High-dose rifampicin, moxifloxacin, and SQ109 for treating tuberculosis: a multi-arm, multi-stage randomised controlled trial

BACKGROUND: Tuberculosis is the world's leading infectious disease killer. We aimed to identify shorter, safer drug regimens for the treatment of tuberculosis. METHODS: We did a randomised controlled, open-label trial with a multi-arm, multi-stage design. The trial was done in seven sites in South Africa and Tanzania, including hospitals, health centres, and clinical trial centres. Patients with newly diagnosed, rifampicin-sensitive, previously untreated pulmonary tuberculosis were randomly assigned in a 1:1:1:1:2 ratio to receive (all orally) either 35 mg/kg rifampicin per day with 15–20 mg/kg ethambutol, 20 mg/kg rifampicin per day with 400 mg moxifloxacin, 20 mg/kg rifampicin per day with 300 mg SQ109, 10 mg/kg rifampicin per day with 300 mg SQ109, or a daily standard control regimen (10 mg/kg rifampicin, 5 mg/kg isoniazid, 25 mg/kg pyrazinamide, and 15–20 mg/kg ethambutol). Experimental treatments were given with oral 5 mg/kg isoniazid and 25 mg/kg pyrazinamide per day for 12 weeks, followed by 14 weeks of 5 mg/kg isoniazid and 10 mg/kg rifampicin per day. Because of the orange discoloration of body fluids with higher doses of rifampicin it was not possible to mask patients and clinicians to treatment allocation. The primary endpoint was time to culture conversion in liquid media within 12 weeks. Patients without evidence of rifampicin resistance on phenotypic test who took at least one dose of study treatment and had one positive culture on liquid or solid media before or within the first 2 weeks of treatment were included in the primary analysis (modified intention to treat). Time-to-event data were analysed using a Cox proportional-hazards regression model and adjusted for minimisation variables. The proportional hazard assumption was tested using Schoelfeld residuals, with threshold p<0·05 for non-proportionality. The trial is registered with ClinicalTrials.gov (NCT01785186). FINDINGS: Between May 7, 2013, and March 25, 2014, we enrolled and randomly assigned 365 patients to different treatment arms (63 to rifampicin 35 mg/kg, isoniazid, pyrazinamide, and ethambutol; 59 to rifampicin 10 mg/kg, isoniazid, pyrazinamide, SQ109; 57 to rifampicin 20 mg/kg, isoniazid, pyrazinamide, and SQ109; 63 to rifampicin 10 mg/kg, isoniazid, pyrazinamide, and moxifloxacin; and 123 to the control arm). Recruitment was stopped early in the arms containing SQ109 since prespecified efficacy thresholds were not met at the planned interim analysis. Time to stable culture conversion in liquid media was faster in the 35 mg/kg rifampicin group than in the control group (median 48 days vs 62 days, adjusted hazard ratio 1·78; 95% CI 1·22–2·58, p=0·003), but not in other experimental arms. There was no difference in any of the groups in time to culture conversion on solid media. 11 patients had treatment failure or recurrent disease during post-treatment follow-up: one in the 35 mg/kg rifampicin arm and none in the moxifloxacin arm. 45 (12%) of 365 patients reported grade 3–5 adverse events, with similar proportions in each arm. INTERPRETATION: A dose of 35 mg/kg rifampicin was safe, reduced the time to culture conversion in liquid media, and could be a promising component of future, shorter regimens. Our adaptive trial design was successfully implemented in a multi-centre, high tuberculosis burden setting, and could speed regimen development at reduced cost. FUNDING: The study was funded by the European and Developing Countries Clinical Trials partnership (EDCTP), the German Ministry for Education and Research (BmBF), and the Medical Research Council UK (MRC)

Non-inferiority trials: are they inferior? A systematic review of reporting in major medical journals

OBJECTIVE: To assess the adequacy of reporting of non-inferiority trials alongside the consistency and utility of current recommended analyses and guidelines. DESIGN: Review of randomised clinical trials that used a non-inferiority design published between January 2010 and May 2015 in medical journals that had an impact factor >10 (JAMA Internal Medicine, Archives Internal Medicine, PLOS Medicine, Annals of Internal Medicine, BMJ, JAMA, Lancet and New England Journal of Medicine). DATA SOURCES: Ovid (MEDLINE). METHODS: We searched for non-inferiority trials and assessed the following: choice of non-inferiority margin and justification of margin; power and significance level for sample size; patient population used and how this was defined; any missing data methods used and assumptions declared and any sensitivity analyses used. RESULTS: A total of 168 trial publications were included. Most trials concluded non-inferiority (132; 79%). The non-inferiority margin was reported for 98% (164), but less than half reported any justification for the margin (77; 46%). While most chose two different analyses (91; 54%) the most common being intention-to-treat (ITT) or modified ITT and per-protocol, a large number of articles only chose to conduct and report one analysis (65; 39%), most commonly the ITT analysis. There was lack of clarity or inconsistency between the type I error rate and corresponding CIs for 73 (43%) articles. Missing data were rarely considered with (99; 59%) not declaring whether imputation techniques were used. CONCLUSIONS: Reporting and conduct of non-inferiority trials is inconsistent and does not follow the recommendations in available statistical guidelines, which are not wholly consistent themselves. Authors should clearly describe the methods used and provide clear descriptions of and justifications for their design and primary analysis. Failure to do this risks misleading conclusions being drawn, with consequent effects on clinical practice

