Clinical Trials

Training our immune systems to fight cancer is an appealing prospect. Why wouldn’t we want to launch our own internal army against one of our most-hated foes? But the process is a bit like learning to spot a single traitor in a stadium full of innocent bystanders. After all, at the most basic level cancer cells are simply our own tissue making bad choices about how to grow and spread.

And there’s the rub: The immune system’s ability to protect against foreign invaders like bacteria or viruses hinges on its ability to differentiate them from our body’s own tissues, to which it must not react (a phenomena called immune tolerance). So it’s a catch-22 when researchers attempt to prime B and T cells, macrophages and all of our many other immune cells to wipe out cancer cells. Often what seems to be a promising response is dulled over time as immune cells called T regulatory cells, or Tregs, recognize the cancerous tissue as ‘self’ and call off the attack.

Now Stanford oncologists Ronald Levy, MD, a pioneer in the field of cancer immunotherapy, and former Stanford postdoctoral scholar Aurelien Marabelle, MD, have shown it’s possible to perpetuate an anti-cancer immune response in laboratory mice by blocking the activity of Tregs with specific antibodies injected directly into the tumor site. The work, which has resulted in the recent initiation of a Phase I/II clinical trial in humans, was published last week in the Journal of Clinical Investigation (subscription required). Levy told me:

These monoclonal antibodies target and eliminate T regulatory cells mixed in with the tumor that dampen the immune response against it. With these negative regulatory cells out of the way, the killer T cells of the immune system are unleashed to seek and destroy the cancer cells wherever they are in the body, including in the brain.

Levy and his colleagues studied laboratory mice in which human lymphoma cells had been implanted under the skin or injected into the blood. Once tumors had been established, they treated the mice with a combination of two highly specific, or monoclonal, antibodies that recognize and bind to two molecules on the surface of the Treg cells.

Although some of these anti-Treg antibodies have already been approved for use in humans (one, ipilimumab, marketed as Yervoy, is currently used to treat metastatic melanoma), they can have negative side effects. That’s because they’re injected in fairly large doses into a patient’s blood stream, inhibiting the Tregs not just in the tumor, but throughout the body. As a result, even normal, healthy tissues is subject to attack from the immune system.

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Does eating red meat increase your risk of being in a traffic accident? Should you be worried about lead in lipstick? These and other provocative medical questions will be analyzed and discussed in the Stanford School of Medicine’s new online course “Statistics in Medicine.”

This nine-week massive open online course — or MOOC, for short — aims to provide students with a foundational understanding of probability and statistics, teaching them the skills required to critically evaluate statistics in medical studies. It also shows students how to analyze and avoid common statistical pitfalls with their own research data.

“Statistics in Medicine” will use real-world examples from medical literature and popular media to reinforce its lessons. The course instructor, Kristin Sainani, PhD, is a clinical assistant professor of health research and policy and is a recipient of several teaching awards from Stanford’s graduate program in epidemiology. Her first MOOC, “Writing in the Sciences,” has had almost 70,000 students register since it launched last fall.  The self-paced version of both of these courses can taken at any time, minus homework evaluations and teaching assistant support.

Previously: Free Stanford online course on child nutrition & cooking
Photo of Bayes’ theorem by MattBuck

Rotavirus, the most common cause of severe diarrhea among infants and young children, causes somewhere approaching a half million deaths annually, 100,000 of them in India and half of those among children less than a year old.

So the positive results announced today for a Phase III clinical trial of a rotavirus vaccine developed and manufactured in India are great news. The new vaccine cut cases of severe rotavirus-induced diarrhea by more than half – 56 percent – during the first year of life, with protection continuing into the second year of life. That compares favorably with the efficacy of the currently licensed rotavirus vaccines in low-income parts of the globe.

An Indian company, Bharat Biotech, sponsored the randomized, double-blind, placebo-controlled study and will soon file for registration of the vaccine in India.

The trial was conducted at three sites in India. About 6,800 infants who were between six and eight weeks old when they were enrolled received either the vaccine or a placebo in three doses spread over about two months, simultaneously with their routine immunizations for polio.

Stanford virologist Harry Greenberg, MD, a professor of medicine and of microbiology and immunology and the medical school’s senior associate dean for research, is a member of the senior scientific advisory group involved in all aspects of the vaccine’s development. Greenberg’s own past research was instrumental in producing the first-ever rotavirus vaccine, licensed in 1998. That vaccine was pulled off the market upon the discovery of a rare but life-threatening side effect called intussusception. But a study published in the New England Journal of Medicine in 2011 showed that intussusception risk is not only vastly outweighed by the benefits of vaccination, but may actually be at least as strongly associated with rotavirus infection itself as with the vaccine.

