Robert Schall

Efficiency and safety of the combination of moxifloxacin, pretomanid (PA-824), and pyrazinamide during the first 8 weeks of antituberculosis treatment: a phase 2b, open-label, partly randomised trial in patients with drug-susceptible or drug-resistant pulmonary tuberculosis

BACKGROUND New antituberculosis regimens are urgently needed to shorten tuberculosis treatment. Following on from favourable assessment in a 2 week study, we investigated a novel regimen for efficacy and safety in drug-susceptible and multidrug-resistant (MDR) tuberculosis during the first 8 weeks of treatment. METHODS We did this phase 2b study of bactericidal activity--defined as the decrease in colony forming units (CFUs) of Mycobacterium tuberculosis in the sputum of patients with microscopy smear-positive pulmonary tuberculosis-at eight sites in South Africa and Tanzania. We enrolled treatment-naive patients with drug-susceptible, pulmonary tuberculosis, who were randomly assigned by computer-generated sequences to receive either 8 weeks of moxifloxacin, 100 mg pretomanid (formerly known as PA-824), and pyrazinamide (MPa100Z regimen); moxifloxacin, 200 mg pretomanid, and pyrazinamide (MPa200Z regimen); or the current standard care for drug-susceptible pulmonary tuberculosis, isoniazid, rifampicin, PZA, and ethambutol (HRZE regimen). A group of patients with MDR tuberculosis received MPa200Z (DRMPa200Z group). The primary outcome was bactericidal activity measured by the mean daily rate of reduction in M tuberculosis CFUs per mL overnight sputum collected once a week, with joint Bayesian non-linear mixed-effects regression modelling. We also assessed safety and tolerability by monitoring adverse events. This study is registered with ClinicalTrials.gov, number NCT01498419. FINDINGS Between March 24, 2012, and July 26, 2013 we enrolled 207 patients and randomly assigned them to treatment groups; we assigned 60 patients to the MPa100Z regimen, 62 to the MPa200Z regimen, and 59 to the HRZE regimen. We non-randomly assigned 26 patients with drug-resistant tuberculosis to the DRMPa200Z regimen. In patients with drug-susceptible tuberculosis, the bactericidal activity of MPa200Z (n=54) on days 0-56 (0·155, 95% Bayesian credibility interval 0·133-0·178) was significantly greater than for HRZE (n=54, 0·112, 0·093-0·131). DRMPa200Z (n=9) had bactericidal activity of 0·117 (0·070-0·174). The bactericidal activity on days 7-14 was strongly associated with bactericidal activity on days 7-56. Frequencies of adverse events were similar to standard treatment in all groups. The most common adverse event was hyperuricaemia in 59 (29%) patients (17 [28%] patients in MPa100Z group, 17 [27%] patients in MPa200Z group, 17 [29%] patients. in HRZE group, and 8 [31%] patients in DRMPa200Z group). Other common adverse events were nausea in (14 [23%] patients in MPa100Z group, 8 [13%] patients in MPa200Z group, 7 [12%] patients in HRZE group, and 8 [31%] patients in DRMPa200Z group) and vomiting (7 [12%] patients in MPa100Z group, 7 [11%] patients in MPa200Z group, 7 [12%] patients in HRZE group, and 4 [15%] patients in DRMPa200Z group). No on-treatment electrocardiogram occurrences of corrected QT interval more than 500 ms (an indicator of potential of ventricular tachyarrhythmia) were reported. No phenotypic resistance developed to any of the drugs in the regimen. INTERPRETATION The combination of moxifloxacin, pretomanid, and pyrazinamide, was safe, well tolerated, and showed superior bactericidal activity in drug-susceptible tuberculosis during 8 weeks of treatment. Results were consistent between drug-susceptible and MDR tuberculosis. This new regimen is ready to enter phase 3 trials in patients with drug-susceptible tuberculosis and MDR-tuberculosis, with the goal of shortening and simplifying treatment. FUNDING Global Alliance for TB Drug Development.

Evidence-based evaluation of calcium channel blockers for hypertension: Equality of mortality and cardiovascular risk relative to conventional therapy