Blinded Outcome Assessment Was Infrequently Used and Poorly Reported in Open Trials

Objective Unblinded outcome assessment can lead to biased estimates of treatment effect in randomised trials. We reviewed published trials to assess how often blinded assessment is used, and whether its use varies according to the type of outcome or assessor. Design and setting A review of parallel group, individually randomised phase III trials published in four general medical journals (BMJ, Journal of the American Medical Association, The Lancet, and New England Journal of Medicine) in 2010. Main outcome measures Whether assessment of the primary outcome was blinded, and whether this differed according to outcome or assessor type. Results We identified 258 eligible trials. Of these, 106 (41%) were reported as double-blind, and 152 (59%) as partially or fully open-label (that is, they included some groups who were unblinded, such as patients, those delivering the intervention, or those in charge of medical care). Of the 152 open trials, 125 required outcome assessment. Of these 125 trials, only 26% stated that outcome assessment was blinded; 51% gave no information on whether assessment was blinded or not. Furthermore, 18% of trials did not state who performed the assessment. The choice of outcome type (e.g. instrument measured, rated, or naturally occurring event) did not appear to influence whether blinded assessment was performed (range 24-32% for the most common outcome types). However, the choice of outcome assessor did influence blinding; independent assessors were blinded much more frequently (71%) than participant (5%) or physician (24%) assessors. Despite this, open trials did not use independent assessors any more frequently than double-blind trials (17% vs. 18% respectively). Conclusions Blinding of outcome assessors is infrequently used and poorly reported. Increased use of independent assessors could increase the frequency of blinded assessment

Risk of selection bias in randomised trials

Background: Selection bias occurs when recruiters selectively enrol patients into the trial based on what the next treatment allocation is likely to be. This can occur even if appropriate allocation concealment is used if recruiters can guess the next treatment assignment with some degree of accuracy. This typically occurs in unblinded trials when restricted randomisation is implemented to force the number of patients in each arm or within each centre to be the same. Several methods to reduce the risk of selection bias have been suggested; however, it is unclear how often these techniques are used in practice. Methods: We performed a review of published trials which were not blinded to assess whether they utilised methods for reducing the risk of selection bias. We assessed the following techniques: (a) blinding of recruiters; (b) use of simple randomisation; (c) avoidance of stratification by site when restricted randomisation is used; (d) avoidance of permuted blocks if stratification by site is used; and (e) incorporation of prognostic covariates into the randomisation procedure when restricted randomisation is used. We included parallel group, individually randomised phase III trials published in four general medical journals (BMJ, Journal of the American Medical Association, The Lancet, and New England Journal of Medicine) in 2010. Results: We identified 152 eligible trials. Most trials (98%) provided no information on whether recruiters were blind to previous treatment allocations. Only 3% of trials used simple randomisation; 63% used some form of restricted randomisation, and 35% did not state the method of randomisation. Overall, 44% of trials were stratified by site of recruitment; 27% were not, and 29% did not report this information. Most trials that did stratify by site of recruitment used permuted blocks (58%), and only 15% reported using random block sizes. Many trials that used restricted randomisation also included prognostic covariates in the randomisation procedure (56%). Conclusions: The risk of selection bias could not be ascertained for most trials due to poor reporting. Many trials which did provide details on the randomisation procedure were at risk of selection bias due to a poorly chosen randomisation methods. Techniques to reduce the risk of selection bias should be more widely implemented

Reducing bias in open-label trials where blinded outcome assessment is not feasible: strategies from two randomised trials

Background Blinded outcome assessment is recommended in open-label trials to reduce bias, however it is not always feasible. It is therefore important to find other means of reducing bias in these scenarios. Methods We describe two randomised trials where blinded outcome assessment was not possible, and discuss the strategies used to reduce the possibility of bias. Results TRIGGER was an open-label cluster randomised trial whose primary outcome was further bleeding. Because of the cluster randomisation, all researchers in a hospital were aware of treatment allocation and so could not perform a blinded assessment. A blinded adjudication committee was also not feasible as it was impossible to compile relevant information to send to the committee in a blinded manner. Therefore, the definition of further bleeding was modified to exclude subjective aspects (such as whether symptoms like vomiting blood were severe enough to indicate the outcome had been met), leaving only objective aspects (the presence versus absence of active bleeding in the upper gastrointestinal tract confirmed by an internal examination). TAPPS was an open-label trial whose primary outcome was whether the patient was referred for a pleural drainage procedure. Allowing a blinded assessor to decide whether to refer the patient for a procedure was not feasible as many clinicians may be reluctant to enrol patients into the trial if they cannot be involved in their care during follow-up. Assessment by an adjudication committee was not possible, as the outcome either occurred or did not. Therefore, the decision pathway for procedure referral was modified. If a chest x-ray indicated that more than a third of the pleural space filled with fluid, the patient could be referred for a procedure; otherwise, the unblinded clinician was required to reach a consensus on referral with a blinded assessor. This process allowed the unblinded clinician to be involved in the patient’s care, while reducing the potential for bias. Conclusions When blinded outcome assessment is not possible, it may be useful to modify the outcome definition or method of assessment to reduce the risk of bias

