Keeping up with the guidelines: design changes to the STREAM stage 2 randomised controlled non-inferiority trial for rifampicin-resistant tuberculosis

Results from the STREAM stage 1 trial showed that a 9-month regimen for patients with rifampicin-resistant tuberculosis was non-inferior to the 20-month regimen recommended by the 2011 WHO treatment guidelines. Similar levels of severe adverse events were reported on both regimens suggesting the need for further research to optimise treatment. Stage 2 of STREAM evaluates two additional short-course regimens, both of which include bedaquiline. Throughout stage 2 of STREAM, new drug choices and a rapidly changing treatment landscape have necessitated changes to the trial's design to ensure it remains ethical and relevant. This paper describes changes to the trial design to ensure that stage 2 continues to answer important questions. These changes include the early closure to recruitment of two trial arms and an adjustment to the definition of the primary endpoint. If the STREAM experimental regimens are shown to be non-inferior or superior to the stage 1 study regimen, this would represent an important contribution to evidence about potentially more tolerable and more efficacious MDR-TB regimens, and a welcome advance for patients with rifampicin-resistant tuberculosis and tuberculosis control programmes globally.Trial registration: ISRCTN ISRCTN18148631 . Registered 10 February 2016

230 GHz VLBI OBSERVATIONS OF M87: EVENT‐HORIZON‐SCALE STRUCTURE DURING AN ENHANCED VERY‐HIGH‐ENERGY γ‐RAY STATE IN 2012

We report on 230 GHz (1.3 mm) very long baseline interferometry (VLBI) observations of M87 with the Event Horizon Telescope using antennas on Mauna Kea in Hawaii, Mt. Graham in Arizona, and Cedar Flat in California. For the first time, we have acquired 230 GHz VLBI interferometric phase information on M87 through measurement of the closure phase on the triangle of long baselines. Most of the measured closure phases are consistent with 0° as expected by physically motivated models for 230 GHz structure such as jet models and accretion disk models. The brightness temperature of the event-horizon-scale structure is ~1 X 10[superscript 10] K derived from the compact flux density of ~1 Jy and the angular size of ~40 µas ~ 5.5 R[subscript s], which is broadly consistent with the peak brightness of the radio cores at 1–86 GHz located within ~10[superscript 2] R[subscript s]. Our observations occurred in the middle of an enhancement in very-high-energy (VHE) γ-ray flux, presumably originating in the vicinity of the central black hole. Our measurements, combined with results of multi-wavelength observations, favor a scenario in which the VHE region has an extended size of ~20–60 R[subscript s]

Pneumococcal carriage in sub-Saharan Africa--a systematic review.

BACKGROUND: Pneumococcal epidemiology varies geographically and few data are available from the African continent. We assess pneumococcal carriage from studies conducted in sub-Saharan Africa (sSA) before and after the pneumococcal conjugate vaccine (PCV) era. METHODS: A search for pneumococcal carriage studies published before 2012 was conducted to describe carriage in sSA. The review also describes pneumococcal serotypes and assesses the impact of vaccination on carriage in this region. RESULTS: Fifty-seven studies were included in this review with the majority (40.3%) from South Africa. There was considerable variability in the prevalence of carriage between studies (I-squared statistic = 99%). Carriage was higher in children and decreased with increasing age, 63.2% (95% CI: 55.6-70.8) in children less than 5 years, 42.6% (95% CI: 29.9-55.4) in children 5-15 years and 28.0% (95% CI: 19.0-37.0) in adults older than 15 years. There was no difference in the prevalence of carriage between males and females in 9/11 studies. Serotypes 19F, 6B, 6A, 14 and 23F were the five most common isolates. A meta-analysis of four randomized trials of PCV vaccination in children aged 9-24 months showed that carriage of vaccine type (VT) serotypes decreased with PCV vaccination; however, overall carriage remained the same because of a concomitant increase in non-vaccine type (NVT) serotypes. CONCLUSION: Pneumococcal carriage is generally high in the African continent, particularly in young children. The five most common serotypes in sSA are among the top seven serotypes that cause invasive pneumococcal disease in children globally. These serotypes are covered by the two PCVs recommended for routine childhood immunization by the WHO. The distribution of serotypes found in the nasopharynx is altered by PCV vaccination

