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BACKGROUND: STREAM (Standardised Treatment Regimen of Anti-tuberculosis Drugs for Patients with Multidrug-resistant Tuberculosis) Stage 1 was a randomised trial of a Short (9-month) regimen for rifampicin-resistant TB (RR-TB). QT or QTcF prolongation ≥500 ms occurred in 31 (11%) of 282 Short regimen participants. The frequent ECG monitoring employed might be challenging for treatment programmes. This analysis aimed to determine whether those at higher risk of severe QT prolongation could be identified early for more targeted monitoring. METHODS: Data from the first month of treatment were used to investigate whether participants were at risk of developing QT/QTcF ≥500 ms. QTcF increases from baseline at different time points were examined. Absolute QTcF measurements were categorised in 5 ms increments at each time-point. The most discriminating time points and QTcF cut-offs were combined to optimise sensitivity and specificity. RESULTS: Absolute QTcF values were more discriminating than magnitude of increase from baseline. More participants who developed QT/QTcF ≥500 ms had a QTcF of respectively ≥425 ms and ≥430 ms at 4 h and Week 3 ( P < 0.05) than those who did not. By combining QTcF values ≥425 ms at 4 h and ≥430 ms at Week 3, we identified high-risk participants with 97% sensitivity and 99% negative predictive value. CONCLUSION: Reduced ECG monitoring may be possible for many Short regimen participants.

BACKGROUND: STREAM (Standardised Treatment Regimens of Anti-tuberculosis drugs for Multidrug-Resistant Tuberculosis) Stage 1 demonstrated non-inferior efficacy of a short regimen for rifampicin-resistant TB (RR-TB) compared to a long regimen as recommended by the WHO. The present paper analyses factors associated with a definite or probable failure or relapse (FoR) event in participants receiving the Short regimen. METHODS: This analysis is restricted to 253 participants allocated to the Short regimen and is based on the protocol-defined modified intention to treat (mITT) population. Multivariable Cox regression models were built using backwards elimination with an exit probability of P = 0.157, equivalent to the Akaike Information Criterion, to identify factors independently associated with a definite or probable FoR event. RESULTS: Four baseline factors were identified as being significantly associated with the risk of definite or probable FoR (male sex, a heavily positive baseline smear grade, HIV co-infection and the presence of costophrenic obliteration). There was evidence of association of culture positivity at Week 8 and FoR in a second model and Week 16 smear positivity, presence of diabetes and of smoking in a third model. CONCLUSION: The factors associated with FoR outcomes identified in this analysis should be considered when determining the optimal shortened treatment regimen.

BACKGROUND: STREAM (Standardized Treatment Regimen of Anti-TB Drugs for Patients with MDR-TB) Stage 1 demonstrated non-inferior efficacy of a shortened regimen (the Short regimen) for rifampicin-resistant TB (RR-TB) compared to the contemporaneous WHO-recommended regimen. This regimen included moxifloxacin and clofazimine, known to cause QT prolongation, and severe prolongation was more common on the Short regimen. Here we investigate risk factors for QT prolongation with the Short regimen. METHODS: Data from patients prescribed the Short regimen ( n = 282) were analysed to identify risk factors for severe QT prolongation (QT/QTcF ≥500 ms or ≥60 ms increase in QTcF from baseline). RESULTS: Of the 282 patients on the Short regimen, 94 (33.3%) developed severe QT prolongation: 31 QT/QTcF ≥500 ms; 92 experienced ≥60 ms QTcF increase from baseline. The median time to QT/QTcF ≥500 ms was 20 weeks (IQR 8-28), and the time to ≥60 ms increase from baseline was 18 weeks (IQR 8-28). Prolongation ≥500 ms was most frequent in patients from Mongolia (10/22, 45.5%) compared with 3.5-11.9% at other sites, P < 0.001. Higher baseline QTcF increased risk of prolongation to ≥500 ms (QTcF ≥400 ms: OR 5.99, 95% CI 2.04-17.62). CONCLUSION: One third of patients on the Short regimen developed severe QT prolongation. QT/QTcF ≥500 ms was more common in patients from Mongolia and in those with a higher baseline QTcF, which may have implications for implementation of treatment.

