their results in several journals but were initially rebuffed because they hadn’t tested their findings in mice to see if the same things happened, according to the article:

“They were so used to doing mouse studies that they thought that was how you validate things,” [Davis] said. “They are so ingrained in trying to cure mice that they forget we are trying to cure humans.”

“That started us thinking,” he continued. “Is it the same in the mouse or not?” The group decided to look, expecting to find some similarities…

But when the investigators looked, there were none at all. In fact, some genes that were “turned on” by sepsis in mice were “turned off” in humans. Further, in humans, similar genes were activated by sepsis, trauma and burns – three conditions in which the immune system overreacts and inflicts more damage to the body than the bacteria, knock to the head or house fire, respectively, that originally caused the problem. But in mice, these three different types of stimuli trigger three quite different gene-activation patterns.

So, a drug that might work in a human could have the opposite effect in a mouse. And vice versa.

The man/mouse mismatch, intriguingly, shows up in other places, too. For instance, a recent study led by Stanford immunologist Mark Davis, PhD, suggests that experimental mice – who spend their entire lives in artificial, ultra-germ-free environments – may be a poor model for adult humans’ more battle-hardened immune systems, which have acquired quite a bit of savoir faire.

And in another study a few months back, Stanford drug-development expert Gary Peltz, MD, PhD, developed mice with humanized livers, explicitly to address another disparity that can easily result in costly failures of new drugs in clinical trials: Mice’s livers, being different from ours, often metabolize new experimental drugs quite differently from the way ours would.

Previously: Professor Ronald Davis wins 2011 genetics prize from the Gruber Foundation, Deja vu: Adults’ immune systems “remember” microscopic monsters they’ve never seen before and Fortune teller: Mice with “humanized” livers predict HCV drug candidate’s behavior in humans
Photo by gliuoo

In a 2011 cover story for Stanford Medicine magazine, my colleague Krista Conger outlined one of the big hurdles in getting new cancer treatments to patients: the clinical-trial process. And, more specifically, the dearth of people enrolled in trials. “We’re going to have to get around the problem that less than 5 percent of adult cancer patients who could be participating in clinical trials are enrolled in one,” Phil Lavori, PhD, chair of the Department of Health Research and Policy, is quoted as saying. “The rate of participation is abysmal.”

I was reminded of this late last week when coming across findings of a new study from the University of Michigan. Researchers there conducted a survey and found that only 11 percent of adults and 5 percent of children had ever participated in medical research (not just cancer-related). In addition, as outlined in a release, only “64 [percent] of adults said they were aware of opportunities to participate in medical research, while only 12 [percent] of parents said they were aware of opportunities for their children to participate.”

In a bit of good news, the researchers did find a significantly greater level of awareness about trials from survey respondents living within 100 miles of four specific Clinical and Translational Science Awards locations. (CTSAs, like Stanford’s Spectrum, are NIH-funded programs designed to improve clinical and translational research.) As the researchers point out in their paper, these higher levels of awareness “merit investigation” to identify what these programs are doing right, and how their approaches might be used elsewhere.

Previously: Advice for caregivers and patients about clinical trials, Patients share clinical trial experiences at Stanford and Clinical trials: My next good chance

Drug therapies with sales exceeding $1 billion should be subject to a mega-trial, a randomized clinical trial with at least 10,000 patients. That’s what  John Ioannidis, MD, DSc, chief of the Stanford Prevention Research Center, argues in a perspective published today in the Journal of the Americal Medical Association.

In the piece, Ioannidis points out that while so-called “blockbuster” drugs are used by hundreds of thousands of individuals, the supporting randomized trials typically include only a few hundred participants, “often with relatively short-term follow-up.” Describing how larger trials could benefit what we know about psychiatric drugs, he writes:

…5 of the top 24 blockbusters are mental health–related drugs: aripiprazole (Abilify), quetiapine (Seroquel), duloxetine (Cymbalta), olanzapine (Zyprexa), and escitalopram (Lexapro). None of them has ever been tested in a mega-trial, and most evidence comes from short-term trials of 3- to 4-months’ duration with only hundreds of participants. Nevertheless, several million doses of each of these drugs are dispensed annually. Mega-trials would help settle and even preemptively address concerns about deaths and suicides associated with some mental health interventions.

Besides mortality outcomes, mega-trials can focus on other specific major questions of interest. For example, for mental-health interventions, these trials would provide sufficient power to address the effects of drug interventions on important outcomes such as suicide attempts, hospitalizations, and job loss instead of relying solely on subjective scales and also would help define the spectrum of disease severity at which these treatments are effective, another issue debated endlessly based on small trials and meta-analyses thereof…

Ioannidis also outlines how challenges relating to cost and recruitment for such large trials could be overcome, and he proposes a framework for carrying out the studies. He calculates that streamlining the design, monitoring, data collection and outcomes of the traditional clinical trial process could greatly reduce the cost of mega-trials. With an intervention with $2 billion in annual sales, for example, the expense of a study consisting of 80,000 participants could be covered with one month of sales – about $167 million.

