Background: Despite the availability of highly-effective first-line treatment regimens, tuberculosis remains a leading cause of global mortality. With increasing incidence of drug-resistant strains of the disease, novel therapeutic strategies are sorely needed to both treat and control the spread of this deadly disease. Unfortunately, determining cure of tuberculosis is challenging, and often takes years of expensive patient monitoring and follow-up. There is therefore also a need for predictive biomarkers, which can serve as surrogate endpoints in clinical trials for assessing the effectiveness of a novel therapy quickly and accurately. The current standard surrogate endpoint in tuberculosis drug development is 2-month sputum culture conversion. However, this standard is controversial, and may not predict stable cure across all mechanisms of drug-disease interaction.
Aim: To map the correlation between 2-month culture conversion and stable cure across a cohort of novel anti-tuberculosis treatments. We hypothesize that 2-month sputum conversion will correlate well with stable cure. However, we also expect to find that efficacy on the surrogate endpoint in pre-pivotal trials (i.e., phase 2) may not correlate with subsequent testing in phase 3. That is, positive results on the biomarker endpoint will often be used to justify pivotal trials, whereas negative results on the biomarker endpoint will rarely be used to disqualify a drug from further testing.
Methods: We will conduct a systematic literature search of Medline, Embase, and Clinicaltrials.gov for all clinical trials of novel anti-tuberculosis therapies from 2005-2015. The resulting reports and registration records will be extracted for demographics, clinical characteristics, study design properties, outcome data, and author recommendations for further testing. We will then perform a descriptive analysis of research and reporting activities, statistical meta-analysis of outcomes and data trends, and AERO graphing to chart the correlation between 2-month sputum conversion and stable cure of tuberculosis, as well as patterns in the use of the biomarker to justify further research.
A pilot search for this protocol identified 21 anti-tuberculosis agents and 179 registered trials of these agents on Clinicaltrials.gov.