Non-inferiority Design Research Articles

Considerations of the non-inferior clinical researches on the anti-vascular endothelial growth factor therapy for fundus diseases

In evidence-based medicine, randomized controlled clinical trials are considered as the gold standard to evaluate the curative effect of the anti-vascular endothelial growth factor drugs on fundus diseases. The non-inferiority design is widely used due to the existence of the "ceiling effect" if vision improvement is used as the primary outcome. It is critical to make several issues clear before non-inferiority studies are performed. For example, patients can benefit from the new therapy other than efficacy; the determination of the non-inferiority margin should be based on the comprehensive consideration of clinical and statistical meanings; the traditional significance test method is not suitable for non-inferiority tests; the superiority test could be further performed if the non-inferiority conclusion has been reached. This article aims to elaborate these hot issues and to provide guidance for clinical researchers to carry out research designs and interpret findings objectively and scientifically. (Chin J Ophthalmol, 2020, 56: 895-898).

A randomised phase 2b study comparing the efficacy and safety of belotecan vs. topotecan as monotherapy for sensitive-relapsed small-cell lung cancer

BackgroundThis study compared the efficacy/safety of the camptothecin analogues belotecan and topotecan for sensitive-relapsed small-cell lung cancer (SCLC).MethodsOne-hundred-and-sixty-four patients were randomised (1:1) to receive five consecutive daily intravenous infusions of topotecan (1.5 mg/m2) or belotecan (0.5 mg/m2), every 3 weeks, for six cycles. Main outcomes were objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), tolerability and toxicity. The study statistical plan was non-inferiority design with ORR as the endpoint.ResultsIn the belotecan vs. topotecan groups, ORR (primary endpoint) was 33% vs. 21% (p = 0.09) and DCR was 85% vs. 70% (p = 0.030). PFS was not different between groups. Median OS was significantly longer with belotecan than with topotecan (13.2 vs. 8.2 months, HR = 0.69, 95% CI: 0.48–0.99), particularly in patients aged <65 years, with more advanced disease (i.e., extensive-stage disease, time to relapse: 3–6 months), or Eastern Cooperative Oncology Group performance status 1 or 2. More belotecan recipients completed all treatment cycles (53% vs. 35%; p = 0.022).ConclusionsThe efficacy/safety of belotecan warrants further evaluation in Phase 3 trials. Belotecan potentially offers an alternative to topotecan for sensitive-relapsed SCLC, particularly in patients aged <65 years, with more advanced disease, or poor performance.

Non-inferiority trials and non-inferiority margin: an overview

The randomized controlled trial (RCT) is considered the best interventional design to assess issues related to treatment and prevention. The RCTs can have different designs including superiority, equivalence, or non-inferiority design. A superiority trial aims to detect the potential superiority of new therapy compared to an active comparator or a placebo, an equivalence trial tends to demonstrate that a new therapy is an equivalent (within margins) to its active comparator, and a non-inferiority trial (NIT) is going to show that the new therapy is not worse than the comparator, as a typical active drug. Increasingly, major trials are conducted to see if the efficacy of a new treatment is as good as a standard treatment. The new treatment usually has some other advantages (e.g., fewer side effects, ease of administration, lower cost), making it worthwhile to demonstrate non-inferiority in respect to efficacy. Thus, NIT is going to determine whether a new treatment is not worse than a reference treatment by more than an acceptable amount. Among the challenges of NITs compared with superiority, trials are the choices of the non-inferiority margin (NIM), the primary population for analysis, and the comparator treatment considering several choices for the comparator arm in an NIT. This article is going to review the current knowledge about NIM.

Head down tilt 15° in experimental intracerebral hemorrhage: a randomized noninferiority safety trial.

