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U.S. Department of Health and Human Services

  

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TB Notes Newsletter

No. 4, 2005

TB Trials Consortium (TBTC) Update

Introducing the TB Trials Network – Enhancing the U.S. Public Health System’s Willingness and Capacity to Engage in Clinical Research

In 2002, Elias A. Zerhouni, MD, Director of the National Institutes of Health (NIH), held meetings with leaders and scientific researchers from NIH and around the country to develop a “roadmap” for medical research in the 21st century. Opportunities to make medical research more efficient and productive were identified. The third of three NIH Roadmap themes established from this process is “re-engineering the clinical research enterprise” (http://nihroadmap.nih.gov/). NIH has funded projects that will contribute to the development of a systematic infrastructure for expanded clinical research networks which will have the capacity to “rapidly conduct high-quality clinical studies that address multiple research questions.” These projects, or feasibility studies, were selected through a Broad Agency Announcement (BAA). In response to the BAA, Dr. Carol Dukes Hamilton, Principal Investigator of TB Trials Consortium (TBTC) site #54 at Duke University, and TB Controller for North Carolina, put together a successful application titled “Enhancing the U.S. Public Health System’s Willingness and Capacity to Engage in Clinical Research.” In October 2004 the TB Trials Network (TBTN) was launched.

Why are clinical research networks needed? Clinical research questions can be answered most clearly and definitively when large numbers of patients are enrolled in a study. And, if a very large number of patients are enrolled, multiple research questions can sometimes be answered in a single study. For some research questions, it may not be possible to even identify the needed number of patients in one location. Even when the number needed can be found in one area, it can take such a long time for one site to enroll enough patients and then more time for the last patient enrolled to complete the study that over 10 to 20 years could pass before the research question would be answered. Additionally, there are occasions when a study has taken so long to be completed that the answer is no longer relevant by the time the study is completed. If the answer can be reached sooner, more patients can be helped with the knowledge gained, and more lives can be saved.

Bringing researchers from multiple locations together in a network makes it possible to recruit large numbers of patients for a clinical study very quickly. Additionally, the studies conducted by a group of researchers will benefit from a broad range of shared expertise. Study subjects recruited from multiple areas will often be more heterogeneous and the study conclusions will thus be applicable to a broader range of patients. Thus, clinical research networks offer the promise of rapidly answering relevant clinical questions. Diseases of public health importance (like TB and STDs) are usually diagnosed and treated at public health clinics. Clinical research questions that address diseases like TB and STDs can best be studied in a network of public health clinics.

Though the advantages of a research network are easy to appreciate, it can be quite challenging to establish the infrastructure needed for such a network to be formed and to be functional. The TBTC is such a network and will serve in a way as the “laboratory” for the TBTN to explore the reasons behind the successes and the opportunities for greater success of clinical research within the U.S. public health system.

The TBTN is a collaboration between TBTC and the Duke Clinical Research Institute (DCRI), which has an established infrastructure, clinical trials expertise, and tools and training programs. Over 40 public health researchers from TBTC, CDC, and DCRI, representing nearly 20 academic and research institutions, are contributing to the effort. The major focus of the proposed TBTN projects will be to enhance the willingness and capacity for clinics within the U.S. public health system to engage in clinical research. Though the specific long-term goal for TBTC is progress toward worldwide TB control and elimination, the process, connections, and products developed by TBTN work will have broad application among clinical research networks in the United States.

Specific aims of the TBTN are as follows:

  • Aim 1: Engage public health leaders in the clinical research enterprise in general, and TB clinical research in particular, by investing them in priority-setting forums that will also help the TBTC to create a relevant, timely, and dynamic future scientific agenda. The first “think-tank” meeting took place September 30, 2005, in Atlanta, Georgia
  • Aim 2: Identify and reduce barriers to clinical trials research in U.S. public health clinics. We will work with representative TBTC-associated public health clinics to identify the most significant barriers to conducting clinical research in their setting and develop a responsive strategy to reduce the barriers. In August, teams began conducting site visits (at TBTC recruiting sites in North Carolina, New York City, Louisiana, Georgia, and Texas) to identify barriers to research in public health clinics. The visiting teams will gather observational data, develop interventions, and measure impact on enrollment over time.
  • Aim 3: Under the leadership of William Burman, MD, develop a model for improving the process of human subjects protection review in multicenter trials. We will explore the impediments to expanded use of central institutional review boards (IRBs) in multicenter trials, and address the complexities associated with informed consent among subjects who do not speak English. The TBTN IRB team is currently contacting over 100 IRBs which oversee multicenter clinical research to determine policies or barriers against use of a central IRB and the use of the short form for people who do not speak English.
  • Aim 4: To improve interoperability between TBTC sites and with public health clinics by 1) standardizing data elements and definitions used in TB-related clinical research, 2) creating a secure Web-based electronic data capture system for adverse events reporting in TBTC Study 26, 3) developing a TBTC website, and 4) determining the feasibility of connecting to NEDSS. Connection to NEDSS would allow us to take advantage of ongoing surveillance data collection to improve our ability to recruit subjects to clinical trials, as well as compare trial populations with the population at large, so we will have a measure of the applicability of our findings. As of August 2005, the TBTN informatics team has
    • Nearly completed development of an electronic data capture adverse event reporting system for a very large multicenter study (Study 26; enrollment goal, 8000 patients).
    • Created a query tracking system (approximately 750 query rules) for TBTC Study 26
    • Developed a fully functional TBTC secure, members-only website www.tbtrialsnetwork.org\tbtc
    • Created TB Trials Network website www.tbtrialsnetwork.org
    • Planned a data standards stakeholders meeting for fall 2005

In the first year of funding, the TBTN has already made significant progress toward project goals. Through TBTN’s work, the U.S. public health system can make important contributions to Dr. Zerhouni’s roadmap initiative and ensure long-term support for programmatically relevant clinical research carried out in public health settings.

Study enrollment updates:

Study 24 is a single-arm study of largely intermittent, short-course therapy for patients with INH-resistant TB or INH intolerance. Enrollment closed December 2004 with a total of 98 patients. By mid 2007, all patients will have reached the end of follow-up for study outcomes (treatment failure and relapse).

Study 26 is a trial of short-course treatment of latent TB infection among contacts of active cases, using a 3-month once-weekly regimen of isoniazid 900 mg and rifapentine 900 mg, compared to standard 9-month therapy with isoniazid 300 mg. As of October 26, 2005, Study 26 enrollment was up to 5,178, over half the intended subjects for total enrollment.

Study 27 is a double-blind, placebo-controlled comparison of 2-month culture conversion rates when substituting moxifloxacin for ethambutol in the initiation phase of treatment of pulmonary TB. Enrollment began in July 2003 and was completed in March 2005, with a total of 337 patients. Over 50% of patients were enrolled from two African study sites. Preliminary results were presented in May 2005 and showed there was no difference between study arms in terms of time to sputum conversion. There were differences, however, between North American sites and African sites, with significantly more North American patients converting their sputum to negative by 2 months (84%) compared to African patients (60%). Further analyses are ongoing.

Study 28 is a double-blind, placebo-controlled comparison of 2-month culture conversion rates when substituting moxifloxacin for isoniazid in the initiation phase of treatment of pulmonary TB. This isoniazid-sparing regimen for TB treatment is based on data from the murine model of tuberculosis; in this model, the substitution of moxifloxacin for isoniazid resulted in significant reductions in the time to culture conversion and the time to sterilization when compared to the standard combination of rifampin, isoniazid, and pyrazinamide. Improved sputum culture conversion after 2 months of treatment with a moxifloxacin-containing regimen would support phase 3 clinical trials of moxifloxacin-based treatment regimens of less than the current 6-month standard regimens. The plan is to enroll 410 patients from both domestic and international TBTC sites. Enrollment is expected to begin in late 2005.

—Submitted by Susan M. Ray, MD
Emory Univ. School of Medicine
Member, Advocacy & External Relations Committee, TBTC

 


Released October 2008
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