A Flexible Multi-Metric Bayesian Framework for Decision-Making in Phase II Multi-Arm Multi-Stage Studies

We propose a multi-metric flexible Bayesian framework to support efficient interim decision-making in multi-arm multi-stage phase II clinical trials. Multi-arm multi-stage phase II studies increase the efficiency of drug development, but early decisions regarding the futility or desirability of a given arm carry considerable risk since sample sizes are often low and follow-up periods may be short. Further, since intermediate outcomes based on biomarkers of treatment response are rarely perfect surrogates for the primary outcome and different trial stakeholders may have different levels of risk tolerance, a single hypothesis test is insufficient for comprehensively summarizing the state of the collected evidence. We present a Bayesian framework comprised of multiple metrics based on point estimates, uncertainty, and evidence towards desired thresholds (a Target Product Profile, TPP) for 1) ranking of arms and 2) comparison of each arm against an internal control. Using a large public-private partnership targeting novel TB arms as a motivating example, we find via simulation study that our multi-metric framework provides sufficient confidence for decision-making with sample sizes as low as 30 patients per arm, even when intermediate outcomes have only moderate correlation with the primary outcome. Our reframing of trial design and the decision-making procedure has been well-received by research partners and is a practical approach to more efficient assessment of novel therapeutics.Comment: 16 pages, 6 main text figures, 3 supplemental figure

Reduced incidence of hypertension after heterotopic cardiac transplantation compared with orthotopic cardiac transplantation Evidence that excision of the native heart contributes to post-transplant hypertension

ObjectivesThis study was designed to test the hypothesis that heterotopic heart transplant (HHT) patients have lower blood pressure than orthotopic cardiac transplant (OCT) patients because their native heart is involved in blood pressure homeostasis.BackgroundHypertension occurs more frequently after OCT than after liver or lung transplantation, suggesting that transplantation of the heart itself contributes to post-transplant hypertension.MethodsBlood pressure and related measurements in 233 OCT and 38 HHT patients were studied retrospectively post-transplant.ResultsSystolic blood pressure (SBP) was persistently lower among HHT patients (means 121 vs. 137, 126 vs. 137, 125 vs. 139, and 128 vs. 143 mm Hg at month 3 and years 1, 3, and 5 respectively, p < 0.005). Left ventricular and aortic systolic pressures were also lower (130 vs. 143 mm Hg, p = 0.01 and 129 vs. 142 mm Hg, p = 0.01). Multivariable analysis with age, gender, body mass index, creatinine, steroids, cyclosporine, use of antihypertensive medication, donor left ventricular ejection fraction, donor weight, and type of transplant as covariables showed HHT to be independently associated with a lower SBP at each time point (beta-coefficients −16.2, −12.1, −13.3, and −14.2 mm Hg, p < 0.01). The adjusted hazard ratio for the development of systolic hypertension among HHT compared with OCT patients was 0.59 (95% confidence interval 0.39 to 0.91, p = 0.017).ConclusionsHeterotopic heart transplant patients had lower SBP than OCT patients, consistent with the hypothesis that the native heart continues to contribute to blood pressure homeostasis