Head down tilt 15° (HDT15°), applied before recanalization, increases collateral flow and improves outcome in experimental ischemic stroke. For its simplicity and low cost, HDT15° holds considerable potential to be developed as an emergency treatment of acute stroke in the prehospital setting, where hemorrhagic stroke is the major mimic of ischemic stroke. In this study, we assessed safety of HDT15° in the acute phase of experimental intracerebral hemorrhage. Intracerebral hemorrhage was produced by stereotaxic injection of collagenase in Wistar rats. A randomized noninferiority trial design was used to assign rats to HDT15° or flat position (n=64). HDT15° was applied for 1h during the time window of hematoma expansion. The primary outcome was hematoma volume at 24h. Secondary outcomes were mass effect, mortality, and functional deficit in the main study and acute changes of intracranial pressure, hematoma growth, and cardiorespiratory parameters in separate sets of randomized animals (n=32). HDT15° achieved the specified criteria of noninferiority for hematoma volume at 24h. Mass effect, mortality, and functional deficit at 24h showed no difference in the two groups. HDT15° induced a mild increase in intracranial pressure with respect to the pretreatment values (+2.91±1.76mmHg). HDT15° had a neutral effect on MRI-based analysis of hematoma growth and cardiorespiratory parameters. Application of HDT15° in the hyperacute phase of experimental intracerebral hemorrhage does not worsen early outcome. Further research is needed to implement HDT15° as an emergency collateral therapeutic for acute stroke.

Road Map to Safe and Well-Designed De-escalation Trials of Systemic Adjuvant Therapy for Solid Tumors.

An important challenge in the field of cancer is finding the balance between delivering effective treatments and avoiding adverse effects and financial toxicity caused by innovative, yet expensive, drugs. To address this, several treatment de-escalation trials have been conducted, but only a few of these have provided clear answers. A few trials had poor accrual or had design flaws that led to conflicting results. Members of the Breast International Group (BIG) and North American Breast Cancer Group (NABCG) believe the way forward is to understand the lessons from these trials and listen more carefully to what truly matters to our patients. We reviewed several adjuvant trials of different cancer types and developed a road map for improving the design and implementation of future de-escalation trials. The road map incorporates patients' insights obtained through focused group discussions across the BIG-NABCG networks. Considerations for the development of de-escalation trials for systemic adjuvant treatment, including noninferiority trial design, choice of end points, and prioritization of a patient's perspectives, are presented in this consensus article.

A noninferiority design for a delayed calcineurin inhibitor substitution trial in kidney transplantation.

Improving long‐term kidney transplant outcomes requires novel treatment strategies, including delayed calcineurin inhibitor (CNI) substitution, tested using informative trial designs. An alternative approach to the usual superiority‐based trial is a noninferiority trial design that tests whether an investigational agent is not unacceptably worse than standard of care. An informative noninferiority design, with biopsy‐proven acute rejection (BPAR) as the endpoint, requires determination of a prespecified, evidence‐based noninferiority margin for BPAR. No such information is available for delayed CNI substitution in kidney transplantation. Herein we analyzed data from recent kidney transplant trials of CNI withdrawal and “real world” CNI‐ based standard of care, containing subjects with well‐documented evidence of immune quiescence at 6 months posttransplant—ideal candidates for delayed CNI substitution. Our analysis indicates an evidence‐based noninferiority margin of 13.8% for the United States Food and Drug Administration's composite definition of BPAR between 6 and 24 months posttransplant. Sample size estimation determined that ~225 randomized subjects would be required to evaluate noninferiority for this primary clinical efficacy endpoint, and superiority for a renal function safety endpoint. Our findings provide the basis for future delayed CNI substitution noninferiority trials, thereby increasing the likelihood they will provide clinically implementable results and achieve regulatory approval.

Additional modifications to the Blumgart pancreaticojejunostomy: Results of a propensity score-matched analysis versus Cattel-Warren pancreaticojejunostomy

