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TB Notes 1, 2000
Current TB Drug Trials: The Tuberculosis Trials
by Andrew Vernon, MD, MHS
Research and Evaluation Branch, DTBE
Image 1: Logo of the TB Trials Consortium
The USPHS and the Veterans Administration (VA) have a distinguished
history of conducting clinical trials to evaluate new drug regimens
for both the treatment and prevention of TB. In 1960, CDC assumed
a major role in these studies when the USPHS Tuberculosis Division
was transferred to CDC. Subsequently, CDC coordinated a series of
multicenter clinical trials that helped to establish rifampin-based,
short-course therapy as the standard for TB treatment. It also conducted
studies to provide the scientific basis for preventive chemotherapy,
which remains a major component of our TB elimination strategy.
Support for the infrastructure required for these studies gradually
diminished, so that the last completed trial, USPHS Study 21, was
nearly terminated several times during its course for lack of adequate
funding. With the infusion of federal support for TB control and
elimination in the early 1990s, CDC established a consortium of
clinical investigators for the specific purpose of conducting USPHS
Study 22, a trial of once-weekly isoniazid and rifapentine in the
continuation phase of therapy for pulmonary TB. This consortium,
whose sites include public health departments, academic medical
centers, and VA medical centers (VAMC), required both time and substantial
financial resources to establish and support, but is now functioning
you know that...
Aspirin was developed as a cure for tuberculosis? Researchers
in Switzerland looking for a cure for TB were excited to discover
that one particular compound was able to relieve the fever and
pain of TB patients. They subsequently found that it only provided
temporary relief, not a cure, and they put the drug aside. The
compound was later rediscovered and named aspirin (from A. Karlen,
Man and Microbes, Putnam & Sons, NY, 1995).
Currently new drugs and regimens for both TB treatment and prevention,
new diagnostic tests, and new vaccine candidates are becoming available
for clinical investigation. Concurrently, the challenges posed by
the goal of TB elimination are increasing, as global rates of drug
resistance increase and as the costs associated with assuring high
rates of adherence rise.
The consortium now provides a unique and important resource for
further clinical studies, and has demonstrated its ability to play
an important role in TB treatment and prevention.
The original group of clinical sites included 12 academic centers
and health departments (7 contracts issued in 1993, and 5 more in
1994), and 15 VAMCs (funded through a Memorandum of Agreement with
the Washington, DC, VAMC). Enrollment into USPHS Study 22 began
in April 1995, and continued to completion in November 1998. In
1997 CDC began working with the USPHS Study 22 investigators to
develop a structure that would engage more fully the capacities
of the study investigators in the work of the group. The TBTC was
thus organized, with formal by-laws adopted in 1998. Several working
committees were established; these are composed of selected Consortium
investigators and coordinators, in collaboration with CDC staff.
One committee (Core Science) oversees the scientific program of
research, a second (Implementation and Quality) supervises the conduct
and quality of ongoing studies, and a third (Executive Affairs)
serves as the executive arm of the steering committee. This structure
is modeled on the Community Programs for Clinical Research on AIDS
(CPCRA), which is supported by the National Institute of Allergy
and Infectious Diseases (NIAID).
In 1999 the TBTC underwent a formal external re-competition. New
10-year contracts were awarded to 13 offerors (7 prior TBTC members
and 6 new sites). The VA side of the consortium underwent a similar
process, and funded 10 VA Medical Centers to continue as members
of the TBTC.
The current studies of the TBTC are as follows:
Study 22: Randomized open-label trial to evaluate
the efficacy of once-weekly isoniazid and rifapentine in the continuation
phase of therapy for pulmonary TB. Enrollment closed in November
1998 with 1,004 HIV-negative participants. Follow-up will continue
Study 22 PK Substudy: Substudy to evaluate isoniazid,
rifampin, and rifapentine pharmacokinetics in 150 patients enrolled
in Study 22. Currently in analysis.
Serum Bank Study: Collection of documented serum
specimens from patients with suspected or proven TB, from baseline
through the course of therapy. Nearing completion.
Study 23: Single-arm clinical trial to evaluate
the safety and efficacy of rifabutin-containing short-course therapy
for HIV-infected TB patients receiving HIV protease inhibitors.
Aims to enroll 200 patients over 2 years, with 2-year follow-up.
Enrollment began in March 1999.
Study 23a: Substudy to evaluate isoniazid and
rifabutin pharmacokinetics in Study 23 TB patients with HIV receiving
antiretroviral therapy. Enrollment began July 1999.
Study 23b: Substudy to evaluate rifabutin and
nelfinavir pharmacokinetics in TB patients with HIV receiving nelfinavir
as part of antiretroviral therapy. CDC IRB approval granted in November
Study 23c: Substudy to evaluate rifabutin and
efavirenz pharmacokinetics in TB patients with HIV receiving efavirenz
as part of antiretroviral therapy. Enrollment began December 1999.
Study 24: Single-arm study of largely intermittent,
short-course therapy for patients with INH-resistant TB or INH intolerance.
Aims to enroll 200 patients over 2 years with 2 years of follow-up.
Enrollment began September 1999.
NAA Substudy: Study of the performance of several
nucleic acid amplification methodologies in the diagnosis and management
of active TB. CDC IRB approval granted in October 1999.
Study 25: Phase I-II dose escalation study of
rifapentine using same design as Study 22, with patients completing
2-month standard induction randomized to 600, 900, and 1200 mg of
once-weekly rifapentine/isoniazid. Expected to demonstrate safety
and tolerability of higher doses of rifapentine, which may improve
efficacy, prevent acquired rifampin resistance in HIV-infected patients,
and permit use of once-weekly treatment in initial phase. Enrollment
began July 1999.
Study 26: Trial of short-course treatment of latent
TB infection among contacts of active cases, using a 3-month once-weekly
regimen of isoniazid and rifapentine, compared to the recently recommended
2-month daily regimen of rifampin and pyrazinamide. Protocol in
For further information about the Consortium, please visit the
TBTC web site at http://www.cdc.gov/nchstp/tb/tbtc