Four-month moxifloxacin-based regimens for drug-sensitive tuberculosis

Supported by the Global Alliance for TB Drug Development with support from the Bill and Melinda Gates Foundation, the European and Developing Countries Clinical Trials Partnership, U.S. Agency for International Development, U.K. Department for International Development, Directorate General for International Cooperation of the Netherlands, Irish Aid, Australia Department of Foreign Affairs and Trade, and National Institutes of Health, AIDS Clinical Trials Group and by grants from the National Institute of Allergy and Infectious Diseases (NIAID) (UM1AI068634, UM1 AI068636, and UM1AI106701) and by NIAID grants to the University of KwaZulu Natal, South Africa, AIDS Clinical Trials Group (ACTG) site 31422 (1U01AI069469); to the Perinatal HIV Research Unit, Chris Hani Baragwanath Hospital, South Africa, ACTG site 12301 (1U01AI069453); and to the Durban International Clinical Trials Unit, South Africa, ACTG site 11201 (1U01AI069426); Bayer Healthcare for the donation of moxifloxacin; and Sanofi for the donation of rifampin.Background: Early-phase and preclinical studies suggest that moxifloxacin-containing regimens could allow for effective 4-month treatment of uncomplicated, smear-positive pulmonary tuberculosis. Methods: We conducted a randomized, double-blind, placebo-controlled, phase 3 trial to test the noninferiority of two moxifloxacin-containing regimens as compared with a control regimen. One group of patients received isoniazid, rifampin, pyrazinamide, and ethambutol for 8 weeks, followed by 18 weeks of isoniazid and rifampin (control group). In the second group, we replaced ethambutol with moxifloxacin for 17 weeks, followed by 9 weeks of placebo (isoniazid group), and in the third group, we replaced isoniazid with moxifloxacin for 17 weeks, followed by 9 weeks of placebo (ethambutol group). The primary end point was treatment failure or relapse within 18 months after randomization. Results: Of the 1931 patients who underwent randomization, in the per-protocol analysis, a favorable outcome was reported in fewer patients in the isoniazid group (85%) and the ethambutol group (80%) than in the control group (92%), for a difference favoring the control group of 6.1 percentage points (97.5% confidence interval [CI], 1.7 to 10.5) versus the isoniazid group and 11.4 percentage points (97.5% CI, 6.7 to 16.1) versus the ethambutol group. Results were consistent in the modified intention-to-treat analysis and all sensitivity analyses. The hazard ratios for the time to culture negativity in both solid and liquid mediums for the isoniazid and ethambutol groups, as compared with the control group, ranged from 1.17 to 1.25, indicating a shorter duration, with the lower bounds of the 95% confidence intervals exceeding 1.00 in all cases. There was no significant difference in the incidence of grade 3 or 4 adverse events, with events reported in 127 patients (19%) in the isoniazid group, 111 (17%) in the ethambutol group, and 123 (19%) in the control group. Conclusions: The two moxifloxacin-containing regimens produced a more rapid initial decline in bacterial load, as compared with the control group. However, noninferiority for these regimens was not shown, which indicates that shortening treatment to 4 months was not effective in this setting. (Funded by the Global Alliance for TB Drug Development and others; REMoxTB ClinicalTrials.gov number, NCT00864383.)Publisher PDFPeer reviewe

A comparison of liquid and solid culture for determining relapse and durable cure in phase III TB trials for new regimens

Supported by the Global Alliance for TB Drug Development with support from the Bill & Melinda Gates Foundation, the Medical Research Council (MC_UU_12023/27), the European and Developing Countries Clinical Trials Partnership (grant IP.2007.32011.011), the US Agency for International Development, the UK Department for International Development, the Directorate General for International Cooperation of the Netherlands, Irish Aid, the Australia Department of Foreign Affairs and Trade and National Institutes of Health, AIDS Clinical Trials Group and by grants from the National Institute of Allergy and Infectious Diseases (NIAID) (UM1AI068634, UM1 AI068636 and UM1AI106701) and by NIAID grants to the University of KwaZulu Natal, South Africa, AIDS Clinical Trials Group (ACTG) site 31422 (1U01AI069469); to the Perinatal HIV Research Unit, Chris Hani Baragwanath Hospital, South Africa, ACTG site 12301 (1U01AI069453); and to the Durban International Clinical Trials Unit, South Africa, ACTG site 11201 (1U01AI069426); Bayer Healthcare for the donation of moxifloxacin; and Sanofi for the donation of rifampin. Additional grants were from Chief Scientist Office, Scottish Government, British Society of Antimicrobial Chemotherapy.Background:  Tuberculosis kills more people than any other infectious disease, and new regimens are essential. The primary endpoint for confirmatory phase III trials for new regimens is a composite outcome that includes bacteriological treatment failure and relapse. Culture methodology is critical to the primary trial outcome. Patients in clinical trials can have positive cultures after treatment ends that may not necessarily indicate relapse, which was ascribed previously to laboratory cross-contamination or breakdown of old lesions. Löwenstein-Jensen (LJ) medium was the previous standard in clinical trials, but almost all current and future trials will use the Mycobacteria Growth Indicator Tube (MGIT) system due to its simplicity and consistency of use, which will affect phase III trial results. LJ was used for the definition of the primary endpoint in the REMoxTB trial, but every culture was also inoculated in parallel into the MGIT system. The data from this trial, therefore, provide a unique opportunity to investigate and compare the incidence of false ‘isolated positives’ in liquid and solid media and their potential impact on the primary efficacy results. Methods:  All post-treatment positive cultures were reviewed in the REMoxTB clinical trial. Logistic regression models were used to model the incidence of isolated positive cultures on MGIT and LJ. Results:  A total of 12,209 sputum samples were available from 1652 patients; cultures were more often positive on MGIT than LJ. In 1322 patients with a favourable trial outcome, 126 (9.5%) had cultures that were positive in MGIT compared to 34 (2.6%) patients with positive cultures on LJ. Among patients with a favourable outcome, the incidence of isolated positives on MGIT differed by study laboratory (p < 0.0001) with 21.9% of these coming from one laboratory investigating only 4.9% of patients. No other baseline factors predicted isolated positives on MGIT after adjusting for laboratory. There was evidence of clustering of isolated positive cultures in some patients even after adjusting for laboratory, p < 0.0001. The incidence of isolated positives on MGIT did not differ by treatment arm (p = 0.845, unadjusted). Compared to negative MGIT cultures, positive MGIT cultures were more likely to be associated with higher grade TB symptoms reported within 7 days either side of sputum collection in patients with an unfavourable primary outcome (p < 0.0001) but not in patients with a favourable outcome (p = 0.481). Conclusions:  Laboratory cross-contamination was a likely cause of isolated positive MGIT cultures which were clustered in some laboratories. Certain patients had repeated positive MGIT cultures that did not meet the definition of a relapse. This pattern was too common to be explained by cross-contamination only, suggesting that host factors were also responsible. We conclude that MGIT can replace LJ in phase III TB trials, but there are implications for the definition of the primary outcome and patient management in trials in such settings. Most importantly, the methodologies differ in the incidence of isolated positives and in their capacity for capturing non-tuberculosis mycobacteria. It emphasises the importance of effective medical monitoring after treatment ends and consideration of clinical signs and symptoms for determining treatment failure and relapse.Publisher PDFPeer reviewe