BackgroundPostoperative pancreatic fistula continues to occur frequently after pancreatoduodenectomy. MethodsWe have described a modification of the Blumgart pancreaticojejunostomy. The modification of the Blumgart pancreaticojejunostomy was compared to the Cattel-Warren pancreaticojejunostomy in cohorts of patients matched by propensity scores based on factors predictive of clinically relevant postoperative pancreatic fistula, which was the primary endpoint of this study. Based on a noninferiority study design, 95 open pancreatoduodenectomies per group were needed. Feasibility of the modification of the Blumgart pancreaticojejunostomy in robotic pancreatoduodenectomy was also shown. All pancreaticojejunostomies were performed by a single surgeon. ResultsBetween October 2011 and May 2019, there were 415 pancreatoduodenectomies with either a Cattel-Warren pancreaticojejunostomy (n = 225) or a modification of the Blumgart pancreaticojejunostomy (n = 190). There was 1 grade C postoperative pancreatic fistula in 190 consecutive modification of the Blumgart pancreaticojejunostomies (0.5%). Logistic regression analysis showed that the rate of clinically relevant postoperative pancreatic fistula was not affected by consecutive case number. After exclusion of robotic pancreatoduodenectomies (the Cattel-Warren pancreaticojejunostomy: 82; modification of the Blumgart pancreaticojejunostomy: 66), 267 open pancreatoduodenectomies were left, among which the matching process identified 109 pairs. The modification of the Blumgart pancreaticojejunostomy was shown to be noninferior to the Cattel-Warren pancreaticojejunostomy with respect to clinically relevant postoperative pancreatic fistula (11.9% vs 22.9%; odds ratio: 0.46 [0.21–0.93]; P = .03), grade B postoperative pancreatic fistula (11.9% vs 18.3%; P = .18), and grade C postoperative pancreatic fistula (0 vs 4.6%; P = .05) as well as to all secondary study endpoints. The modification of the Blumgart pancreaticojejunostomy was feasible in 66 robotic pancreatoduodenectomies. In this subgroup with 1 conversion to open surgery (1.5%), a clinically relevant postoperative pancreatic fistula occurred after 9 procedures (13.6%) with no case of grade C postoperative pancreatic fistula and a 90-day mortality of 3%. ConclusionThe modification of the Blumgart pancreaticojejunostomy described herein is noninferior to the Cattel-Warren pancreaticojejunostomy in open pancreatoduodenectomy. This technique is also feasible in robotic pancreatoduodenectomy.

The impact of communicating personal mental ill-health risk: Arandomized controlled non-inferiority trial.

Risk algorithms predicting personal mental ill-health will form an important component of digital and personalized preventive interventions, yet it is unknown whether informing people of personal risk may cause unintended harm. This trial evaluated the comparative effect of communicating personal mental ill-health risk profiles on psychological distress. Australian participants using a mood-monitoring app were randomly allocated to receiving their current personal mental ill-health risk profile (n=119), their achievable personal risk profile (n=118) or to a control group (n=118) in which no risk information was communicated, in a non-inferiority trial design. The primary outcome was psychological distress at four-weeks as assessed on the Kessler Psychological Distress Scale. There was high attrition in the trial with 64% of data missing at follow up. Per-protocol (completer) analysis found that the lower bounds of the confidence intervals of the estimated mean change of the current risk (m=0.19, 95% CI: -2.59- 2.98) and achievable risk (m=-0.09, 95% CI: -2.84 to 2.66) groups were within the non-inferiority margin of the control group's mean at follow up. Supplementary intention-to-treat analysis using Multivariate Imputation by Chained Equations (MICE) found that 98/100 imputed datasets of the current risk profile group, and all imputed datasets of the achievable risk profile group showed non-inferiority to the control group. This study provides preliminary support that providing personal mental health risk profiles does not lead to unacceptable worsening of distress compared to no risk feedback, although this needs to be replicated in a fully powered RCT.

Comparative Effectiveness of Microdecompression Alone vs Decompression Plus Instrumented Fusion in Lumbar Degenerative Spondylolisthesis