Primary versus secondary source of data in observational studies and heterogeneity in meta-analyses of drug effects: a survey of major medical journals

The data from individual observational studies included in meta-analyses of drug effects are collected either from ad hoc methods (i.e. "primary data") or databases that were established for non-research purposes (i.e. "secondary data"). The use of secondary sources may be prone to measurement bias and confounding due to over-the-counter and out-of-pocket drug consumption, or non-adherence to treatment. In fact, it has been noted that failing to consider the origin of the data as a potential cause of heterogeneity may change the conclusions of a meta-analysis. We aimed to assess to what extent the origin of data is explored as a source of heterogeneity in meta-analyses of observational studies.publishe

Using system dynamics for collaborative design: a case study

<p>Abstract</p> <p>Background</p> <p>In order to facilitate the collaborative design, system dynamics (SD) with a group modelling approach was used in the early stages of planning a new stroke unit. During six workshops a SD model was created in a multiprofessional group.</p> <p>Aim</p> <p>To explore to which extent and how the use of system dynamics contributed to the collaborative design process.</p> <p>Method</p> <p>A case study was conducted using several data sources.</p> <p>Results</p> <p>SD supported a collaborative design, by facilitating an explicit description of stroke care process, a dialogue and a joint understanding. The construction of the model obliged the group to conceptualise the stroke care and experimentation with the model gave the opportunity to reflect on care.</p> <p>Conclusion</p> <p>SD facilitated the collaborative design process and should be integrated in the early stages of the design process as a quality improvement tool.</p

Effect of Home Noninvasive Ventilation With Oxygen Therapy vs Oxygen Therapy Alone on Hospital Readmission or Death After an Acute COPD Exacerbation

Importance: Outcomes after exacerbations of chronic obstructive pulmonary disease (COPD) requiring acute noninvasive ventilation (NIV) are poor and there are few treatments to prevent hospital readmission and death. Objective: To investigate the effect of home NIV plus oxygen on time to readmission or death in patients with persistent hypercapnia after an acute COPD exacerbation. Design, Setting, and Participants: A randomized clinical trial of patients with persistent hypercapnia (Paco2 >53 mm Hg) 2 weeks to 4 weeks after resolution of respiratory acidemia, who were recruited from 13 UK centers between 2010 and 2015. Exclusion criteria included obesity (body mass index [BMI] >35), obstructive sleep apnea syndrome, or other causes of respiratory failure. Of 2021 patients screened, 124 were eligible. Interventions: There were 59 patients randomized to home oxygen alone (median oxygen flow rate, 1.0 L/min [interquartile range {IQR}, 0.5-2.0 L/min]) and 57 patients to home oxygen plus home NIV (median oxygen flow rate, 1.0 L/min [IQR, 0.5-1.5 L/min]). The median home ventilator settings were an inspiratory positive airway pressure of 24 (IQR, 22-26) cm H2O, an expiratory positive airway pressure of 4 (IQR, 4-5) cm H2O, and a backup rate of 14 (IQR, 14-16) breaths/minute. Main Outcomes and Measures: Time to readmission or death within 12 months adjusted for the number of previous COPD admissions, previous use of long-term oxygen, age, and BMI. Results: A total of 116 patients (mean [SD] age of 67 [10] years, 53% female, mean BMI of 21.6 [IQR, 18.2-26.1], mean [SD] forced expiratory volume in the first second of expiration of 0.6 L [0.2 L], and mean [SD] Paco2 while breathing room air of 59 [7] mm Hg) were randomized. Sixty-four patients (28 in home oxygen alone and 36 in home oxygen plus home NIV) completed the 12-month study period. The median time to readmission or death was 4.3 months (IQR, 1.3-13.8 months) in the home oxygen plus home NIV group vs 1.4 months (IQR, 0.5-3.9 months) in the home oxygen alone group, adjusted hazard ratio of 0.49 (95% CI, 0.31-0.77; P = .002). The 12-month risk of readmission or death was 63.4% in the home oxygen plus home NIV group vs 80.4% in the home oxygen alone group, absolute risk reduction of 17.0% (95% CI, 0.1%-34.0%). At 12 months, 16 patients had died in the home oxygen plus home NIV group vs 19 in the home oxygen alone group. Conclusions and Relevance: Among patients with persistent hypercapnia following an acute exacerbation of COPD, adding home noninvasive ventilation to home oxygen therapy prolonged the time to readmission or death within 12 months. Trial Registration: clinicaltrials.gov Identifier: NCT00990132