Small budget, big output mark trial consortium
Investigators want to tackle preventive therapies
The Tuberculosis Trials Consortium (TBTC) certainly isn’t short on ideas, enthusiasm, or projects. Compared with more lavishly funded consortia (the Clinical Program for Community Research in AIDS comes to mind), the TBTC could use more money; but even on a $4 million-a-year shoestring budget, it’s a powerhouse, its proponents say.
"The level of enthusiasm is incredibly high," says Rick O’Brien, MD, chief of scientific activities at the division of tuberculosis elimination at the Centers for Disease Control and Prevention. "I’ve had people who’ve worked with similar operations tell me that this one [is] a real pleasure to work with."
"I think you could accurately say that we’re suffering from growing pains," says William J. Burman, MD, infectious disease specialist at Denver Medical Health Center and an investigator for one of the division’s 26 sites. "We’ve got interesting investigators, great topics, and interesting ideas for studies, but given the current budget, we have to make some tough choices."
Preventive therapy is one subject Burman and his colleagues especially would like to tackle. "There’s some really exciting stuff out there," he says. "In animal models, rifapentine once weekly was highly effective as preventive therapy, even more effective than daily isoniazid for six to 12 months." That raises the tantalizing prospect of a preventive regimen that could be given just once a week for only three months for a total of only 12 doses, he adds.
Also on Burman’s wish list is an anti-TB candidate now in Phase II studies at PathoGenesis Corp. in Seattle (see article, p. 141). That drug, rifalazil, which has an extremely long half-life, produces exceptionally high concentrations in macrophages, studies have shown. Together, the two traits of therapy hold the promise of a much shorter course of therapy.
A third drug has proven to be useful against standard bacterial infections in Phase III trials and is showing substantial activity against TB, says Burman; the list goes on.
Where the patients are
The trial network was established in 1993 for the specific purpose of testing a once-weekly regimen of rifapentine and isoniazid in the continuation phase of therapy for TB, formally designated U.S. Public Health Service (PHS) Study 22. Once the network was up and running, the decision was made to go ahead and formalize it, O’Brien adds.
As a CDC-funded entity, the TBTC holds a unique position in several ways. "It’s the largest and perhaps the only consortium for which the CDC provides direct support for clinical trials," says O’Brien. One reason for that is historical: In 1960, the PHS tuberculosis division, with its long and distinguished history of conducting trials for TB drugs, was transferred to the CDC, he says.
The consortium is purely practical because the CDC has links with public health departments, "and that’s where the patients are," says Burman. Consortia that lack that critical advantage sometimes have had to fold trials for lack of available subjects, O’Brien adds.
The division of tuberculosis elimination also has strong ties to the U.S. Veterans Administration, which maintains more than a dozen of the 26 sites and enrolls about a third of all trial subjects, he says. Plans call for expanding links to the National Institutes of Health and its tuberculosis research unit, a contract currently held by Gerald Ellner, MD, vice chair of the division of infectious diseases in the department of medicine and director of the TB research unit at Case Western Reserve University in Cleveland.
In the field of TB research, entities such as the tuberculosis research unit and the TBTC serve a critical need, Burman and O’Brien note. Whereas with other diseases, the pharmaceutical industry often is strongly motivated to conduct trials, that’s not always the case with TB. "There’s less financial incentive for large pharmaceutical firms to undertake drug development [for TB]," says Burman.
"There’s a relative lack of profitability in drugs whose potential purchasers have little income. And when a drug acquires a TB indication, public health has been conditioned to ask whether we should restrict access to the drug in order to limit the development of resistance."
The TBTC may well have played a critical role in the recent decision by the Food and Drug Administration to grant approval to rifapentine, Burman says. With the exception of Study 22, only two other studies of the drug have been conducted. The first was a Chinese trial that used a form of the drug suspected of having low bio-availability. The drug’s manufacturers conducted a second trial; but that study turned up an increased rate of relapse in the rifapentine arm. "So it’s a fair question why the FDA approved the drug," he says.
He suggests two reasons. For one thing, a subsequent analysis of the manufacturer’s trial found the rate of relapse was acceptable among subjects who’d shown a high rate of compliance. What helped tip the weight of evidence, he says, probably were data from the TBTC study. "I suspect it had an effect on the decision to license the drug."
Modeled after the structure of the highly regarded Clinical Program for Community Research in AIDS (even to the point of adopting its trial nomenclature), the TBTC now has formally adopted by-laws, a steering committee, and a scientific study committee. The trial network includes 26 principal investigators in the United States and Canada; other staff include nurse-clinicians and outreach workers at each of the 26 sites.
The consortium recently completed enrollment for Study 22, including two substudies, one of which aims to look at the pharmacokinetics of rifapentine. Plans also are under way to start more new studies in the next 12 months, O’Brien says.
Study 23 will evaluate the safety and efficacy of rifabutin short-course therapy for HIV-positive TB patients receiving HIV protease inhibitors. Study 24 will look at the efficacy of largely intermittent, short-course therapy for patients with isoniazid-resistant TB.
Study 25 will consist of a dose-escalation trial of rifapentine, with patients randomized to 600, 900, and 1,200 mg of once-weekly rifapentine plus isoniazid. The expectation is that the new drug will show good results in higher does by preventing the emergence of rifamycin resistance among HIV-positive patients.
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