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TB Notes NewsletterReturn to Main Menu - TB Notes 2, 2007No. 2, 2007CLINICAL AND HEALTH SYSTEMS RESEARCH BRANCH UPDATES
MDR TB and XDR TB Clinical Trials Design Working Group FormedIn 2004, over 424,000 cases of multidrug-resistant (MDR) TB are estimated to have occurred worldwide, representing an increase of 55% from 20001. These cases accounted for 4.3% of all new and previously treated TB cases. Persons with MDR TB are 54% more likely to die or have treatment failure2. The recent identification of outbreaks of XDR TB among HIV-infected persons3 has emphasized the lack of controlled studies to define optimal treatment regimens for MDR and XDR TB. A working group has been formed under the aegis of the TB Trials Consortium and is actively working to identify strategies to best evaluate new TB drugs for the treatment of MDR and XDR TB. The goals of the working group include-
The working group is developing a management plan to guide policymakers and scientists, both clinical and preclinical, in the effort to develop new therapies for MDR TB. The group is emphasizing the need for development of new MDR regimens in parallel with new drug development for drug-susceptible TB. Members of the group include Bill Burman (Denver Public Health), Peter Cegielski (Division of TB Elimination, CDC), Mary Ann de Groote (Colorado State University), Mark Harrington (Treatment Action Group), Bob Horsburgh (Boston University School of Public Health), Dikoe Makhene (DMID, NIAID, NIH), Carole Mitnick (Harvard Medical School), Sonal Munsiff (Division of TB Elimination, CDC), Nesri Padayatchi (CAPRISA: Centre for the Program for AIDS Research in South Africa), Jussi Saukkonen (Boston University Medical Center), Neil Schluger (Columbia University), Barbara Seaworth (University of Texas, Tyler), Tim Sterling (Vanderbilt University School of Medicine), and Elsa Villarino (Division of TB Elimination, CDC). —Submitted by C. Robert Horsburgh, Jr.,
MD References
The Long Road to a Shorter, Stronger, Safer Cure for TB – How to Get There FasterHow short is shorter, how strong is stronger, how safe is safer? There are common worldwide goals for a TB treatment regimen: duration of 2 months or less; high efficacy (99% cure rate) and intermittent dosing (once or twice a week), with a relapse rate approaching 0%; and better-tolerated therapy (decreased common and serious side effects; fewer drug interactions, especially with anti-HIV medicines). The good news in TB treatment is that there are now at least six new TB drugs in development. The bad news: it could be several decades before we arrive at a shorter, more effective treatment regimen which employs these drugs. In 1962, TB treatment lasted 24 months, requiring 1460 doses and hospitalization, and was associated with treatment failure rates of 10%, relapse in 2%, and acquired resistance in 7% (Tubercle 1962, 43:201-67). In 1979, less than 20 years later, it had been shown that treatment duration could be shortened to 6 months, requiring 96 doses and no hospitalization, and with 0% treatment failure, 2% relapse, and 0% acquired resistance (Am Rev Respir Dis 1979;579-85). It has now been 28 years since “short-course” therapy was proven effective. For most of that time, there were no new candidate TB drugs; no movement down the road was even possible. Now, with six new drugs in the pipeline, can we expect to make the kind of exciting progress that was witnessed in the 1960s and 1970s? The recent recognition of extensively drug-resistant (XDR) TB in South Africa and other sites adds urgency to the need for evaluation of novel agents to treat TB (MMWR 2006;55: 301-305). Traditionally, clinical trials for new TB drugs are based on 6- to 9-month treatment regimens, with follow-up efficacy evaluations lasting 1 to 2 years to detect any cases of relapse. Accounting for the completion of phase I, II, and III trials, it can take 6–7 years or more to register a new drug for TB. Most experts anticipate that more than a single drug substitution in the multidrug TB treatment regimen will be required to achieve a regimen that is dramatically shorter and more effective than current treatment. Because the effect of single substitutions doesn’t predict the effect of combining multiple new drugs in a treatment regimen, it would theoretically be necessary to conduct trials with all possible permutations of the six or eight drug classes contributing to a three- or four-drug regimen to discover the “correct” combination. This approach would take centuries to complete, and only dumb luck could be expected to shorten the process! Four strategies have the potential to provide significant shortcuts to our destination: the use of preclinical data from mouse models; the use of surrogate markers (biomarkers) to predict relapse risk; a clinical trials format designed to speed the evaluation of multiple new agents in a multidrug regimen; and clinical evaluation of novel agents through compassionate-use protocols for patients with XDR TB. The first shortcut to consider is the use of mouse models to assist in choosing candidate regimens for study. Despite the many obvious biologic differences between mice and people, and the fact that the overall course of TB infection in mice does not closely follow the course of TB infection in humans (no real correlate of latent TB infection), the mouse model of TB disease has proved very useful in predicting the results of human TB treatment. In the early development of TB treatment, mouse models predicted some important tenets of now-proven regimens: that INH provides two phases of killing (early and rapid, then prolonged and slow) and