BACKGROUND: Treatment for TB is lengthy and toxic, and new regimens are needed. METHODS: Participants with pulmonary drug-susceptible TB (DS-TB) were randomised to receive: 200 mg pretomanid (Pa, PMD) daily, 400 mg moxifloxacin (M) and 1500 mg pyrazinamide (Z) for 6 months (6Pa 200 MZ) or 4 months (4Pa 200 MZ); 100 mg pretomanid daily for 4 months in the same combination (4Pa 100 MZ); or standard DS-TB treatment for 6 months. The primary outcome was treatment failure or relapse at 12 months post-randomisation. The non-inferiority margin for between-group differences was 12.0%. Recruitment was paused following three deaths and not resumed. RESULTS: Respectively 4/47 (8.5%), 11/57 (19.3%), 14/52 (26.9%) and 1/53 (1.9%) DS-TB outcomes were unfavourable in patients on 6Pa 200 MZ, 4Pa 200 MZ, 4Pa 100 MZ and controls. There was a 6.6% (95% CI -2.2% to 15.4%) difference per protocol and 9.9% (95%CI -4.1% to 23.9%) modified intention-to-treat difference in unfavourable responses between the control and 6Pa 200 MZ arms. Grade 3+ adverse events affected 68/203 (33.5%) receiving experimental regimens, and 19/68 (27.9%) on control. Ten of 203 (4.9%) participants on experimental arms and 2/68 (2.9%) controls died. CONCLUSION: PaMZ regimens did not achieve non-inferiority in this under-powered trial. An ongoing evaluation of PMD remains a priority.

Drug-resistant tuberculosis (DR-TB) is a growing public health problem, and for the first time in decades, new drugs for the treatment of this disease have been developed. These new drugs have prompted strengthened efforts in DR-TB clinical trials research, and there are now multiple ongoing and planned DR-TB clinical trials. To facilitate comparability and maximise policy impact, a common set of core research definitions is needed, and this paper presents a core set of efficacy and safety definitions as well as other important considerations in DR-TB clinical trials work. To elaborate these definitions, a search of clinical trials registries, published manuscripts and conference proceedings was undertaken to identify groups conducting trials of new regimens for the treatment of DR-TB. Individuals from these groups developed the core set of definitions presented here. Further work is needed to validate and assess the utility of these definitions but they represent an important first step to ensure there is comparability in clinical trials on multidrug-resistant TB.

Study C was an open-label, non-inferiority, randomised controlled trial of fixed-dose combination (FDC) or separate drugs given during the intensive phase of treatment to 1585 patients with smear-positive pulmonary tuberculosis conducted at 11 sites in Africa, Asia and Latin America. Thirty months post-randomisation, the failure/relapse rates in the per protocol population were 7.4% of 591 patients on FDCs and 6.5% of 587 patients on separate drugs; the site-adjusted difference was 0.3% (90%CI -1.8 to 2.3). In the modified intention-to-treat analysis, the corresponding results were respectively 17.9% of 683 and 16.1% of 671; the site-adjusted difference was 2.0% (90%CI -1.2 to 5.2).

A recent trial evaluating a 4-month regimen of standard drugs in adults with non-cavitary tuberculosis (TB) and negative cultures at 2 months failed to demonstrate equivalence compared to the same regimen given for 6 months. To contribute further evidence, data from two trials conducted by the British Medical Research Council (BMRC) comparing 4 and 6 month regimens were re-analysed. The results from the BMRC trials in patients with non-cavitary TB and negative cultures at 2 months were consistent with those from the recent trial. However, given that there was no acquired drug resistance, the estimated 6.6% relapse rate (95%CI 4.3-10.1) across all three trials might be considered acceptable for a 4-month regimen in patients with non-cavitary pulmonary TB.

Setting: An 8-month isoniazid (INH, H) and ethambutol (EMB, E) based regimen recommended by the World Health Organization (WHO) had never been evaluated in a randomised controlled multicentre trial., Objective: To compare, in a non-inferiority study design, two 8-month INH+EMB-based regimens with a standard INH and rifampicin (RMP, R) based regimen., Design: A total of 1355 patients with newly diagnosed smear-positive pulmonary tuberculosis were randomly allocated to receive 1) daily EMB, INH, RMP and pyrazinamide (PZA, Z) for 2 months, followed by EMB+INH for 6 months (2EHRZ/6HE); 2) the same drugs in the intensive phase but given three times weekly, followed by the same continuation phase of daily EMB+INH (2(EHRZ)(3)/6HE); or 3) a control regimen with the same intensive phase as in regimen 1, followed by 4 months of daily RMP+INH (2EHRZ/4HR). All patients were to be seen and sputum examinations for microscopy and culture carried out at regular intervals up to 30 months after randomisation., Results: At 30 months, failure/relapse rates were 11.7% of 281 2EHRZ/6HE, 15.3% of 301 2(EHRZ)(3)/6HE and 6.0% of 282 2EHRZ/4HR patients (χ(2), 2 degrees of freedom = 12.8, P = 0.002)., Conclusion: These results confirm earlier findings demonstrating the inferiority of the INH+EMB-based regimens to the standard 6-month regimen. The WHO has withdrawn its recommendation of these regimens.

