The 4-month regimen of rifampin was not inferior to the 9-month regimen of isoniazid for the prevention of active tuberculosis and was associated with a higher rate of treatment completion and better safety. (Funded by the Canadian Institutes of Health Research and the Australian National Health and Medical Research Council; ClinicalTrials.gov number, NCT00931736 .).

Phase I of the International Study of Asthma and Allergies in Childhood has provided valuable information regarding international prevalence patterns and potential risk factors in the development of asthma, allergic rhinoconjunctivitis and eczema. However, in Phase I, only six African countries were involved (Algeria, Tunisia, Morocco, Kenya, South Africa and Ethiopia). Phase III, conducted 5–6 years later, enrolled 22 centres in 16 countries including the majority of the centres involved in Phase I and new centres in Morocco, Tunisia, Democratic Republic of Congo, Togo, Sudan, Cameroon, Gabon, Reunion Island and South Africa. There were considerable variations between the various centres of Africa in the prevalence of the main symptoms of the three conditions: wheeze (4.0–21.5%), allergic rhinoconjunctivitis (7.2–27.3%) and eczema (4.7–23.0%). There was a large variation both between countries and between centres in the same country. Several centres, including Cape Town (20.3%), Polokwane (18.0%), Reunion Island (21.5%), Brazzaville (19.9%), Nairobi (18.0%), Urban Ivory Coast (19.3%) and Conakry (18.6%) showed relatively high asthma symptom prevalences, similar to those in western Europe. There were also a number of centres showing high symptom prevalences for allergic rhinoconjunctivitis (Cape Town, Reunion Island, Brazzaville, Eldoret, Urban Ivory Coast, Conakry, Casablanca, Wilays of Algiers, Sousse and Eldoret) and eczema (Brazzaville, Eldoret, Addis Ababa, Urban Ivory Coast, Conakry, Marrakech and Casablanca).

The currently recommended doses of rifampin are believed to be at the lower end of the dose-response curve. Rifampin induces its own metabolism, although the effect of dose on the extent of autoinduction is not known. This study aimed to investigate rifampin autoinduction using a semimechanistic pharmacokinetic-enzyme turnover model. Four different structural basic models were explored to assess whether different scaling methods affected the final covariate selection procedure. Covariates were selected by using a linearized approach. The final model included the allometric scaling of oral clearance and apparent volume of distribution. Although HIV infection was associated with a 30% increase in the apparent volume of distribution, simulations demonstrated that the effect of HIV on rifampin exposure was slight. Model-based simulations showed close-to-maximum induction achieved after 450-mg daily dosing, since negligible increases in oral clearance were observed following the 600-mg/day regimen. Thus, dosing above 600 mg/day is unlikely to result in higher magnitudes of autoinduction. In a typical 55-kg male without HIV infection, the oral clearance, which was 7.76 liters · h ؊1 at the first dose, increased 1.82-and 1.85-fold at steady state after daily dosing with 450 and 600 mg, respectively. Corresponding reductions of 41 and 42%, respectively, in the area under the concentration-versus-time curve from 0 to 24 h were estimated. The turnover of the inducible process was estimated to have a half-life of approximately 8 days in a typical patient. Assuming 5 half-lives to steady state, this corresponds to a duration of approximately 40 days to reach the induced state for rifampin autoinduction. Rifampin is an indispensable constituent of first-line therapy used to treat drug-susceptible Mycobacterium tuberculosis. During the 2-month intensive phase of standard short-course antituberculosis treatment, patients receive rifampin together with isoniazid, pyrazinamide, and ethambutol. Rifampin and isoniazid are given for a further 4-month continuation phase, completing the 6-month treatment regimen. Isoniazid is responsible for killing the majority of organisms within the first 2 days of treatment. From the third to the seventh day of treatment, rifampin and pyrazinamide continue the bactericidal function (30), while ethambutol protects against the development of rifampin resistance in the event of preexisting isoniazid resistance (8). The ability of rifampin to eradicate persisting organisms has allowed the shortening of treatment from 12 to 6 months (43).Rifampin is a potent activator of the nuclear pregnane X receptor (PXR), which regulates the transcription of multiple drugmetabolizing enzymes and drug transporters (9, 13). Although the exact mechanism is not known, following chronic intravenous or oral dosing, rifampin induces its own metabolism by increasing its systemic and presystemic clearances (27,31). This effect might, in part, be attributed to the PXR-mediated induction of P-glycoprotein (P-gp), a trans-mem...

Among children under the age of 18 years, treatment with 4 months of rifampin had similar rates of safety and efficacy but a better rate of adherence than 9 months of treatment with isoniazid. (Funded by the Canadian Institutes of Health Research and Conselho Nacional de Pesquisa; ClinicalTrials.gov number, NCT00170209 .).

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.