Conflicting evidence and large practice variation are present in the surgical treatment of degenerative spondylolisthesis. More than 90% of surgical procedures in the United States include instrumented fusion compared with 50% or less in other countries. To evaluate whether the effectiveness of microdecompression alone is noninferior to decompression with instrumented fusion in a real-world setting. This multicenter comparative effectiveness study with a noninferiority design assessed prospective data from the Norwegian Registry for Spine Surgery. From September 19, 2007, to December 21, 2015, 1376 patients at 35 Norwegian orthopedic and neurosurgical departments underwent surgery for lumbar spinal stenosis with degenerative spondylolisthesis without scoliosis. After excluding patients undergoing laminectomy alone, fusion without instrumentation, or surgery in more than 2 levels and those with a former operation at the index level, 794 patients were included in the analyses, regardless of missing or incomplete follow-up data, before propensity score matching. Data were analyzed from March 20 to October 30, 2018. Microdecompression alone or decompression with instrumented fusion. A reduction from baseline of 30% or greater in the Oswestry Disability Index at 12-month follow-up. After propensity score matching, 570 patients (413 female [72%]; mean [SD] age, 64.7 [9.5] years) were included for comparison, with 285 undergoing microdecompression (mean [SD] age, 64.6 [9.8] years; 205 female [72%]) and 285 undergoing decompression with instrumented fusion (mean [SD] age, 64.8 [9.2] years; 208 female [73%]). The proportion of each type of procedure varied between departments. However, changes in outcome scores varied within patients but not between departments. The proportion of patients with improvement in the Oswestry Disability Index of at least 30% was 150 of 219 (68%) in the microdecompression group and 155 of 215 (72%) in the instrumentation group. The 95% CI (-12% to 5%) for the difference of -4% was above the predefined margin of noninferiority (-15%). Microdecompression alone was associated with shorter operation time (mean [SD], 89 [44] vs 180 [65] minutes; P < .001) and shorter hospital stay (mean [SD], 2.5 [2.4] vs 6.4 [3.0] days; P < .001). Among patients with degenerative spondylolisthesis, the clinical effectiveness of microdecompression alone was noninferior to that of decompression with instrumented fusion. Microdecompression alone was also associated with shorter durations of surgery and hospital stay, supporting the suggestion that the less invasive procedure should be considered for most patients.

Short-Term Outcomes following Virtual Surgery-Assisted Immediate Dental Implant Placement in Free Fibula Flaps for Oncologic Mandibular Reconstruction.

Despite reports demonstrating feasibility of immediate dental implant placement in mandibular reconstruction with free fibula flaps for benign disease, this practice is not routinely used in the oncologic setting. The authors aim to demonstrate the safety of immediate dental implant placement for oncologic mandible reconstruction. In 2017, the authors' center began immediate dental implant placement in free fibula flaps for oncologic patients undergoing mandibulectomy reconstruction. Immediate dental implant placement patients were compared to a historical cohort also reconstructed with computer-aided design and manufacturing technology beginning in 2011 (n = 34) as a noninferiority study design. Primary outcomes of interest included 90-day complications, time to radiotherapy, and time to and number of patients achieving dental restoration. Sixty-one patients underwent free fibula flaps following mandibulectomy using computer-aided design and manufacturing. Seventy-two dental implants were placed in the immediate dental implant placement cohort (n = 27). No differences were noted in major or minor 90-day complications between groups (p > 0.05). Radiotherapy was required in 55 percent in the immediate dental implant placement cohort versus 62 percent in the historical cohort, with no significant difference in time to radiotherapy (67.6 days versus 62.2 days, respectively). One dental implant was removed for nonosseointegration noted during vestibuloplasty. Fourteen (51.8 percent) immediate dental implant patients had complete dental restoration at 90 days compared with none in the historical cohort (p < 0.05). Immediate dental implant placement is a safe procedure with an unchanged short-term complication profile and no delay in radiotherapy initiation. Patients undergoing immediate dental implant placement are more likely to complete full dental rehabilitation. Long-term and health-related quality-of-life outcomes remain to be determined. Therapeutic, III.

Clinically SUspected ScaPhoid fracturE: treatment with supportive bandage or CasT? ‘Study protocol of a multicenter randomized controlled trial’ (SUSPECT study)

IntroductionSome scaphoid fractures become visible on radiographs weeks after a trauma which makes normal radiographs directly after trauma unreliable. Untreated scaphoid fractures can lead to scaphoid non-union progressing to osteoarthritis....

The Cost of Innovation and Evidence in Cardiac Surgery.

This review summarizes a systematic analysis of 216 randomized trials of cardiovascular interventions performed during 2008-2019, according to the source of trial funding. The systematic analysis showed that on average the results of each trial would change significance if only 5 patients experienced different outcomes. Industry-sponsored trials were more likely to use composite endpoints, noninferiority designs, and twice as likely as nonindustry trials to report results favoring the device arm. Over 80% of industry trials used reporting strategies or "spin" suggesting the device arm was advantageous versus fewer than half of non-industry trials. The review discusses the implications of these findings.

Non-inferiority trials using a surrogate marker as the primary endpoint: An increasing phenotype in cardiovascular trials.

