The standard 6-month four-drug regimen for the treatment of drug-sensitive tuberculosis has remained unchanged for decades and is inadequate to control the epidemic. Shorter, simpler regimens are urgently needed to defeat what is now the world’s greatest infectious disease killer. We describe the Phase IIC Selection Trial with Extended Post-treatment follow-up (STEP) as a novel hybrid phase II/III trial design to accelerate regimen development. In the Phase IIC STEP trial, the experimental regimen is given for the duration for which it will be studied in phase III (presently 3 or 4 months) and patients are followed for clinical outcomes of treatment failure and relapse for a total of 12 months from randomisation. Operating characteristics of the trial design are explored assuming a classical frequentist framework as well as a Bayesian framework with flat and sceptical priors. A simulation study is conducted using data from the RIFAQUIN phase III trial to illustrate how such a design could be used in practice. With 80 patients per arm, and two (2.5 %) unfavourable outcomes in the STEP trial, there is a probability of 0.99 that the proportion of unfavourable outcomes in a potential phase III trial would be less than 12 % and a probability of 0.91 that the proportion of unfavourable outcomes would be less than 8 %. With six (7.5 %) unfavourable outcomes, there is a probability of 0.82 that the proportion of unfavourable outcomes in a potential phase III trial would be less than 12 % and a probability of 0.41 that it would be less than 8 %. Simulations using data from the RIFAQUIN trial show that a STEP trial with 80 patients per arm would have correctly shown that the Inferior Regimen should not proceed to phase III and would have had a high chance (0.88) of either showing that the Successful Regimen could proceed to phase III or that it might require further optimisation. Collection of definitive clinical outcome data in a relatively small number of participants over only 12 months provides valuable information about the likelihood of success in a future phase III trial. We strongly believe that the STEP trial design described herein is an important tool that would allow for more informed decision-making and accelerate regimen development.

Diabetes mellitus (DM) is associated with poor TB treatment outcome. Previous studies examining the effect of DM on TB drug concentrations yielded conflicting results. No studies have been conducted to date in an African population. To compare exposure to TB drugs in Tanzanian TB patients with and without DM. A prospective pharmacokinetic study was performed among 20 diabetic and 20 non-diabetic Tanzanian TB patients during the intensive phase of TB treatment. Plasma pharmacokinetic parameters of isoniazid, rifampicin, pyrazinamide and ethambutol were compared using an independent-sample t-test on log-transformed data. Multiple linear regression analysis was performed to assess the effects of DM, gender, age, weight, HIV status and acetylator status on exposure to TB drugs. A trend was shown for 25% lower total exposure (AUC_0–24) to rifampicin among diabetics versus non-diabetics (29.9 versus 39.9 mg·h/L, P=0.052). The AUC_0–24 and peak concentration (C_max) of isoniazid were also lower in diabetic TB patients (5.4 versus 10.6 mg·h/L, P=0.015 and 1.6 versus 2.8 mg/L, P=0.013). Pyrazinamide AUC_0–24 and C_max values were non-significantly lower among diabetics (P=0.08 and 0.09). In multivariate analyses, DM remained an independent predictor of exposure to isoniazid and rifampicin, next to acetylator status for isoniazid. There is a need for individualized dosing of isoniazid and rifampicin based on plasma concentration measurements (therapeutic drug monitoring) and for clinical trials on higher doses of these TB drugs in patients with TB and DM.

Rifampicin is the most important antibiotic in use for the treatment of tuberculosis (TB). Preclinical and clinical data suggest that higher doses of rifampicin, resulting in disproportionally higher systemic exposures to the drug, are more effective. Serum concentrations of rifampicin are the intermediary link between the dose administered and eventual response and only protein-unbound (free) rifampicin is pharmacologically active. The objective of this work was to develop an ultra performance liquid chromatography assay for protein-unbound rifampicin in serum with ultrafiltration, carried out at a sample temperature of 37°C, suitable for measurement of concentrations achieved after currently used and higher doses of rifampicin. Human serum was equilibrated at 37°C and ultrafiltrated at the same temperature in a Centrifree YM-30 ultrafiltration device, followed by dilution of the ultrafiltrate with methanol and ascorbic acid. Unbound rifampicin was analyzed using ultra performance liquid chromatography with a BEH C18 column, isocratic elution and ultra-violet (UV) detection. The run time was 5min. The assay was linear over the concentration range of 0.065-26mg/L rifampicin in ultrafiltrate. Accuracies for measurement of rifampicin in ultrafiltrate were 97% and 102% at the higher and lower limits of quantitation. Accuracy of the ultrafiltration process cannot be established, as it is not possible to spike blank serum with known amounts of protein-unbound rifampicin. Within- and between-day precision of the method including ultrafiltration as well as after ultrafiltration were within prespecified limits (CV<10%). Dilution of the ultrafiltrate with methanol and ascorbic acid kept rifampicin in solution and prevented it from degradation. Rifampicin loss during the ultrafiltration process and variation in analytical results when using two different batches of ultrafiltration devices were both limited. Processed ultrafiltrate samples were stable for 3days in the autosampler. The developed method can be applied in pharmacokinetic research, studying exposure-response relationships for rifampicin when administered at higher than currently used doses.

Adherence to tuberculosis (TB) treatment is challenging because of many factors. The World Health Organization has recommended the use of digital adherence monitoring technologies in its End TB Strategy. However, evidence on improving adherence is limited. EvriMED is a real-time medication-monitoring device which was found to be feasible and acceptable in a few studies in Asia. In Tanzania, however, there may be challenges in implementing evriMED due to stigmatization, network and power access, accuracy, and cost effectiveness, which may have implications for treatment outcome. We propose a pragmatic cluster randomized trial to investigate the effectiveness of evriMED with reminder cues and tailored feedback on adherence to TB treatment in Kilimanjaro, Tanzania. We will create clusters in Kilimanjaro based on level of health care facility. Clusters will be randomized in an intervention arm, where evriMED will be implemented, or a control arm, where standard practice directly observed treatment will be followed. TB patients in intervention clusters will take their medication from the evriMED pillbox and receive tailored feedback. We will use the ‘Stages of Change’ model, which assumes that a person has to go through the stages of pre-contemplation, contemplation, preparation, action, and evaluation to change behavior for tailored feedback on adherence reports from the device. If the intervention shows a significant effect on adherence and the devices are accepted, accurate, and sustainable, the intervention can be scaled up within the National Tuberculosis Programmes. Pan African Clinical Trials Registry, PACTR201811755733759 . Registered on 8 November 2018.