Under Ioannidis’ proposal, companies would be required to pay one month’s worth of previous year’s sales into a special fund, which would be used for funding mega-trials. In return, companies with drugs that performed well during the trials could receive incentives such as a patent extension. Ioannidis notes, “For instance, a 4-year extension of the patent would offset by 50 times the cost of the mega-trial.”

Previously: NIH funding mechanism “totally broken,” says Stanford researcher, Research shows small studies may overestimate the effects of many medical interventions, Animal studies: necessary, but often flawed, says Stanford’s Ioannidis and Outing bias in scientific research
Photo by Keith Ramsey

When I first interviewed Brian Kobilka, MD, winner of the 2012 Nobel Prize for Chemistry in October, I was struck by an off-hand comment about his motivation for his near-obsessive two-decades long research quest to uncover the workings of GPCRs, or G-protein-coupled receptors, which serve as one of the main methods of molecular communication within the body.

The research, which it’s believed will lead to the creation of new drugs for clinical care, was not originally done for this purpose. It was motivated by simple scientific curiosity – the kind that often leads to amazing discoveries that help cure suffering or save lives. Initially, Kobilka just really wanted to know how it worked.

In a story published in today’s Inside Stanford Medicine,  I describe the success of research based on scientific curiosity in leading to clinical care breakthroughs. The story describes the 30-year history of scientific breakthroughs that led to the approval of a new drug called vismodegib that is used to treat inoperable basal cell carcinomas, and how the drug helped save the eyesight of 101-year-old Winnie Bazurto of San Mateo, Calif. It’s a story that begins with a similar motivation – basic scientific interest – and ends with discoveries that help patients in a very practical way. As Jean Tang, MD, PhD, Bazurto’s dermatologist and vismodegib researcher, says in the article:

If a patient only knew the whole story — how the happenstance of science led to their treatment… If they could go back to when this molecular pathway was first discovered in fruit flies, they’d be amazed. It’s not until the dots are connected 30 years later that it begins to make sense.

Stanford’s Matthew Scott, PhD, one of the key players in this basic-science success story, commented to me in an e-mail just how essential it is for future clinical discoveries that basic science continues to be funded. He expressed concern about a current trend toward conservatism in funding that requires much quicker results that lead to treatment options for patients saying, “Current conservatism in funding asks for translational work that gives cures in a few years (which never happens). Far-sighted funding of basic science … pays off big time.”

The vismodegib story illustrates just how essential basic science is to the future of clinical discoveries:

For many of the basic scientists involved in this research, the clinical use of hedgehog-inhibiting drugs to treat patients like Bazurto — while not the original goal of their research — is the ultimate success.

Previously: Why basic research is the venture capital of the biomedical world, Future of medical research is at risk, says Stanford medical school dean and The economic benefits of publicly funded medical research
Photo by Norbert von der Groeben

In a previous Scope entry, Inspire contributor and cancer patient Linnea Duff explained why she no longer views clinical trials as a last resort, but rather as her “next good chance.” Similarly, in a video series produced by the Stanford Cancer Institute a group of patients discuss how clinical trials offered not just the opportunity for a potentially more effective avenue of treatment but also the chance to contribute to medical research.

A piece today in the Huffington Post offers a simple breakdown of the key facts for other patients considering participating in a clinical trial, and two Stanford experts provide comment on the potential risks:

…Observational studies — such as the sharing of medical files — typically pose no added risk, and the risk of interventional studies depends on numerous factors. For example, if two known drugs are being compared to see which is more effective in the treatment of a particular illness, the risk is low. It is important to note that even if a medication is FDA approved, an individual may suffer adverse side effects. If an unknown drug is being tested, however, the risk depends on how far along that drug is in the R&D phase: The more it has been tested, the less risky it is. Even tried-and-true drugs or procedures may be risky, adds Rebecca McCue, division research manager of the Stanford Systems Neuroscience & Pain Laboratory (SNAPL), such as in the case where an FDA-approved drug is used to treat an illness other than that for which it was approved.

While holistic intervention such as cognitive behavioral therapy poses negligible risk, other alternative medicine therapies may pose some risk. “A number of alternative therapies don’t go through approval with the FDA,” explains Sean Mackey, MD, PhD, Chief of the Division of Pain Management at Stanford University. For example, he says, nutritional supplements are unregulated by the FDA and therefore “have not been through the close scrutiny that pharmaceuticals go through. The vast majority are not dangerous agents, but we simply don’t know their long-term safety and efficacy… We haven’t studied a lot of these over-the-counter supplements in large-scale trials, because there are not drug companies interested in doing that.”