Limited role of culture conversion for decision-making in individual patient care and for advancing novel regimens to confirmatory clinical trials

Supported by the European and Developing Country Clinical Trials Partnership (grant IP.2007.32011.011) and the Global Alliance for TB Drug Development, with support from the Bill & Melinda Gates Foundation, US Agency for International Development, UK Department for International Development, Directorate-General for International Cooperation of the Netherlands, Irish Aid and Australian Department of Foreign Affairs and Trade.Background Despite recent increased clinical trials activity, no regimen has proved able to replace the standard 6-month regimen for drug-sensitive tuberculosis. Understanding the relationship between microbiological markers measured during treatment and long-term clinical outcomes is critical to evaluate their usefulness for decision-making for both individual patient care and for advancing novel regimens into time-consuming and expensive pivotal phase III trials. Methods Using data from the randomized controlled phase III trial REMoxTB, we evaluated sputum-based markers of speed of clearance of bacilli: time to smear negative status; time to culture negative status on LJ or in MGIT; daily rate of change of log10(TTP) to day 56; and smear or culture results at weeks 6, 8 or 12; as individual- and trial-level surrogate endpoints for long-term clinical outcome. Results Time to culture negative status on LJ or in MGIT, time to smear negative status and daily rate of change in log10(TTP) were each independent predictors of clinical outcome, adjusted for treatment (p <0.001). However, discrimination between low and high risk patients, as measured by the c-statistic, was modest and not much higher than the reference model adjusted for BMI, history of smoking, HIV status, cavitation, gender and MGIT TTP. Conclusions Culture conversion during treatment for tuberculosis, however measured, has only a limited role in decision-making for advancing regimens into phase III trials or in predicting the outcome of treatment for individual patients. REMoxTB ClinicalTrials.gov number: NCT00864383.Publisher PDFPeer reviewe

Limited role of culture conversion for decision-making in individual patient care and for advancing novel regimens to confirmatory clinical trials

