Efficacy and Safety of High-Dose Rifampin in Pulmonary Tuberculosis. A Randomized Controlled Trial.

RATIONALE: We examined whether increased rifampin doses could shorten standard therapy for tuberculosis without increased toxicity. OBJECTIVES: To assess the differences across three daily oral doses of rifampin in change in elimination rate of Mycobacterium tuberculosis in sputum and frequency of rifampin-related adverse events. METHODS: We conducted a blinded, randomized, controlled phase 2 clinical trial of 180 adults with new smear-positive pulmonary tuberculosis, susceptible to isoniazid and rifampin. We randomized 1:1:1 to rifampin at 10, 15, and 20 mg/kg/d during the intensive phase. We report the primary efficacy and safety endpoints: change in elimination rate of M. tuberculosis log10 colony-forming units and frequency of grade 2 or higher rifampin-related adverse events. We report efficacy by treatment arm and by primary (area under the plasma concentration-time curve [AUC]/minimum inhibitory concentration [MIC]) and secondary (AUC) pharmacokinetic exposure. MEASUREMENTS AND MAIN RESULTS: Each 5-mg/kg/d increase in rifampin dose resulted in differences of -0.011 (95% confidence interval, -0.025 to +0.002; P = 0.230) and -0.022 (95% confidence interval, -0.046 to -0.002; P = 0.022) log10 cfu/ml/d in the modified intention-to-treat and per-protocol analyses, respectively. The elimination rate in the per-protocol population increased significantly with rifampin AUC0-6 (P = 0.011) but not with AUC0-6/MIC99.9 (P = 0.053). Grade 2 or higher rifampin-related adverse events occurred with similar frequency across the three treatment arms: 26, 31, and 23 participants (43.3%, 51.7%, and 38.3%, respectively) had at least one event (P = 0.7092) up to 4 weeks after the intensive phase. Treatment failed or disease recurred in 11 participants (6.1%). CONCLUSIONS: Our findings of more rapid sputum sterilization and similar toxicity with higher rifampin doses support investigation of increased rifampin doses to shorten tuberculosis treatment. Clinical trial registered with www.clinicaltrials.gov (NCT 01408914) .

Building clinical trial capacity to develop a new treatment for multidrug-resistant tuberculosis.

PROBLEM: New drugs for infectious diseases often need to be evaluated in low-resource settings. While people working in such settings often provide high-quality care and perform operational research activities, they generally have less experience in conducting clinical trials designed for drug approval by stringent regulatory authorities. APPROACH: We carried out a capacity-building programme during a multi-centre randomized controlled trial of delamanid, a new drug for the treatment of multidrug-resistant tuberculosis. The programme included: (i) site identification and needs assessment; (ii) achieving International Conference on Harmonization - Good Clinical Practice (ICH-GCP) standards; (iii) establishing trial management; and (iv) increasing knowledge of global and local regulatory issues. LOCAL SETTING: Trials were conducted at 17 sites in nine countries (China, Egypt, Estonia, Japan, Latvia, Peru, the Philippines, the Republic of Korea and the United States of America). Eight of the 10 sites in low-resource settings had no experience in conducting the requisite clinical trials. RELEVANT CHANGES: Extensive capacity-building was done in all 10 sites. The programme resulted in improved local capacity in key areas such as trial design, data safety and monitoring, trial conduct and laboratory services. LESSONS LEARNT: Clinical trials designed to generate data for regulatory approval require additional efforts beyond traditional research-capacity strengthening. Such capacity-building approaches provide an opportunity for product development partnerships to improve health systems beyond the direct conduct of the specific trial.

Evaluation of high-dose rifampin in patients with new, smear-positive tuberculosis (HIRIF): study protocol for a randomized controlled trial.

BACKGROUND: Evidence has existed for decades that higher doses of rifampin may be more effective, but potentially more toxic, than standard doses used in tuberculosis treatment. Whether increased doses of rifampin could safely shorten treatment remains an open question. METHODS/DESIGN: The HIRIF study is a phase II randomized trial comparing rifampin doses of 20 and 15 mg/kg/day to the standard 10 mg/kg/day for the first 2 months of tuberculosis treatment. All participants receive standard doses of companion drugs and a standard continuation-phase treatment (4 months, 2 drugs). They are followed for 6 months post treatment. Study participants are adults with newly diagnosed, previously untreated, smear positive (≥2+) pulmonary tuberculosis. The primary outcome is rifampin area under the plasma concentration-time curve (AUC0-24) after at least 14 days of study treatment/minimum inhibitory concentration. 180 randomized participants affords 90 % statistical power to detect a difference of at least 14 mcg/mL*hr between the 20 mg/kg group and the 10 mg/kg group, assuming a loss to follow-up of up to 17 %. DISCUSSION: Extant evidence suggests the potential for increased doses of rifampin to shorten tuberculosis treatment duration. Early studies that explored this potential using intermittent, higher dosing were derailed by toxicity. Given the continued large, global burden of tuberculosis with nearly 10 million new cases annually, shortened regimens with existing drugs would offer an important advantage to patients and health systems. TRIAL REGISTRATION: This trial was registered with clinicaltrials.gov (registration number: NCT01408914 ) on 2 August 2011.