Previously: Patients share clinical trial experiences at Stanford and Clinical trials: My next good chance
Photo by Stanford EdTech

A shortage of a cancer drug used to treat Hodgkin lymphoma has been linked to increased cancer relapses among children with this type of lymphoma, or cancer of the lymph glands, according to a report released today in the New England Journal of Medicine.

Chemotherapy drug shortages have been in the news a lot this year, with heart-wrenching reports focusing on families who were told their children’s chemo might become unavailable. So far, most chemotherapy shortages have been resolved in time to give patients the treatment they needed, but the drug shortages continue to threaten the treatment of many pediatric and adult patients.

The finding implies that some pediatric cancer patients [experienced] more acute and long-term side effects than they would have had the mechlorethamide shortage not occurred

The mechlorethamine shortage, which began in 2009 and ended recently, was different. The drug, one of a group of chemotherapy medications typically used to treat Hodgkin lymphoma, was completely unavailable for more than two years. In its absence, doctors had no choice but to substitute a different drug, cyclophosphamide, into the chemo regimens of their patients with Hodgkin lymphoma. This substitution seemed very reasonable because the two drugs are close relatives and work by similar mechanisms.  In fact, cyclophosphamide has been used to treat patients with Hodgkin lymphoma for many years.

Three pediatric cancer researchers, including scientists at St. Jude Children’s Research Hospital, the Dana-Farber Cancer Institute, and Stanford’s Michael Link, MD, analyzed the consequences of the substitution. Initially, they thought the two drugs would work equally well, but they found something quite different.

Using a chemotherapy regimen that included mechlorethamide, 88 percent of patients were cancer-free two years after completing therapy; among patients who received the same regimen but with cyclophosphamide instead of mechlorethamide, only 75 percent were cancer-free two years after therapy ended. The patients who developed relapse required additional, intensive therapies, including bone marrow transplants to treat recurrence. Although doctors gave the best treatments they had available and all patients are still living, the finding implies that some pediatric cancer patients received additional therapy associated with more acute and long-term side effects than they would have had the mechlorethamide shortage not occurred.

From our press release about the findings:

“This is a devastating example of how drug shortages affect patients and why these shortages must be prevented,” said Monika Metzger, MD, an associate member of the St. Jude Department of Oncology and the study’s principal investigator. “Our results demonstrate that, for many chemotherapy drugs, there are no adequate substitute drugs available.”

…

“This puts a face on the problem of drug shortages and shows that the problem is real, not theoretical. This is about a curative therapy that we were unable to administer because the drug we needed was not available,” Link said. “Despite heroic efforts by the drug shortage office of the Food and Drug Administration to solve the shortages of a number of medically necessary drugs, it is clear that patients are still suffering from the unavailability of life-saving drugs. A more systematic solution to the problem is needed.”

Previously: A Q&A on cancer-drug supply shortage; An in-depth look at the even-deeper problem of drug supply and Childhood leukemia patient on methotrexate shortage

From Dec. 24 to Jan. 7, Scope will be on a limited holiday publishing schedule. During that time, it may also take longer than usual for comments to be approved.

Systemic juvenile idiopathic arthritis (JIA) is a chronic disease that takes a real toll on its young patients. In addition to painful, arthritic swelling and stiffening of some of their joints, these children experience whole-body (systemic) symptoms such as fevers, rashes, enlarged lymph nodes and anemia. Patients’ blood shows elevated levels of inflammatory markers, signaling that inflammation plays an important, though poorly understood, role in the disease.

The most severe form of the disease, systemic JIA can be extremely difficult to treat. That’s why the medical community is closely watching reports of two new potential drugs for the disease, whose Phase 3 trials were published this week in the New England Journal of Medicine. The drugs, called canakinumab and tocilizumab, inhibit interleukin-1 beta and interleukin-6, respectively. The interleukin molecules are part of the body’s inflammatory response.

In an accompanying editorial (subscription required), two Stanford rheumatologists describe the promise and challenges of these drugs. The doctors, Christy Sandborg, MD, and Elizabeth Mellins, MD, note that the drugs produced remarkable reductions in the frequency of patients’ fevers and the severity of other JIA symptoms, with more than 70 percent of patients hitting the benchmark that the study scientists had set for evaluating the medications’ success. Many patients were also able to reduce their use of the steroid hormones (glucocorticoids) they take to manage the disease, a desirable outcome because of glucocorticoids’ many side effects.

However, as the editorial also explains, it will be quite challenging to figure out the safety profile of the new drugs. Based on their assumed mechanisms, these drugs could increase patients’ risk of infection, neutropenia and liver dysfunction. These drugs’ safety will be more complicated than most to evaluate, for several reasons: systemic JIA is rare, so it’s challenging to assemble enough patients to study; the patients’ disease is complicated, making it difficult to tease apart drug side effects from the effects of the disease itself; and the patients are usually taking several medications.

