Of the nearly 9 million new case of tuberculosis (TB) in 2011, it is estimated that 500,000 were multidrug-resistant (MDR), but less than 20% were started on MDR-TB treatment. The inability to make the diagnosis of MDR-TB in the ambulatory setting, limited bed capacity at specialized treatment centers, and resource-intensive, prolonged treatment courses of toxic medication regimens, contribute to the failure to initiate MDR-TB treatment which drives mortality and fuels community transmission. Fortunately rapid diagnostics like the Xpert MTB/RIF can now detect MDR-TB in the time of a single clinic visit, and large scale roll-out to ambulatory screening sites are underway (including at our study sites in Bangladesh and Tanzania). Yet the swell of new, largely ambulatory, patients will further create a treatment bottleneck unless governmental TB programs are massively expanded, or the duration of treatment regimens can be shortened and administered outside of the hospital. The latter is most immediately achievable. To do so, we propose an innovative approach to both minimize the necessity for prolonged hospitalization and to shorten the total treatment duration. We will test this approach by (1) employing a regimen of optimized pharmacokinetics based on local quantitative susceptible testing, (2) limiting the exposure to the most resource-intensive and toxic component of the multidrug regimen, the injectable aminoglycoside, and (3) applying the regimen to an ambulatory population with low bacterial burden. Thus, the proposed phase IIb non-inferiority trial, Reduced Injectable, Short-course for (E)Xpert MDR-TB (RISE trial), will randomize ambulatory patients newly diagnosed with MDR-TB by the Xpert MTB/RIF assay to the novel regimen (1 month injectable aminoglycoside, 12 months total treatment duration) or the current standard of care (6+ months injectable aminoglycoside, 20+ months total treatment duration) to compare rates of treatment success, and medication related adverse events. This proposal leverages strong collaboration with the University of Virginia and the clinical trials infrastructure of the Kilimanjaro Clinical Research Institute in Tanzania and the ICDDR,B in Bangladesh. The R34 will allow critical assessment of trial design, provide support for development of a complete study protocol, operations manual, and data management system, and securing of preliminary approvals.

Public Health Relevance

Less than 20% of the estimated 500,000 annual cases of multidrug-resistant tuberculosis (MDR-TB) are started on treatment, a resource-intensive endeavor of prolonged hospitalization and nearly 2 years of total treatment. Yet in the era of rapid MDR-TB diagnosis in the ambulatory setting, the number of patients awaiting treatment will only increase. The RISE trial is a multicenter, international, phase IIb, non-inferiority, randomized controlled trial for MDR-TB treatment comparing a resource-sparing drug regimen of shorter treatment duration to the standard of care. Results of the RISE trial will immediately impact MDR-TB treatment in the most burdened of TB endemic countries.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Planning Grant (R34)
Project #
1R34AI112371-01
Application #
8732395
Study Section
Special Emphasis Panel (ZAI1-BLG-M (M2))
Program Officer
Mason, Robin M
Project Start
2014-08-11
Project End
2015-07-31
Budget Start
2014-08-11
Budget End
2015-07-31
Support Year
1
Fiscal Year
2014
Total Cost
$241,000
Indirect Cost
$87,000
Name
University of Virginia
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904