Clinical trials are sometimes classified as being explanatory or pragmatic, although they are rarely reported in that way. Explanatory trials may seek to investigate the efficacy of new treatments by imposing strict limitations on many aspects of trial design, including, for example, recruiting only those patients who are most likely to respond. In contrast, the objective of pragmatic trials is to assess whether treatments work in conditions more appropriate to routine practice. This dichotomy is, however, over-simplistic; there is usually a continuum, which is a consequence of there being many areas of trial design that can vary between the extremities of the explanatory and pragmatic approaches. The PRECIS (pragmatic-explanatory continuum indicator summary) wheel based on 10 domains, which include inclusion criteria, flexibility of delivery of the intervention and intensity of follow-up, has been proposed as a way of enabling researchers to assess the extent to which the trials they are designing could be considered explanatory or pragmatic. In this article, we consider how the PRECIS tool can be applied to trials of tuberculosis treatment. In view of the well-recognised delay in getting results from well-conducted clinical trials into practice, we would suggest that if more pragmatic trials were to be conducted, physicians would better understand the implications of the results for their own practice and be more ready to adopt new treatments.

Setting: Royal Free Hospital, London., Objective: To investigate the relationship between sputum mycobacterial load, assessed by time to positivity (TTP) in liquid culture, radiological cavitation and change in sputum bacterial load in response to anti-tuberculosis treatment., Design: The study was conducted on 95 patients treated for sputum culture-positive pulmonary tuberculosis (TB), with pre-treatment TTP and baseline chest X-ray (CXR). Of these, 31 had chest computed tomography scans assessed for number and volume of cavities. The microbiological treatment response was measured in 56 patients with serial TTP, and related to baseline radiological cavitation., Results: Cavitation was present in 48% of patients, and was associated with a shorter TTP at baseline (P < 0.001). Patients with more cavities and greater total cavitary volume had a shorter TTP (P < 0.001 for both). No difference was demonstrated in the rate of change in TTP on treatment (P = 0.36) between patients with and without cavities., Conclusion: This study confirms that cavitation is associated with higher baseline sputum mycobacterial load. The rate of decline in bacterial load in response to treatment is similar in patients with and without radiologically demonstrable cavities, suggesting that response to, and hence duration of, effective treatment may be predicted by the initial number of organisms present in the sputum.

We have reviewed the results from 15 tuberculosis treatment trials initiated by the British Medical Research Council between 1970 and 1983 in Africa and East Asia. Of 574 relapses, 447 (78%) occurred within 6 months of stopping treatment and 525 (91%) within 12 months. We suggest that investigators should consider terminating follow-up after the last enrolled patient completes 6 months following treatment, while continuing to follow patients enrolled earlier until that time. Compared to following all patients to 24 months, the total trial duration could be reduced by 18 months, with no increase in patient numbers in a non-inferiority design.

Objective: Controlled trials have failed to show an effect of Mycobacterium vaccae immunotherapy on treatment outcome and mortality in patients with tuberculosis (TB); however, several studies have suggested improvement in radiographic clearing and resolution of cavitary disease., Methods: To assess the effect of M. vaccae immunotherapy on radiographic healing in pulmonary TB, chest X-rays from three randomized placebo-controlled trials of M. vaccae given as a single injection during the first 2 weeks of treatment were interpreted by a single, masked assessor using a standard scheme. Endpoints were the overall degree of radiographic improvement or deterioration and changes in cavitary disease at the end of antituberculosis treatment and follow-up., Results: Of 1018 patients (478 HIV-infected; 540 HIV-uninfected) with an end of treatment or end of follow-up X-ray analyzed, 496 received M. vaccae and 522 received placebo. There was no difference in radiographic improvement or deterioration or cavitary disease at the end of treatment or follow-up comparing the M. vaccae and placebo groups. Results were similar comparing HIV-infected and HIV-uninfected patients., Conclusion: Adjunctive immunotherapy of drug-susceptible pulmonary TB with M. vaccae during the first 2 weeks of treatment did not improve radiographic responses to treatment or resolution of cavitary disease.