Efficacy and safety of a VWF/FVIII concentrate (wilate®) in inherited von Willebrand disease patients undergoing surgical procedures

Introduction: Surgical procedures in von Willebrand disease (VWD) patients may require prophylactic treatment with exogenous von Willebrand factor (VWF) and coagulation factor VIII (FVIII) to prevent excessive bleeding. Wilate\uc2\uaeis a plasma-derived, double virus-inactivated, highly purified, freeze-dried VWF/FVIII concentrate, containing both factors in a physiological activity ratio of 1:1. Aim: To investigate the efficacy and safety of wilate\uc2\uaein maintaining haemostasis in VWD patients undergoing surgical procedures. Methods: This prospective, open-label multinational clinical study documents 28 individuals who underwent 30 surgical procedures managed with wilate\uc2\uae. Twenty-one patients had VWD Type 3, and 21 surgeries were major. Efficacy was assessed intra- and postoperatively by the surgeon and investigator, respectively, and adjudicated by an Independent Data Monitoring Committee, using an objective scale based on blood loss, transfusion requirements and postoperative bleeding and oozing. Treatment success (primary endpoint) was determined using a composite assessment algorithm and was formally assessed. Results: Surgical prophylaxis with wilate\uc2\uaewas successful in 29 of 30 procedures. The overall rate of success was 96.7% (98.75% CI: 0.784, 1.000). All 21 surgeries in patients with VWD Type 3 were managed successfully. There was no accumulation of VWF or FVIII after multiple dosing, and no thromboembolic events or inhibitors to VWF or FVIII were observed. Conclusions: Wilate\uc2\uaedemonstrated effective prevention and treatment of bleeding in inherited VWD patients undergoing surgery, with no clinically significant safety concerns

Evaluation of two short standardised regimens for the treatment of rifampicin-resistant tuberculosis (STREAM stage 2): an open-label, multicentre, randomised, non-inferiority trial.

The STREAM stage 1 trial showed that a 9-month regimen for the treatment of rifampicin-resistant tuberculosis was non-inferior to the 20-month 2011 WHO-recommended regimen. In STREAM stage 2, we aimed to compare two bedaquiline-containing regimens with the 9-month STREAM stage 1 regimen. We did a randomised, phase 3, non-inferiority trial in 13 hospital clinics in seven countries, in individuals aged 15 years or older with rifampicin-resistant tuberculosis without fluoroquinolone or aminoglycoside resistance. Participants were randomly assigned 1:2:2:2 to the 2011 WHO regimen (terminated early), a 9-month control regimen, a 9-month oral regimen with bedaquiline (primary comparison), or a 6-month regimen with bedaquiline and 8 weeks of second-line injectable. Randomisations were stratified by site, HIV status, and CD4 count. Participants and clinicians were aware of treatment-group assignments, but laboratory staff were masked. The primary outcome was favourable status (negative cultures for Mycobacterium tuberculosis without a preceding unfavourable outcome) at 76 weeks; any death, bacteriological failure or recurrence, and major treatment change were considered unfavourable outcomes. All comparisons used groups of participants randomly assigned concurrently. For non-inferiority to be shown, the upper boundary of the 95% CI should be less than 10% in both modified intention-to-treat (mITT) and per-protocol analyses, with prespecified tests for superiority done if non-inferiority was shown. This trial is registered with ISRCTN, ISRCTN18148631. Between March 28, 2016, and Jan 28, 2020, 1436 participants were screened and 588 were randomly assigned. Of 517 participants in the mITT population, 133 (71%) of 187 on the control regimen and 162 (83%) of 196 on the oral regimen had a favourable outcome: a difference of 11·0% (95% CI 2·9-19·0), adjusted for HIV status and randomisation protocol (p<0·0001 for non-inferiority). By 76 weeks, 108 (53%) of 202 participants on the control regimen and 106 (50%) of 211 allocated to the oral regimen had an adverse event of grade 3 or 4; five (2%) participants on the control regimen and seven (3%) on the oral regimen had died. Hearing loss (Brock grade 3 or 4) was more frequent in participants on the control regimen than in those on the oral regimen (18 [9%] vs four [2%], p=0·0015). Of 134 participants in the mITT population who were allocated to the 6-month regimen, 122 (91%) had a favourable outcome compared with 87 (69%) of 127 participants randomly assigned concurrently to the control regimen (adjusted difference 22·2%, 95% CI 13·1-31·2); six (4%) of 143 participants on the 6-month regimen had grade 3 or 4 hearing loss. Both bedaquiline-containing regimens, a 9-month oral regimen and a 6-month regimen with 8 weeks of second-line injectable, had superior efficacy compared with a 9-month injectable-containing regimen, with fewer cases of hearing loss. USAID and Janssen Research & Development