Sandborg and Mellins conclude:

To address the challenge of evaluating long-term and infrequent adverse events that occur with these therapies, new approaches are needed, such as consolidated disease registries designed to evaluate safety signals in the context of the underlying disease and exposure to multiple agents.

…

Despite important remaining questions about regulation of inflammation, the pathogenesis of systemic JIA, and appropriate interventions, there is no doubt that the agents tested in these trials signal a new era in the treatment of systemic JIA and will shed light on the mechanisms driving this enigmatic disorder. Continued investigation of systemic JIA is likely to inform our understanding of other multigenic autoinflammatory diseases — a growing category that now includes type 2 diabetes and inflammatory bowel disease — as well as our understanding of the regulation of inflammation.

About one in four breast-cancer survivors eventually develops lymphedema, a painful inflammatory condition resulting from the blockage of lymphatic vessels that ordinarily drain fluid from the tissues throughout the body. While in the developed world lymphedema most often arises as an unintended consequence of radiation therapy for cancer, there are numerous other causes as well. An estimated 10 million people in the U.S. alone suffer from it.

But by the time the main symptom of lymphedema — swelling of one or more limbs — is detectable, the condition may have gotten such a foothold that it becomes difficult or impossible to reverse, at least given the treatment choices now available.

In a study just published in PLoS ONE, veteran vascular expert Stan Rockson, PhD, and his Stanford colleagues have identified a set of proteins circulating in blood whose levels accurately flag lymphedema’s presence. This could make a difference. As I wrote in my release about this study:

The only known way to diagnose lymphedema now is via physical inspection, and all too often it is misdiagnosed or overlooked altogether. But the biological events underpinning this condition may be present five years or more before symptoms become evident, said Rockson. Moreover, there are no effective drugs for combating lymphedema, just costly, time-consuming and annoying physical therapy, which virtually never completely eliminates the symptoms. While physical therapy can arrest progression and reduce swelling by as much as half, the condition typically remains a long-term problem. “Lymphedema virtually never just goes away on its own,” said Rockson. Indeed, it tends to progress in severity over time, whether it is treated or not.

When I asked Rockson about the findings’ significance, he told me,  “A standardized, accurate bioassay for lymphedema could help to pave the road for future human clinical trials of drugs to treat it.” Monitoring trial subjects at the molecular level with a lymphedema-detecting blood test could provide early evidence regarding whether an experimental treatment was working. Rockson is conducting clinical trials of pharmaceutical agents for lymphedema, and expects to incorporate the new test into those trials.

The upshot: some reason for optimism that a common but relatively neglected condition finally will be amenable to detection and, eventually, treatment with 21^st-century techniques.

Previously: New Stanford registry to track lymphedema in breast cancer patients and New breast cancer finding suggests limiting surgery
Photo by Kalyber

Stanford researchers are currently recruiting participants for a clinical trial to study the immune response to an experimental, seasonal DNA flu vaccine and boosted by one of two licensed seasonal flu vaccines.

As my colleague describes in a release, the immediate goals of the trial are to test the safety of the experimental DNA vaccine given alone or at the same time as the licensed vaccines, and to assess the immune responses they produce. Overall, researchers hope the study, which is sponsored by the National Institutes of Health, will increase the scientific community’s understanding about how to safely improve the immune response to seasonal flu vaccines.

Below, study participant Johan Andreasson discusses his experience with the trial. Those interested in enrolling themselves can learn more here.

Why did you decide to enroll in this clinical trial? Had you been in one before?

I’ve never participated in a trial before. When I saw the advertisement in the elevator at work, I thought that this would be a great opportunity to learn more about this type of research. I also recognize that researchers involved in projects like these are working really hard to find and validate new treatments that benefit us all, so we should do our best to help them. Sufficient patient recruitment is essential for the success of any trial. Finally, medical research excites me and I was going to get a flu shot anyway – so why not make the most of it?

Going into this experience, what did you know about research studies? What were you expecting?

As a graduate student in a biomedical related area, I’m familiar with both lab research and clinical studies. However, no two studies are the same so I didn’t have any clear expectations.

What has your participation in the trial involved so far?

Since signing up for the trial, I have visited the clinic twice and participated in a follow-up call over the phone. In the week following the vaccination, patients take their temperature daily and document any side-effects. Overall I found their process to be very smooth, and I don’t think the time commitment should deter anyone from participating.

Did you have any concerns going into the trial and, if so, how did the researchers address them?

I personally didn’t have any major concerns, especially after learning more about the study. The researchers were very conscientious in explaining what the study entailed and making sure that I fully understood what I was consenting to. The researchers I interacted with were very professional, and it was evident that patient safety was their primary concern.

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