Two companies’ competing rotavirus vaccines are already licensed. But with one costing about $37 per two-dose course and the other going for about $50 per three-dose course, they’re prohibitively expensive for the vast majority of Indians. Bharat, the Indian biotech, has stated that it will sell this vaccine (its brand name is ROTAVAC) for a dollar a dose. At that price, assuming the product’s approval, it will save many, many thousands of lives every year.

Previously: Trials, and tribulations, of a rotavirus vaccine
Photo by QUOI Media

In response to recent questioning of the integrity of the dissemination of results in biomedical literature, three medical researchers from Stanford and Duke University are pointing to the need for increased access to data from clinical research.

In a viewpoint article published online today in JAMA Internal Medicine, the authors, Robert Califf, MD, and Jonathan McCall of Duke, and Robert Harrington, MD, of Stanford, write that it’s time for both industry and academia to “catch up to other areas of society:”

The liberation of information once held in secret has toppled regimes and transformed societal expectations regarding progress and possibilities. Access to data from clinical research should be truly democratized.

The goal of clinical research should be to add to the body of evidence that can guide decisions about personal health and health policies, the authors write – but things like selective omission of important findings, inaccuracies in published studies, and the use of unreliable data systems are all hindering this. Harrington and his colleagues outline the critical issues that need to be addressed  – issues that concern “(1) the value of the research question, (2) the quality of the execution of the research, and (3) the complete and balanced presentation of all relevant data in the publication” – and sound a hopeful note:

The good news is that powerful tools exist to address and potentially surmount these issues. These tools are the ClinicalTrials.gov registry and the ongoing movement toward data transparency.

ClinicalTrials.gov was originally created to provide researchers, physicians, and the public with ready access to information on clinical trials. More recently, legal requirements to register studies have expanded to encompass the reporting of results, including adverse events, within 1 year of ascertainment of the last primary end point. These requirements are designed to ensure that findings from almost all trials relevant to US medical practice that involve a drug or device are available in a single, accessible public registry. If the requirements of ClinicalTrials.gov and other international registries are maintained and strengthened in areas where they are currently deficient, the benefits should be substantial…

Previously: Research shows small studies may overestimate the effects of many medical interventions, Outing bias in scientific research, A critical look at the difficulty of publishing “negative” results, Examining the impact of unpublished research on medicine and Testing medical ‘truths’

A recent blog entry on the Huffington Post focuses on an issue I haven’t seen much written about: the role of caregivers in the clinical-trial process. Noting that the caregiver “is the closest and most constant observer of the patient,” writer Tory Zellick outlines how caregivers can help study investigators by, for example, reporting any side-effects or changes experienced by their loved one during the trial. She also offers a few suggestions, courtesy of the National Alliance for Caregiving, on how trial leaders can better partner with caregivers:

• Speak not only in patient-centered language, but also caregiver-centered language. For example, when discussing protocol, ask the caregiver whether she is able and/or willing to perform certain duties.

• Support the caregiver in figuring out the most effective and realistic way to comply with protocol requirements.

• Explain the medical jargon used throughout the clinical trial. The caregiver needs to understand what the researcher is saying, so as to effectively communicate this information to the patient.

• Guide the caregiver on being an effective observer– explicitly stating what to look out for, how to identify it and how to respond to it.

• Prepare the caregiver and patient for the emotional aspect of ending treatment, at the conclusion of a clinical trial.

Previously: Advice for caregivers and patients about clinical trials and Clinical trials: My next good chance

This last winter has been a tough one for my small rural community. Every time I turned around, more people were sniffling and sneezing, coughing and feverish. We’ve all been just as likely to compare doctors’ recommendations as our children’s report cards, and more than one of my friends walked away from the physician with a prescription for a Z-pack: a five-day regimen of an antibiotic called Zithromax that’s effective in treating many common infections.

Last week, however, the Food and Drug Administration strengthened their warning about Zithromax: Mounting evidence has shown that the drug can be dangerous for people with certain preexisting heart conditions, or those who may be taking other drugs that affect the heart’s rhythm.

