This R34 will support preparation for a multi-site Phase II trial of high-dose rifampin (RIF). The trial will provide proof of principle that an increased dose of RIF could shorten the course of standard therapy for tuberculosis (TB), and improve treatment outcomes, without increased toxicity.
The aims of the R34 are: 1) to complete development of the clinical trial protocol; informed consents in English, Portuguese, and Spanish; procedure manuals for laboratory (bacteriology and pharmacokinetic), hospitalization, and sample (sputum and blood) collection, processing, storage, and shipping; training materials; and other documents essential for trial implementation; 2) Secure IRB approval for the trial in all study sites; 3) Develop and refine trial infrastructure and network; 4) Finalize selection of tertiary endpoints; 5) Acquire study agent. The investigators assembled from around the world represent all the disciplines and have built the collaborations required for a successful trial; together they can claim well over 100 person-years of TB clinical trials experience. This trial will advance substantially the pharmacokinetic, pharmacodynamic, and tolerability evidence available from observational studies and clinical trials performed in an era in which less rigorous safety criteria were applied. The trial will also provide additional evidence on the sensitivity and specificity of several interim endpoints to predict failure and relapse. This information will serve the numerous ongoing TB drug-development activities. More than 8 million cases of TB and 2 million deaths due to TB occur annually. Shortening therapy and improving outcomes using a well-tolerated, inexpensive, globally available anti-tuberculosis agent would contribute dramatically to the Millennium Development Goal target of reducing TB prevalence and mortality by 50% before 2015. Moreover, this trial will contribute to the existing evidence base about possible surrogate endpoints, thereby simplifying future trials of investigational new anti-tuberculosis ? ? ?