UNLABELLED OBJECTIVES; We present a meta-analysis based on three recent, substantial, randomized outcome trials and several smaller trials that compared calcium channel blockers (CCBs) with conventional therapy (diuretics or beta-blockers) or with angiotensin-converting enzyme (ACE) inhibitors. BACKGROUND There is continuing uncertainty about the safety and efficacy of CCBs in the treatment of hypertension. Previous meta-analyses conflict and suggest that CCBs increase myocardial infarction (MI) or protect from stroke. METHODS Standard procedures for meta-analysis were used to analyze three major trials on 21,611 patients and another three lesser studies to a total of 24,322 patients. RESULTS Calcium channel blockers have a strikingly similar risk of total and cardiovascular mortality and of major cardiovascular events to conventional therapy. Calcium channel blockers give a lower risk of nonfatal stroke (-25%, p = 0.001) and a higher risk of total MI (18%, p = 0.013), chiefly nonfatal (18%). After performing the Bonferroni correction for multiplicity, these p values become 0.004 and 0.052, respectively. When compared with ACE inhibitors in 1,318 diabetic patients, CCBs had a substantially higher risk of nonfatal (relative risk [RR] = 2.259) and total MI (RR = 2.204, confidence interval 1.501 to 3.238; p = 0.001 or 0.004 with Bonferroni correction). Total and cardiovascular mortality rates are similar. To confirm the hypothesis that ACE inhibitors are superior to CCBs in diabetic patients requires more trial data, especially with renal end points. CONCLUSIONS Mortality (total and cardiovascular) and major cardiovascular events with CCBs were apparently similar to those events seen with conventional first-line therapy (diuretics or beta-blockers). Stroke reduction more than balanced increased MI. In diabetics, CCBs may be less safe than ACE inhibitors.

Comparative Evaluation of the Roche Cobas AmpliPrep/Cobas TaqMan HIV-1 Version 2 Test Using the TaqMan 48 Analyzer and the Abbott RealTime HIV-1 Assay

ABSTRACT Acceptable precision was achieved in a comparison study of the Abbott RealTime (RT) and Roche CAP/CTM-48 V2 HIV-1 assays, but viral load quantification was under- and overestimated, respectively, compared to the 2nd HIV-1 WHO International Standard. The same quantification patterns were observed for patient cohorts from Africa and the United States.

Comparison of the Pharmacokinetic Profiles of Soluble Aspirin and Solid Paracetamol Tablets in Fed and Fasted Volunteers

The aim of this study was to investigate the absorption of popular preparations of two common analgesics--soluble aspirin and solid paracetamol tablets. An open, randomised, crossover study design was used to compare the pharmacokinetic parameters of soluble aspirin and solid paracetamol tablets in 16 healthy, male volunteers from the University of the Witwatersrand, South Africa, in both fed and fasted states. Plasma concentrations of paracetamol, aspirin and salicylic acid were measured. It was found that the rate of absorption was significantly faster for soluble aspirin than for solid paracetamol, regardless of fed or fasting state, considering time to maximum concentration (p < 0.01), time to first quantifiable concentrations (p < 0.05) and absorption rate (p < 0.01). Absorption rate was significantly affected by food for both soluble aspirin (p = 0.028) and for solid paracetamol (p = 0.0003). Time to maximum concentration was not significantly affected by food for soluble aspirin (p = 0.17) but significantly lengthened for solid paracetamol (p = 0.0003). The extent of absorption was affected by food in terms of maximum concentration for both drugs (p = 0.0001), with a reduction of 49% in the fed state for solid paracetamol compared to 18% for soluble aspirin, the difference between the drugs being statistically significant (p = 0.0024). The overall bioavailability of soluble aspirin was unaffected by food and the bioavailability of salicylic acid was increased in the fed state, whereas that of solid paracetamol was lowered in the fed state. Greater inter-individual variation was seen in paracetamol concentrations compared with aspirin or salicylic acid levels. In conclusion, these results show that the absorption of soluble aspirin is largely unaffected by food, whereas, in the same volunteers, the absorption of solid paracetamol tablets is greatly affected. In some volunteers, maximum plasma concentrations of paracetamol following food did not reach levels previously reported to be required for effective analgesia, and this may have implications for pain relief in some individuals. The practice in some individuals of taking aspirin tablets after food to minimise potential gastric disturbance should not affect the level of analgesia.

No Pharmacokinetic or Pharmacodynamic Interaction Between Rivastatin and Warfarin

Twenty‐one healthy, male volunteers completed this double‐blind, randomized, two‐period, crossover study to determine the possible pharmacodynamic and pharmacokinetic interaction of the concomitant administration of rivastatin and warfarin sodium in healthy volunteers. The study comprised 2 treatment periods of 8 days each, with a medication‐free period of 14 days between the 2 treatment periods.

Bioequivalence of controlled-release calcium antagonists.