Supported by the European and Developing Country Clinical Trials Partnership (grant IP.2007.32011.011) and the Global Alliance for TB Drug Development, with support from the Bill & Melinda Gates Foundation, US Agency for International Development, UK Department for International Development, Directorate-General for International Cooperation of the Netherlands, Irish Aid and Australian Department of Foreign Affairs and Trade.Background Despite recent increased clinical trials activity, no regimen has proved able to replace the standard 6-month regimen for drug-sensitive tuberculosis. Understanding the relationship between microbiological markers measured during treatment and long-term clinical outcomes is critical to evaluate their usefulness for decision-making for both individual patient care and for advancing novel regimens into time-consuming and expensive pivotal phase III trials. Methods Using data from the randomized controlled phase III trial REMoxTB, we evaluated sputum-based markers of speed of clearance of bacilli: time to smear negative status; time to culture negative status on LJ or in MGIT; daily rate of change of log10(TTP) to day 56; and smear or culture results at weeks 6, 8 or 12; as individual- and trial-level surrogate endpoints for long-term clinical outcome. Results Time to culture negative status on LJ or in MGIT, time to smear negative status and daily rate of change in log10(TTP) were each independent predictors of clinical outcome, adjusted for treatment (p <0.001). However, discrimination between low and high risk patients, as measured by the c-statistic, was modest and not much higher than the reference model adjusted for BMI, history of smoking, HIV status, cavitation, gender and MGIT TTP. Conclusions Culture conversion during treatment for tuberculosis, however measured, has only a limited role in decision-making for advancing regimens into phase III trials or in predicting the outcome of treatment for individual patients. REMoxTB ClinicalTrials.gov number: NCT00864383.Publisher PDFPeer reviewe

Assessing the Accuracy of Adherence and Sexual Behaviour Data in the MDP301 Vaginal Microbicides Trial Using a Mixed Methods and Triangulation Model

Background: Accurate data on adherence and sexual behaviour are crucial in microbicide (and other HIV-related) research. In the absence of a “gold standard” the collection of such data relies largely on participant self-reporting. The Microbicides Development Programme has developed a mixed method/triangulation model for generating more accurate data on adherence and sexual behaviour. Methodology/Principal Findings: Data were collected from a random subsample of 725 women using structured case record form (CRF) interviews, coital diaries (CD) and in-depth interviews (IDI). Returned used and unused gel applicators were counted and additional data collected through focus group discussions and ethnography. The model is described in detail in a companion paper [1]. When CRF, CD and IDI are compared there is some inconsistency with regard to reporting of sexual behaviour, gel or condom use in more than half. Inaccuracies are least prevalent in the IDI and most prevalent in the CRF, where participants tend to under-report frequency of sex and gel and condom use. Women reported more sex, gel and condom use than their partners. IDI data on adherence match the applicator-return data more closely than the CRF. The main reasons for inaccuracies are participants forgetting, interviewer error, desirability bias, problems with the definition and delineation of key concepts (e.g. “sex act”). Most inaccuracies were unintentional and could be rectified during data collection. Conclusions/Significance: The CRF – the main source of self-report data on behaviour and adherence in many studies – was the least accurate with regard to measuring sexual behaviour, gel and condom use. This has important implications for the use of structured questionnaires for the collection of data on sexual behaviour and adherence. Integrating in-depth interviews and triangulation into clinical trials could increase the richness and accuracy of behavioural and adherence data

A pilot study of rapid benchtop sequencing of Staphylococcus aureus and Clostridium difficile for outbreak detection and surveillance

OBJECTIVES: To investigate the prospects of newly available benchtop sequencers to provide rapid whole-genome data in routine clinical practice. Next-generation sequencing has the potential to resolve uncertainties surrounding the route and timing of person-to-person transmission of healthcare-associated infection, which has been a major impediment to optimal management. DESIGN: The authors used Illumina MiSeq benchtop sequencing to undertake case studies investigating potential outbreaks of methicillin-resistant Staphylococcus aureus (MRSA) and Clostridium difficile. SETTING: Isolates were obtained from potential outbreaks associated with three UK hospitals. PARTICIPANTS: Isolates were sequenced from a cluster of eight MRSA carriers and an associated bacteraemia case in an intensive care unit, another MRSA cluster of six cases and two clusters of C difficile. Additionally, all C difficile isolates from cases over 6 weeks in a single hospital were rapidly sequenced and compared with local strain sequences obtained in the preceding 3 years. MAIN OUTCOME MEASURE: Whole-genome genetic relatedness of the isolates within each epidemiological cluster. RESULTS: Twenty-six MRSA and 15 C difficile isolates were successfully sequenced and analysed within 5 days of culture. Both MRSA clusters were identified as outbreaks, with most sequences in each cluster indistinguishable and all within three single nucleotide variants (SNVs). Epidemiologically unrelated isolates of the same spa-type were genetically distinct (≥21 SNVs). In both C difficile clusters, closely epidemiologically linked cases (in one case sharing the same strain type) were shown to be genetically distinct (≥144 SNVs). A reconstruction applying rapid sequencing in C difficile surveillance provided early outbreak detection and identified previously undetected probable community transmission. CONCLUSIONS: This benchtop sequencing technology is widely generalisable to human bacterial pathogens. The findings provide several good examples of how rapid and precise sequencing could transform identification of transmission of healthcare-associated infection and therefore improve hospital infection control and patient outcomes in routine clinical practice