Non-inferiority trials are increasing in cardiovascular medicine, with approval of many drugs and devices on the basis of such studies. Surrogate markers as primary endpoints have been also more frequently used for efficient assessment of cardiovascular interventions. However, there is uncertainty about their concordance with clinical outcomes. Non-inferiority design using a surrogate marker as a primary endpoint may pose particular challenges in clinical interpretation. We sought to explore the publication trends, methodology, and reporting features of non-inferiority cardiovascular trials that used a primary surrogate marker as the primary endpoint. We searched six high-impact journals (The New England Journal of Medicine, The Journal of the American Medical Association, The Lancet, The Journal of the American College of Cardiology, Circulation, and European Heart Journal) from 1 January 1990 to 31 December 2018 and identified non-inferiority cardiovascular trials that used a surrogate marker as the primary endpoint. We assessed the non-inferiority margin reported in the manuscript and other publicly available platforms (e.g. protocol, clinicaltrials.gov). We also determined whether the included non-inferiority trials with surrogate markers as primary endpoints were followed by clinical outcome trials. We screened 15,553 publications and identified 247 cardiovascular trials that used a non-inferiority design. Of these, 37 had a surrogate marker as a primary endpoint (18 drug trials, 13 device trials, 6 others). All of these non-inferiority trials with surrogate outcomes were published after 2000, mostly in cardiology journals (13 in The Journal of the American College of Cardiology, 9 in European Heart Journal, 8 in Circulation, 6 in The Lancet, 1 in The New England Journal of Medicine), and their publication rate increased over time (p < 0.001 for linear trend). The median number of patients in the primary analysis was 300 (interquartile range: 202-465). The study protocol or a methods paper was publicly available for only 13 (35.1%) trials, of which the non-inferiority margin was not reported in 4 trials. In 16 studies (43.2%), the manuscript did not acknowledge the limitations of using a surrogate endpoint or the need for a definitive clinical outcome trial. Thirty-four trials (91.9%) concluded that the tested intervention met non-inferiority criteria. However, only five (13.5%) were followed by clinical outcomes trials the results of which did not always confirm non-inferiority. Non-inferiority trials that use a surrogate marker as the primary endpoint are being increasingly performed. However, these trials pose particular challenges with design, reporting, and interpretation, which are not systematically and consistently addressed or reported.

Efficacy and Safety of Guilingji Capsules () for Treating Mild-to-Moderate Cognitive Impairment: Study Protocol for A Randomized, Double-Blind, Positive-Controlled, Multicenter and Noninferiority Trial.

The incidence of cognitive impairment (CI) is gradually increasing, which has attracted more attention from medical researchers worldwide. Definitive mechanisms of pathogenesis remain elusive, and there are few medications that have been proven effective for CI. The utilization of Chinese herbal medicine has shown positive therapeutic effects for a broad spectrum of diseases, including CI. The purpose of this study is to evaluate the safety and efficacy of Guilingji Capsules (GLJC, ) in treating mild-to-moderate CI with Shen (Kidney) and marrow deficiency syndrome. This is a randomized, double-blind, positive-controlled, multicenter clinical trial with a noninferiority design that included 348 participants randomly divided into an experimental arm and an active comparator arm. Individuals in the experimental arm (174 cases) took 0.6 g of GLJC once a day and 19.2 mg of Gingko biloba extract mimetic 3 times a day. Individuals in the active comparator arm (174 cases) took 0.6 g of GLJC mimetic once a day and 19.2 mg of Gingko biloba extract in tablet form 3 times a day. The intervention period included two sessions over 24 weeks. The primary outcome be the effectiveness of GLJC on cognitive improvement after 24 weeks of treatment, which was defined as an increase in the Mini Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) Scale. The secondary outcomes were improvement in independence, daily living ability, and Chinese medicine (CM) syndrome, which were measured with the Alzheimer's disease Rating Scale-Cognitive Project (ADAS-Cog), Clinical Dementia Rating (CDR) Total Score, Activities of Daily Living (ADL) Total Score and the Chinese Medicine Symptom Scale (CM-SS), respectively. Serum acetylcholine, acetylcholinesterase, bax and bcl-2 were monitored to explore the mechanism of GLJC on CI. In addition, safety measures, including vital signs, electrocardiography, laboratory indicators (full blood count, kidney and liver function tests, routine urine test and routine stool test) and adverse events, were also recorded. The purpose of this trial is to evaluate the efficacy and safety of GLJC in patients with mild-to-moderate CI with kidney and marrow deficiency syndrome. If successful, the results would provide a viable treatment for patients with mild-to-moderate CI. (Clinical Trials.gov. ID: NCT03647384. Registered on 23 August 2018).