SummaryIn this review, several deficiencies of publisged bioequivalence studies for controlled-release calcium antagonists have become apparent. As a consequence, some of the published conclusions based on such studies must be viewed with care.A proper statistical analysis of bioequivalence is not frequently reported. A proper statistical analysis of the pharmacokinetic variables involves the calculation of 90% confidence intervals (CI) for the test : reference ratio of the means of the pharmacokinetic variables of the test and reference product. The CI must fall completely within the predetermined bioequivalence range (usually 0.8 to 1.25) for the products to be declared bioequivalent. Serious methodological errors, such as a conclusion of bioequivalence based on a lack of statistically significant difference between products, and conversely, a conclusion of bioequivalence because of a statistically significant difference, or because of a mere failure to show bioequivalence, are still made.With calcium antagonists in particular, an assessment of the rate of absorption and of the maximum concentration is important, as those characteristics may have implications for the safety profile with this class of drugs. As a minimum, in single doses studies the maximum concentration (Cmax), and the time to the maximum concentration (tmax), and in multiple-dose studies the Cmax, and the peak-trough fluctuation (%PTF) must be considered. SOme bioequivalence studies of calcium antagonists are deficient in this respect.To show bioequivalence for controlled-release formulations, multiple-dose studies are required but some published bioequivalence studies contain only single-dose assessments. Similarly, bioequivalence studies under fed conditions are rarely published, although food may have a significant effect on the absorption rate of these drugs. SOme calcium antagonists, such as verpamil, show stereoselective pharmacokinetics, so that enantiomers may have to be investigated.Unfortunately, few of the published studies of controlled-release calcium antagonists satisfy all requirements. One would expect that data submitted to regulatory authorities for approval of generic formulations are more complete; published data are in many cases not satisfactory

Diagnostics for Regression-Arma Time Series

In the context of ARMA time series, two types of outlier have been treated in the literature. These are the observation (type I) and the innovation (type II) outlier. Commonly these outliers have been modelled as mean-shift outliers, but variance-shift outliers may also be considered. In this paper we formulate the resulting 4 outlier types (mean-shift observation outlier, variance-shift observation outlier, mean-shift innovation outlier, and variance-shift innovation outlier) as perturbation schemes, in the manner of Cook(1986). Then we propose 3 types of diagnostics for these perturbation schemes, namely residuals, which will indicate the size of the perturbation in question, diagnostics for the potential influence of a perturbation, and diagnostics for the actual or observed influence of a perturbation.

Residuals and Outliers in Replicate Design Crossover Studies

Outliers in bioequivalence trials may arise through various mechanisms, requiring different interpretation and handling of such data points. For example, regulatory authorities might permit exclusion from analysis of outliers caused by product or process failure, while exclusion of outliers caused by subject-by-treatment interaction generally is not acceptable. In standard 2 × 2 crossover studies it is not possible to distinguish between relevant types of outliers based on statistical criteria alone. However, in replicate design (2-treatment, 4-period) crossover studies three types of outliers can be distinguished: (i) Subject outliers are usually unproblematic, at least regarding the analysis of bioequivalence, and may require no further action; (ii) Subject-by-formulation outliers may affect the outcome of the bioequivalence test but generally cannot simply be removed from analysis; and (iii) Removal of single-data-point outliers from analysis may be justified in certain cases. As a very simple but effective diagnostic tool for the identification and classification of outliers in replicate design crossover studies we propose to calculate and plot three types of residual corresponding to the three different types of outliers that can be distinguished. The residuals are obtained from four mutually orthogonal linear contrasts of the four data points associated with each subject. If preferred, outlier tests can be applied to the resulting sets of residuals after suitable standardization.

A Bayesian Nonlinear Mixed-Effects Regression Model for the Characterization of Early Bactericidal Activity of Tuberculosis Drugs

Trials of the early bactericidal activity (EBA) of tuberculosis (TB) treatments assess the decline, during the first few days to weeks of treatment, in colony forming unit (CFU) count of Mycobacterium tuberculosis in the sputum of patients with smear-microscopy-positive pulmonary TB. Profiles over time of CFU data have conventionally been modeled using linear, bilinear, or bi-exponential regression. We propose a new biphasic nonlinear regression model for CFU data that comprises linear and bilinear regression models as special cases and is more flexible than bi-exponential regression models. A Bayesian nonlinear mixed-effects (NLME) regression model is fitted jointly to the data of all patients from a trial, and statistical inference about the mean EBA of TB treatments is based on the Bayesian NLME regression model. The posterior predictive distribution of relevant slope parameters of the Bayesian NLME regression model provides insight into the nature of the EBA of TB treatments; specifically, the posterior predictive distribution allows one to judge whether treatments are associated with monolinear or bilinear decline of log(CFU) count, and whether CFU count initially decreases fast, followed by a slower rate of decrease, or vice versa.

Parameter Estimation Through Weighted Least-Squares Rank Regression with Specific Reference to the Weibull and Gumbel Distributions

Probability plots are often used to estimate the parameters of distributions. Using large sample properties of the empirical distribution function and order statistics, weights to stabilize the variance in order to perform weighted least squares regression are derived. Weighted least squares regression is then applied to the estimation of the parameters of the Weibull, and the Gumbel distribution. The weights are independent of the parameters of the distributions considered. Monte Carlo simulation shows that the weighted least-squares estimators outperform the usual least-squares estimators totally, especially in small samples.