How could such a common medication carry such risks? It’s simple, explain Stanford scientists. The current methods of testing a prospective new drug’s heart safety profile depend primarily on the use of non-heart cells that are genetically modified to mimic some aspects of real ones. But they’re no substitute for the real thing. Unfortunately, the “real thing” is hard to get. After all, we’re not all lining up for heart biopsies so scientists can have a steady supply of material on which to test each drug.

Today cardiologist Joseph Wu, MD, PhD, medical student Andrew Lee, and postdocs Ping Liang, PhD, and Feng Lan, PhD, published some really exciting new work  in the journal Circulation (subscription required) that presents an alternative. In short, the researchers collected painless skin samples from patients with one of three inherited cardiac conditions, as well as from healthy family members. They then used induced pluripotent stem, or iPS, cell technology to convert the skin cells in the laboratory into functioning heart cells that reflected each patient’s specific heart aliment. Finally, they tested the response of the cells to specific medications – some of which have been shown to be relatively safe for the heart and another that had been withdrawn from the market due to unexpected cardiotoxicity. As Lee explained in our release:

It’s clear that individual patients will respond uniquely to specific drugs. If you have a hereditary disease or a problem with your ion channels, you’re going to respond differently than members of the general population. Even companies relying on genetically normal human embryonic-stem-cell-derived cardiac cells won’t be able to see all these effects. But our ‘clinical trial in a dish’ with patient-specific iPS cells allows us to model this personalized response and identify high-risk groups who should not receive the drug.

The researchers found that the heart cells in the dish responded in much the same way to the medications as did human patients. They anticipate that this type of “clinical trial in a dish” may become a standard method of testing drugs for cardiotoxicity on healthy and diseased hearts. It may also allow researchers and clinicians to test the effect of combinations of drugs while limiting the risk to real patients. Although none of my antibiotic-toting friends have been harmed by Zithromax (and thank goodness, we all seem to be feeling a bit better!), who would argue with better, faster and safer testing of all drugs? According to Wu:

Our hope is that, instead of a physician using a patient as a guinea pig, trying one medication after another until something is found to be effective, this method will one day lead to personalized drug screening to find out exactly which medication is the best for you.

I’m really excited about this research, and in this use for iPS cells in general. We’ll likely be hearing more about this approach; earlier this week Wu, who co-directs the Stanford Cardiovascular Institute, received$1.44 million from the California Institute for Regenerative Medicine to collect tissue samples to create iPS cells from several hundred patients with idiopathic familial dilated cardiomyopathy - that is, members of families with a predisposition to develop enlarged and weakened hearts without an obvious cause.

Previously: Sudden cardiac death has a cellular cause, say Stanford researchers, New leaders in heart medicine at Stanford and Lab-made heart cells mimic common cardiac disease in Stanford study
Photo by kaibara87

We’ve written here about the food-allergy work being done by Kari Nadeau, MD, PhD. But what’s it like for the parents of children with severe allergies who participate in one of Nadeau’s trials? As the kids are gradually exposed to foods they are highly allergic to, how do their moms and dads feel? That was the focus today of an NBC online piece, which includes excerpts from e-mails written by a mom of one study participant. A few of the passages jumped out at me:

January 27, 2012: Tessa will officially start the clinical trial at Stanford Hospital Friday morning!

This journey we are about to embark on is a massive one … and not to be underestimated. Not only is the time commitment great … this will be physically and emotionally taxing on Tessa as well. It will be scary for her (and us) at times as she will be reacting to the foods all throughout. Kids can have anything from stomachaches to hives to vomiting, etc.

We were in bed tonight and [Tessa] said “Mommy, I am scared. What if I can’t tell that I am having a reaction and it gets out of control like the last two times when I almost died?” It was a heart-wrenching conversation.

…

February 26, 2012: Tessa is now up to the equivalent of …  about one ounce of milk, four peanuts, [and] three whole crackers.

She has now had three home doses at this level and has not even had the slightest reaction (knock on wood) … I watched her eating crackers with her friends the other day … which was a very weird sight to see her eating “normal” food socially like that among friends… and had to make sure that her friends were very clear that she is only able to eat this food because of the drug she is on [Xolair, which suppresses the allergic reaction].

Mentally she is doing very well, too … In fact, she is the one that keeps telling me to “chillax”.

…

April 10, 2012: … There were a few extra M&M’s on the side and Tessa asked me to eat them and I said, “No thank you” and she insisted that I eat them. It was the first time in nine years that I have ever eaten anything “unsafe” in front of Tessa. It was a very odd moment and a feeling that I just don’t think I will ever get used to.