Regional consistency and sample size considerations in a multiregional equivalence trial.

The main objective of a confirmatory multiregional clinical trial (MRCT) is to demonstrate the overall efficacy of test drugs in all participating regions as well as to evaluate the possibility of extrapolating the overall results to each region. With the emergence of the demands of biosimilar drugs development, some guidelines recommended using equivalence design to demonstrate the comparability of efficacy between biosimilar and reference drugs. Previous discussions about assessing regional consistency in MRCT are mainly focused on superiority or non-inferiority designs, while the extensions to equivalence designs were limited. In this work, we proposed a flexible regional consistency criterion for the MRCT with equivalence design. Based on this criterion, sample size determination and sample allocation were also discussed.

A comparison of online and in-person counseling outcomes using solution-focused brief therapy for college students with anxiety

Objective This study compared online, synchronous video counseling to in-person counseling using solution-focused brief therapy for college students with mild to moderate anxiety. Participants: Participants were 49 undergraduate students who were seeking counseling for mild to moderate anxiety. The study was conducted from November, 2017 to December 2018. Methods: In a randomized, non-inferiority design, undergraduate participants were randomly assigned to online, synchronous video counseling or in-person treatment for anxiety using solution-focused brief therapy (SFBT). Participants completed the Beck’s Anxiety Inventory (BAI) and College Counseling Assessment of Psychological Symptoms (CCAPS) to assess outcomes. Results: The results showed significant changes in scores on the BAI and the CCAPS Generalized Anxiety and Social Anxiety subscales for participants in both study conditions, and no significant differences in effectiveness of the two delivery methods. Conclusions: The findings provide support for the treatment of college students with anxiety with SFBT through online, synchronous video counseling. Limitations related to sample size and diversity are discussed.

Single-Sampling Strategy vs. Multi-Sampling Strategy for Blood Cultures in Sepsis: A Prospective Non-inferiority Study.

BackgroundOptimal sampling is critical for the performance of blood cultures (BCs). Most guidelines recommend collecting 40 ml of blood, divided between two venipuncture sites, i.e., multi-sampling strategy (MSS). Sampling through a single venipuncture site, i.e., single-sampling strategy (SSS) is easier; however, the diagnostic performance of SSS compared to MSS remains unknown. Thus, we aimed to study if SSS is non-inferior to MSS for detection of pathogenic microorganisms.MethodsA prospective, paired, non-inferiority design was used. Patients with clinically suspected sepsis admitted to an Emergency Department were included. Six BC bottles were simultaneously collected, consisting of four BC bottles from the first arm and two from the other arm. SSS consisted of BC bottles 1, 2, 3, and 4, and MSS consisted of BC bottles 1, 2, 5, and 6. Samples were incubated in a BacT/ALERT BC system.ResultsThe final analysis included 549 episodes. Pathogenic microorganisms were detected in 162 cases (29.5%) with MSS and 160 cases (29.1%) with SSS, yielding an absolute difference of 0.36%, with a 95% confidence interval of -1.33 to 2.06%, which did not exceed the predefined non-inferiority margin of 5%. MSS tended to produce more contaminant growth (7.3% of cases) than SSS (5.3% of cases; p = 0.072).ConclusionThe study showed that SSS was non-inferior to MSS in detecting pathogenic microorganisms and supports the use of SSS as a routine method.

Antimicrobial Treatment Duration in Sepsis and Serious Infections.

Sepsis mortality has improved following advancements in early recognition and standardized management, including emphasis on early administration of appropriate antimicrobials. However, guidance regarding antimicrobial duration in sepsis is surprisingly limited. Decreased antibiotic exposure is associated with lower rates of de novo resistance development, Clostridioides difficile-associated disease, antibiotic-related toxicities, and health care costs. Consequently, data weighing safety versus adequacy of shorter treatment durations in sepsis would be beneficial. We provide a narrative review of evidence to guide antibiotic duration in sepsis. Evidence is significantly limited by noninferiority trial designs and exclusion of critically ill patients in many trials. Potential challenges to shorter antimicrobial duration in sepsis include inadequate source control, treatment of multidrug-resistant organisms, and pharmacokinetic alterations that predispose to inadequate antimicrobial levels. Additional studies specifically targeting patients with clinical indicators of sepsis are needed to guide measures to safely reduce antimicrobial exposure in this high-risk population while preserving clinical effectiveness.