that the addition of rifampin and/or PZA provides sterilizing activity (J Exp Med 1956;104:737-62,Tubercle 1978;59:287-97). Recent data from mouse models predict the utility of quinolones in combination with a rifamycin; these data were used to inform the design of Study 28 (Nuermberger et al. Am J Respir Crit Care Med 2004;169:421-6). The second shortcut strategy is to find and employ biomarkers that can predict the risk that TB treatment will be unsuccessful. TB treatment can fail in two ways: 1) it can fail to effect a clinical response (such as weight gain or defervescence) or a microbiologic response (sputum cultures rendered sterile) while the therapy is being given; and 2) it can lead to relapse of disease within 2 years after completion of therapy. Because these failures of treatment will not be directly evident for months or years after the start of a treatment regimen, clinical trials can take several years to reach these important endpoints. It is possible to identify biomarkers that can be measured early during the treatment period and for which a threshold value can predict later treatment failure or relapse. Once the predictive value of such a biomarker is established, the biomarker result could become the primary outcome of a clinical trial. For example, the lack of 2-month culture conversion has been associated with increased risk of treatment failure and relapse; this endpoint is a primary outcome for a current TBTC phase II trial, Study 28. Using a biomarker measured at 2 months after starting therapy (instead of 2½ years), it would be feasible to complete a clinical trial in a year or less. The problem with using a biomarker that has a dichotomous result (positive or negative), instead of a continuous result for a primary study endpoint, is the relatively large sample size required to demonstrate a difference in study arms. Potentially useful biomarkers that provide results on a continuum include quantitative sputum cultures, quantitative nucleic acid amplification tests, and therapeutic drug levels (pharmacokinetic sampling). In the past, quantitative sputum cultures were frequently employed to determine the early bactericidal activity of individual TB drugs (Jindani et al. Am Rev Respir Dis 1980; 121: 939-49), but have not been used as a primary endpoint for multidrug treatment trials. The third shortcut strategy is to pursue the identification of a very promising new multidrug TB regimen (utilizing one or more new agents) for evaluation in a phase III trial by first conducting sequential phase II trials. Concurrent phase II trials can be used to efficiently identify the optimal dose of each new drug (e.g., for each candidate drug, a trial with two dose arms of 150 patients each with enrollment and follow-up completed in 8 months). The next step would be to use a multiarm phase II study to identify the place of a new drug (X) or drugs within a regimen, e.g., Arm 1: HRZX, Arm 2: MRX, Arm 3: MRZX, with 150 patients per arm with enrollment and follow-up completed in 6 to 8 months (H=INH, R=rifamycin, Z=PZA, M=moxifloxacin, X=new drug). As mentioned above, data from the mouse model can be very useful in choosing arms for these trials. A phase III trial of a new TB regimen will require enrollment of 1400 patients or more (based on 80% power to detect a decrease of relapse or toxicity from 5% to 2%) and require a minimum of 3 years to complete enrollment and follow-up. By using sequential phase II trials to design optimal new regimens for inclusion in phase III trials, it is feasible to reach the goal of a shorter regimen in the next decade. The design of clinical trials to evaluate the effectiveness of novel TB drugs could also be based on the approach used for studying therapies for drug-resistant HIV in treatment-experienced patients. A common approach to the evaluation of novel agents for HIV treatment has been to use 1 (or more) novel agent in a controlled trial in which all patients (with drug-resistant HIV) receive optimized background therapy (or salvage therapy) based on currently approved or available medications and a proportion are randomized to receive the novel agent in addition (Lazarrin et al. N Engl J Med 2003;348:2186-95). Indeed, novel drugs for TB will likely have the greatest impact on the treatment of MDR TB and studying new TB agents in patients with MDR TB is a reasonable approach to demonstrate effectiveness. Studies could be designed as add-on studies in which a placebo is compared against the new agent in the context of the background regimen containing the best options that would otherwise be available to the patient (optimized background therapy or OBT). In such a design, patients with differing drug resistance patterns may be enrolled because each patient will have individualized OBT. The discussion above was based on presentations given by William Burman, MD, at TBTC Semiannual meetings. 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 March 17, 2007, Study 26 enrollment was up to 7046, over 88% of the intended 8000 subjects for total enrollment. Enrollment completion is anticipated by October 2007. Study 27 was 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. The primary study results were published in 2006 and showed there was no difference between study arms in terms of time to sputum conversion (Burman WJ et al. Am J Respir Crit Care Med 2006; 174: 331-338). 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 TB; 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 began in March 2006 and was completed in March 2007 with 433 enrolled. —Submitted by Susan M. Ray, MD
Last Reviewed: 05/18/2008 |
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