Economic evaluation of shortened, bedaquiline-containing treatment regimens for rifampicin-resistant tuberculosis (STREAM stage 2) : a within-trial analysis of a randomised controlled trial

Background: The STREAM stage 2 trial assessed two bedaquiline-containing regimens for rifampicin-resistant tuberculosis: a 9-month all-oral regimen and a 6-month regimen containing an injectable drug for the first 2 months. We did a within-trial economic evaluation of these regimens. Methods: STREAM stage 2 was an international, phase 3, non-inferiority randomised trial in which participants with rifampicin-resistant tuberculosis were randomly assigned (1:2:2:2) to the 2011 WHO regimen (terminated early), a 9-month injectable-containing regimen (control regimen), a 9-month all-oral regimen with bedaquiline (oral regimen), or a 6-month regimen with bedaquiline and an injectable for the first 2 months (6-month regimen). We prospectively collected direct and indirect costs and health-related quality of life data from trial participants until week 76 of follow-up. Cost-effectiveness of the oral and 6-month regimens versus control was estimated in four countries (oral regimen) and two countries (6-month regimen), using health-related quality of life for cost-utility analysis and trial efficacy for cost-effectiveness analysis. This trial is registered with ISRCTN, ISRCTN18148631. Findings: 300 participants were included in the economic analyses (Ethiopia, 61; India, 142; Moldova, 51; Uganda, 46). In the cost-utility analysis, the oral regimen was not cost-effective in Ethiopia, India, Moldova, and Uganda from either a provider or societal perspective. In Moldova, the oral regimen was dominant from a societal perspective. In the cost-effectiveness analysis, the oral regimen was likely to be cost-effective from a provider perspective at willingness-to-pay thresholds per additional favourable outcome of more than US$4500 in Ethiopia,$1900 in India, $3950 in Moldova, and$7900 in Uganda, and from a societal perspective at thresholds of more than $15 900 in Ethiopia,$3150 in India, and $4350 in Uganda, while in Moldova the oral regimen was dominant. In Ethiopia and India, the 6-month regimen would cost tuberculosis programmes and participants less than the control regimen and was highly likely to be cost-effective in both cost-utility analysis and cost-effectiveness analysis. Reducing the bedaquiline price from$1·81 to $1·00 per tablet made the oral regimen cost-effective in the provider-perspective cost-utility analysis in India and Moldova and dominate over the control regimen in the provider-perspective cost-effectiveness analysis in India. Interpretation: At current costs, the oral bedaquiline-containing regimen for rifampicin-resistant tuberculosis is unlikely to be cost-effective in many low-income and middle-income countries. The 6-month regimen represents a cost-effective alternative if injectable use for 2 months is acceptable. Funding: USAID and Janssen Research & Development