A pivotal registration phase III, multicenter, randomized tuberculosis controlled trial: design issues and lessons learnt from the Gatifloxacin for TB (OFLOTUB) project

Abstract

BackgroundThere have been no major advances in tuberculosis (TB) drug development since the first East African/British Medical Research Council short course chemotherapy trial 35 years ago. Since then, the landscape for conducting TB clinical trials has profoundly changed with the emergence of HIV infection, the spread of resistant TB bacilli strains, recent advances in mycobacteriological capacity, and drug discovery. As a consequence questions have arisen on the most appropriate approach to design and conduct current TB trials. To highlight key issues discussed: Is a superiority, equivalence, or non-inferiority design most appropriate? What should be the primary efficacy outcome? How to consider re-infections in the definition of the outcome? What is the optimal length of patient follow-up? Is blinding appropriate when treatment duration in test arm is shorter? What are the appropriate assumptions for sample size calculation?MethodsVarious drugs are currently in the development pipeline. We are presenting in this paper the design of the most recently completed phase III TB trial, the OFLOTUB project, which is the pivotal trial of a registration portfolio for a gatifloxacin-containing TB regimen. It is a randomized, open-label, multicenter, controlled trial aiming to evaluate the efficacy and safety of a gatifloxacin-containing 4-month regimen (trial registration: ClinicalTrial.gov database: NCT00216385).ResultsIn the light of the recent scientific and regulatory discussions, we discuss some of the design issues in TB clinical trials and more specifically the reasons that guided our choices, in order to best answer the trial objectives, while at the same time satisfying regulatory authority requirements.ConclusionWhen shortening TB treatment, we are advocating for a non-inferiority, non-blinded design, with a composite unfavorable endpoint assessed 12 months post treatment completion, and added trial procedures specifically aiming to: (1) minimize endpoint unavailability; and (2) distinguish between relapse and re-infection.

Evaluation of Initial and Steady-State Gatifloxacin Pharmacokinetics and Dose in Pulmonary Tuberculosis Patients by Using Monte Carlo Simulations

“…Newly diagnosed pulmonary tuberculosis patients participating in the multicenter phase 3 randomized controlled trial (OFLOTUB trial [ClinicalTrials.gov registration no. NCT00216385]) (16) at clinics in South Africa, Senegal, Guinea, and Benin were enrolled in the pharmacokinetic study, and those randomized to the 4-month regimen of gatifloxacin, rifampin, isoniazid, and pyrazinamide (n ϭ 169) were included in this analysis. Written informed consent was obtained prior to enrollment.…”

Perspectives on Advances in Tuberculosis Diagnostics, Drugs, and Vaccines

“…The Rapid Evaluation of Moxifloxacin in Tuberculosis (REMoxTB) study was a randomized, double-blind, placebo-controlled trial evaluating 2 regimens in which either ethambutol or isoniazid was substituted by moxifloxacin in a single 4-month combination therapy [84]. The Ofloxacine-Containing, Short-Course Regimen for the Treatment of Pulmonary Tuberculosis trial [85,86] evaluated a standard 6-month regimen that included ethambutol during the 2-month intensive phase against a 4-month regimen in which ethambutol was substituted with gatifloxacin during the intensive phase and continued, along with rifampicin and isoniazid, during the continuation phase. The High-Dose Rifapentine with Moxifloxacin for Pulmonary Tuberculosis trial [87] evaluated 2 regimens in which moxifloxacin replaced isoniazid in an intensive phase.…”

Analysis of mutations in the gyrA and gyrB genes and their association with the resistance of Mycobacterium tuberculosis to levofloxacin, moxifloxacin and gatifloxacin

“…The most promising drugs undergoing phase III trials are the fourth generation FQs, such as moxifloxacin (MFX) and gatifloxacin (GAT), which demonstrated high in vivo and in vitro activities against MDR strains and OFX-resistant and ciprofloxacin-resistant MDR strains (Zhao et al, 1999;Rodríguez et al, 2002;Poissy et al, 2010;Merle et al, 2012).…”

“…Moreover, the initial occurrences of resistance to FQs were observed in MDR strains and isoniazid (IHN)-and rifampicin (RIF)-susceptible strains isolated from newly diagnosed TB patients (Delgado & Telenti, 1996;Xu et al, 2009). The most promising drugs undergoing phase III trials are the fourth generation FQs, such as moxifloxacin (MFX) and gatifloxacin (GAT), which demonstrated high in vivo and in vitro activities against MDR strains and OFX-resistant and ciprofloxacin-resistant MDR strains (Zhao et al, 1999;Rodríguez et al, 2002;Poissy et al, 2010;Merle et al, 2012).Recent studies have shown that resistance to all FQs is due to mutations (single nucleotide polymorphisms, SNPs) not only in the gyrA (320 bp) gene, but also in the gyrB (375 bp) gene, which encode the respective subunits of the DNA topoisomerase gyrase (Takiff et al, 1994;Ginsburg et al, 2003;Shi et al, 2006;Lau et al, 2011). The most common mutations in the gyrA gene are Ala90Val, Asp94 (Gly, Ala, His, Asn or Tyr) and Ser91Pro, the Gly88Cys mutation is found less frequently (Shi et al, 2006;Wang et al, 2007; van Doorn et al, 2008;Feuerriegel et al, 2009).…”