The article accompanied a Today Show segment during which Nadeau talked more about her work. And, as a reminder, she’s taking questions about food allergies this week as part of our Ask Stanford Medicine series.

Previously: Ask Stanford Med: Pediatric immunologist taking questions on children’s food allergy research and Searching for a cure for pediatric food allergies

Pediatric surgeons have been slow to adopt a technique that could keep their patients safer during a common but risky hospital procedure. But the Stanford scientist behind a new study of the procedure hopes his new research findings will provide the push they need to change their ways.

The procedure is insertion of a central venous catheter, a type of intravenous line that gives access to the largest vein in the body. It’s used when the a peripheral IV (the kind that goes in the patient’s hand or arm) is not appropriate – for instance, if a patient needs to receive a large volume of IV fluid, or needs a chemotherapy drug that could damage small veins. Inserting a central line requires poking a needle deep inside the body, into one of three major veins that feed to the very biggest vein, the vena cava. Once the needle is in the vein, it provides a pathway for threading in the catheter.

Since 2010, the American College of Surgeons has recommended that surgeons use ultrasound to see what they’re doing during this procedure. The new study provides fresh, kid-focused evidence that this is the right thing to do, as our press release on the research explains:

“Although it’s a common procedure and is sometimes perceived as benign, it’s not,” said Sanjeev Dutta, MD, senior author of the new study. “We found that, even in the hands of experienced pediatric surgeons, the use of ultrasound can mitigate the risk of complications when placing central lines.” Dutta is a pediatric surgeon at Packard Children’s and an associate professor of surgery at the School of Medicine. The research was published online today in the Journal of the American College of Surgeons.

In the study, when pediatric surgeons used ultrasound, they were able to successfully guide the needle safely into a vein 65 percent of the time on the first try, and 95 percent of the time within three tries. In contrast, when they used only anatomic landmarks to guide insertion, success rates were 45 percent on the first attempt and 74 percent after three attempts. Previous research has shown that needle placement into a vein for central line insertion is associated with few complications if it succeeds on the first try, but after three attempts, the risk of complications jumps sharply. Complications of a failed insertion can include bleeding in the chest cavity, lung puncture that causes air to be trapped in the chest cavity, puncture of the carotid artery and, rarely, fatal complications such as strokes

In case you missed it yesterday, NPR had a segment discussing the importance of having more diversity among participants of clinical trials:

…[A]ccording to the National Cancer Institute, African-Americans only accounted for 9.2 percent of the patients involved in its clinical trials, even though African-Americans are more likely than any other racial group to die of the disease.

But bringing more African-Americans into clinical trials means overcoming decades of suspicion and distrust.

The reporter goes on to talk with Junius Hayes, a retired federal worker and the first African-American participant in a clinical trial for a potential prostate-cancer treatment. When asked if anyone in his family discouraged him from being part of the trial, he said:

No, but if they knew about it they would say no. They would say no because of trust. We just don’t trust people to experiment with us. The black male – just like the while male – they don’t want to go to the doctor anyway, regardless of your race. When you put the color – we grew up going through Jim Crow. And when you come up going through Jim Crow days we weren’t educated. So it’s education has a lot to do with the disparity in the participation.

Research published online yesterday in the New England Journal of Medicine shows a novel anti-clotting drug to be superior at preventing blood clots during coronary stenting procedures compared to the currently used medication.

The study included about 11,000 patients from 153 centers around the world and was led by co-investigators Robert Harrington, MD, chair of the Department of Medicine at Stanford, and Deepak Bhatt, MD, at Harvard. The results of the trial, which were presented at the American College of Cardiology conference in San Francisco yesterday, showed that the drug, called cangrelor, reduced the odds of negative outcomes from stenting procedures such as blood clots, heart attacks and strokes, by 22 percent when compared to the routinely used anti-platelet drug clopidogrel (tradename Plavix).

We need a very potent agent to prevent clotting when we are putting things in the heart artery like wires and stents. We want a fast acting reversible agent, which is why a drug like cangrelor could be useful and why we tested it.

Coronary artery stents are used in the majority of patients who undergo percutaneous coronary intervention (PCI). In the United States, an estimated 600,000 of these procedures are done per year on patients who suffer from  coronary artery disease, which causes arteries to become narrowed or blocked.

In our press release, Bhatt comments on why the discovery of a new drug like this is important to patients. He said, “We need a very potent agent to prevent clotting when we are putting things in the heart artery like wires and stents. We want a fast acting reversible agent, which is why a drug like cangrelor could be useful and why we tested it.”