Delamanid for multidrug-resistant pulmonary tuberculosis.

BACKGROUND: Delamanid (OPC-67683), a nitro-dihydro-imidazooxazole derivative, is a new antituberculosis medication that inhibits mycolic acid synthesis and has shown potent in vitro and in vivo activity against drug-resistant strains of Mycobacterium tuberculosis. METHODS: In this randomized, placebo-controlled, multinational clinical trial, we assigned 481 patients (nearly all of whom were negative for the human immunodeficiency virus) with pulmonary multidrug-resistant tuberculosis to receive delamanid, at a dose of 100 mg twice daily (161 patients) or 200 mg twice daily (160 patients), or placebo (160 patients) for 2 months in combination with a background drug regimen developed according to World Health Organization guidelines. Sputum cultures were assessed weekly with the use of both liquid broth and solid medium; sputum-culture conversion was defined as a series of five or more consecutive cultures that were negative for growth of M. tuberculosis. The primary efficacy end point was the proportion of patients with sputum-culture conversion in liquid broth medium at 2 months. RESULTS: Among patients who received a background drug regimen plus 100 mg of delamanid twice daily, 45.4% had sputum-culture conversion in liquid broth at 2 months, as compared with 29.6% of patients who received a background drug regimen plus placebo (P=0.008). Likewise, as compared with the placebo group, the group that received the background drug regimen plus 200 mg of delamanid twice daily had a higher proportion of patients with sputum-culture conversion (41.9%, P=0.04). The findings were similar with assessment of sputum-culture conversion in solid medium. Most adverse events were mild to moderate in severity and were evenly distributed across groups. Although no clinical events due to QT prolongation on electrocardiography were observed, QT prolongation was reported significantly more frequently in the groups that received delamanid. CONCLUSIONS: Delamanid was associated with an increase in sputum-culture conversion at 2 months among patients with multidrug-resistant tuberculosis. This finding suggests that delamanid could enhance treatment options for multidrug-resistant tuberculosis. (Funded by Otsuka Pharmaceutical Development and Commercialization; ClinicalTrials.gov number, NCT00685360.).

Características epidemiológicas y complicaciones obstétricas en gestantes con diagnóstico de COVID-19 en un hospital público

RESUMEN Introducción: La COVID-19 en embarazadas ha supuesto un desafío en la atención materna, puesto que podría incrementar el riesgo de padecer algunas enfermedades obstétricas y resultados perinatales negativos. Objetivo: Describir las características epidemiológicas y complicaciones obstétricas en gestantes con diagnóstico de COVID-19. Métodos: Estudio descriptivo y transversal, realizado en una muestra de 235 gestantes con diagnóstico de COVID-19, seleccionadas de forma no aleatoria. Se estudiaron las características epidemiológicas y las complicaciones obstétricas, que fueron reportadas mediante estadística descriptiva. Resultados: La edad promedio de las gestantes fue de 27,6 ± 3,7 años, el 65,5 % era conviviente y 77,4 % tenía instrucción secundaria. Además, el 71,5 % tenía entre 37 y 40 semanas de gestación, 28,5 % no tuvo ninguna atención prenatal, 68,9 % era multigesta y 27,7 % tuvo antecedente de aborto. El 90,6 % fue asintomática y la cefalea fue el síntoma más frecuente (7,4 %). Entre las complicaciones obstétricas, el 30,6 % tuvo un parto por cesárea, 20 % presentó anemia y 15,7 % ruptura prematura de membrana. El síndrome de Hellp (0,9 %) y la eclampsia (0,4 %), fueron las menos frecuentes. Conclusiones: En las gestantes con la COVID-19 existe una elevada tasa de complicaciones obstétricas, principalmente la cesárea y la anemia. La mayoría de las gestantes es asintomática y tiene un resultado serológico IgM/IgG.

ABSTRACT Introduction: COVID-19 in pregnant women has been a challenge in maternal care, since it could increase the risk of suffering from some obstetric diseases and negative perinatal results. Objective: To describe the epidemiological characteristics and obstetric complications in pregnant women diagnosed with COVID-19. Methods: Descriptive, and cross-sectional study, carried out in a sample of 235 pregnant women with a diagnosis of COVID-19, selected in a non-random way. Epidemiological characteristics and obstetric complications were studied, which were reported by descriptive statistics in univariate tables. Results: The average age of the pregnant women was 27.6 ± 3.7 years, 65.5 % were cohabiting and 77.4 % had secondary education. In addition, 71.5 % were between 37 and 40 weeks' gestation, 28.5 % had no prenatal care, 68.9 % were multi-pregnant, and 27.7 % had a history of abortion; 90.6 % were asymptomatic and headache was the most frequent symptom (7.4 %). Among obstetric complications, 30.6 % had a cesarean birth, 20 % had anemia and 15.7 % premature rupture of the membrane. Hellp syndrome (0.9 %) and eclampsia (0.4 %) were the least frequent. Conclusions: In pregnant women with COVID-19 there is a high rate of obstetric complications, which are mainly caesarean section and anemia. Most pregnant women are asymptomatic and have an IgM / IgG serological result.