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How hard is it to design a clinical study? When you're giving stool enemas, very

03/26/2012 12:50 EDT | Updated 05/26/2012 05:12 EDT
TORONTO - How hard could it be to set up a scientific study to test a possible cure for C. difficile diarrhea? If the treatment in question involves someone else's stool, a one word answer suffices.

Very.

Four years after some Toronto researchers received initial approval to test whether fecal transplants are as effective at curing C. difficile as they appear to be, the study is still in the early stages, with only 10 of a required 140 patients enrolled. Some infectious disease specialists who are eager for the answers the study might provide worry it may never be completed.

"There's always that possibility," admits principal investigator Dr. Susy Hota.

"It would be such a shame. I think everyone's kind of waiting to get this kind of information. But it's a really difficult study to try and get going."

An infectious diseases specialist who works in infection prevention and control at Toronto's University Health Network, Hota is trying to find funds to expand the trial to other hospitals across Canada in the hopes of enrolling enough patients to generate usable data.

Confirming the efficacy of a low-cost, low-tech treatment for recurrent Clostridium difficile diarrhea would be a welcome step towards solving an enormous problem facing health care these days.

People who contract the disease — generally after using antibiotics, often after being in hospital — can suffer for months or longer, unable to shake a condition that shrinks their world. In the most persistent of cases, sufferers have to use extremely costly antibiotics to try to control the diarrhea. Some have failed multiple attempts to be weaned off antibiotics without triggering a recurrence and face the prospect of a lifetime on the drugs.

But an unconventional treatment first used in the 1950s is gaining popularity among people with recurrent C. diff and the doctors struggling to treat them.

The therapy is called a fecal transplant and it is exactly what it sounds like. Stool from a healthy donor is blended with saline and deposited into the gastrointestinal tract of the patient in an attempt to re-establish a healthy balance of bacteria in a bowel that has been overrun by C. difficile.

The transplant can be administered one of three ways: into the stomach via a tube snaked through a nostril and down the esophagus; up into the intestinal tract using the type of scope normally employed in colonoscopies or into the lower bowel in a procedure that is essentially a reverse enema.

Though some hospitals refuse to have anything to do with fecal transplants, doctors who use the technique as a last-ditch effort to treat their most persistent C. diff cases say they cure about 90 per cent of the people who submit to the treatment. But that statistic is based on the results of small groups of patients, not a robust clinical trial.

Given the paucity of other options, you might think the research world would encourage, even embrace a study designed to see whether fecal transplants are actually that effective. But Hota and her colleagues had to clear some high hurdles just to get this study off the ground.

For starters, how do you design such a study?

The best scientific evidence is generated by what's called a randomized controlled trial, in which a group of subjects are divided into two — sometimes more — groups. One gets the drug or therapy or intervention being tested, the other doesn't. In the best randomized controlled trials neither the subjects nor the researchers know which group is which, a process called "blinding."

Good luck figuring out how to blind a study involving stool. "You can't replicate the smell," Hota says matter-of-factly.

She says she and her colleagues spent a lot of time trying to find a safe placebo they could test against the fecal transplant. They even thought about autoclaving stool — subjecting it to high heat in a device used to sterilize medical equipment. In the end, they decided it might jeopardize the study.

While it's assumed the transplants work by restocking the diseased bowel with the array of bacteria found in a healthy one, no one is really sure that's true. If something else in the stool is actually the active agent, there might be no difference between the control group (those getting placebo) and the treatment group, and the study would fail to the question it was designed to explore.

As well, the researchers worried they wouldn't get approval from the hospital ethics board if they asked the people in their control group — who are, after all, people who suffer from persistent diarrhea — to undergo a sham enema. And they were pretty sure the idea wouldn't go down well with would-be participants.

"People are not excited about the thought of a sham enema," Hota says. "They want to know that if they're going to get the transplant, they're going to get the transplant."

In the end, patients who enrol are randomly assigned to get either a fecal transplant or a six-week course of the antibiotic vancomycin. The antibiotic is given in what's called a tapering course — a gradual reduction of the amount of drug given to wean the patient off the antibiotic without triggering a recurrence of the diarrhea.

Health Canada had to give its blessing for this study to proceed, and there were serious hurdles at that stage too. The regulatory agency was interested, even sympathetic, Hota suggests. But questions and demands that were tough to answer or meet arose.

The first: How should a fecal transplant be categorized? Stool is clearly not a drug. Nor is it a device. After much discussion, it was decided fecal transplants should be regulated as a biologic, the term used for therapies, such as vaccines, that are made from living organisms.

But a tougher question followed: How do you standardize stool? How do you ensure that the treatment Patient A is receiving is similar enough to the treatment Patient Q is receiving that you can draw any conclusions from the results of the study?

Hota's study wasn't designed to use stool from a single approved donor or stool produced by following a standardized diet. People accepted into the study are asked to find their own donor; often a family member steps forward. Though all donors must be screened to ensure they are healthy, there is no way to make sure that one donor's stool is identical to another donor's stool.

The team came up with the idea of measuring growth of bacteria in the stool. Not each individual type of bacteria, but en masse — or as Hota calls it, "gross growth." They then set a cut-off for the point beyond which they wouldn't use stool, because the gross growth had dropped off too much.

They also had to figure out whether donors should refrigerate the donated stool — yes — and how to screen would-be donors. Health Canada insisted donors be subjected to the type of screening used for living organ transplant donors, which means Hota and her team have to ask questions about diseases — rabies, Creutzfeldt-Jakob disease — that probably have no bearing here.

Once the study was cleared to go, the researchers faced yet another challenge — getting patients to agree to enrol. There the snag isn't what you might expect. It's not that people don't want to undergo a fecal transplant. As word of the success of the treatment spreads, desperate C. diff patients don't want to run the risk they won't get the transplant, which they can get with the help of some sympathetic doctors.

"It can be very disappointing for them if they get randomized to the vancomycin," Hota says, adding that as an incentive, patients randomized to the drug are promised that if the antibiotic treatment fails and their diarrhea recurs, they will be offered the option of having a transplant.

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