Spot sputum samples are at least as good as early morning samples for identifying Mycobacterium tuberculosis

Supported by the Global Alliance for TB Drug Development with support from the Bill and Melinda Gates Foundation, the European and Developing Countries Clinical Trials Partnership (Grant IP.2007.32011.011), US Agency for International Development, UK Department for International Development, Directorate General for International Cooperation of the Netherlands, Irish Aid, Australia Department of Foreign Affairs and Trade, National Institutes of Health, AIDS Clinical Trials Group. The study was also supported by grants from the National Institute of Allergy and Infectious Diseases (NIAID) (UM1AI068634, UM1 AI068636, and UM1AI106701) and by NIAID grants to the University of KwaZulu Natal, South Africa, AIDS Clinical Trials Group (ACTG) site 31422 (1U01AI069469); to the Perinatal HIV Research Unit, Chris Hani Baragwanath Hospital, South Africa, ACTG site 12301 (1U01AI069453); and to the Durban International Clinical Trials Unit, South Africa, ACTG site 11201 (1U01AI069426). Bayer Healthcare for donated moxifloxacin and Sanofi donated rifampin.Background:  The use of early morning sputum samples (EMS) to diagnose tuberculosis (TB) can result in treatment delay given the need for the patient to return to the clinic with the EMS, increasing the chance of patients being lost during their diagnostic workup. However, there is little evidence to support the superiority of EMS over spot sputum samples. In this new analysis of the REMoxTB study, we compare the diagnostic accuracy of EMS with spot samples for identifying Mycobacterium tuberculosis pre- and post-treatment. Methods:  Patients who were smear positive at screening were enrolled into the study. Paired sputum samples (one EMS and one spot) were collected at each trial visit pre- and post-treatment. Microscopy and culture on solid LJ and liquid MGIT media were performed on all samples; those missing corresponding paired results were excluded from the analyses. Results:  Data from 1115 pre- and 2995 post-treatment paired samples from 1931 patients enrolled in the REMoxTB study were analysed. Patients were recruited from South Africa (47%), East Africa (21%), India (20%), Asia (11%), and North America (1%); 70% were male, median age 31 years (IQR 24–41), 139 (7%) co-infected with HIV with a median CD4 cell count of 399 cells/μL (IQR 318–535). Pre-treatment spot samples had a higher yield of positive Ziehl–Neelsen smears (98% vs. 97%, P = 0.02) and LJ cultures (87% vs. 82%, P = 0.006) than EMS, but there was no difference for positivity by MGIT (93% vs. 95%, P = 0.18). Contaminated and false-positive MGIT were found more often with EMS rather than spot samples. Surprisingly, pre-treatment EMS had a higher smear grading and shorter time-to-positivity, by 1 day, than spot samples in MGIT culture (4.5 vs. 5.5 days, P < 0.001). There were no differences in time to positivity in pre-treatment LJ culture, or in post-treatment MGIT or LJ cultures. Comparing EMS and spot samples in those with unfavourable outcomes, there were no differences in smear or culture results, and positive results were not detected earlier in Kaplan–Meier analyses in either EMS or spot samples. Conclusions:  Our data do not support the hypothesis that EMS samples are superior to spot sputum samples in a clinical trial of patients with smear positive pulmonary TB. Observed small differences in mycobacterial burden are of uncertain significance and EMS samples do not detect post-treatment positives any sooner than spot samples.Publisher PDFPeer reviewe