Minimum Dietary Diversity for Women of Reproductive Age (MDD-W) Data Collection: Validity of the List-Based and Open Recall Methods as Compared to Weighed Food Record.

Minimum dietary diversity for women of reproductive age (MDD-W) was validated as a population-level proxy of micronutrient adequacy, with indicator data collection proposed as either list-based or open recall. No study has assessed the validity of these two non-quantitative proxy methods against weighed food records (WFR). We assessed the measurement agreement of list-based and open recall methods as compared to WFR (i.e., reference method of individual quantitative dietary assessment) for achieving MDD-W and an ordinal food group diversity score. Applying a non-inferiority design, data were collected from non-pregnant women of reproductive age in Cambodia (n = 430), Ethiopia (n = 431), and Zambia (n = 476). For the pooled sample (n = 1337), proportions achieving MDD-W from both proxy methods were compared to WFR proportion by McNemar’s chi-square tests, Cohen’s kappa, and receiver operating characteristic (ROC) analysis. Ordinal food group diversity (0–10) was compared by Wilcoxon matched-pairs signed-rank tests, intraclass correlation coefficients (ICC), and weighted kappa. MDD-W food groups that were most frequently misreported (i.e., type I and II errors) by the proxy methods were determined. Our findings indicate statistically significant differences in proportions achieving MDD-W, ordinal food group diversity scores, and ROC curves between both proxy methods and WFR (p < 0.001). List-based and open recall methods overreported women achieving MDD-W by 16 and 10 percentage points, respectively, as compared to WFR (proportion achieving MDD-W: 30%). ICC values between list-based or open recall and WFR were 0.50 and 0.55, respectively. Simple and weighted kappa values both indicated moderate agreement between list-based or open recall against WFR. Food groups most likely to be misreported using proxy methods were beans and peas, dark green leafy vegetables, vitamin A-rich fruit and vegetables, and other fruits. Our study provides statistical evidence for overreporting of both list-based and open recall methods for assessing prevalence of MDD-W or ordinal food group diversity score in women of reproductive age in low- and middle-income countries. Operationalizing MDD-W through qualitative recall methods should consider potential trade-offs between accuracy and simplicity.

Disseminating an Evidence-Based Tobacco Control Intervention for School Teachers in India: Overview and Preliminary Findings

PURPOSE In India in 2010, tobacco use accounted for more than 1 million deaths. There is a profound need for evidence-based interventions (EBIs) that promote tobacco control on a large scale, particularly in low- and middle-income countries. Our goal was to identify creative strategies for the broad-based implementation of tobacco control EBIs that can be embedded in existing organizational infrastructures and accommodate the realities of low-resource settings. We built on an intervention for schoolteachers, called the Tobacco-Free Teachers/Tobacco-Free Society (TFT-TFS) program, which had been shown to be efficacious in increasing tobacco use cessation and tobacco policy implementation in a cluster randomized controlled trial in the Bihar School Teachers’ Study. Teachers in India are an important channel for promoting tobacco control given their roles as community leaders and role models. This study tested whether TFT-TFS can be successfully implemented by building capacity within the education department to train and support headmasters to implement TFT-TFS in their schools. METHODS Six blocks from 3 districts in Bihar, India, were randomly assigned into either the intervention or control arm. Using a cascade-training model, intervention cluster coordinators—who routinely interact with headmasters—were trained to train headmasters from their respective clusters to implement TFT-TFS over 1 academic year. This study used a noninferiority design to test if program implementation will not be inferior to the high standards demonstrated in the Bihar School Teachers’ Study and assessed program effectiveness in improving cessation and policy implementation. RESULTS Nearly all of the 46 trained intervention cluster coordinators further trained more than 90% of the 218 headmasters to implement TFT-TFS. Preliminary data also indicate that two thirds of headmasters reported implementing 3 of 4 program components. Additional findings will be available Spring 2020. CONCLUSION This research is innovative because it systematically examines the process of scaling up one of the first EBIs to promote tobacco use cessation among teachers in India.